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Int. J. Mol. Sci., Volume 25, Issue 23 (December-1 2024) – 748 articles

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10 pages, 2960 KiB  
Article
Characterising a Novel Therapeutic Target for Psoriasis, TYK2, Using Functional Genomics
by Shraddha S. Rane, Sarah Elyoussfi, Elan Shellard, Steve Eyre and Richard B. Warren
Int. J. Mol. Sci. 2024, 25(23), 13229; https://doi.org/10.3390/ijms252313229 - 9 Dec 2024
Viewed by 557
Abstract
Psoriasis (Ps) is a debilitating immune-mediated chronic skin condition. It affects about 1–3% of the world population, with an 8–11% prevalence in Northern European populations. Tyrosine kinase 2 (TYK2) is a newly identified target for Ps. An independent non-coding genetic association with Ps [...] Read more.
Psoriasis (Ps) is a debilitating immune-mediated chronic skin condition. It affects about 1–3% of the world population, with an 8–11% prevalence in Northern European populations. Tyrosine kinase 2 (TYK2) is a newly identified target for Ps. An independent non-coding genetic association with Ps has been identified ~400 kb upstream of TYK2. The variants making up the credible Ps Single-Nucleotide Polymorphism (SNP) set were identified in their genomic context with the potential to influence TYK2 expression by interacting with regulatory elements involved in gene regulation. Previous evidence from our laboratory has suggested that credible SNP sets in intronic regions can be distal regulators of the genes of interest through long-range chromatin interactions. We hypothesise that SNPs at ILF3 are distal regulators of TYK2 expression via long-range chromatin interactions and Ps risk. The dysregulation of the TYK2 pathway in Ps may be mediated by a combination of GWAS risk SNPs at ILF3 and TYK2 and downstream genes. We investigated this by employing functional genomics and molecular biology methods. We developed a CD4 T cell model system with Jurkat-dCAS9-VP64 and Jurkat-dCAS9-KRAB cells using CRISPR activation and CRISPR inhibition of the risk variants rs892086 and rs7248205, selected from the latest Ps GWAS SNP set for their long-range interaction and light Linkage Disequilibrium (R2 > 0.8), respectively. Using CRISPR activation, we demonstrate here that these risk SNPs, although distal to TYK2, do indeed regulate the TYK2 gene. Investigations into annotating the TYK2 pathway using RNA-seq analysis revealed differentially regulated genes, including VEGFA, C1R, ADORA1, GLUD2, NDUFB8, and FCGR2C, which are thought to be implicated in Ps. These genes were observed to be associated with conditions such as psoriatic arthritis, atopic dermatitis, and systemic sclerosis when compared using published databases, which confirms their relevance and importance in inflammatory conditions. With the developed cell model systems using CRISPR technology and differential gene regulation, we demonstrate here that these genes have the potential to define the TYK2/Ps pathway and our understanding of the disease biology. Full article
(This article belongs to the Special Issue Skin Diseases: From Molecular Mechanisms to Pathology)
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17 pages, 1741 KiB  
Article
Effect of Organic Anion Transporting Polypeptide 1B1 on Plasma Concentration Dynamics of Clozapine in Patients with Treatment-Resistant Schizophrenia
by Toshihiro Sato, Takeshi Kawabata, Masaki Kumondai, Nagomi Hayashi, Hiroshi Komatsu, Yuki Kikuchi, Go Onoguchi, Yu Sato, Kei Nanatani, Masahiro Hiratsuka, Masamitsu Maekawa, Hiroaki Yamaguchi, Takaaki Abe, Hiroaki Tomita and Nariyasu Mano
Int. J. Mol. Sci. 2024, 25(23), 13228; https://doi.org/10.3390/ijms252313228 - 9 Dec 2024
Viewed by 309
Abstract
The involvement of drug-metabolizing enzymes and transporters in plasma clozapine (CLZ) dynamics has not been well examined in Japanese patients with treatment-resistant schizophrenia (TRS). Therefore, this clinical study investigated the relationship between single nucleotide polymorphisms (SNPs) of various pharmacokinetic factors (drug-metabolizing enzymes and [...] Read more.
