Biomolecules doi: 10.3390/biom14030362
Authors: Barbara Viljetić Senka Blažetić Irena Labak Vedrana Ivić Milorad Zjalić Marija Heffer Marta Balog
Lipid rafts, specialised microdomains within cell membranes, play a central role in orchestrating various aspects of neurodevelopment, ranging from neural differentiation to the formation of functional neuronal networks. This review focuses on the multifaceted involvement of lipid rafts in key neurodevelopmental processes, including neural differentiation, synaptogenesis and myelination. Through the spatial organisation of signalling components, lipid rafts facilitate precise signalling events that determine neural fate during embryonic development and in adulthood. The evolutionary conservation of lipid rafts underscores their fundamental importance for the structural and functional complexity of the nervous system in all species. Furthermore, there is increasing evidence that environmental factors can modulate the composition and function of lipid rafts and influence neurodevelopmental processes. Understanding the intricate interplay between lipid rafts and neurodevelopment not only sheds light on the fundamental mechanisms governing brain development but also has implications for therapeutic strategies aimed at cultivating neuronal networks and addressing neurodevelopmental disorders.
]]>Biomolecules doi: 10.3390/biom14030361
Authors: Janne Sepp Oleh Koshovyi Valdas Jakštas Vaidotas Žvikas Iryna Botsula Igor Kireyev Hanna Severina Oleksandr Kukhtenko Kaisa Põhako-Palu Karin Kogermann Jyrki Heinämäki Ain Raal
Pineapple weed (Matricaria discoidea DC.) is a widespread plant in Europe and North America. In ethnomedicine, it is well-known for its anti-inflammatory and spasmolytic activities. The aim of this research was to develop novel methods of M. discoidea processing to obtain essential oil and dry extracts and to investigate their phytochemical compositions. Moreover, the molecular docking of the main substances and the in vivo studies on their soporific and analgesic activities were conducted. The essential oil and two dry extracts from M. discoidea were prepared. A total of 16 phenolic compounds (seven flavonoids, seven hydroxycinnamic acids, and two phenolic acids) in the dry extracts were identified by means of UPLC-MS/MS. In the essential oil, nine main terpenoids were identified by gas chromatography (GC). It was shown that phenolic extraction from the herb was successful when using 70% ethanol in a triple extraction method and at a ratio of 1:14–1:16. The in vivo studies with rodents demonstrated the analgesic activity of the M. discoidea extracts and improvements in the sleep of animals. The dry extracts of M. discoidea did not show any toxicity. The molecular docking analysis showed a high probability of COX-1,2 inhibition and NMDA receptor antagonism by the extracts.
]]>Biomolecules doi: 10.3390/biom14030360
Authors: Dan Van Bui Linh Manh Nguyen Akira Kanda Hanh Hong Chu Nhi Kieu Thi Le Yasutaka Yun Yoshiki Kobayashi Kensuke Suzuki Akitoshi Mitani Akihiro Shimamura Kenta Fukui Shunsuke Sawada David Dombrowicz Hiroshi Iwai
Introduction: Eosinophils contribute to the pathogenesis of allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis. We previously reported that human tissue eosinophils have high CD69 expression compared to blood eosinophils, and its expression is correlated with disease severity and the number of infiltrated eosinophils. However, biological CD69 signaling activity in eosinophils remains unclear. Methods: CD69 expression on lung tissue eosinophils obtained from mice with ovalbumin-induced asthma was measured using flow cytometry. CD69 crosslinking was performed on eosinophils purified from the spleen of IL-5 transgenic mice to investigate CD69 signaling and its function in eosinophils. Then, qPCR, Western blot, enzyme-linked immunosorbent assay, and survival assay results were analyzed. Results: Surface CD69 expression on lung tissue eosinophils in the asthma mice model was 2.91% ± 0.76%, whereas no expression was detected in the healthy group. CD69-expressed eosinophils intrinsically have an upregulation of IL-10 mRNA expression. Moreover, CD69 crosslinking induced further pronounced IL-10 production and apoptosis; these responses were mediated via the Erk1/2 and JNK pathways, respectively. Conclusions: Our results suggested that CD69+ eosinophils play an immunoregulator role in type 2 inflammation, whereas activated tissue eosinophils contribute to the pathogenesis of asthma.
]]>Biomolecules doi: 10.3390/biom14030359
Authors: Hibiki Sugita Shunsuke Takarabe Atsuko Kageyama Yui Kawata Junya Ito
During mammalian fertilization, repetitive intracellular Ca2+ increases known as Ca2+ oscillations occur. These oscillations are considered crucial for successful fertilization and subsequent embryonic development. Numerous researchers have endeavored to elucidate the factors responsible for inducing Ca2+ oscillations across various mammalian species. Notably, sperm-specific phospholipase C zeta (PLCζ) emerged as a prominent candidate capable of initiating Ca2+ oscillations, particularly in mammals. Genetic mutation of PLCζ in humans results in the absence of Ca2+ oscillations in mouse oocytes. Recent studies further underscored PLCζ’s significance, revealing that sperm from PLCζ-deficient (Plcz1−/−) mice fail to induce Ca2+ oscillations upon intracytoplasmic sperm injection (ICSI). Despite these findings, observations from in vitro fertilization (IVF) experiments using Plcz1−/− sperm revealed some residual intracellular Ca2+ increases and successful oocyte activation, hinting at potential alternative mechanisms. In this review, we introduced the current hypothesis surrounding oocyte activation in mammals, informed by contemporary literature, and probed into the enigmatic mechanisms underlying mammalian fertilization-induced oocyte activation.
]]>Biomolecules doi: 10.3390/biom14030358
Authors: Lauren S. Hughes Alexander Fröhlich Abigail L. Pfaff Vivien J. Bubb John P. Quinn Sulev Kõks
Transposable elements (TEs) are repetitive elements which make up around 45% of the human genome. A class of TEs, known as SINE-VNTR-Alu (SVA), demonstrate the capacity to mobilise throughout the genome, resulting in SVA polymorphisms for their presence or absence within the population. Although studies have previously highlighted the involvement of TEs within neurodegenerative diseases, such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS), the exact mechanism has yet to be identified. In this study, we used whole-genome sequencing and RNA sequencing data of ALS patients and healthy controls from the New York Genome Centre ALS Consortium to elucidate the influence of reference SVA elements on gene expressions genome-wide within central nervous system (CNS) tissues. To investigate this, we applied a matrix expression quantitative trait loci analysis and demonstrate that reference SVA insertion polymorphisms can significantly modulate the expression of numerous genes, preferentially in the trans position and in a tissue-specific manner. We also highlight that SVAs significantly regulate mitochondrial genes as well as genes within the HLA and MAPT loci, previously associated within neurodegenerative diseases. In conclusion, this study continues to bring to light the effects of polymorphic SVAs on gene regulation and further highlights the importance of TEs within disease pathology.
]]>Biomolecules doi: 10.3390/biom14030357
Authors: Anastasia Diolintzi Mst Shaela Pervin Edward C. Hsiao
Background: Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized. Purpose of review: This review will examine recent findings on the roles of inflammation and the immune system in fibrodysplasia ossificans progressiva (FOP). FOP is a genetic condition of aggressive and progressive HO formation. We also examine how inflammation may be a valuable target for the treatment of HO. Rationale/Recent findings: Multiple lines of evidence indicate a key role for the immune system in driving FOP pathogenesis. Critical cell types include macrophages, mast cells, and adaptive immune cells, working through hypoxia signaling pathways, stem cell differentiation signaling pathways, vascular regulatory pathways, and inflammatory cytokines. In addition, recent clinical reports suggest a potential role for immune modulators in the management of FOP. Future perspectives: The central role of inflammatory mediators in HO suggests that the immune system may be a common target for blocking HO in both FOP and non-genetic forms of HO. Future research focusing on the identification of novel inflammatory targets will help support the testing of potential therapies for FOP and other related conditions.
]]>Biomolecules doi: 10.3390/biom14030356
Authors: Georges Maestroni
In all mammals, the circulating pool of MLTs is synthesized in the pineal gland during the night’s darkness hours. Its main function is synchronizing the organism in the photoperiod. In contrast, extra-pineal MLT is synthesized in peripheral organs, does not follow any circadian rhythm or circulate, and plays a detoxifying and cytoprotective role. Circulating MLT may stimulate both innate and acquired immune responses through its circadian action and by activating high-affinity receptors on immunocompetent cells. Extra-pineal MLT may have antioxidant and anti-inflammatory effects that dampen the innate immune response. These two seemingly divergent roles may be considered to be two sides of the same coin. In fact, the integration of both circulating and extra-pineal MLT functions might generate a balanced and effective immune response against microbial pathogens. The studies described in this review investigated the effects of exogenous MLT in various models of infectious diseases using extremely different doses and treatment schedules. None of them evaluated the possibility of integrating the non-circadian anti-inflammatory effect with the circadian immunoenhancing action of MLT. As a consequence, in spite of the fact that most studies agree that MLT has a beneficial effect against infections, it seems difficult to draw any definite conclusion about its possible therapeutic use.
]]>Biomolecules doi: 10.3390/biom14030355
Authors: Mingrui Zou Zhenxing Shao
Osteoarthritis (OA) is a common degenerative disease. Although some biomarkers and drug targets of OA have been discovered and employed, limitations and challenges still exist in the targeted therapy of OA. Mendelian randomization (MR) analysis has been regarded as a reliable analytic method to identify effective therapeutic targets. Thus, we aimed to identify novel therapeutic targets for OA and investigate their potential side effects based on MR analysis. In this study, two-sample MR, colocalization analysis, summary-data-based Mendelian randomization (SMR) and Mendelian randomization phenome-wide association study (MR-PheWAS) were conducted. We firstly analyzed data from 4907 plasma proteins to identify potential therapeutic targets associated with OA. In addition, blood expression quantitative trait loci (eQTLs) data sources were used to perform additional validation. A protein–protein interaction (PPI) network was also constructed to delve into the interactions among identified proteins. Then, MR-PheWASs were utilized to assess the potential side effects of core therapeutic targets. After MR analysis and FDR correction, we identified twelve proteins as potential therapeutic targets for knee OA or hip OA. Colocalization analysis and additional validation supported our findings, and PPI networks revealed the interactions among identified proteins. Finally, we identified MAPK3 (OR = 0.855, 95% CI: 0.791–0.923, p = 6.88 × 10−5) and GZMK (OR = 1.278, 95% CI: 1.131–1.444, p = 8.58 × 10−5) as the core therapeutic targets for knee OA, and ITIH1 (OR = 0.847, 95% CI: 0.784–0.915, p = 2.44 × 10−5) for hip OA. A further MR phenome-wide association study revealed the potential side effects of treatments targeting MAPK3, GZMK, and ITIH1. This comprehensive study indicates twelve plasma proteins with potential roles in knee and hip OA as therapeutic targets. This advancement holds promise for the progression of OA drug development, and paves the way for more efficacious treatments of OA.
]]>Biomolecules doi: 10.3390/biom14030354
Authors: Jinling Zhang Ying Zhang Jiafeng Chen Weimin Gong Xiaolin Tu
The enhancement of bioactivity in materials has become an important focus within the field of bone tissue engineering. Four-dimensional intelligent osteogenic module, an innovative fusion of 3D printing with the time axis, shows immense potential in augmenting the bioactivity of these materials, thereby facilitating autologous bone regeneration efficiently. This study focuses on novel bone repair materials, particularly bioactive scaffolds with a developmental osteogenic microenvironment prepared through 3D bioprinting technology. This research mainly creates a developmental osteogenic microenvironment named “DOME”. This is primed by the application of a small amount of the small molecule drug SB216763, which activates canonical Wnt signaling in osteocytes, promoting osteogenesis and mineralization nodule formation in bone marrow stromal cells and inhibiting the formation of adipocytes. Moreover, DOME enhances endothelial cell migration and angiogenesis, which is integral to bone repair. More importantly, the DOME-PCI3D system, a 4D intelligent osteogenic module constructed through 3D bioprinting, stably supports cell growth (91.2% survival rate after 7 days) and significantly increases the expression of osteogenic transcription factors in bone marrow stromal cells and induces osteogenic differentiation and mineralization for 28 days. This study presents a novel approach for bone repair, employing 3D bioprinting to create a multifunctional 4D intelligent osteogenic module. This innovative method not only resolves challenges related to shape-matching and biological activity but also demonstrates the vast potential for applications in bone repair.
]]>Biomolecules doi: 10.3390/biom14030353
Authors: Nina Devrnja Boban Anđelković Jovana Ljujić Tatjana Ćosić Sofija Stupar Milica Milutinović Jelena Savić
β-cyclodextrin (β-CD) is a good host for the encapsulation of fennel and basil essential oils (FEO and BEO, respectively) and the formation of inclusion complexes (ICs) using the co-precipitation method. According to the results of the GC/MS analysis conducted in this study, monoterpenes and monoterpenoids were the dominant chemical groups in total FEO, while in BEO, these two groups occurred along with sesquiterpenes and sesquiterpenoids. The presence of dominant compounds from both EOs was validated using the FT-IR spectra of ICs, which indicated successful complexation. Analyses conducted using SPME/GC-MS showed the continuous emission of volatiles over 24 h from both ICs. Under SEM, particles of both ICs appeared to have a rectangular or rhomboid morphology and few aggregates. The insecticidal properties of EOs and ICs with β-CD were tested on the Colorado potato beetle (CPB) as a model pest. The inclusion complex of β-CD with FEO altered the developmental dynamic and body mass of the CPB. The initial increase in the proteolytic activity of CPB larvae fed with potato plants sprayed with ICs was not maintained for long, and the proteolytic efficacy of treated larvae remained in line with that of the control larvae. Future investigations will focus on manipulating the volume of EOs used and the treatment duration for optimal efficacy and potential application.
]]>Biomolecules doi: 10.3390/biom14030352
Authors: Lixia He Hanmin Jiang Yaotong Li Xu Zhang Wenting Sun Ce Liu Zekai Zhao Chengrong Yun Hui Li Chunguo Wang
Sulforaphane (SFN) is one of the hydrolysates of glucosinolates (GSLs), primarily derived from Brassica vegetables like broccoli. In clinical therapy, SFN has been proven to display antimicrobial, anticancer, antioxidant, and anti-inflammatory properties. However, the antimicrobial effects and mechanism of SFN against plant pathogens need to be further elucidated, which limits its application in agriculture. In this study, the genetic factors involved in SFN biosynthesis in 33 B. oleracea varieties were explored. The finding showed that besides the genetic background of different B. oleracea varieties, myrosinase and ESP genes play important roles in affecting SFN content. Subsequently, the molecular identification cards of these 33 B. oleracea varieties were constructed to rapidly assess their SFN biosynthetic ability. Furthermore, an optimized protocol for SFN extraction using low-cost broccoli curds was established, yielding SFN-enriched extracts (SFN-ee) containing up to 628.44 μg/g DW of SFN. The antimicrobial activity assay confirmed that SFN-ee obtained here remarkably inhibit the proliferation of nine tested microorganisms including four plant pathogens by destroying their membrane integrity. Additionally, the data demonstrated that exogenous application of SFN-ee could also induce ROS accumulation in broccoli leaves. These results indicated that SFN-ee should play a dual role in defense against plant pathogens by directly killing pathogenic cells and activating the ROS signaling pathway. These findings provide new evidence for the antimicrobial effect and mechanism of SFN against plant pathogens, and suggest that SFN-ee can be used as a natural plant antimicrobial agent for crop protection and food preservation.
]]>Biomolecules doi: 10.3390/biom14030351
Authors: Nabil A. Alhakamy Shaimaa M. Badr-Eldin Osama A. A. Ahmed Abdulrahman A. Halwani Hibah M. Aldawsari Mohamed A. El-Moselhy Aliaa Anter Sara S. Sharkawi Muhammad H. Sultan Osama A. A. Madkhali Muhammed A. Bakhrebah Mohammad N. Alomary Wesam H. Abdulaal Usama A. Fahmy
The journal retracts the article, “Optimized Ellagic Acid–Ca Pectinate Floating Beads for Gastroprotection against Indomethacin-Induced Gastric Injury in Rats” [...]
]]>Biomolecules doi: 10.3390/biom14030350
Authors: Shu-Wei Yuan Hong-Ling Shi Mu-Ran Fu Xi-Chuan Zhang Xiao-Qi Xi Yao Wang Tai-Song Shen Jin-Liang Ma Cun-Duo Tang
Cyclic dinucleotides (CDNs) are cyclic molecules consisting of two nucleoside monophosphates linked by two phosphodiester bonds, which act as a second messenger and bind to the interferon gene stimulating factor (STING) to activate the downstream signaling pathway and ultimately induce interferon secretion, initiating an anti-infective immune response. Cyclic dinucleotides and their analogs are lead compounds in the immunotherapy of infectious diseases and tumors, as well as immune adjuvants with promising applications. Many agonists of pathogen recognition receptors have been developed as effective adjuvants to optimize vaccine immunogenicity and efficacy. In this work, the binding mechanism of human-derived interferon gene-stimulating protein and its isoforms with cyclic dinucleotides and their analogs was theoretically investigated using computer simulations and combined with experimental results in the hope of providing guidance for the subsequent synthesis of cyclic dinucleotide analogs.
]]>Biomolecules doi: 10.3390/biom14030349
Authors: Conan Juan Alec C. Bancroft Ji Hae Choi Johanna H. Nunez Chase A. Pagani Yen-Sheng Lin Edward C. Hsiao Benjamin Levi
Heterotopic ossification (HO) is a debilitating pathology where ectopic bone develops in areas of soft tissue. HO can develop as a consequence of traumatic insult or as a result of dysregulated osteogenic signaling, as in the case of the orphan disease fibrodysplasia ossificans progressiva (FOP). Traumatic HO (tHO) formation is mediated by the complex interplay of signaling between progenitor, inflammatory, and nerve cells, among others, making it a challenging process to understand. Research into the pathogenesis of genetically mediated HO (gHO) in FOP has established a pathway involving uninhibited activin-like kinase 2 receptor (ALK2) signaling that leads to downstream osteogenesis. Current methods of diagnosis and treatment lag behind pre-mature HO detection and progressive HO accumulation, resulting in irreversible decreases in range of motion and chronic pain for patients. As such, it is necessary to draw on advancements made in the study of tHO and gHO to better diagnose, comprehend, prevent, and treat both.
]]>Biomolecules doi: 10.3390/biom14030348
Authors: Luying Guo Sulin Luo Xingxia Wang Nengbo Zhang Yamei Cheng Jia Shen Jianghua Chen Rending Wang
Mitochondria are essential organelles that possess their own DNA. Mitochondrial dysfunction has been revealed in many kidney diseases, including BK polyomavirus-associated nephropathy (BKPyVAN). In this study, we introduce an innovative approach for non-invasive monitoring of mitochondrial impairment through urinary donor-derived cell-free mitochondrial DNA (ddcfmtDNA), addressing the crucial challenge of BKPyVAN diagnosis. Urinary samples were collected at the time of biopsy from a total of 60 kidney transplant recipients, comprising 12 with stable function, 22 with T cell-mediated rejection, and 21 with biopsy-proven BKPyVAN. Our findings reveal that the ddcfmtDNA-to-ddcfDNA ratio exhibits superior capability in distinguishing BKPyVAN from other conditions, with a cutoff value of 4.96% (area under curve = 0.933; sensitivity: 71.4%; and specificity: 97.1%). Notably, an elevation of ddcfmtDNA levels is associated with mitochondrial damage, as visualized through electron microscopy. These results underscore the promise of non-invasive monitoring for detecting subtle mitochondrial damage and its potential utility in BKPyVAN diagnosis. Further investigations are required to advance this field of research.
]]>Biomolecules doi: 10.3390/biom14030347
Authors: Qian Cong Yingzi Yang
Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder characterized by abnormal bone formation due to ACVR1 gene mutations. The identification of the molecular mechanisms underlying the ectopic bone formation and expansion in FOP is critical for the effective treatment or prevention of HO. Here we find that Hh signaling activation is required for the aberrant ectopic bone formation in FOP. We show that the expression of Indian hedgehog (Ihh), a Hh ligand, as well as downstream Hh signaling, was increased in ectopic bone lesions in Acvr1R206H; ScxCre mice. Pharmacological treatment with an Ihh-neutralizing monoclonal antibody dramatically reduced chondrogenesis and ectopic bone formation. Moreover, we find that the activation of Yap in the FOP mouse model and the genetic deletion of Yap halted ectopic bone formation and decreased Ihh expression. Our mechanistic studies showed that Yap and Smad1 directly bind to the Ihh promoter and coordinate to induce chondrogenesis by promoting Ihh expression. Therefore, the Yap activation in FOP lesions promoted ectopic bone formation and expansion in both cell-autonomous and non-cell-autonomous manners. These results uncovered the crucial role of the Yap-Ihh axis in FOP pathogenesis, suggesting the inhibition of Ihh or Yap as a potential therapeutic strategy to prevent and reduce HO.
]]>Biomolecules doi: 10.3390/biom14030346
Authors: Crystal Woods Amanda R. Flockton Jaime Belkind-Gerson
Phosphatase and tensin homolog (Pten) is a key regulator of cell proliferation and a potential target to stimulate postnatal enteric neuro- and/or gliogenesis. To investigate this, we generated two tamoxifen-inducible Cre recombinase murine models in which Pten was conditionally ablated, (1) in glia (Plp1-expressing cells) and (2) in neurons (Calb2-expressing cells). Tamoxifen-treated adult (7–12 weeks of age; n = 4–15) mice were given DSS to induce colitis, EdU to monitor cell proliferation, and were evaluated at two timepoints: (1) early (3–4 days post-DSS) and (2) late (3–4 weeks post-DSS). We investigated gut motility and evaluated the enteric nervous system. Pten inhibition in Plp1-expressing cells elicited gliogenesis at baseline and post-DSS (early and late) in the colon, and neurogenesis post-DSS late in the proximal colon. They also exhibited an increased frequency of colonic migrating motor complexes (CMMC) and slower whole gut transit times. Pten inhibition in Calb2-expressing cells did not induce enteric neuro- or gliogenesis, and no alterations were detected in CMMC or whole gut transit times when compared to the control at baseline or post-DSS (early and late). Our results merit further research into Pten modulation where increased glia and/or slower intestinal transit times are desired (e.g., short-bowel syndrome and rapid-transit disorders).
]]>Biomolecules doi: 10.3390/biom14030345
Authors: Yang Jiang Qi Zhang Zixia Zeng Yi Wang Mingzhu Zhao Kangyu Wang Meiping Zhang
Ginseng (Panax ginseng C.A. Meyer) is a perennial herb belonging to the family Araliaceae and has been used for thousands of years in East Asia as an essential traditional medicine with a wide range of pharmacological activities of its main active ingredient, ginsenosides. The AP2/ERF gene family, widely present in plants, is a class of transcription factors capable of responding to ethylene regulation that has an influential role in regulating the synthesis of major active ingredients in medicinal plants and in response to biotic and abiotic stresses, which have not been reported in Panax ginseng. In this study, the AP2/ERF gene was localized on the ginseng chromosome, and an AP2/ERF gene duplication event was also discovered in Panax ginseng. The expression of seven ERF genes and three key enzyme genes related to saponin synthesis was measured by fluorescence quantitative PCR using ethylene treatment of ginseng hairy roots, and it was observed that ethylene promoted the expression of genes related to the synthesis of ginsenosides, among which the PgERF120 gene was the most sensitive to ethylene. We analyzed the sequence features and expression patterns of the PgERF120 gene and found that the expression of the PgERF120 gene was specific in time and space. The PgERF120 gene was subsequently cloned, and plant overexpression and RNA interference vectors were constructed. Ginseng adventitious roots were transformed using the Agrobacterium tumefaciens-mediated method to obtain transgenic ginseng hairy roots, and the gene expression, ginsenoside content and malondialdehyde content in overexpression-positive hairy roots were also analyzed. This study preliminarily verified that the PgERF120 gene can be involved in the regulation of ginsenoside synthesis, which provides a theoretical basis for the study of functional genes in ginseng and a genetic resource for the subsequent use of synthetic biology methods to improve the yield of ginsenosides.
]]>Biomolecules doi: 10.3390/biom14030344
Authors: Charumathi Anbalagan Sangeetha Kadapakkam Nandabalan Pavithra Sankar Prasanna Srinivasan Rajaram Karthick Govindaraj Secunda Rupert Jeswanth Sathyanesan
The eubiotic state of the gut microbiota is primarily brought about by various probiotic species that colonize the gut. It is becoming very clear that the probiotic-metabolite mixtures in the gut luminal milieu is central in establishing cross-kingdom signalling networks to maintain gut-multi-organ axes health. Culturally, different fermented foods and beverages have been regional staples since ancient times, and are known to be enriched with probiotics. However, regional variations including the environment, the staple food source (prebiotics), and fermentation methods, among other factors, influence the fermenting probiotic species. Fermented rice water (FRW), an economical, easy to make, simple beverage is a rich source of synbiotics. Therefore, consumption of fermented rice water allows for the intake of a variety of region-specific live probiotics. The secondary metabolites (postbiotics) present in such symbiotic mixtures may also contribute toward maintaining normal intestinal cellular functions. In this study, we highlight that regional staples such as rice consumed in their fermented form may hold promise in alleviating gut-related diseases. Our results show that simple overnight fermentation of cooked edible rice enables the growth of probiotic bacterial species belonging to the Lactic Acid Bacteria group (Leuconostoc lactis, Weisella confusa, Weisella cibacria, Lactococcus lactis, lactococcus taiwanensis, Lactobacillus fermentum, Lactobacillus nagelii, and Lactobacillus delbrueckii ssp. indicus). Metabolomic analysis of the overnight fermented and over two-nights fermented rice water identified more than 200 postbiotic metabolites. Our results show that postbiotics contributing to energy metabolism, gut-multiorgan axes, and microbial paraprobiotics are enriched in the overnight (~10 h) fermented rice water as compared to the over two-nights fermented rice water. Functional analysis via gene expression studies for nutrient absorption (mct-1 and mct-2) and barrier integrity (occludin and zo-1) reveals significant upregulation of these genes upon FRW treatment of HT29 colon cells. This study is a first-of-its-kind to demonstrate the proof-of-principle that postbiotics of naturally fermented rice water positively modulates colonocyte health.
]]>Biomolecules doi: 10.3390/biom14030343
Authors: Carmen Ciavarella Ilenia Motta Miriam Capri Mauro Gargiulo Gianandrea Pasquinelli
Human arteries show structural and functional peculiarities according to the nutrient and oxygen needs of a specific vascular district. This architectural heterogeneity is reflected in the pathological setting of cardiovascular diseases (CVDs). Indeed, the responsiveness to cardiovascular risk factors, and the morphological and molecular patterns are discriminating factors among CVDs affecting different vascular beds. MicroRNAs (miRNAs) are endogenous regulators of gene expression and fine-tuners of vascular cell differentiation; thus, these non-coding RNAs can modulate arterial heterogeneity. The identification of an artery-specific miRNA signature would be promising in the therapy of CVDs, especially in patients who are frail and elderly. In the present review, we will provide a concise description of the arterial tree heterogeneity on a structural and cellular basis, mainly in the pathological context. Secondly, we will address the miRNA potential as crucial mediators of arterial heterogeneity, focusing on the abdominal aorta and femoral artery, with the final goal of strengthening the search for more targeted therapies in CVDs and stratification approaches in patients who are frail and elderly.
]]>Biomolecules doi: 10.3390/biom14030342
Authors: Haidong Liu Xiao Li Yin Shi Zu Ye Xiangdong Cheng
Protein phosphatases are primarily responsible for dephosphorylation modification within signal transduction pathways. Phosphatase of regenerating liver-3 (PRL-3) is a dual-specific phosphatase implicated in cancer pathogenesis. Understanding PRL-3’s intricate functions and developing targeted therapies is crucial for advancing cancer treatment. This review highlights its regulatory mechanisms, expression patterns, and multifaceted roles in cancer progression. PRL-3’s involvement in proliferation, migration, invasion, metastasis, angiogenesis, and drug resistance is discussed. Regulatory mechanisms encompass transcriptional control, alternative splicing, and post-translational modifications. PRL-3 exhibits selective expressions in specific cancer types, making it a potential target for therapy. Despite advances in small molecule inhibitors, further research is needed for clinical application. PRL-3-zumab, a humanized antibody, shows promise in preclinical studies and clinical trials. Our review summarizes the current understanding of the cancer-related cellular function of PRL-3, its prognostic value, and the research progress of therapeutic inhibitors.
]]>Biomolecules doi: 10.3390/biom14030341
Authors: Sriganesh Ramachandra Rao Steven J. Fliesler
Sterol homeostasis in mammalian cells and tissues involves balancing three fundamental processes: de novo sterol biosynthesis; sterol import (e.g., from blood-borne lipoproteins); and sterol export. In complex tissues, composed of multiple different cell types (such as the retina), import and export also may involve intratissue, intercellular sterol exchange. Disruption of any of these processes can result in pathologies that impact the normal structure and function of the retina. Here, we provide a brief overview of what is known currently about sterol homeostasis in the vertebrate retina and offer a proposed path for future experimental work to further our understanding of these processes, with relevance to the development of novel therapeutic interventions for human diseases involving defective sterol homeostasis.
]]>Biomolecules doi: 10.3390/biom14030340
Authors: Alexa K. Pius Masakazu Toya Qi Gao Max L. Lee Yasemin Sude Ergul Simon Kwoon-Ho Chow Stuart Barry Goodman
Max L. Lee was not included as an author in the original publication [...]
]]>Biomolecules doi: 10.3390/biom14030339
Authors: Xinru Qiu Han Li Greg Ver Steeg Adam Godzik
Recent advancements in AI-driven technologies, particularly in protein structure prediction, are significantly reshaping the landscape of drug discovery and development. This review focuses on the question of how these technological breakthroughs, exemplified by AlphaFold2, are revolutionizing our understanding of protein structure and function changes underlying cancer and improve our approaches to counter them. By enhancing the precision and speed at which drug targets are identified and drug candidates can be designed and optimized, these technologies are streamlining the entire drug development process. We explore the use of AlphaFold2 in cancer drug development, scrutinizing its efficacy, limitations, and potential challenges. We also compare AlphaFold2 with other algorithms like ESMFold, explaining the diverse methodologies employed in this field and the practical effects of these differences for the application of specific algorithms. Additionally, we discuss the broader applications of these technologies, including the prediction of protein complex structures and the generative AI-driven design of novel proteins.
]]>Biomolecules doi: 10.3390/biom14030338
Authors: Yaír Adonaí Sánchez-Nuño Martín Zermeño-Ruiz Olga Deli Vázquez-Paulino Karla Nuño Angélica Villarruel-López
Pigmented corn is a gramineae food of great biological, cultural and nutritional importance for many Latin American countries, with more than 250 breeds on the American continent. It confers a large number of health benefits due to its diverse and abundant bioactive compounds. In this narrative review we decided to organize the information on the nutrients, bioactive compounds and phytochemicals present in pigmented corn, as well as their effects on human health. Phenolic compounds and anthocyanins are some of the most studied and representative compounds in these grasses, with a wide range of health properties, mainly the reduction of pro-oxidant molecules. Carotenoids are a group of molecules belonging to the terpenic compounds, present in a large number of pigmented corn breeds, mainly the yellow ones, whose biological activity incorporates a wide spectrum. Bioactive peptides can be found in abundance in corn, having very diverse biological effects that include analgesic, opioid and antihypertensive activities. Other compounds with biological activity found in pigmented corn are resistant starches, some fatty acids, phytosterols, policosanols, phospholipids, ferulic acid and phlobaphenes, as well as a great variety of vitamins, elements and fibers. This review aims to disseminate and integrate the existing knowledge on compounds with biological activity in pigmented corn in order to promote their research, interest and use by scientists, nutrition professionals, physicians, industries and the general population.
]]>Biomolecules doi: 10.3390/biom14030337
Authors: Zhi-Shuai Hou Hong-Kui Zhao Pedro Perdiguero Meng-Qun Liu Kai-Wen Xiang Chu Zeng Zhao Li Xiao-Dong Yang Qian Yang Yuan-Ru Xin Ji-Fang Li Carolina Tafalla Hai-Shen Wen
Chemokines are cytokines with chemoattractant capacities that exert their physiological functions through the binding of chemokine receptors. Thus, chemokine and receptor complexes exert important roles in regulating development and homeostasis during routine immune surveillance and inflammation. Compared to mammals, the physiology and structure of chemokine receptors in fish have not been systematically studied. Furthermore, the salmonid-specific whole genome duplication has significantly increased the number of functional paralogs of chemokine receptors. In this context, in the current study, trout exhibited 17 cxcr genes, including 12 newly identified and 5 previously identified receptors. Interestingly, gene expression of brain cxcr1 and cxcr4, kidney cxcr3 and cxcr4, and spleen cxcr3, cxcr4, and cxcr5 subtypes were altered by bacterial infection, whereas brain cxcr1, kidney cxcr1 and cxcr7, and liver cxcr2, cxcr3, and cxcr4 subtypes were changed in response to environmental changes. Based on protein structures predicted by ColabFold, the conserved amino acids in binding pockets between trout CXCR4.1 subtypes and human CXCR4 were also analyzed. Our study is valuable from a comparative point of view, providing new insights into the identification and physiology of salmonid chemokine receptors.
]]>Biomolecules doi: 10.3390/biom14030336
Authors: Monika Novak Babič Sara Ragucci Adrijana Leonardi Miha Pavšič Nicola Landi Igor Križaj Nina Gunde-Cimerman Kristina Sepčić Antimo Di Maro
Sodin 5 is a type 1 ribosome-inactivating protein isolated from the seeds of Salsola soda L., an edible halophytic plant that is widespread in southern Europe, close to the coast. This plant, known as ‘agretti’, is under consideration as a new potential crop on saline soils. Considering a possible defence role of sodin 5 in the plant, we report here its antifungal activity against different halophilic and halotolerant fungi. Our results show that sodin 5 at a concentration of 40 µg/mL (1.4 µM) was able to inhibit the growth of the fungi Trimmatostromma salinum (35.3%), Candida parapsilosis (24.4%), Rhodotorula mucilaginosa (18.2%), Aspergillus flavus (12.2%), and Aureobasidium melanogenum (9.1%). The inhibition observed after 72 h was concentration-dependent. On the other hand, very slight growth inhibition was observed in the fungus Hortaea werneckii (4.2%), which commonly inhabits salterns. In addition, sodin 5 showed a cytotoxic effect on the Sf9 insect cell line, decreasing the survival of these cells to 63% at 1.0 µg/mL (34.5 nM). Structural analysis of sodin 5 revealed that its N-terminal amino acid residue is blocked. Using mass spectrometry, sodin 5 was identified as a homologous to type 1 polynucleotide:adenosine glycosylases, commonly known as ribosome-inactivating proteins from the Amaranthaceae family. Twenty-three percent of its primary structure was determined, including the catalytic site.
]]>Biomolecules doi: 10.3390/biom14030335
Authors: Ismael Sánchez-Gomar Noelia Geribaldi-Doldán Celeste Santos-Rosendo Ciro Sanguino-Caneva Carlos Carrillo-Chapman Ornella Fiorillo-Moreno José Luis Villareal Camacho Elkin Navarro Quiroz Cristina Verástegui
Neurogenesis is the process of forming new neurons from neural stem cells (NSCs). In adults, this process takes place in specific areas of the brain, known as neurogenic niches. These regions have unique anatomical features that have been studied in animal models and in the human brain; however, there are differences between these models that need to be addressed. The most studied areas are the subventricular zone, the lateral and latero-dorsal walls of the lateral ventricles, and the dentate gyrus of the hippocampus (Hp), which are known as the canonical areas. Other, less-studied niches, such as the hypothalamus, the cerebellum, and the amygdala, are known as non-canonical areas. Anatomy occupies a relevant place in adult neurogenesis, in which the tissue architecture and cellular location are necessities for the interaction and release of diverse molecules that allow this phenomenon. The cell arrangement within the niche and the location of the niche itself are of particular relevance to the state in which the NSCs are found. Consequently, the majority of previous discoveries have been related to pathology. While many studies are based on animal models, discoveries related to neurogenesis in humans have also been made; however, in this case, opinions vary, leading to extensive controversy in recent years. In this review, we address the anatomical characteristics of the different brain regions to better understand their relationships within neurogenesis.