The involvement of drug-metabolizing enzymes and transporters in plasma clozapine (CLZ) dynamics has not been well examined in Japanese patients with treatment-resistant schizophrenia (TRS). Therefore, this clinical study investigated the relationship between single nucleotide polymorphisms (SNPs) of various pharmacokinetic factors (drug-metabolizing enzymes and transporters) and dynamic changes in CLZ. Additionally, we aimed to determine whether CLZ acts as a substrate for pharmacokinetic factors using in vitro assays and molecular docking calculations. We found that 6 out of 10 patients with TRS and with multiple organic anion transporting polypeptide (OATP) variants (OATP1B1: *1b, *15; OATP1B3: 334T>G, 699G>A; and OATP2B1: *3, 935G>A, 601G>A, 76_84del) seemed to be highly exposed to CLZ and/or N-desmethyl CLZ. A CLZ uptake study using OATP-expressing HEK293 cells showed that CLZ was a substrate of OATP1B1 with Km and Vmax values of 38.9 µM and 2752 pmol/mg protein/10 min, respectively. The results of molecular docking calculations supported the differences in CLZ uptake among OATP molecules and the weak inhibitory effect of cyclosporine A, which is a strong inhibitor of OATPs, on CLZ uptake via OATP1B1. This is the first study to show that CLZ is an OATP1B1 substrate and that the presence of SNPs in OATPs potentially alters CLZ pharmacokinetic parameters. Full article
(This article belongs to the Special Issue Transporters in Health and Disease)
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23 pages, 680 KiB  
Review
The Role of the Vaginal and Endometrial Microbiomes in Infertility and Their Impact on Pregnancy Outcomes in Light of Recent Literature
by Bernadett Balla, Anett Illés, Bálint Tobiás, Henriett Pikó, Artúr Beke, Miklós Sipos, Péter Lakatos and János P. Kósa
Int. J. Mol. Sci. 2024, 25(23), 13227; https://doi.org/10.3390/ijms252313227 - 9 Dec 2024
Viewed by 302
Abstract
The Human Microbiome Project (HMP), initiated in 2007, aimed to gather comprehensive knowledge to create a genetic and metabolic map of human-associated microorganisms and their contribution to physiological states and predisposition to certain diseases. Research has revealed that the human microbiome is highly [...] Read more.
The Human Microbiome Project (HMP), initiated in 2007, aimed to gather comprehensive knowledge to create a genetic and metabolic map of human-associated microorganisms and their contribution to physiological states and predisposition to certain diseases. Research has revealed that the human microbiome is highly diverse and exhibits significant interpersonal variability; consequently, its exact impact on health remains unclear. With the development of next-generation sequencing (NGS) technologies, the broad spectrum of microbial communities has been better characterized. The lower female genital tract, particularly the vagina, is colonized by various bacterial species, with Lactobacillus spp. predominating. The upper female genital tract, especially the uterus, was long considered sterile. However, recent studies have identified a distinct endometrial microbiome. A Lactobacillus-dominated microbiome of the female genital tract is associated with favorable reproductive outcomes, including higher success rates in natural conception and assisted reproductive technologies (ART). Conversely, microbial imbalances, or dysbiosis, marked by reduced Lactobacilli as well as an increased diversity and abundance of pathogenic species (e.g., Gardnerella vaginalis or Prevotella spp.), are linked to infertility, implantation failure, and pregnancy complications such as miscarriage and preterm birth. Dysbiosis can impair the vaginal or endometrial mucosal barrier and also trigger pro-inflammatory responses, disrupting essential reproductive processes like implantation. Despite growing evidence supporting the associations between the microbiome of the female genital tract and certain gynecological and obstetric conditions, clear microbial biomarkers have yet to be identified, and there is no consensus on the precise composition of a normal or healthy microbiome. The lack of standardized protocols and biomarkers limits the routine use of microbiome screening tests. Therefore, larger patient cohorts are needed to facilitate comparative studies and improve our understanding of the physiological microbiome profiles of the uterus and vagina, as well as how dysbiosis may influence clinical outcomes. Further research is required to refine diagnostic tools and develop personalized therapeutic strategies to improve fertility and pregnancy outcomes. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Pregnancy Complications)
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14 pages, 2101 KiB  
Article
Fabrication of Porous MXene/Cellulose Nanofibers Composite Membrane for Maximum Osmotic Energy Harvesting
by Sha Wang, Zhe Sun, Mehraj Ahmad and Mengyu Miao
Int. J. Mol. Sci. 2024, 25(23), 13226; https://doi.org/10.3390/ijms252313226 - 9 Dec 2024
Viewed by 233
Abstract
Two-dimensional (2D) nanofluidic channels are emerging as potential candidates for harnessing osmotic energy from salinity gradients. However, conventional 2D nanofluidic membranes suffer from high transport resistance and low ion selectivity, leading to inefficient transport dynamics and limiting energy conversion performance. In this study, [...] Read more.