]]>Biomolecules doi: 10.3390/biom14030334
Authors: Sarmed H. Kathem Yasameen Sh. Nasrawi Shihab H. Mutlag Surya M. Nauli
The human gastrointestinal system is a complex ecosystem crucial for well-being. During sepsis-induced gut injury, the integrity of the intestinal barrier can be compromised. Lipopolysaccharide (LPS), an endotoxin from Gram-negative bacteria, disrupts the intestinal barrier, contributing to inflammation and various dysfunctions. The current study explores the protective effects of limonene, a natural compound with diverse biological properties, against LPS-induced jejunal injury in mice. Oral administration of limonene at dosages of 100 and 200 mg/kg was used in the LPS mouse model. The Murine Sepsis Score (MSS) was utilized to evaluate the severity of sepsis, while serum levels of urea and creatinine served as indicators of renal function. Our results indicated that LPS injection induced renal function deterioration, evidenced by elevated serum urea and creatinine levels compared to control mice. However, pretreatment with limonene at doses of 100 and 200 mg/kg mitigated this decline in renal function, evidenced from the reduced levels of serum urea and creatinine. Limonene demonstrated anti-inflammatory effects by reducing pro-inflammatory cytokines (TNF-α, IL-1β, COX-2), suppressing the TLR4/NF-κB/AP-1 but not IRF3 signaling pathways, and modulating oxidative stress through Nrf2 activation. The results suggest that limonene holds promise as a potential therapeutic agent for mitigating intestinal inflammation and preserving gastrointestinal health.
]]>Biomolecules doi: 10.3390/biom14030333
Authors: Ruohan Shan Yuxiang Zhang Yiping Shi Xiaowen Wang Xueke Wang Guanying Ma Qian Li
Background: Studies have shown that the chronic use of cannabis is associated with a decrease in blood pressure. Our previous studies prove that activating the cannabinoid type 2 (CB2) receptor in the brain can effectively reduce blood pressure in spontaneously hypertensive rats; however, the exact mechanism has not been clarified. The objective of this study is to demonstrate that activation of microglial CB2 receptors can effectively reduce the levels of TNF-α, IL-1β, and IL-6 in the paraventricular nucleus (PVN) through inhibiting aerobic glycolysis, thereby relieving hypertension. Methods: AngiotensinII (AngII) was administered to BV2 cells and C57 mice to induce hypertension and the release of proinflammatory cytokines. The mRNA and protein expression of the CB2 receptor, TNF-α, IL-1β, IL-6, and the PFK and LDHa enzymes were detected using RT-qPCR and Western blotting. The Seahorse XF Energy Metabolism Analyzer was used to measure the oxidative phosphorylation and aerobic glycolysis metabolic pathways in BV2 cells. The long-term effects of injecting JWH133, a selective CB2 receptor agonist, intraperitoneally on blood pressure were ascertained. ELISA was used to measure norepinephrine and lactic acid levels while immunofluorescence labeling was used to locate the CB2 receptor and c-Fos. By injecting pAAV-F4/80-GFP-mir30shRNA (AAV2-r-CB2shRNA) into the lateral cerebral ventricle, the CB2 receptor in microglia was specifically knocked down. Results: Activation of CB2 receptors by the agonist JWH133 suppressed TNF-α, IL-1β, and IL-6 by inhibiting PFK and LDHa enzymes involved in glycolysis, as well as lactic acid accumulation, along with a reduction in glycoPER levels (marks of aerobic glycolysis) in AngII-treated BV2 cells. In AngII-treated mice, the administration of JWH133 specifically activated CB2 receptors on microglia, resulting in decreased expression levels of PFK, LDHa, TNF-α, IL-1β, and IL-6, subsequently leading to a decrease in c-Fos protein expression within PVN neurons as well as reduced norepinephrine levels in plasma, ultimately contributing to blood pressure reduction. Conclusion: The results suggest that activation of the microglia CB2 receptor decreases the neuroinflammation to relieve hypertension; the underlying mechanism is related to inhibiting aerobic glycolysis of microglia.
]]>Biomolecules doi: 10.3390/biom14030332
Authors: Pavel A. Mironov Alexander S. Paramonov Olesya V. Reznikova Victoria N. Safronova Pavel V. Panteleev Ilia A. Bolosov Tatiana V. Ovchinnikova Zakhar O. Shenkarev
Capitellacin is the β-hairpin membrane-active cationic antimicrobial peptide from the marine polychaeta Capitella teleta. Capitellacin exhibits antibacterial activity, including against drug-resistant strains. To gain insight into the mechanism of capitellacin action, we investigated the structure of the peptide in the membrane-mimicking environment of dodecylphosphocholine (DPC) micelles using high-resolution NMR spectroscopy. In DPC solution, two structural forms of capitellacin were observed: a monomeric β-hairpin was in equilibrium with a dimer formed by the antiparallel association of the N-terminal β-strands and stabilized by intermonomer hydrogen bonds and Van der Waals interactions. The thermodynamics of the enthalpy-driven dimerization process was studied by varying the temperature and molar ratios of the peptide to detergent. Cooling the peptide/detergent system promoted capitellacin dimerization. Paramagnetic relaxation enhancement induced by lipid-soluble 12-doxylstearate showed that monomeric and dimeric capitellacin interacted with the surface of the micelle and did not penetrate into the micelle interior, which is consistent with the “carpet” mode of membrane activity. An analysis of the known structures of β-hairpin AMP dimers showed that their dimerization in a membrane-like environment occurs through the association of polar or weakly hydrophobic surfaces. A comparative analysis of the physicochemical properties of β-hairpin AMPs revealed that dimer stability and hemolytic activity are positively correlated with surface hydrophobicity. An additional positive correlation was observed between hemolytic activity and AMP charge. The data obtained allowed for the provision of a more accurate description of the mechanism of the oligomerization of β-structural peptides in biological membranes.
]]>Biomolecules doi: 10.3390/biom14030331
Authors: Luis Puelles
Brain models present a viewpoint on the fundamental structural components of the brain and their mutual organization, generally relative to a particular concept of the brain axis. A model may be based on adult brain structure or on developmental morphogenetic aspects. Brain models usually have functional implications, depending on which functional properties derive from the postulated organization. This essay examines the present scenario about brain models, emphasizing the contrast between columnar or other longitudinal models and transverse subdivisional neuromeric models. In each case, the main functional implications and apparent problems are explored and commented. Particular attention is given to the modern molecularly based ‘prosomeric model’, which postulates a set of 20 transverse prosomeres as the developmental units that serve to construct all the cerebral parts and the particular typology of many different neuronal populations within the forebrain and the hindbrain, plus a number of additional spinal cord units. These metameric developmental units (serially repeated, but with unique molecular profiles) confer to this model remarkable functional properties based mainly on its multiplicity and modularity. Many important brain functions can be decomposed into subfunctions attended to by combined sets of neuronal elements derived from different neuromeres. Each neuromere may participate in multiple functions. Most aspects related to creation of precise order in neural connections (axonal navigation and synaptogenesis) and function is due to the influence of neuromeric anteroposterior and dorsoventral positional information. Research on neuromeric functionality aspects is increasing significantly in recent times.
]]>Biomolecules doi: 10.3390/biom14030330
Authors: Qingyue Kong Yujie Wang Nan Jiang Yifan Wang Rui Wang Xiaohan Hu Jing Mao Xin Shi
Pulpitis is a common and frequent disease in dental clinics. Although vital pulp therapy and root canal treatment can stop the progression of inflammation, they do not allow for genuine structural regeneration and functional reconstruction of the pulp–dentin complex. In recent years, with the development of tissue engineering and regenerative medicine, research on stem cell-based regenerative endodontic therapy (RET) has achieved satisfactory preliminary results, significantly enhancing its clinical translational prospects. As one of the crucial paracrine effectors, the roles and functions of exosomes in pulp–dentin complex regeneration have gained considerable attention. Due to their advantages of cost-effectiveness, extensive sources, favorable biocompatibility, and high safety, exosomes are considered promising therapeutic tools to promote dental pulp regeneration. Accordingly, in this article, we first focus on the biological properties of exosomes, including their biogenesis, uptake, isolation, and characterization. Then, from the perspectives of cell proliferation, migration, odontogenesis, angiogenesis, and neurogenesis, we aim to reveal the roles and mechanisms of exosomes involved in regenerative endodontics. Lastly, immense efforts are made to illustrate the clinical strategies and influencing factors of exosomes applied in dental pulp regeneration, such as types of parental cells, culture conditions of parent cells, exosome concentrations, and scaffold materials, in an attempt to lay a solid foundation for exploring and facilitating the therapeutic strategy of exosome-based regenerative endodontic procedures.
]]>Biomolecules doi: 10.3390/biom14030329
Authors: Lin Zheng Mingqing Li Huaping Li
Hyperglycemia in pregnancy (HIP) is linked to fetoplacental endothelial dysfunction, which might be a result of hyperglycemia. Hyperglycemia is associated with cell senescence; however, the role and mechanism of high glucose and cell senescence in HIP endothelial cell failure are largely unknown. Our study discovered that human umbilical vein endothelial cells (HUVECs) obtained from HIP pregnant women exhibit excessive senescence, with significantly elevated expression of senescence markers senescence-associated beta-galactosidase (SA-β-gal), p16, p21, and p53. Subsequently, we found that exposing primary HUVECs and cell lines to high glucose resulted in an increase in the synthesis of these senescence indicators, similar to what had been observed in pregnant women with HIP. A replicate senescence model and stress-induced premature senescence (SIPS) model showed higher amounts of vascular damage indicators, including von Willebrand factor (vWF), chemotactic C-C motif chemokine ligand 2 (CCL2), intercellular adhesion molecule 1 (ICAM-1), along with the anti-apoptotic protein BCL2. However, lower expressions of the pro-apoptotic component BAX, in addition to defective proliferation and tubulogenesis, were seen. Further studies indicated that hyperglycemia can not only induce these alterations in HUVECs but also exacerbate the aforementioned changes in both aging HUVECs. The experiments outlined above have also been validated in pregnant women with HIP. Collectively, these data suggest that exposure to high glucose accelerates cell senescence-mediated vein endothelial cell dysfunction, including excessive inflammation, cell adhesion, impaired angiogenesis, and cell proliferation possibly contributing to pregnancy complications and adverse pregnancy outcomes.
]]>Biomolecules doi: 10.3390/biom14030328
Authors: Qiuyang Zhang Qing Liu Siguo Feng Xiumiao Li Qin Jiang
Ocular neovascularization can impair vision and threaten patients’ quality of life. However, the underlying mechanism is far from transparent. In all mammals, macrophages are a population of cells playing pivotal roles in the innate immune system and the first line of defense against pathogens. Therefore, it has been speculated that the disfunction of macrophage homeostasis is involved in the development of ocular vascular diseases. Moreover, various studies have found that non-coding RNAs (ncRNAs) regulate macrophage homeostasis. This study reviewed past studies of the regulatory roles of ncRNAs in macrophage homeostasis in ocular vascular diseases.
]]>Biomolecules doi: 10.3390/biom14030327
Authors: Julia Krüger Peter Richter Julia Stoltze Binod Prasad Sebastian M. Strauch Marcus Krüger Adeel Nasir Michael Lebert
Age-dependent changes in the transcription levels of 5-day-old Euglena gracilis cells, which showed positive gravitaxis, 6-day-old cells without gravitactic orientation, and older cells (9- and 11-day-old, which displayed a precise negative gravitaxis) were determined through microarray analysis. Hierarchical clustering of four independent cell cultures revealed pronounced similarities in transcription levels at the same culture age, which proves the reproducibility of the cultivation method. Employing the non-oriented cells from the 6-day-old culture as a reference, about 2779 transcripts were found to be differentially expressed. While positively gravitactic cells (5-day-old culture) showed only minor differences in gene expression compared to the 6-day reference, pronounced changes of mRNAs (mainly an increase) were found in older cells compared to the reference culture. Among others, genes coding for adenylyl cyclases, photosynthesis, and metabolic enzymes were identified to be differentially expressed. The investigated cells were grown in batch cultures, so variations in transcription levels most likely account for factors such as nutrient depletion in the medium and self-shading. Based on these findings, a particular transcript (e.g., transcript 19556) was downregulated using the RNA interference technique. Gravitaxis and phototaxis were impaired in the transformants, indicating the role of this transcript in signal transduction. Results of the experiment are discussed regarding the increasing importance of E. gracilis in biotechnology as a source of valuable products and the possible application of E. gracilis in life-support systems.
]]>Biomolecules doi: 10.3390/biom14030326
Authors: Vandana Sekhar Houssine Ikhlef Alexandra Bunea Viet S. Nguyen Johan Joo Mukund P. Tantak Holly Moots Otto Phanstiel
Amino acid restriction induces cellular stress and cells often respond via the induction of autophagy. Autophagy or ‘self-eating’ enables the recycling of proteins and provides the essential amino acids needed for cell survival. Of the naturally occurring amino acids, methionine restriction has pleiotropic effects on cells because methionine also contributes to the intracellular methyl pools required for epigenetic controls as well as polyamine biosynthesis. In this report, we describe the chemical synthesis of four diastereomers of a methionine depletion agent and demonstrate how controlled methionine efflux from cells significantly reduces intracellular methionine, S-adenosylmethionine (SAM), S-adenosyl homocysteine (SAH), and polyamine levels. We also demonstrate that human pancreatic cancer cells respond via a lipid signaling pathway to induce autophagy. The methionine depletion agent causes the large amino acid transporter 1 (LAT1) to preferentially work in reverse and export the cell’s methionine (and leucine) stores. The four diastereomers of the lead methionine/leucine depletion agent were synthesized and evaluated for their ability to (a) efflux 3H-leucine from cells, (b) dock to LAT1 in silico, (c) modulate intracellular SAM, SAH, and phosphatidylethanolamine (PE) pools, and (d) induce the formation of the autophagy-associated LC3-II marker. The ability to modulate the intracellular concentration of methionine regardless of exogenous methionine supply provides new molecular tools to better understand cancer response pathways. This information can then be used to design improved therapeutics that target downstream methionine-dependent processes like polyamines.
]]>Biomolecules doi: 10.3390/biom14030325
Authors: Alexis S. Molfetas Nikiforos Boutris Anastasia Tomatsidou Michael Kokkinidis Vasiliki E. Fadouloglou
Enzymes of the carbohydrate esterase family 4 (CE4) deacetylate a broad range of substrates, including linear, branched and mesh-like polysaccharides. Although they are enzymes of variable amino acid sequence length, they all comprise the conserved catalytic domain NodB. NodB carries the metal binding and active site residues and is characterized by a set of conserved sequence motifs, which are linked to the deacetylation activity. Besides a non-structured, flexible peptide of variable length that precedes NodB, several members of the CE4 family contain additional domains whose function or contribution to substrate specificity are not efficiently characterized. Evidence suggests that CE4 family members comprising solely the NodB domain have developed features linked to a variety of substrate specificities. To understand the NodB-based substrate diversity within the CE4 family, we perform a comparative analysis of all NodB domains structurally characterized so far. We show that amino acid sequence variations, topology diversities and excursions away from the framework structure give rise to different NodB domain classes associated with different substrate specificities and particular functions within and beyond the CE4 family. Our work reveals a link between specific NodB domain characteristics and substrate recognition. Thus, the details of the fold are clarified, and the structural basis of its variations is deciphered and associated with function. The conclusions of this work are also used to make predictions and propose specific functions for biochemically/enzymatically uncharacterized NodB-containing proteins, which have generally been considered as putative CE4 deacetylases. We show that some of them probably belong to different enzymatic families.
]]>Biomolecules doi: 10.3390/biom14030324
Authors: Le Thanh Mai Pham Kai Deng Hemant Choudhary Trent R. Northen Steven W. Singer Paul D. Adams Blake A. Simmons Kenneth L. Sale
Laccases from white-rot fungi catalyze lignin depolymerization, a critical first step to upgrading lignin to valuable biodiesel fuels and chemicals. In this study, a wildtype laccase from the basidiomycete Fomitiporia mediterranea (Fom_lac) and a variant engineered to have a carbohydrate-binding module (Fom_CBM) were studied for their ability to catalyze cleavage of β-O-4′ ether and C–C bonds in phenolic and non-phenolic lignin dimers using a nanostructure-initiator mass spectrometry-based assay. Fom_lac and Fom_CBM catalyze β-O-4′ ether and C–C bond breaking, with higher activity under acidic conditions (pH < 6). The potential of Fom_lac and Fom_CBM to enhance saccharification yields from untreated and ionic liquid pretreated pine was also investigated. Adding Fom_CBM to mixtures of cellulases and hemicellulases improved sugar yields by 140% on untreated pine and 32% on cholinium lysinate pretreated pine when compared to the inclusion of Fom_lac to the same mixtures. Adding either Fom_lac or Fom_CBM to mixtures of cellulases and hemicellulases effectively accelerates enzymatic hydrolysis, demonstrating its potential applications for lignocellulose valorization. We postulate that additional increases in sugar yields for the Fom_CBM enzyme mixtures were due to Fom_CBM being brought more proximal to lignin through binding to either cellulose or lignin itself.
]]>Biomolecules doi: 10.3390/biom14030323
Authors: Panagiotis E. Athanasiou Christina I. Gkountela Michaela Patila Renia Fotiadou Alexandra V. Chatzikonstantinou Stamatina N. Vouyiouka Haralambos Stamatis
Laccase from Trametes versicolor was applied to produce phenolic polymeric compounds with enhanced properties, using a wine lees extract as the phenolic source. The influence of the incubation time on the progress of the enzymatic oxidation and the yield of the formed polymers was examined. The polymerization process and the properties of the polymeric products were evaluated with a variety of techniques, such as high-pressure liquid chromatography (HPLC) and gel permeation chromatography (GPC), Fourier-transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopies, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The enzymatic polymerization reaction resulted in an 82% reduction in the free phenolic compounds of the extract. The polymeric product recovery (up to 25.7%) and the molecular weight of the polymer depended on the incubation time of the reaction. The produced phenolic polymers exhibited high antioxidant activity, depending on the enzymatic oxidation reaction time, with the phenolic polymer formed after one hour of enzymatic reaction exhibiting the highest antioxidant activity (133.75 and 164.77 μg TE mg−1 polymer) towards the ABTS and DPPH free radicals, respectively. The higher thermal stability of the polymeric products compared to the wine lees phenolic extract was confirmed with TGA and DSC analyses. Finally, the formed phenolic polymeric products were incorporated into chitosan films, providing them with increased antioxidant activity without affecting the films’ cohesion.
]]>Biomolecules doi: 10.3390/biom14030322
Authors: Wenxin Hu Chance Parkinson Hongjin Zheng
Recently, several ATP-binding cassette (ABC) importers have been found to adopt the typical fold of type IV ABC exporters. Presumably, these importers would function under the transport scheme of “alternating access” like those exporters, cycling through inward-open, occluded, and outward-open conformations. Understanding how the exporter-like importers move substrates in the opposite direction requires structural studies on all the major conformations. To shed light on this, here we report the structure of yersiniabactin importer YbtPQ from uropathogenic Escherichia coli in the occluded conformation trapped by ADP-vanadate (ADP-Vi) at a 3.1 Å resolution determined by cryo-electron microscopy. The structure shows unusual local rearrangements in multiple helices and loops in its transmembrane domains (TMDs). In addition, the dimerization of the nucleotide-binding domains (NBDs) promoted by the vanadate trapping is highlighted by the “screwdriver” action at one of the two hinge points. These structural observations are rare and thus provide valuable information to understand the structural plasticity of the exporter-like ABC importers.
]]>Biomolecules doi: 10.3390/biom14030321
Authors: Peter Demjanenko Sam Zheng John K. Crane
Our laboratory recently reported that induction of the SOS response, triggered by SOS-inducing drugs, was accompanied by a large release of DNA from enteric bacteria. The SOS response release had not previously been reported to include release of extracellular DNA from bacterial cells. We followed up on those observations in this current study and found that not just double-stranded DNA was being released, but also single-stranded DNA, RNA, and protein. SOS-inducing drugs also triggered formation of biofilm at the air–fluid interface on glass, and the biofilms contained DNA. We extended our study to test whether inhibitors of the SOS response would block DNA release and found that SOS inhibitors, including zinc salts, nitric oxide donors, and dequalinium, inhibited SOS-induced DNA release. The understanding that SOS-induced DNA release is associated with formation of biofilms increases our appreciation of the role of the SOS response in pathogenesis, as well as in emergence of new antibiotic resistance. Our findings with SOS inhibitors also suggest that regimens might be devised that could block the deleterious effects of the SOS response, at least temporarily, when this is desired.
]]>Biomolecules doi: 10.3390/biom14030320
Authors: Surajit Bhattacharjya Zhizhuo Zhang Ayyalusamy Ramamoorthy
Antimicrobial peptides (AMPs), as well as host defense peptides (HDPs), constitute the first line of defense as part of the innate immune system. Humans are known to express antimicrobial precursor proteins, which are further processed to generate AMPs, including several types of α/β defensins, histatins, and cathelicidin-derived AMPs like LL37. The broad-spectrum activity of AMPs is crucial to defend against infections caused by pathogenic bacteria, viruses, fungi, and parasites. The emergence of multi-drug resistant pathogenic bacteria is of global concern for public health. The prospects of targeting antibiotic-resistant strains of bacteria with AMPs are of high significance for developing new generations of antimicrobial agents. The 37-residue long LL37, the only cathelicidin family of AMP in humans, has been the major focus for the past few decades of research. The host defense activity of LL37 is likely underscored by its expression throughout the body, spanning from the epithelial cells of various organs—testis, skin, respiratory tract, and gastrointestinal tract—to immune cells. Remarkably, apart from canonical direct killing of pathogenic organisms, LL37 exerts several other host defense activities, including inflammatory response modulation, chemo-attraction, and wound healing and closure at the infected sites. In addition, LL37 and its derived peptides are bestowed with anti-cancer and anti-amyloidogenic properties. In this review article, we aim to develop integrative, mechanistic insight into LL37 and its derived peptides, based on the known biophysical, structural, and functional studies in recent years. We believe that this review will pave the way for future research on the structures, biochemical and biophysical properties, and design of novel LL37-based molecules.
]]>Biomolecules doi: 10.3390/biom14030319
Authors: Alin Finkelshtein Hala Khamesa-Israelov Daniel A. Chamovitz
ICT1 is an Arabidopsis thaliana line that overexpresses the gene encoding the S30 ribosomal subunit, leading to tolerance to exogenous indole-3-carbinol. Indole-3-carbinol (I3C) is a protective chemical formed as a breakdown of I3M in cruciferous vegetables. The overexpression of S30 in ICT1 results in transcriptional changes that prime the plant for the I3C, or biotic insult. Emerging evidence suggests that ribosomal proteins play important extra-ribosomal roles in various biochemical and developmental processes, such as transcription and stress resistance. In an attempt to elucidate the mechanism leading to I3C and stress resistance in ICT1, and using a multi-pronged approach employing transcriptomics, metabolomics, phenomics, and physiological studies, we show that overexpression of S30 leads to specific transcriptional alterations, which lead to both changes in metabolites connected to biotic and oxidative stress tolerance and, surprisingly, to photomorphogenesis.
]]>Biomolecules doi: 10.3390/biom14030318
Authors: Sang Beom Han Yu-Chi Liu Melina Setiawan Isabelle Xin Yu Lee Moushmi Patil Hon Shing Ong Jodhbir S. Mehta
Purpose. This study was conducted to evaluate the effects of different capsulotomy and fragmentation energy levels on the production of oxidative free radicals following femtosecond laser-assisted cataract surgery (FLACS) with a low-energy platform. Methods. The experimental study included 60 porcine eyes (12 groups). In each group, capsulotomies with 90% or 150% energy, and fragmentations with 90%, 100%, or 150% energy or 150% with high spot density, respectively, were performed. Control samples were obtained from non-lasered eyes at the beginning (five eyes) and end (five eyes) of the experiment. In the clinical study, 104 eyes were divided into 5 groups, and they received conventional phacoemulsification (20 eyes), FLACS with 90% capsulotomy and 100% fragmentation energy levels without NSAIDs (16 eyes), FLACS with 90% (26 eyes) or 150% (22 eyes) capsulotomy energy levels, respectively, with a 100% fragmentation energy level and NSAIDs, and FLACS with 90% capsulotomy and 150% fragmentation energy levels and NSAIDs (20 eyes). Aqueous samples were analyzed for their malondialdehyde (MDA) and superoxide dismutase (SOD) levels. Results. In the experimental study, there were no significant differences in the MDA and SOD levels between the groups with different capsulotomy energy levels. An increase in the fragmentation energy from 100% to 150% led to significantly higher MDA levels in the groups with both 90% (p = 0.04) and 150% capsulotomy energy levels (p = 0.03), respectively. However, increased laser spot densities did not result in significant changes in MDA or SOD levels. In the clinical study, all four of the FLACS groups showed higher MDA levels than the conventional group. Similarly, the increase in the fragmentation energy from 100% to 150% resulted in significantly elevated levels of MDA and SOD, respectively. Conclusions. Although increasing the FSL capsulotomy energy level may not have increased free radicals, higher fragmentation energy levels increased the generation of aqueous free radicals. However, fragmentation with high spot density did not generate additional oxidative stress. Increased spot density did not generate additional oxidative stress, and this can be helpful for dense cataracts.
]]>Biomolecules doi: 10.3390/biom14030317
Authors: Thamara Gonçalves Reis Alice Marcela Sampaio Del Colletto Luiz Augusto Santana Silva Bruna Andrade Aguiar Koga Mari Cleide Sogayar Ana Claudia Oliveira Carreira
Bone morphogenetic protein (BMP) and platelet-derived growth factor (PDGF) are known to regulate/stimulate osteogenesis, playing vital roles in bone homeostasis, rendering them strong candidates for osteoporosis treatment. We evaluated the effects of recombinant human BMP-7 (rhBMP7) and PDGF-BB (rhPDGF-BB) in an oophorectomy-induced osteoporosis rat model. Forty Sprague Dawley rats underwent oophorectomy surgery; treatments commenced on the 100th day post-surgery when all animals exhibited signs of osteoporosis. These peptide growth factors were administered intraocularly (iv) once or twice a week and the animals were monitored for a total of five weeks. Two weeks after the conclusion of the treatments, the animals were euthanized and tissues were collected for assessment of alkaline phosphatase, X-ray, micro-CT, and histology. The results indicate that the most promising treatments were 20 µg/kg rhPDGF-BB + 30 µg/kg rhBMP-7 twice a week and 30 µg/kg BMP-7 twice a week, showing significant increases of 15% (p < 0.05) and 13% (p < 0.05) in bone volume fraction and 21% (p < 0.05) and 23% (p < 0.05) in trabecular number, respectively. In conclusion, rhPDGF-BB and rhBMP-7 have demonstrated the ability to increase bone volume and density in this osteoporotic animal model, establishing them as potential candidates for osteoporosis treatment.
]]>Biomolecules doi: 10.3390/biom14030316
Authors: Mikhail V. Dubinin Irina B. Mikheeva Anastasia E. Stepanova Anastasia D. Igoshkina Alena A. Cherepanova Alena A. Semenova Vyacheslav A. Sharapov Igor I. Kireev Konstantin N. Belosludtsev
Duchenne muscular dystrophy is caused by loss of the dystrophin protein. This pathology is accompanied by mitochondrial dysfunction contributing to muscle fiber instability. It is known that mitochondria-targeted in vivo therapy mitigates pathology and improves the quality of life of model animals. In the present work, we applied mitochondrial transplantation therapy (MTT) to correct the pathology in dystrophin-deficient mdx mice. Intramuscular injections of allogeneic mitochondria obtained from healthy animals into the hind limbs of mdx mice alleviated skeletal muscle injury, reduced calcium deposits in muscles and serum creatine kinase levels, and improved the grip strength of the hind limbs and motor activity of recipient mdx mice. We noted normalization of the mitochondrial ultrastructure and sarcoplasmic reticulum/mitochondria interactions in mdx muscles. At the same time, we revealed a decrease in the efficiency of oxidative phosphorylation in the skeletal muscle mitochondria of recipient mdx mice accompanied by a reduction in lipid peroxidation products (MDA products) and reduced calcium overloading. We found no effect of MTT on the expression of mitochondrial signature genes (Drp1, Mfn2, Ppargc1a, Pink1, Parkin) and on the level of mtDNA. Our results show that systemic MTT mitigates the development of destructive processes in the quadriceps muscle of mdx mice.
]]>Biomolecules doi: 10.3390/biom14030315
Authors: Martina Milella Monica Rutigliano Francesco Lasorsa Matteo Ferro Roberto Bianchi Giuseppe Fallara Felice Crocetto Savio Pandolfo Biagio Barone Antonio d’Amati Marco Spilotros Michele Battaglia Pasquale Ditonno Giuseppe Lucarelli
Mucins are a family of high-molecular-weight glycoproteins. MUC1 is widely studied for its role in distinct types of cancers. In many human epithelial malignancies, MUC1 is frequently overexpressed, and its intracellular activities are crucial for cell biology. MUC1 overexpression can enhance cancer cell proliferation by modulating cell metabolism. When epithelial cells lose their tight connections, due to the loss of polarity, the mucins become dispersed on both sides of the epithelial membrane, leading to an abnormal mucin interactome with the membrane. Tumor-related MUC1 exhibits certain features, such as loss of apical localization and aberrant glycosylation that might cause the formation of tumor-related antigen epitopes. Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and it is the most common kidney cancer. The exact role of MUC1 in this tumor is unknown. Evidence suggests that it may play a role in several oncogenic pathways, including proliferation, metabolic reprogramming, chemoresistance, and angiogenesis. The purpose of this review is to explore the role of MUC1 and the meaning of its overexpression in epithelial tumors and in particular in RCC.
]]>Biomolecules doi: 10.3390/biom14030314
Authors: Xuhui Qin Bing Wang Xia Lu Yanyang Song Wei Wang
Gliomas, the most prevalent and lethal form of brain cancer, are known to exhibit metabolic alterations that facilitate tumor growth, invasion, and resistance to therapies. Peroxisomes, essential organelles responsible for fatty acid oxidation and reactive oxygen species (ROS) homeostasis, rely on the receptor PEX5 for the import of metabolic enzymes into their matrix. However, the prognostic significance of peroxisomal enzymes for glioma patients remains unclear. In this study, we elucidate that PEX5 is indispensable for the cell growth, migration, and invasion of glioma cells. We establish a robust prognosis model based on the expression of peroxisomal enzymes, whose localization relies on PEX5. This PEX5-dependent signature not only serves as a robust prognosis model capable of accurately predicting outcomes for glioma patients, but also effectively distinguishes several clinicopathological features, including the grade, isocitrate dehydrogenase (IDH) mutation, and 1p19q codeletion status. Furthermore, we developed a nomogram that integrates the prognostic model with other clinicopathological factors, demonstrating highly accurate performance in estimating patient survival. Patients classified into the high-risk group based on our prognostic model exhibited an immunosuppressive microenvironment. Finally, our validation reveals that the elevated expression of GSTK1, an antioxidant enzyme within the signature, promotes the cell growth and migration of glioma cells, with this effect dependent on the peroxisomal targeting signal recognized by PEX5. These findings identify the PEX5-dependent signature as a promising prognostic tool for gliomas.
]]>Biomolecules doi: 10.3390/biom14030313
Authors: Graham E. Jackson Marc-Antoine Sani Heather G. Marco Frances Separovic Gerd Gäde
Neuropeptides are the main regulators of physiological, developmental, and behavioural processes in insects. Three insect neuropeptide systems, the adipokinetic hormone (AKH), corazonin (Crz), and adipokinetic hormone/corazonin-related peptide (ACP), and their cognate receptors, are related to the vertebrate gonadotropin (GnRH) system and form the GnRH superfamily of peptides. In the current study, the two signalling systems, AKH and ACP, of the yellow fever mosquito, Aedes aegypti, were comparatively investigated with respect to ligand binding to their respective receptors. To achieve this, the solution structure of the hormones was determined by nuclear magnetic resonance distance restraint methodology. Atomic-scale models of the two G protein-coupled receptors were constructed with the help of homology modelling. Thereafter, the binding sites of the receptors were identified by blind docking of the ligands to the receptors, and models were derived for each hormone system showing how the ligands are bound to their receptors. Lastly, the two models were validated by comparing the computational results with experimentally derived data available from the literature. This mostly resulted in an acceptable agreement, proving the models to be largely correct and usable. The identification of an antagonist versus a true agonist may, however, require additional testing. The computational data also explains the exclusivity of the two systems that bind only the cognate ligand. This study forms the basis for further drug discovery studies.
]]>Biomolecules doi: 10.3390/biom14030312
Authors: Yihong Li Chenglong Zhou Huina Liu Ting Cai Huadong Fan
A growing number of studies have indicated that extracellular vesicles (EVs), such as exosomes, are involved in the development of neurodegenerative diseases. Components of EVs with biological effects like proteins, nucleic acids, or other molecules can be delivered to recipient cells to mediate physio-/pathological processes. For instance, some aggregate-prone proteins, such as β-amyloid and α-synuclein, had been found to propagate through exosomes. Therefore, either an increase of detrimental molecules or a decrease of beneficial molecules enwrapped in EVs may fully or partly indicate disease progression. Numerous studies have demonstrated that dysbiosis of the gut microbiota and neurodegeneration are tightly correlated, well-known as the “gut–brain axis”. Accumulating evidence has revealed that the gut bacteria-derived EVs play a pivotal role in mediating microbe–host interactions and affect the function of the “gut–brain axis”, which subsequently contributes to the pathogenesis of neurodegenerative diseases. In this review, we first briefly discuss the role of EVs from mammalian cells and microbes in mediating the progression of neurodegenerative diseases, and then propose a novel strategy that employs EVs of plants (plant cell-derived exosome-like nanoparticles) for treating neurodegeneration.
]]>Biomolecules doi: 10.3390/biom14030311
Authors: Robert A. Niederman
A Type I reaction center (RC) (Fe-S type, ferredoxin reducing) is found in several phyla containing anoxygenic phototrophic bacteria. These include the heliobacteria (HB), the green sulfur bacteria (GSB), and the chloracidobacteria (CB), for which high-resolution homodimeric RC-photosystem (PS) structures have recently appeared. The 2.2-Å X-ray structure of the RC-PS of Heliomicrobium modesticaldum revealed that the core PshA apoprotein (PshA-1 and PshA-2 homodimeric pair) exhibits a structurally conserved PSI arrangement comprising five C-terminal transmembrane α-helices (TMHs) forming the RC domain and six N-terminal TMHs coordinating the light-harvesting (LH) pigments. The Hmi. modesticaldum structure lacked quinone molecules, indicating that electrons were transferred directly from the A0 (81-OH-chlorophyll (Chl) a) acceptor to the FX [4Fe-4S] component, serving as the terminal RC acceptor. A pair of additional TMHs designated as Psh X were also found that function as a low-energy antenna. The 2.5-Å resolution cryo-electron microscopy (cryo-EM) structure for the RC-PS of the green sulfur bacterium Chlorobaculum tepidum included a pair of Fenna–Matthews–Olson protein (FMO) antennae, which transfer excitations from the chlorosomes to the RC-PS (PscA-1 and PscA-2) core. A pair of cytochromes cZ (PscC) molecules was also revealed, acting as electron donors to the RC bacteriochlorophyll (BChl) a’ special pair, as well as PscB, housing the [4Fe-4S] cluster FA and FB, and the associated PscD protein. While the FMO components were missing from the 2.6-Å cryo-EM structure of the Zn- (BChl) a’ special pair containing RC-PS of Chloracidobacterium thermophilum, a unique architecture was revealed that besides the (PscA)2 core, consisted of seven additional subunits including PscZ in place of PscD, the PscX and PscY cytochrome c serial electron donors and four low mol. wt. subunits of unknown function. Overall, these diverse structures have revealed that (i) the HB RC-PS is the simplest light–energy transducing complex yet isolated and represents the closest known homolog to a common homodimeric RC-PS ancestor; (ii) the symmetrically localized Ca2+-binding sites found in each of the Type I homodimeric RC-PS structures likely gave rise to the analogously positioned Mn4CaO5 cluster of the PSII RC and the TyrZ RC donor site; (iii) a close relationship between the GSB RC-PS and the PSII Chl proteins (CP)43 and CP47 was demonstrated by their strongly conserved LH-(B)Chl localizations; (iv) LH-BChls of the GSB-RC-PS are also localized in the conserved RC-associated positions of the PSII ChlZ-D1 and ChlZ-D2 sites; (v) glycosylated carotenoids of the GSB RC-PS are located in the homologous carotenoid-containing positions of PSII, reflecting an O2-tolerance mechanism capable of sustaining early stages in the evolution of oxygenic photosynthesis. In addition to the close relationships found between the homodimeric RC-PS and PSII, duplication of the gene encoding the ancestral Type I RC apoprotein, followed by genetic divergence, may well account for the appearance of the heterodimeric Type I and Type II RCs of the extant oxygenic phototrophs. Accordingly, the long-held view that PSII arose from the anoxygenic Type II RC is now found to be contrary to the new evidence provided by Type I RC-PS homodimer structures, indicating that the evolutionary origins of anoxygenic Type II RCs, along with their distinct antenna rings are likely to have been preceded by the events that gave rise to their oxygenic counterparts.
]]>Biomolecules doi: 10.3390/biom14030310
Authors: Chiranjeev Sharma Abu Hamza Emily Boyle Dickson Donu Yana Cen
Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement therapy for type 1 diabetes (T1D) and small-molecule drugs for type 2 diabetes (T2D). Despite these advances, the complex nature of diabetes necessitates innovative clinical interventions for effective treatment and complication prevention. Accumulative evidence suggests that protein post-translational modifications (PTMs), including glycosylation, phosphorylation, acetylation, and SUMOylation, play important roles in diabetes and its pathological consequences. Therefore, the investigation of these PTMs not only sheds important light on the mechanistic regulation of diabetes but also opens new avenues for targeted therapies. Here, we offer a comprehensive overview of the role of several PTMs in diabetes, focusing on the most recent advances in understanding their functions and regulatory mechanisms. Additionally, we summarize the pharmacological interventions targeting PTMs that have advanced into clinical trials for the treatment of diabetes. Current challenges and future perspectives are also provided.
]]>Biomolecules doi: 10.3390/biom14030309
Authors: Roberto Licordari Michele Correale Salvatore Bonanno Matteo Beltrami Michele Ciccarelli Antonio Micari Alberto Palazzuoli Giuseppe Dattilo
Heart failure (HF) represents a significant global health challenge, characterized by high morbidity and mortality rates, and imposes considerable burdens on healthcare systems and patient quality of life. Traditional management strategies, primarily relying on clinical assessments and standard biomarkers like natriuretic peptides, face limitations due to the heterogeneity of HF. This review aims to delve into the evolving landscape of non-natriuretic biomarkers and the transformative potential of omics technologies, underscoring their roles in advancing HF treatment towards precision medicine. By offering novel insights into the biological underpinnings of HF, including inflammation, myocardial stress, fibrosis, and metabolic disturbances, these advancements facilitate more accurate patient phenotyping and individualized treatment strategies. The integration of non-natriuretic biomarkers and omics technologies heralds a pivotal shift in HF management, enabling a move towards tailored therapeutic interventions. This approach promises to enhance clinical outcomes by improving diagnostic accuracy, risk stratification, and monitoring therapeutic responses. However, challenges such as the variability in biomarker levels, cost-effectiveness, and the standardization of biomarker testing across different healthcare settings pose hurdles to their widespread adoption. Despite these challenges, the promise of precision medicine in HF, driven by these innovative biomarkers and technologies, offers a new horizon for improving patient care and outcomes. This review advocates for the further integration of these advancements into clinical practice, highlighting the need for ongoing research to fully realize their potential in transforming the landscape of heart failure management.
]]>Biomolecules doi: 10.3390/biom14030308
Authors: Zixuan Liu Chaorui Liu Teng Zhao Lulu Yang Qiqi Shang Gefan Wang Zhaoyang Liu Yingping Gai Xianling Ji
Phytoplasma disease is one of the most serious infectious diseases that affects the growth and development of mulberry. Long non-coding RNAs (lncRNAs) play an important role in plants’ defense systems; however, the contribution of lncRNAs in the response to phytoplasma infection in mulberry is still largely unknown. Herein, strand-specific RNA sequencing was performed to profile the mRNAs and lncRNAs involved in the response to phytoplasma infection in mulberry, and a total of 4169 genes were found to be differentially expressed (DE) between healthy and phytoplasma-infected leaves. Moreover, 1794 lncRNAs were identified, of which 742 lncRNAs were DE between healthy and infected leaves. Target prediction showed that there were 68 and 44 DE lncRNAs which may function as cis and trans-regulators, targeting 54 and 44 DE genes, respectively. These DE target genes are associated with biological processes such as metabolism, signaling, development, transcriptional regulation, etc. In addition, it was found that the expression of the antisense lncRNA (MuLRR-RLK-AS) of the leucine-rich repeat receptor-like protein kinase gene (MuLRR-RLK) was decreased in the phytoplasma-infected leaves. Interestingly, it was found that overexpression of MuLRR-RLK-AS can inhibit the expression of MuLRR-RLK. Moreover, it was found that the expression levels of PTI-related and MAPK genes in the transgenic MuLRR-RLK Arabidopsis plants were significantly higher than those in the wild-type plants when inoculated with pathogens, and the transgenic plants were conferred with strong disease resistance. Our results demonstrate that MuLRR-RLK-AS, as a trans-regulatory factor, can inhibit the expression of the MuLRR-RLK gene and is a negative regulatory factor for mulberry resistance. The information provided is particularly useful for understanding the functions and mechanisms of lncRNAs in the response to phytoplasma infection in mulberry.
]]>Biomolecules doi: 10.3390/biom14030307
Authors: Jianming Xu Changzhen Fu Yaru Sun Xin Wen Chong-Bo Chen Chukai Huang Tsz Kin Ng Qingping Liu Mingzhi Zhang
Purpose: to determine the metabolomics profiles in the plasma samples of primary open-angle glaucoma (POAG) patients. Methods: The plasma samples from 20 POAG patients under intraocular pressure (IOP)-lowering medication treatment and 20 control subjects were subjected to the untargeted metabolomics analysis, among which 10 POAG patients and 10 control subjects were further subjected to the oxylipin-targeted metabolomics analysis by liquid chromatography–mass spectrometry analysis. The prediction accuracy of the differentially abundant metabolites was assessed by the receiver operating characteristic curves. Pathway analysis and correlation analysis on the differentially abundant metabolites and clinical and biochemical parameters were also conducted. Results: Untargeted metabolomics profiling identified 33 differentially abundant metabolites in the POAG patients, in which the metabolism of linoleic acid, α-linolenic acid, phenylalanine, and tricarboxylic acid cycle were enriched. The correlation analysis indicated that the differentially abundant metabolites were associated with central corneal thickness, peripapillary retinal nerve fiber layer thickness, visual field defects, and lymphocytes. The oxylipin-targeted metabolomics analysis identified 15-keto-Prostaglandin F2 alpha, 13,14-Dihydro-15-keto-prostaglandin D2, 11-Dehydro-thromboxane B2, 8,9-Epoxyeicosatrienoic acid, and arachidonic acid to be significantly decreased in the POAG patients and enriched in the arachidonic acid (AA) pathway. Conclusions: This study revealed that the metabolites in the arachidonic acid metabolism pathway are differentially abundant, suggesting high IOP may not be the only detrimental factor for optic nerve cell damage in this group of POAG patients. Lipid metabolism instability-mediated alterations in oxylipins and AA pathways may be important in POAG, suggesting that oxidative stress and immune-related inflammation could be valuable directions for future therapeutic strategies.
]]>Biomolecules doi: 10.3390/biom14030306
Authors: Andrea Etrusco Antonio Simone Laganà Vito Chiantera Mislav Mikuš Hafiz Muhammad Arsalan Antonio d’Amati Amerigo Vitagliano Ettore Cicinelli Alessandro Favilli Antonio D’Amato
Background: Endometrial cancer (EC) is the most common gynecological malignancy in both Europe and the USA. Approximately 3–5% of cases occur in women of reproductive age. Fertility-sparing treatment (FST) options are available, but very limited evidence regarding grade 2 (G2) ECs exists in the current literature. This systematic review aimed to comprehensively evaluate reproductive and oncologic outcomes among young women diagnosed with stage IA or G2EC disease who underwent FST. Methods: A comprehensive search of the literature was carried out on the following databases: MEDLINE, EMBASE, Global Health, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), the Health Technology Assessment Database, and Web of Science. Only original studies that reported the oncologic and reproductive outcomes of patients with stage IA and G2EC tumors who underwent FST were considered eligible for inclusion in this systematic review (CRD42023484892). Studies describing only the FST for endometrial hyperplasia or G1 EC were excluded. Results: Twenty-two papers that met the abovementioned inclusion criteria were included in the present systematic review. Preliminary analysis suggested encouraging oncologic and reproductive outcomes after FST. Conclusions: The FST approach may represent a feasible and safe option for women of childbearing age diagnosed with G2EC. Despite these promising findings, cautious interpretation is warranted due to inherent limitations, including heterogeneity in study designs and potential biases. Further research with standardized methodologies and larger sample sizes is imperative for obtaining more robust conclusions.
]]>Biomolecules doi: 10.3390/biom14030305
Authors: Maryam A. Salaudeen Nura Bello Rabiu N. Danraka Maryam L. Ammani
The majority of approved therapies for many diseases are developed to target their underlying pathophysiology. Understanding disease pathophysiology has thus proven vital to the successful development of clinically useful medications. Stroke is generally accepted as the leading cause of adult disability globally and ischemic stroke accounts for the most common form of the two main stroke types. Despite its health and socioeconomic burden, there is still minimal availability of effective pharmacological therapies for its treatment. In this review, we take an in-depth look at the etiology and pathophysiology of ischemic stroke, including molecular and cellular changes. This is followed by a highlight of drugs, cellular therapies, and complementary medicines that are approved or undergoing clinical trials for the treatment and management of ischemic stroke. We also identify unexplored potential targets in stroke pathogenesis that can be exploited to increase the pool of effective anti-stroke and neuroprotective agents through de novo drug development and drug repurposing.
]]>Biomolecules doi: 10.3390/biom14030304
Authors: Jaime Gosálvez Carmen López Fernández Stephen D. Johnston Javier Bartolomé-Nebreda
In this clinical era of intracytoplasmic sperm injection (ICSI), where a single spermatozoon is chosen for fertilization, the diagnostic functionality of the classical parameters typically associated with fertilization, such as sperm concentration, sperm motility, acrosome integrity, and mitochondria, is perhaps becoming less critical. In contrast, the contribution of sperm DNA quality to our understanding of the impact of male fertility within the context of ICSI is gaining increasing interest and importance. Even with respect to natural conception, high levels of sperm DNA fragmentation (SDF) in the ejaculate can adversely affect reproductive outcomes. However, the precise origin of SDF pathology in sperm cells is often ambiguous and most likely to be multifactorial. Hence, the genetic makeup of an individual, unbalanced REDOX processes, enzymatic activity, environmental and lifestyle factors, and even damage during sperm handling in the laboratory all operate in a unique and often synergistic manner to produce or induce sperm DNA damage. Surprisingly, the contribution of active enzymes as potential agents of SDF has received much less attention and, therefore, is likely to be underrated. This review highlights the roles of different enzymes related to the degradation of sperm DNA as possible effectors of DNA molecules in spermatozoa.
]]>Biomolecules doi: 10.3390/biom14030303
Authors: Roland Benz
Mitochondria are most likely descendants of strictly aerobic prokaryotes from the class Alphaproteobacteria. The mitochondrial matrix is surrounded by two membranes according to its relationship with Gram-negative bacteria. Similar to the bacterial outer membrane, the mitochondrial outer membrane acts as a molecular sieve because it also contains diffusion pores. However, it is more actively involved in mitochondrial metabolism because it plays a functional role, whereas the bacterial outer membrane has only passive sieving properties. Mitochondrial porins, also known as eukaryotic porins or voltage-dependent anion-selective channels (VDACs) control the permeability properties of the mitochondrial outer membrane. They contrast with most bacterial porins because they are voltage-dependent. They switch at relatively small transmembrane potentials of 20 to 30 mV in closed states that exhibit different permeability properties than the open state. Whereas the open state is preferentially permeable to anionic metabolites of mitochondrial metabolism, the closed states prefer cationic solutes, in particular, calcium ions. Mitochondrial porins are encoded in the nucleus, synthesized at cytoplasmatic ribosomes, and post-translationally imported through special transport systems into mitochondria. Nineteen beta strands form the beta-barrel cylinders of mitochondrial and related porins. The pores contain in addition an α-helical structure at the N-terminal end of the protein that serves as a gate for the voltage-dependence. Similarly, they bind peripheral proteins that are involved in mitochondrial function and compartment formation. This means that mitochondrial porins are localized in a strategic position to control mitochondrial metabolism. The special features of the role of mitochondrial porins in apoptosis and cancer will also be discussed in this article.
]]>Biomolecules doi: 10.3390/biom14030302
Authors: Ena Španić Popovački Dora Vogrinc Heidi R. Fuller Lea Langer Horvat Davor Mayer Janja Kopić Klara Pintarić Mirjana Babić Leko Mihaela Pravica Željka Krsnik Darko Marčinko Marina Šagud Patrick R. Hof Mihovil Mladinov Goran Šimić
Schizophrenia is a complex mental condition, with key symptoms marked for diagnosis including delusions, hallucinations, disorganized thinking, reduced emotional expression, and social dysfunction. In the context of major developmental hypotheses of schizophrenia, notably those concerning maternal immune activation and neuroinflammation, we studied NLRP1 expression and content in the postmortem brain tissue of 10 schizophrenia and 10 control subjects. In the medial orbitofrontal cortex (Brodmann’s area 11/12) and dorsolateral prefrontal cortex (area 46) from both hemispheres of six schizophrenia subjects, the NLRP1 mRNA expression was significantly higher than in six control brains (p < 0.05). As the expression difference was highest for the medial orbitofrontal cortex in the right hemisphere, we assessed NLRP1-immunoreactive pyramidal neurons in layers III, V, and VI in the medial orbitofrontal cortex in the right hemisphere of seven schizophrenia and five control brains. Compared to controls, we quantified a significantly higher number of NLRP1-positive pyramidal neurons in the schizophrenia brains (p < 0.01), suggesting NLRP1 inflammasome activation in schizophrenia subjects. Layer III pyramidal neuron dysfunction aligns with working memory deficits, while impairments of pyramidal neurons in layers V and VI likely disrupt predictive processing. We propose NLRP1 inflammasome as a potential biomarker and therapeutic target in schizophrenia.
]]>Biomolecules doi: 10.3390/biom14030301
Authors: Ziwei Wang Jingwen Zhou Jianghua Li Guocheng Du Jian Chen Xinrui Zhao
Phycocyanobilin (PCB) is a natural blue tetrapyrrole chromophore that is found in phycocyanin and plays an essential role in photosynthesis. Due to PCB’s antioxidation, anti-inflammatory and anti-cancer properties, it has been utilized in the food, pharmaceutical and cosmetic industries. Currently, the extraction of PCB from Spirulina involves complex processes, which has led to increasing interest in the biosynthesis of PCB in Escherichia coli. However, the PCB titer remains low because of the poor activity of key enzymes and the insufficient precursor supply. Here, the synthesis of PCB was firstly improved by screening the optimal heme oxygenase (HO) from Thermosynechococcus elongatus BP-1(HOT) and PCB: ferredoxin oxidoreductase from Synechocystis sp. PCC6803 (PcyAS). In addition, based on a rational design and the infrared fluorescence method for high-throughput screening, the mutants of HOT(F29W/K166D) and PcyAS(D220G/H74M) with significantly higher activities were obtained. Furthermore, a DNA scaffold was applied in the assembly of HOT and PcyAS mutants to reduce the spatial barriers, and the heme supply was enhanced via the moderate overexpression of hemB and hemH, resulting in the highest PCB titer (184.20 mg/L) obtained in a 5 L fermenter. The strategies applied in this study lay the foundation for the industrial production of PCB and its heme derivatives.
]]>Biomolecules doi: 10.3390/biom14030300
Authors: Tadasu Sugimori Masaru Yamaguchi Jun Kikuta Mami Shimizu Shinichi Negishi
A recent study reported that micro-osteoperforations (MOPs) accelerated tooth movement by activating alveolar bone remodeling. However, very little is known about the relationship between MOPs and external apical root resorption during orthodontic treatment. In this study, in order to investigate the mechanism through which MOPs accelerate tooth movement without exacerbating the progression of root resorption, we measured the volume of the resorbed root, and performed the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) method on exposed MOPs during experimental tooth movements in rats. Male Wistar rats (11 weeks old) were divided into three groups: 10 g orthodontic force (optimal force) applied to the maxillary first molar (optimal force: OF group), 50 g orthodontic force application (heavy force: HF group), and 10 g force application plus three small perforations of the cortical plate (OF + MOPs group). On days 1, 4, 7, 10, and 14 after force application, the tooth movement and root volume were investigated by micro-computed tomography. Furthermore, the number of apoptotic cells in the pressured sides of the periodontal ligament (PDL) and surrounding hard tissues were determined by TUNEL staining. The OF + MOPs group exhibited a 1.8-fold increase in tooth movement on days 7, 10, and 14 compared with the OF group. On days 14, the HF group had a higher volume of root loss than the OF and OF + MOPs groups. On the same day, the number of TUNEL-positive cells in the HF group increased at the root (cementum) site whereas that in the OF group increased at the alveolar bone site. Furthermore, the number of TUNEL-positive cells in the OF + MOPs group increased at the alveolar bone site compared with the OF group. These results suggest that MOPs accelerate orthodontic tooth movement without exacerbating the progression of root resorption.
]]>Biomolecules doi: 10.3390/biom14030299
Authors: Otsile O. Mojanaga Timothy J. Woodman Matthew D. Lloyd K. Ravi Acharya
α-Methylacyl-CoA racemase in M. tuberculosis (MCR) has an essential role in fatty acid metabolism and cholesterol utilization, contributing to the bacterium’s survival and persistence. Understanding the enzymatic activity and structural features of MCR provides insights into its physiological and pathological significance and potential as a therapeutic target. Here, we report high-resolution crystal structures for wild-type MCR in a new crystal form (at 1.65 Å resolution) and for three active-site mutants, H126A, D156A and E241A, at 2.45, 1.64 and 1.85 Å resolutions, respectively. Our analysis of the new wild-type structure revealed a similar dimeric arrangement of MCR molecules to that previously reported and details of the catalytic site. The determination of the structures of these H126A, D156A and E241A mutants, along with their detailed kinetic analysis, has now allowed for a rigorous assessment of their catalytic properties. No significant change outside the enzymatic active site was observed in the three mutants, establishing that the diminution of catalytic activity is mainly attributable to disruption of the catalytic apparatus involving key hydrogen bonding and water-mediated interactions. The wild-type structure, together with detailed mutational and biochemical data, provide a basis for understanding the catalytic properties of this enzyme, which is important for the design of future anti-tuberculosis drug molecules.
]]>Biomolecules doi: 10.3390/biom14030298
Authors: Hasna Ahyayauch Massimo E. Masserini Félix M. Goñi Alicia Alonso
The amyloidogenic Aβ peptides are widely considered as a pathogenic agent in Alzheimer’s disease. Aβ(1-42) would form aggregates of amyloid fibrils on the neuron plasma membranes, thus perturbing neuronal functionality. Conflicting data are available on the influence of bilayer order on Aβ(1-42) binding to membranes. In the present study, a biophysical approach was used in which isothermal calorimetry and surface pressure measurements were applied to explore the interaction of Aβ(1-42) in either monomeric, oligomeric, or fibrillar form with model membranes (bilayers or monolayers) in the liquid-ordered state that were either electrically neutral or negatively charged. In the latter case, this contained phosphatidic acid, cardiolipin, or ganglioside. The calorimetric studies showed that Aβ(1-42) fibrils, oligomers, and monomers could bind and/or be inserted into bilayers, irrespective of electric charge, in the liquid-ordered state, except that monomers could not interact with electrically neutral bilayers. The monolayer studies in the Langmuir balance demonstrated that Aβ(1-42) aggregation hindered peptide insertion into the monolayer, hindered insertion in the decreasing order of monomer > oligomer > fibril, and that lipid composition did not cause large differences in insertion, apart from a slight facilitation of monomer and oligomer insertion by gangliosides.
]]>Biomolecules doi: 10.3390/biom14030297
Authors: Ahmed Elzainy Abir El Sadik Waleed Mohammad Altowayan
Background: The distinctive feature of liver fibrosis is the progressive replacement of healthy hepatic cells by the extracellular matrix protein, which is abundant in collagen I and III, with impaired matrix remodeling. The activation of myofibroblastic cells enhances the fibrogenic response of complex interactions of hepatic stellate cells, fibroblasts, and inflammatory cells to produce the excessive deposition of the extracellular protein matrix. This process is activated by multiple fibrogenic mediators and cytokines, such as TNF-α and IL-1β, accompanied with a decrease in the anti-fibrogenic factor NF-κβ. Mesenchymal stem cells (MSCs) represent a promising therapy for liver fibrosis, allowing for a more advanced regenerative influence when cultured with extrinsic or intrinsic proliferative factors, cytokines, antioxidants, growth factors, and hormones such as melatonin (MT). However, previous studies showed conflicting findings concerning the therapeutic effects of adipose (AD) and bone marrow (BM) MSCs; therefore, the present work aimed to conduct a comparative and comprehensive study investigating the impact of MT pre-treatment on the immunomodulatory, anti-inflammatory, and anti-apoptotic effects of AD- and BM-MSCs and to critically analyze whether MT-pre-treated AD-MSCs and BM-MSCs reveal equal or different therapeutic and regenerative potentials in a CCl4-injured liver experimental rat model. Materials and methods: Six groups of experimental rats were used, with ten rats in each group: group I (control group), group II (CCl4-treated group), group III (CCl4- and BM-MSC-treated group), group IV (CCl4 and MT-pre-treated BM-MSC group), group V (CCl4- and AD-MSC-treated group), and group VI (CCl4 and MT-pre-treated AD-MSC group). Liver function tests and the gene expression of inflammatory, fibrogenic, apoptotic, and proliferative factors were analyzed. Histological and immunohistochemical changes were assessed. Results: The present study compared the ability of AD- and BM-MSCs, with and without MT pre-treatment, to reduce hepatic fibrosis. Both types of MSCs improved hepatocyte function by reducing the serum levels of ALT, aspartate aminotransferase (AST), alkaline phosphatase (AKP), and total bilirubin (TBIL). In addition, the changes in the hepatocellular architecture, including the hepatocytes, liver sinusoids, central veins, portal veins, biliary ducts, and hepatic arteries, showed a decrease in hepatocyte injury and cholestasis with a reduction in inflammation, apoptosis, and necrosis of the hepatic cells, together with an inhibition of liver tissue fibrosis. These results were augmented by an analysis of the expression of the pro-inflammatory cytokines TNFα and IL-1β, the anti-fibrogenic factor NF-κβ, the apoptotic factor caspase-3, and the proliferative indicators antigen Ki-67 and proliferating cell nuclear antigen (PCNA). These findings were found to be statistically significant, with the restoration of normal parameters in the rats that received AD-MSCs pre-treated with MT, denoting optimal regenerative and therapeutic effects. Conclusions: AD-MSCs pre-treated with MT are the preferred choice in improving hepatic fibrosis and promoting the therapeutic and regenerative ability of liver tissue. They represent a very significant tool for future stem cell use in the tissue regeneration strategy for the treatment of liver diseases.
]]>Biomolecules doi: 10.3390/biom14030296
Authors: Zhengzheng Zhang Naama Karu Alida Kindt Madhulika Singh Lieke Lamont Adriaan J. van Gammeren Anton A. M. Ermens Amy C. Harms Lutzen Portengen Roel C. H. Vermeulen Willem A. Dik Anton W. Langerak Vincent H. J. van der Velden Thomas Hankemeier
The severity of COVID-19 is linked to an imbalanced immune response. The dysregulated metabolism of small molecules and bioactive lipids has also been associated with disease severity. To promote understanding of the disease biochemistry and provide targets for intervention, we applied a range of LC-MS platforms to analyze over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (>30 immune markers). This is the third publication in a series, and it reports the results of comprehensive lipidome profiling using targeted LC-MS/MS. We identified 1076 lipid features across 25 subclasses, including glycerophospholipids, sterols, glycerolipids, and sphingolipids, among which 531 lipid features were dramatically changed in the plasma of intensive care unit (ICU) patients compared to patients in the ward. Patients in the ICU showed 1.3–57-fold increases in ceramides, (lyso-)glycerophospholipids, diglycerides, triglycerides, and plasmagen phosphoethanolamines, and 1.3–2-fold lower levels of a cyclic lysophosphatidic acid, sphingosine-1-phosphates, sphingomyelins, arachidonic acid-containing phospholipids, lactosylceramide, and cholesterol esters compared to patients in the ward. Specifically, phosphatidylinositols (PIs) showed strong fatty acid saturation-dependent behavior, with saturated fatty acid (SFA)- and monosaturated fatty acid (MUFA)-derived PI decreasing and polystaturated (PUFA)-derived PI increasing. We also found ~4000 significant Spearman correlations between lipids and multiple clinical markers of immune response with |R| ≥ 0.35 and FDR corrected Q < 0.05. Except for lysophosphatidic acid, lysophospholipids were positively associated with the CD4 fraction of T cells, and the cytokines IL-8 and IL-18. In contrast, sphingosine-1-phosphates were negatively correlated with innate immune markers such as CRP and IL-6. Further indications of metabolic changes in moderate COVID-19 disease were demonstrated in recovering ward patients compared to those at the start of hospitalization, where 99 lipid species were altered (6 increased by 30–62%; 93 decreased by 1.3–2.8-fold). Overall, these findings support and expand on early reports that dysregulated lipid metabolism is involved in COVID-19.
]]>Biomolecules doi: 10.3390/biom14030295
Authors: Susana Junceda María Cruz-Alonso Beatriz Fernandez Rosario Pereiro Eva Martínez-Pinilla Ana Navarro
Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder characterized by cognitive decline and neuropathological hallmarks, including β-amyloid (Aβ) plaques, Tau tangles, synaptic dysfunction and neurodegeneration. Emerging evidence suggests that abnormal iron (Fe) metabolism plays a role in AD pathogenesis, but the precise spatial distribution of the Fe and its transporters, such as ferroportin (FPN), within affected brain regions remains poorly understood. This study investigates the distribution of Fe and FPN in the CA1 region of the human hippocampus in AD patients with a micrometer lateral resolution using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). For this purpose, we visualized and quantified Fe and FPN in three separated CA1 layers: stratum molecular–radial (SMR), stratum pyramidal (SP) and stratum oriens (SO). Additionally, chromogenic immunohistochemistry was used to examine the distribution and colocalization with Tau and Aβ proteins. The results show that Fe accumulation was significantly higher in AD brains, particularly in SMR and SO. However, FPN did not present significantly changes in AD, although it showed a non-uniform distribution across CA1 layers, with elevated levels in SP and SO. Interestingly, minimal overlap was observed between Fe and FPN signals, and none between Fe and areas rich in neurofibrillary tangles (NFTs) or neuritic plaques (NP). In conclusion, the lack of correlation between Fe and FPN signals suggests complex regulatory mechanisms in AD Fe metabolism and deposition. These findings highlight the complexity of Fe dysregulation in AD and its potential role in disease progression.
]]>Biomolecules doi: 10.3390/biom14030294
Authors: Takahiro Matsuyama Brittany Marie Salter Nahal Emami Fard Kentaro Machida Roma Sehmi
Eosinophilic asthma is the most prevalent and well-defined phenotype of asthma. Despite a majority of patients responding to corticosteroid therapy and T2 biologics, there remains a subset that have recurrent asthma exacerbations, highlighting a need for additional therapies to fully ameliorate airway eosinophilia. Group 2 innate lymphoid cells (ILC2) are considered key players in the pathogenesis of eosinophilic asthma through the production of copious amounts of type 2 cytokines, namely IL-5 and IL-13. ILC2 numbers are increased in the airways of asthmatics and with the greatest numbers of activated ILC2 detected in sputa from severe prednisone-dependent asthma with uncontrolled eosinophilia. Although epithelial-derived cytokines are important mediators of ILC2 activation, emerging evidence suggests that additional pathways stimulate ILC2 function. The tumor necrosis factor super family (TNFSF) and its receptors (TNFRSF) promote ILC2 activity. In this review, we discuss evidence supporting a relationship between ILC2 and TNFSF/TNFRSF axis in eosinophilic asthma and the role of this relationship in severe asthma with airway autoimmune responses.
]]>Biomolecules doi: 10.3390/biom14030293
Authors: Qunhua Wang Yan Fang Yuan Li Huali Liu Maoni Zhu Xue Hu Jinzhuo Zhou Anqi Deng Bing Shen Hongbo Chen
The impaired invasion ability of trophoblast cells is related to the occurrence of preeclampsia (PE). We previously found that pregnancy-specific beta-1-glycoprotein 1 (PSG1) levels were decreased in the serum of individuals with early-onset preeclampsia (EOPE). This study investigated the effect of PSG1 on Orai1-mediated store-operated calcium entry (SOCE) and the Akt signaling pathway in human trophoblast cell migration. An enzyme-linked immunosorbent assay (ELISA) was used to determine the level of PSG1 in the serum of pregnant women with EOPE. The effects of PSG1 on trophoblast proliferation and migration were examined using cell counting kit-8 (CCK8) and wound healing experiments, respectively. The expression levels of Orai1, Akt, and phosphorylated Akt (p-Akt) were determined through Western blotting. The results confirmed that the serum PSG1 levels were lower in EOPE women than in healthy pregnant women. The PSG1 treatment upregulated the protein expression of Orai1 and p-Akt. The selective inhibitor of Orai1 (MRS1845) weakened the migration-promoting effect mediated by PSG1 via suppressing the Akt signaling pathway. Our findings revealed one of the mechanisms possibly involved in EOPE pathophysiology, which was that downregulated PSG1 may reduce the Orai1/Akt signaling pathway, thereby inhibiting trophoblast migration. PSG1 may serve as a potential target for the treatment and diagnosis of EOPE.
]]>Biomolecules doi: 10.3390/biom14030292
Authors: Changshun Chen Fei Yang Rongjin Chen Chenhui Yang Hefang Xiao Bin Geng Yayi Xia
Osteoarthritis (OA) is a debilitating joint disorder that affects millions of people worldwide. Despite its prevalence, our understanding of the underlying mechanisms remains incomplete. In recent years, transient receptor potential vanilloid (TRPV) channels have emerged as key players in OA pathogenesis. This review provides an in-depth exploration of the role of the TRPV pathway in OA, encompassing its involvement in pain perception, inflammation, and mechanotransduction. Furthermore, we discuss the latest research findings, potential therapeutic strategies, and future directions in the field, shedding light on the multifaceted nature of TRPV channels in OA.
]]>Biomolecules doi: 10.3390/biom14030291
Authors: Irene Karampela Natalia G. Vallianou Dimitrios Tsilingiris Gerasimos Socrates Christodoulatos Sotiria Psallida Dimitris Kounatidis Theodora Stratigou Ioanna Marinou Evaggelos Vogiatzakis Maria Dalamaga
Irisin, a novel adipo-myokine with metabolic regulatory functions, exerts anti-inflammatory, antioxidant, and anti-apoptotic actions that may confer protection against sepsis-induced organ injury in experimental studies. Until now, only one human study has explored circulating irisin at sepsis onset. We aimed to examine serum irisin and its kinetics in critically ill patients with sepsis and septic shock with regard to sepsis severity and outcome. We enrolled 102 critically ill patients with sepsis or septic shock within 48 h of diagnosis and 102 age- and gender-matched healthy controls. Irisin was determined in serum upon enrollment in all participants and one week later in patients using an immunoenzymatic method. The outcome of sepsis was recorded 28 days after enrollment. At enrollment, circulating irisin was significantly lower in patients than controls (22.3 ± 6.8 μg/L vs. 28.1 ± 6.7 μg/L, p < 0.001), and increased significantly one week later (22.3 ± 6.8 μg/L vs. 26.6 ± 9.5 μg/L, p < 0.001). Irisin was significantly lower in patients who presented with septic shock than those with sepsis, and in non-survivors than survivors both at enrollment and one week later. However, kinetics of irisin did not differ between the groups (p > 0.05). Patients with higher circulating irisin during the first week of sepsis had a better outcome (p < 0.001). Lower irisin was independently associated with 28-day mortality (sepsis onset: HR 0.44, 95% C.I. 0.26–0.77, p = 0.004 and one week after: HR 0.37, 95% C.I. 0.23–0.58, p < 0.001). Irisin was negatively correlated with severity scores, metabolic, and inflammatory biomarkers. Circulating irisin decreases early in sepsis and is an independent predictor of 28-day mortality. Irisin may be a promising diagnostic and prognostic sepsis biomarker; nevertheless, larger studies are needed to explore its role in sepsis.
]]>Biomolecules doi: 10.3390/biom14030290
Authors: Markus M. Heimesaat Luis Q. Langfeld Niklas Schabbel Nizar W. Shayya Soraya Mousavi Stefan Bereswill
Human Campylobacter jejuni infections are of worldwide importance and represent the most commonly reported bacterial enteritis cases in middle- and high-income countries. Since antibiotics are usually not indicated and the severity of campylobacteriosis is directly linked to the risk of developing post-infectious complications, non-toxic antibiotic-independent treatment approaches are highly desirable. Given its health-promoting properties, including anti-microbial and anti-inflammatory activities, we tested the disease-alleviating effects of oral menthol in murine campylobacteriosis. Therefore, human gut microbiota-associated IL-10−/− mice were orally subjected to synthetic menthol starting a week before C. jejuni infection and followed up until day 6 post-infection. Whereas menthol pretreatment did not improve campylobacteriosis symptoms, it resulted in reduced colonic C. jejuni numbers and alleviated both macroscopic and microscopic aspects of C. jejuni infection in pretreated mice vs. controls. Menthol pretreatment dampened the recruitment of macrophages, monocytes, and T lymphocytes to colonic sites of infection, which was accompanied by mitigated intestinal nitric oxide secretion. Furthermore, menthol pretreatment had only marginal effects on the human fecal gut microbiota composition during the C. jejuni infection. In conclusion, the results of this preclinical placebo-controlled intervention study provide evidence that menthol application constitutes a promising way to tackle acute campylobacteriosis, thereby reducing the risk for post-infectious complications.
]]>Biomolecules doi: 10.3390/biom14030289
Authors: Katarina Stoklund Dittlau Kristine Freude
Today, neurodegenerative disorders like Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, and as the average human lifespan increases, similarly grows the number of patients. For many decades, cognitive and motoric decline has been explained by the very apparent deterioration of neurons in various regions of the brain and spinal cord. However, more recent studies show that disease progression is greatly influenced by the vast population of glial cells. Astrocytes are traditionally considered star-shaped cells on which neurons rely heavily for their optimal homeostasis and survival. Increasing amounts of evidence depict how astrocytes lose their supportive functions while simultaneously gaining toxic properties during neurodegeneration. Many of these changes are similar across various neurodegenerative diseases, and in this review, we highlight these commonalities. We discuss how astrocyte dysfunction drives neuronal demise across a wide range of neurodegenerative diseases, but rather than categorizing based on disease, we aim to provide an overview based on currently known mechanisms. As such, this review delivers a different perspective on the disease causes of neurodegeneration in the hope to encourage further cross-disease studies into shared disease mechanisms, which might ultimately disclose potentially common therapeutic entry points across a wide panel of neurodegenerative diseases.
]]>Biomolecules doi: 10.3390/biom14030288
Authors: Di Wang Lingbo Liu
Both the senescence of cancer cells and the maintenance of cancer stem cells seem to be mutually exclusive because senescence is considered a physiological mechanism that effectively suppresses tumor growth. Recent studies have revealed common signaling pathways between cellular senescence and the maintenance of stemness in cancer cells, thus challenging the conventional understanding of this process. Although the links between these processes have not yet been fully elucidated, emerging evidence indicates that senescent cancer cells can undergo reprograming to recover stemness. Herein, we provide a comprehensive overview of the close correlation between senescence and stemness reprograming in cancer cells, with a particular focus on the mechanisms by which senescent cancer cells recover their stemness in various tumor systems.
]]>Biomolecules doi: 10.3390/biom14030287
Authors: Kui Wang Gang Hu Zhonghua Wu Vladimir N. Uversky Lukasz Kurgan
Disordered linkers (DLs) are intrinsically disordered regions that facilitate movement between adjacent functional regions/domains, contributing to many key cellular functions. The recently completed second Critical Assessments of protein Intrinsic Disorder prediction (CAID2) experiment evaluated DL predictions by considering a rather narrow scenario when predicting 40 proteins that are already known to have DLs. We expand this evaluation by using a much larger set of nearly 350 test proteins from CAID2 and by investigating three distinct scenarios: (1) prediction residues in DLs vs. in non-DL regions (typical use of DL predictors); (2) prediction of residues in DLs vs. other disordered residues (to evaluate whether predictors can differentiate residues in DLs from other types of intrinsically disordered residues); and (3) prediction of proteins harboring DLs. We find that several methods provide relatively accurate predictions of DLs in the first scenario. However, only one method, APOD, accurately identifies DLs among other types of disordered residues (scenario 2) and predicts proteins harboring DLs (scenario 3). We also find that APOD’s predictive performance is modest, motivating further research into the development of new and more accurate DL predictors. We note that these efforts will benefit from a growing amount of training data and the availability of sophisticated deep network models and emphasize that future methods should provide accurate results across the three scenarios.
]]>Biomolecules doi: 10.3390/biom14030286
Authors: Andrea Mazzatenta Tiziana Pietrangelo Roberto Demontis Cristian D’Ovidio
Death is a multifaceted process wherein each individual cell and tissue has a metabolic homeostasis and a time of functional cessation defined by the dying process as well as by intrinsic and extrinsic factors. Decomposition is physiologically associated with the release of different types of volatile organic compounds (VOCs), and these form volaboloma mortis. The main purpose of this study was to record the volabolomic fingerprint produced by volatile molecules during the physiological decomposition process of human tissue and muscle cells. The volatile chemical signature has important implications for an open issue in forensics and pathology, namely the estimation of the postmortem interval (PMI), which decreases in accuracy with the passage of time. Volatile metabolites emitted from human tissues and muscle cells at 0, 24, 48, and 72 h were recorded in real time with an electronic nose sensor device. The key findings were the continuous sampling of VOCs emitted from tissues and cells. These showed a common behavior as time progressed; particularly, after 48 h the distributions became dispersed, and after 72 h they became more variable. Volabolomic fingerprinting associated with time progression relevant to the study of PMIs was reconstructed. Additionally, there may be broader applications, such as in dog training procedures for detecting human remains, and perhaps even for studying scavenger and insect attractants.
]]>Biomolecules doi: 10.3390/biom14030285
Authors: William T. Heller
The HIV-1 fusion peptide, which is a short hydrophobic peptide from the gp41 coat glycoprotein that participates in the infection of a cell, interacts with model lipid bilayer membranes in a concentration-dependent manner. The interaction of the peptide with the bilayer also strongly depends on the lipid composition. Here, molecular dynamics simulations were performed to investigate lipid-specific interactions that arise shortly after the binding of a less-fusogenic variant of the HIV-1 fusion peptide to a lipid bilayer composed of a mixture of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol. The impact of peptide concentration was also studied. An improved understanding was gained of the lipid-specific interactions experienced by the FP. New insight was also gained into how the peptide concentration changes these interactions.
]]>Biomolecules doi: 10.3390/biom14030284
Authors: Srijana Upadhyay Amanuel Esayas Hailemariam Fuada Mariyam Zahin Hafiz Gregory Martin Jainish Kothari Evan Farkas Gargi Sivaram Logan Bell Ronald Tjalkens Stephen Safe
Bis-indole derived compounds such as 1,1-bis(3′-indolyl)-1-(3,5-disubstitutedphenyl) methane (DIM-3,5) and the corresponding 4-hydroxyl analogs (DIM8-3,5) are NR4A1 ligands that act as inverse NR4A1 agonists and are potent inhibitors of tumor growth. The high potency of several DIM-3,5 analogs (IC50 < 1 mg/kg/day), coupled with the >60% similarity of the ligand-binding domains (LBDs) of NR4A1 and NR4A2 and the pro-oncogenic activities of both receptors lead us to hypothesize that these compounds may act as dual NR4A1 and NR4A2 ligands. Using a fluorescence binding assay, it was shown that 22 synthetic DIM8-3,5 and DIM-3,5 analogs bound the LBD of NR4A1 and NR4A2 with most KD values in the low µM range. Moreover, the DIM-3,5 and DIM8-3,5 analogs also decreased NR4A1- and NR4A2-dependent transactivation in U87G glioblastoma cells transfected with GAL4-NR4A1 or GAL4-NR4A2 chimeras and a UAS-luciferase reporter gene construct. The DIM-3,5 and DIM8-3,5 analogs were cytotoxic to U87 glioblastoma and RKO colon cancer cells and the DIM-3,5 compounds were more cytotoxic than the DIM8-3,5 compounds. These studies show that both DIM-3,5 and DIM8-3,5 compounds previously identified as NR4A1 ligands bind both NR4A1 and NR4A2 and are dual NR4A1/2 ligands.
]]>Biomolecules doi: 10.3390/biom14030283
Authors: Yue-Hua Chen Zhou-Feng Rao Yu-Jie Liu Xiang-Sheng Liu Yu-Fei Liu Lan-Ju Xu Ze-Qi Wang Jing-Yue Guo Lin Zhang Yun-Sheng Dong Chun-Xiao Qi Chao Yang Shu-Fang Wang
The authors would like to replace Figure 4A of the following published paper [...]
]]>Biomolecules doi: 10.3390/biom14030282
Authors: Chiranjeevi Pasala Sahil Sharma Tanaya Roychowdhury Elisabetta Moroni Giorgio Colombo Gabriela Chiosis
Glycosylation, a prevalent post-translational modification, plays a pivotal role in regulating intricate cellular processes by covalently attaching glycans to macromolecules. Dysregulated glycosylation is linked to a spectrum of diseases, encompassing cancer, neurodegenerative disorders, congenital disorders, infections, and inflammation. This review delves into the intricate interplay between glycosylation and protein conformation, with a specific focus on the profound impact of N-glycans on the selection of distinct protein conformations characterized by distinct interactomes—namely, protein assemblies—under normal and pathological conditions across various diseases. We begin by examining the spike protein of the SARS virus, illustrating how N-glycans regulate the infectivity of pathogenic agents. Subsequently, we utilize the prion protein and the chaperone glucose-regulated protein 94 as examples, exploring instances where N-glycosylation transforms physiological protein structures into disease-associated forms. Unraveling these connections provides valuable insights into potential therapeutic avenues and a deeper comprehension of the molecular intricacies that underlie disease conditions. This exploration of glycosylation’s influence on protein conformation effectively bridges the gap between the glycome and disease, offering a comprehensive perspective on the therapeutic implications of targeting conformational mutants and their pathologic assemblies in various diseases. The goal is to unravel the nuances of these post-translational modifications, shedding light on how they contribute to the intricate interplay between protein conformation, assembly, and disease.
]]>Biomolecules doi: 10.3390/biom14030281
Authors: Sandra Almeida-Reis Alexandra Carvalho Conceição Dias Raquel Brito Rita Silva Teresa Almeida-Santos João Ramalho-Santos Ana Paula Sousa
Age-related changes in the mitochondrial status of human cumulus cells (hCCs) impact oocyte quality; however, the relationship between hCC mitochondrial (dys)function and reproductive aging remains poorly understood. This study aimed to establish the interplay between hCC mitochondrial dysfunction and women’s reproductive potential. In this investigation, 266 women were enrolled and categorized into two groups based on their age: a young group (<35 years old) and an advanced maternal age (AMA) group (≥35 years old). Comprehensive analysis of reproductive outcomes was conducted in our population. Various mitochondrial-related parameters were analyzed across distinct subsets. Specifically, mitochondrial membrane potential (∆Ψm) and mitochondrial mass were examined in 53 samples, mtDNA content in 25 samples, protein levels in 23 samples, bioenergetic profiles using an XF24 Extracellular Flux Analyzer in 6 samples, and levels of reactive oxygen species (ROS) and adenosine triphosphate (ATP) in 39 and 43 samples, respectively. In our study, the reproductive potential of AMA women sharply decreased, as expected. Additionally, an impairment in the mitochondrial function of hCCs in older women was observed; however, no differences were found in terms of mitochondrial content. Regarding oxidative phosphorylation, metabolic profiling of hCCs from AMA women indicated a decrease in respiratory capacity, which was correlated with an age-dependent decrease in the ATP synthase (ATP5A1) protein level. However, intracellular ROS and ATP levels did not differ between groups. In conclusion, our study indicates that age-related dysfunction in hCCs is associated with impaired mitochondrial function, and, although further studies are required, ATP synthase could be relevant in this impairment.
]]>Biomolecules doi: 10.3390/biom14030280
Authors: Md Jakir Hossain Perpetual Nyame Kazuaki Monde
Endogenous retroviruses (ERVs) became a part of the eukaryotic genome through endogenization millions of years ago. Moreover, they have lost their innate capability of virulence or replication. Nevertheless, in eukaryotic cells, they actively engage in various activities that may be advantageous or disadvantageous to the cells. The mechanisms by which transcription is triggered and implicated in cellular processes are complex. Owing to the diversity in the expression of transcription factors (TFs) in cells and the TF-binding motifs of viruses, the comprehensibility of ERV initiation and its impact on cellular functions are unclear. Currently, several factors are known to be related to their initiation. TFs that bind to the viral long-terminal repeat (LTR) are critical initiators. This review discusses the TFs shown to actively associate with ERV stimulation across species such as humans, mice, pigs, monkeys, zebrafish, Drosophila, and yeast. A comprehensive summary of the expression of previously reported TFs may aid in identifying similarities between animal species and endogenous viruses. Moreover, an in-depth understanding of ERV expression will assist in elucidating their physiological roles in eukaryotic cell development and in clarifying their relationship with endogenous retrovirus-associated diseases.
]]>Biomolecules doi: 10.3390/biom14030279
Authors: Seonju Lee Sanghyun Ye Mina Kim Hyejin Lee Seung-Hyun Jun Nae-Gyu Kang
Skin aging is a multifaceted biological phenomenon influenced by a combination of intrinsic or extrinsic factors. There is an increasing interest in anti-aging materials including components that improve skin wrinkles. Despite the availability of several such wrinkle-improving materials, the demand for ingredients with outstanding efficacy is increasing. Therefore, this study aimed to explore the mechanisms of wrinkle-related genes reported in previous genome-wide association studies (GWASs), identify materials that regulate these genes, and develop an effective anti-wrinkle formula containing the active ingredients that regulate the expression of these genes. We selected two candidate genes, EDAR and BNC2, that are reportedly related to periorbital wrinkles. We investigated their functions in the skin through in vitro experiments using human skin cell lines (keratinocytes and fibroblasts). Moreover, we identified ingredients that regulate the expression of these two genes and confirmed their efficacy through in vitro experiments using the skin cell lines. Finally, we developed a formula containing these ingredients and confirmed that it enhanced dermal collagen in the 3D skin and improved fine wrinkles under the eyes more effectively than retinol in humans, when applied for 8 weeks. Our results are significant and relevant, as we have discovered a special formula for wrinkle improvement with reliable efficacy that surpasses the efficacy of retinol and does not cause side-effects such as skin irritation.
]]>Biomolecules doi: 10.3390/biom14030278
Authors: Ana Karina de Oliveira Alexandra Rucavado Teresa Escalante José María Gutiérrez Jay W. Fox
Viperid snake venoms induce severe tissue damage, characterized by the direct toxic action of venom components, i.e., phospholipases A2 (PLA2s) and metalloproteinases (SVMPs), concomitantly with the onset of endogenous inflammatory processes, in an intricate scenario of tissue alterations. Understanding the expression of relevant genes in muscle tissue will provide valuable insights into the undergoing pathological and inflammatory processes. In this study, we have used the Nanostring technology to evaluate the patterns of gene expression in mouse skeletal muscle 1 h, 6 h, and 24 h after injection of the venoms of Bothrops asper and Daboia russelii, two medically relevant species in Latin America and Asia, respectively, with somewhat different clinical manifestations. The dose of venoms injected (30 µg) induced local pathological effects and inflammation in muscle tissue. We focused our analysis on genes related to extracellular matrix (ECM) metabolism, immune system, programmed cell death, and autophagy. The results revealed a complex pattern of expression of genes. Regarding ECM metabolism and regulation, up-regulated genes included proteinase inhibitor Serpine 1, thrombospondin 1, collagens 1A1 and 4A1 (at 1 h in the case of B. asper), TIMP1, MMP-3 (at 24 h), and lysil oxidase (LOX). In contrast, collagen chains 5A3 and 5A1 were down-regulated, especially at 6 h. Transforming growth factor β (TGF-β) and several genes related to myofibroblast regulation were also up-regulated, which might be related to the development of fibrosis. Several genes related to cytokine and chemokine synthesis and regulation and NFκB signaling were also up-regulated. Our observations show a variable expression of genes associated with programmed cell death and autophagy, thus revealing a hitherto unknown role of autophagy in tissue affected by snake venoms. These results provide clues to understanding the complex pattern of gene expression in tissue affected by viperid snake venoms, which likely impacts the final pathophysiology of damaged tissue in envenomings.
]]>Biomolecules doi: 10.3390/biom14030277
Authors: Arianna Ferro Gabriele Saccu Simone Mattivi Andrea Gaido Maria Beatriz Herrera Sanchez Shafiul Haque Lorenzo Silengo Fiorella Altruda Marilena Durazzo Sharmila Fagoonee
In recent years, EVs have emerged as promising vehicles for coding and non-coding RNAs (ncRNAs), which have demonstrated remarkable potential as biomarkers for various diseases, including chronic liver diseases (CLDs). EVs are small, membrane-bound particles released by cells, carrying an arsenal of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and other ncRNA species, such as piRNAs, circRNAs, and tsRNAs. These ncRNAs act as key regulators of gene expression, splicing, and translation, providing a comprehensive molecular snapshot of the cells of origin. The non-invasive nature of EV sampling, typically via blood or serum collection, makes them highly attractive candidates for clinical biomarker applications. Moreover, EV-encapsulated ncRNAs offer unique advantages over traditional cell-free ncRNAs due to their enhanced stability within the EVs, hence allowing for their detection in circulation for extended periods and enabling more sensitive and reliable biomarker measurements. Numerous studies have investigated the potential of EV-enclosed ncRNAs as biomarkers for CLD. MiRNAs, in particular, have gained significant attention due to their ability to rapidly respond to changes in cellular stress and inflammation, hallmarks of CLD pathogenesis. Elevated levels of specific miRNAs have been consistently associated with various CLD subtypes, including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and chronic hepatitis B and C. LncRNAs have also emerged as promising biomarkers for CLD. These transcripts are involved in a wide range of cellular processes, including liver regeneration, fibrosis, and cancer progression. Studies have shown that lncRNA expression profiles can distinguish between different CLD subtypes, providing valuable insights into disease progression and therapeutic response. Promising EV-enclosed ncRNA biomarkers for CLD included miR-122 (elevated levels of miR-122 are associated with MASLD progression and liver fibrosis), miR-21 (increased expression of miR-21 is linked to liver inflammation and fibrosis in CLD patients), miR-192 (elevated levels of miR-192 are associated with more advanced stages of CLD, including cirrhosis and HCC), LncRNA HOTAIR (increased HOTAIR expression is associated with MASLD progression and MASH development), and LncRNA H19 (dysregulation of H19 expression is linked to liver fibrosis and HCC progression). In the present review, we focus on the EV-enclosed ncRNAs as promising tools for the diagnosis and monitoring of CLD of various etiologies.
]]>Biomolecules doi: 10.3390/biom14030276
Authors: Deborah Giordano Simone Bonora Ilenia D’Orsi Domenico D’Alelio Angelo Facchiano
Lipoxygenases make several biological functions in cells, based on the products of the catalyzed reactions. In diatoms, microalgae ubiquitous in aquatic ecosystems, lipoxygenases have been noted for the oxygenation of fatty acids with the production of oxylipins, which are involved in many physiological and pathological processes in marine organisms. The interest in diatoms’ lipoxygenases and oxylipins has increased due to their possible biotechnological applications, ranging from ecology to medicine. We investigated using bioinformatics and molecular docking tools the lipoxygenases of diatoms and the possible interaction with substrates. A large-scale analysis of sequence resources allowed us to retrieve 45 sequences of lipoxygenases from diatoms. We compared and analyzed the sequences by multiple alignments and phylogenetic trees, suggesting the possible clustering in phylogenetic groups. Then, we modelled the 3D structure of representative enzymes from the different groups and investigated in detail the structural and functional properties by docking simulations with possible substrates. The results allowed us to propose a classification of the lipoxygenases from diatoms based on their sequence features, which may be reflected in specific structural differences and possible substrate specificity.
]]>Biomolecules doi: 10.3390/biom14030275
Authors: Miguel A. Ortega Diego De Leon-Oliva Maria José Gimeno-Longas Diego Liviu Boaru Oscar Fraile-Martinez Cielo García-Montero Amador Velazquez de Castro Silvestra Barrena-Blázquez Laura López-González Silvia Amor Natalio García-Honduvilla Julia Buján Luis G. Guijarro Elisa Castillo-Ruiz Miguel Ángel Álvarez-Mon Agustin Albillos Melchor Álvarez-Mon Raul Diaz Miguel A. Saez
Calcification is a process of accumulation of calcium in tissues and deposition of calcium salts by the crystallization of PO43− and ionized calcium (Ca2+). It is a crucial process in the development of bones and teeth. However, pathological calcification can occur in almost any soft tissue of the organism. The better studied is vascular calcification, where calcium salts can accumulate in the intima or medial layer or in aortic valves, and it is associated with higher mortality and cardiovascular events, including myocardial infarction, stroke, aortic and peripheral artery disease (PAD), and diabetes or chronic kidney disease (CKD), among others. The process involves an intricate interplay of different cellular components, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), fibroblasts, and pericytes, concurrent with the activation of several signaling pathways, calcium, Wnt, BMP/Smad, and Notch, and the regulation by different molecular mediators, growth factors (GFs), osteogenic factors and matrix vesicles (MVs). In the present review, we aim to explore the cellular players, molecular pathways, biomarkers, and clinical treatment strategies associated with vascular calcification to provide a current and comprehensive overview of the topic.
]]>Biomolecules doi: 10.3390/biom14030274
Authors: Caitlin M. Carroll Ruth M. Benca
Alzheimer’s disease (AD) is a neurodegenerative disorder affecting nearly one in nine older adults in the US. This number is expected to grow exponentially, thereby increasing stress on caregivers and health systems. While some risk factors for developing AD are genetic, an estimated 1/3 of AD cases are attributed to lifestyle. Many of these risk factors emerge decades before clinical symptoms of AD are detected, and targeting them may offer more efficacious strategies for slowing or preventing disease progression. This review will focus on two common risk factors for AD, metabolic dysfunction and sleep impairments, and discuss potential mechanisms underlying their relationship to AD pathophysiology. Both sleep and metabolism can alter AD-related protein production and clearance, contributing to an imbalance that drives AD progression. Additionally, these risk factors have bidirectional relationships with AD, where the presence of AD-related pathology can further disrupt sleep and worsen metabolic functioning. Sleep and metabolism also appear to have a bidirectional relationship with each other, indirectly exacerbating AD pathophysiology. Understanding the mechanisms involved in these relationships is critical for identifying new strategies to slow the AD cascade.
]]>Biomolecules doi: 10.3390/biom14030273
Authors: Maria Dolores Setzu Ignazia Mocci Davide Fabbri Paola Carta Patrizia Muroni Andrea Diana Maria Antonietta Dettori Maria Antonietta Casu
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons responsible for unintended or uncontrollable movements. Mutations in the leucine-rich repeat kinase 2 locus contribute to genetic forms of PD. The fruit fly Drosophila melanogaster carrying this mutation (LRRK2-Dm) is an in vivo model of PD that develops motor impairment and stands for an eligible non-mammalian paradigm to test novel therapeutic approaches. Dehydrozingerone (DHZ) is a natural phenolic compound isolated from ginger and presents anti-inflammatory, antioxidant and neuroprotective properties, making it a potential therapeutic target for PD. We administered DHZ and its C2-symmetric dimer (DHZ-DIM) at 0.5 and 1 mM for 14 and 21 days in the LRRK2-Dm, with the aim of assessing changes in rescuing motor behavior, brain dopaminergic neurons, mitochondria and synapses (T-bars). The shorter treatment with both molecules revealed efficacy at the higher dose, improving climbing behavior with a prevention of dopaminergic neuronal demise. After 21 days, a recovery of the motor disability, dopaminergic neuron loss, mitochondrial damage and T-bars failure was observed with the DHZ-DIM. Our data indicate that the DHZ-DIM exerts a more potent neuroprotective effect with respect to the monomer in LRRK2-Dm, prompting further investigation of these compounds in rodent models of PD.
]]>Biomolecules doi: 10.3390/biom14030272
Authors: Kristin E. Cox Shanglei Liu Robert M. Hoffman Surinder K. Batra Punita Dhawan Michael Bouvet
Claudins (CLDN1–CLDN24) are a family of tight junction proteins whose dysregulation has been implicated in tumorigeneses of many cancer types. In colorectal cancer (CRC), CLDN1, CLDN2, CLDN4, and CLDN18 have been shown to either be upregulated or aberrantly expressed. In the normal colon, CLDN1 and CLDN3–7 are expressed. Although a few claudins, such as CLDN6 and CLDN7, are expressed in CRC their levels are reduced compared to the normal colon. The present review outlines the expression profiles of claudin proteins in CRC and those that are potential biomarkers for prognostication.
]]>Biomolecules doi: 10.3390/biom14030271
Authors: Satomi Adegawa Yonghao Wang Ryusei Waizumi Tetsuya Iizuka Yoko Takasu Kenji Watanabe Ryoichi Sato
Recent studies have suggested that ABC transporters are the main receptors of Cry toxins. However, the receptors of many Cry toxins have not been identified. In this study, we used a heterologous cell expression system to identify Bombyx mori ABC transporter subfamily C members (BmABCCs) that function as receptors for five Cry toxins active in Lepidopteran insects: Cry1Aa, Cry1Ca, Cry1Da, Cry8Ca, and Cry9Aa. All five Cry toxins can use multiple ABCCs as low-efficiency receptors, which induce cytotoxicity only at high concentrations. Surface plasmon resonance analysis revealed that the KD values between the toxins and BmABCC1 and BmABCC4 were 10−5 to 10−9 M, suggesting binding affinities 8- to 10,000-fold lower than those between Cry1Aa and BmABCC2, which are susceptibility-determining receptors for Cry1Aa. Bioassays in BmABCC-knockout silkworm strains showed that these low-efficiency receptors are not involved in sensitivity to Cry toxins. The findings suggest that each family of Cry toxins uses multiple BmABCCs as low-efficiency receptors in the insect midgut based on the promiscuous binding of their receptor-binding regions. Each Cry toxin seems to have evolved to utilize one or several ABC transporters as susceptibility-determining receptors.
]]>Biomolecules doi: 10.3390/biom14030270
Authors: Adina Stoian Zoltan Bajko Rodica Bălașa Sebastian Andone Mircea Stoian Ioana Ormenișan Carmen Muntean Claudia Bănescu
Background: Developmental and epileptic encephalopathies (DEE) encompass a group of rare diseases with hereditary and genetic causes as well as acquired causes such as brain injuries or metabolic abnormalities. The phosphofurin acidic cluster sorting protein 2 (PACS2) is a multifunctional protein with nuclear gene expression. The first cases of the recurrent c.625G>A pathogenic variant of PACS2 gene were reported in 2018 by Olson et al. Since then, several case reports and case series have been published. Methods: We performed a systematic review of the PUBMED and SCOPUS databases using Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Our search parameters included DEE66 with a pathogenic PACS2 gene p.Glu209Lys mutation published cases to which we added our own clinical experience regarding this pathology. Results: A total of 11 articles and 29 patients were included in this review, to which we added our own experience for a total of 30 patients. There was not a significant difference between sexes regarding the incidence of this pathology (M/F: 16/14). The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait. Facial dysmorphism and other organs’ involvement were also frequently reported. Brain MRIs evidenced anomalies of the posterior cerebellar fossa, foliar distortion of the cerebellum, vermis hypoplasia, white matter reduction, and lateral ventricles enlargement. Genetic testing is more frequent in children. Only 4 cases have been reported in adults to date. Conclusions: It is important to maintain a high suspicion of new pathogenic gene variants in adult patients presenting with a characteristic clinical picture correlated with radiologic changes. The neurologist must gradually recognize the distinct evolving phenotype of DEE66 in adult patients, and genetic testing must become a scenario with which the neurologist attending adult patients should be familiar. Accurate diagnosis is required for adequate treatment, genetic counseling, and an improved long-term prognosis.
]]>Biomolecules doi: 10.3390/biom14030269
Authors: Magdalena Rudzińska Anna Gramza-Michałowska Monika Radzimirska-Graczyk Eliza Gruczyńska-Sękowska
This study explores the impact of rotational frying of three different food products on degradation of sterols, as well as their migration between frying oils and food. The research addresses a gap in the existing literature, which primarily focuses on changes in fat during the frying of single food items, providing limited information on the interaction of sterols from the frying medium with those from the food product. The frying was conducted at 185 ± 5 °C for up to 10 days where French fries, battered chicken, and fish sticks were fried in succession. The sterol content was determined by Gas Chromatography. This research is the first to highlight the influence of the type of oil on sterol degradation in both oils and food. Notably, sterols were found to be most stable when food products were fried in high-oleic low-linolenic rapeseed oil (HOLLRO). High-oleic soybean oil (HOSO) exhibited higher sterol degradation than high-oleic rapeseed oil (HORO). It was proven that cholesterol from fried chicken and fish sticks did not transfer to the fried oils or French fries. Despite initially having the highest sterol content in fish, the lowest sterol amount was recorded in fried fish, suggesting rapid degradation, possibly due to prefrying in oil with a high sterol content, regardless of the medium used.
]]>Biomolecules doi: 10.3390/biom14030268
Authors: Guanhao Wang Lining Cao Shuanqing Li Meihui Zhang Yingqi Li Jinjin Duan You Li Zhangsen Hu Jiaan Wu Tianming Li Ming Jiang Jianfeng Lu
Stress is known to induce a reduction in adult hippocampal neurogenesis (AHN) and anxiety-like behaviors. Glucocorticoids (GCs) are secreted in response to stress, and the hippocampus possesses the greatest levels of GC receptors, highlighting the potential of GCs in mediating stress-induced hippocampal alterations and behavior deficits. Herein, RNA-sequencing (RNA-seq) analysis of the hippocampus following corticosterone (CORT) exposure revealed the central regulatory role of the p21 (Cdkna1a) gene, which exhibited interactions with oxidative stress-related differentially expressed genes (DEGs), suggesting a potential link between p21 and oxidative stress-related pathways. Remarkably, p21-overexpression in the hippocampal dentate gyrus partially recapitulated CORT-induced phenotypes, including reactive oxygen species (ROS) accumulation, diminished AHN, dendritic atrophy, and the onset of anxiety-like behaviors. Significantly, inhibiting ROS exhibited a partial rescue of anxiety-like behaviors and hippocampal alterations induced by p21-overexpression, as well as those induced by CORT, underscoring the therapeutic potential of targeting ROS or p21 in the hippocampus as a promising avenue for mitigating anxiety disorders provoked by chronic stress.
]]>Biomolecules doi: 10.3390/biom14030267
Authors: Taian Yi Jiesi Luo Ruixue Liao Long Wang Anguo Wu Yueyue Li Ling Zhou Chengyang Ni Kai Wang Xiaoqin Tang Wenjun Zou Jianming Wu
(1) Background: Radiation-induced thrombocytopenia (RIT) often occurs in cancer patients undergoing radiation therapy, which can result in morbidity and even death. However, a notable deficiency exists in the availability of specific drugs designed for the treatment of RIT. (2) Methods: In our pursuit of new drugs for RIT treatment, we employed three deep learning (DL) algorithms: convolutional neural network (CNN), deep neural network (DNN), and a hybrid neural network that combines the computational characteristics of the two. These algorithms construct computational models that can screen compounds for drug activity by utilizing the distinct physicochemical properties of the molecules. The best model underwent testing using a set of 10 drugs endorsed by the US Food and Drug Administration (FDA) specifically for the treatment of thrombocytopenia. (3) Results: The Hybrid CNN+DNN (HCD) model demonstrated the most effective predictive performance on the test dataset, achieving an accuracy of 98.3% and a precision of 97.0%. Both metrics surpassed the performance of the other models, and the model predicted that seven FDA drugs would exhibit activity. Isochlorogenic acid A, identified through screening the Chinese Pharmacopoeia Natural Product Library, was subsequently subjected to experimental verification. The results indicated a substantial enhancement in the differentiation and maturation of megakaryocytes (MKs), along with a notable increase in platelet production. (4) Conclusions: This underscores the potential therapeutic efficacy of isochlorogenic acid A in addressing RIT.
]]>Biomolecules doi: 10.3390/biom14030266
Authors: Xin-Yi Sun Mian Xiao Min Fu Qian Gao Rui-Feng Li Jing Wang Sheng-Lin Li Xi-Yuan Ge
Disulfidptosis is a newly discovered form of programmed cell death that is induced by disulfide stress. It is closely associated with various cancers, including head and neck squamous cell carcinoma (HNSCC). However, the factors involved in the modulation of disulfidptosis-related genes (DRGs) still remain unknown. In this study, we established and validated a novel risk score model composed of 11 disulfidptosis-related lncRNAs (DRLs) based on 24 DRGs in HNSCC. The results revealed strong correlations between the 11-DRL prognostic signature and clinicopathological features, immune cell infiltration, immune-related functions, and disulfidptosis-associated pathways, including NADPH and disulfide oxidoreductase activities. Furthermore, we studied and verified the involvement of ALMS1-IT1, one of the 11 model DRLs, in the disulfidptosis of HNSCC cell lines. A series of assays demonstrated that ALMS1-IT1 modulated cell death under starvation conditions in a pentose phosphate pathway (PPP)-dependent manner. Knockdown of ALMS1-IT1 inhibited the PPP, contributing to a decline in NADPH levels, which resulted in the formation of multiple intermolecular disulfide bonds between actin cytoskeleton proteins and the collapse of F-actin in the cytoplasm. Therefore, ALMS1-IT1, which is highly expressed in SLC7A11high cells, can be considered a promising therapeutic target for disulfidptosis-focused treatment strategies for cancer and other diseases.
]]>Biomolecules doi: 10.3390/biom14030265
Authors: Chunyuan Yang Limei Guo Juan Du Qiulu Zhang Lingfu Zhang
Low efficacy of treatments and chemoresistance are challenges in addressing refractory hepatocellular carcinoma (HCC). SPINK1, an oncogenic protein, is frequently overexpressed in many HCC cases. However, the impact of SPINK1 on HCC treatment resistance remains poorly understood. Here, we elucidate the functions of SPINK1 on HCC therapy resistance. Analysis of SPINK1 protein level reveals a correlation between elevated SPINK1 expression and unfavorable prognosis. Furthermore, intercellular variations in SPINK1 expression levels are observed. Subsequent examination of single cell RNA-sequencing data from two HCC cohorts further suggest that SPINK1-high cells exhibit heightened activity in drug metabolic pathways compared to SPINK1-low HCC cells. High SPINK1 expression is associated with reduced sensitivities to both chemotherapy drugs and targeted therapies. Moreover, spatial transcriptomics data indicate that elevated SPINK1 expression correlates with non-responsive phenotype during treatment with targeted therapy and immune checkpoint inhibitors. This is attributed to increased levels of drug metabolic regulators, especially CES2 and CYP3A5, in SPINK1-high cells. Experimental evidence further demonstrates that SPINK1 overexpression induces the expression of CES2 and CYP3A5, consequently promoting chemoresistance to sorafenib and oxaliplatin. In summary, our study unveils the predictive role of SPINK1 on HCC treatment resistance, identifying it as a potential therapeutic target for refractory HCC.
]]>Biomolecules doi: 10.3390/biom14030262
Authors: Brie M. Reid Christopher Desjardins Bharat Thyagarajan Michael A. Linden Megan Gunnar
Early life stress (ELS) is linked to an elevated risk of poor health and early mortality, with emerging evidence pointing to the pivotal role of the immune system in long-term health outcomes. While recent research has focused on the impact of ELS on inflammation, this study examined the impact of ELS on immune function, including CMV seropositivity, inflammatory cytokines, and lymphocyte cell subsets in an adolescent cohort. This study used data from the Early Life Stress and Cardiometabolic Health in Adolescence Study (N = 191, aged 12 to 21 years, N = 95 exposed to ELS). We employed multiple regression to investigate the association between ELS, characterized by early institutional care, cytomegalovirus (CMV) seropositivity (determined by chemiluminescent immunoassay), inflammation (CRP, IL-6, and TNF-a determined by ELISA), and twenty-one immune cell subsets characterized by flow cytometry (sixteen T cell subsets and five B cell subsets). Results reveal a significant association between ELS and lymphocytes that was independent of the association between ELS and inflammation: ELS was associated with increased effector memory helper T cells, effector memory cytotoxic T cells, senescent T cells, senescent B cells, and IgD− memory B cells compared to non-adopted youth. ELS was also associated with reduced percentages of helper T cells and naive cytotoxic T cells. Exploratory analyses found that the association between ELS and fewer helper T cells and increased cytotoxic T cells remained even in cytomegalovirus (CMV) seronegative youth. These findings suggest that ELS is associated with cell subsets that are linked to early mortality risk in older populations and markers of replicative senescence, separate from inflammation, in adolescents.
]]>Biomolecules doi: 10.3390/biom14030264
Authors: Othman Al Musaimi
Peptides continue to gain significance in the pharmaceutical arena. Since the unveiling of insulin in 1921, the Food and Drug Administration (FDA) has authorised around 100 peptides for various applications. Peptides, although initially derived from endogenous sources, have evolved beyond their natural origins, exhibiting favourable therapeutic effectiveness. Medicinal chemistry has played a pivotal role in synthesising valuable natural peptide analogues, providing synthetic alternatives with therapeutic potential. Furthermore, key chemical modifications have enhanced the stability of peptides and strengthened their interactions with therapeutic targets. For instance, selective modifications have extended their half-life and lessened the frequency of their administration while maintaining the desired therapeutic action. In this review, I analyse the FDA approval of natural peptides, as well as engineered peptides for diabetes treatment, growth-hormone-releasing hormone (GHRH), cholecystokinin (CCK), adrenocorticotropic hormone (ACTH), and α-melanocyte stimulating hormone (α-MSH) peptide analogues. Attention will be paid to the structure, mode of action, developmental journey, FDA authorisation, and the adverse effects of these peptides.
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