Two-dimensional (2D) nanofluidic channels are emerging as potential candidates for harnessing osmotic energy from salinity gradients. However, conventional 2D nanofluidic membranes suffer from high transport resistance and low ion selectivity, leading to inefficient transport dynamics and limiting energy conversion performance. In this study, we present a novel composite membrane consisting of porous MXene (PMXene) nanosheets featuring etched nanopores, in conjunction with cellulose nanofibers (CNF), yielding enhancement in ion flux and ion selectivity. A mild H2O2 oxidant is employed to etch and perforate the MXene sheets to create a robust network of cation transportation nanochannels that effectively reduces the energy barrier for cation transport. Additionally, CNF with a unique nanosize and high charge density further enhances the charge density and mechanical stability of the nanofluidic system. Under neutral pH and room temperature, the PMXene/CNF membrane demonstrates a maximum output power density of 0.95 W·m−2 at a 50-fold KCl gradient. Notably, this represents a 43% improvement over the performance of the pristine MXene/CNF membrane. Moreover, 36 nanofluidic devices connected in series are demonstrated to achieve a stable voltage output of 5.27 V and power a calculator successfully. This work holds great promise for achieving sustainable energy harvesting with efficient osmotic energy conversion utilization. Full article
(This article belongs to the Special Issue Organic/Inorganic Nanocomposites on the Basis of 'Three Pillars' (Organic Compounds, Metal Nanoparticles, and Carbon Nanomaterials))
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15 pages, 4771 KiB  
Article
Long-Term Yo-Yo Dieting Exaggerates Liver Steatosis and Lesions but Preserves Muscle Performance in Male Zebrafish
by Tzu-Chieh Hsu, Chun-Hsien Chiang, I-Hsuan Liu, Chih-Yun Wang and Ching-Yi Chen
Int. J. Mol. Sci. 2024, 25(23), 13225; https://doi.org/10.3390/ijms252313225 - 9 Dec 2024
Viewed by 300
Abstract
Weight regain within one year after weight loss is frequently observed and is referred to as yo-yo dieting or weight cycling. In this study, we explore the effects of yo-yo dieting on the liver, adipose tissue, and muscle characteristics of male zebrafish. Four-month-old [...] Read more.
Weight regain within one year after weight loss is frequently observed and is referred to as yo-yo dieting or weight cycling. In this study, we explore the effects of yo-yo dieting on the liver, adipose tissue, and muscle characteristics of male zebrafish. Four-month-old AB wild-type male zebrafish were randomly assigned to three groups: high-calorie intake (H, seven meals per day), low-calorie intake (L, two meals per day), and yo-yo diet (the low- and high-calorie alternation switched every two weeks) groups. Feeding the fish the H diet for over 8 weeks led to steatosis and damage to the liver. The yo-yo diet reduced liver lipid accumulation at week eight but caused a similar degree of lipid accumulation as the H diet thereafter. It was found that twenty weeks of yo-yo dieting actually exacerbated hepatic damage. Compared to the L diet, feeding the fish on the yo-yo and H diets for a period of 20 weeks significantly increased the size of muscle fibers, resulting in higher speed during burst swimming and a significant increase in the size and number of adipocytes in the abdominal tissue. To summarize, short-term yo-yo dieting was found to attenuate hepatosteatosis and maintain fast-twitch muscle function. Long-term yo-yo dieting preserved fast-twitch muscle function and muscle fiber size; however, it exacerbated the pathological changes in the liver. Full article
(This article belongs to the Special Issue Diet and Lifestyle: Impact on the Molecular and Cellular Mechanism of NCDs)
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19 pages, 4061 KiB  
Article
Discovery of a Small Molecule with an Inhibitory Role for RAB11
by Camille Lempicki, Julian Milosavljevic, Christian Laggner, Simone Tealdi, Charlotte Meyer, Gerd Walz, Konrad Lang, Carlo Cosimo Campa and Tobias Hermle
Int. J. Mol. Sci. 2024, 25(23), 13224; https://doi.org/10.3390/ijms252313224 - 9 Dec 2024
Viewed by 248
Abstract
RAB11, a pivotal RabGTPase, regulates essential cellular processes such as endocytic recycling, exocytosis, and autophagy. The protein was implicated in various human diseases, including cancer, neurodegenerative disorders, viral infections, and podocytopathies. However, a small-molecular inhibitor is lacking. The complexity and workload associated with [...] Read more.
RAB11, a pivotal RabGTPase, regulates essential cellular processes such as endocytic recycling, exocytosis, and autophagy. The protein was implicated in various human diseases, including cancer, neurodegenerative disorders, viral infections, and podocytopathies. However, a small-molecular inhibitor is lacking. The complexity and workload associated with potential assays make conducting large-scale screening for RAB11 challenging. We employed a tiered approach for drug discovery, utilizing deep learning-based computational screening to preselect compounds targeting a specific pocket of RAB11 protein with experimental validation by an in vitro platform reflecting RAB11 activity through the exocytosis of GFP. Further validation included the exposure of Drosophila by drug feeding. In silico pre-screening identified 94 candidates, of which 9 were confirmed using our in vitro platform for Rab11 activity. Focusing on compounds with high potency, we assessed autophagy, which independently requires RAB11, and validated three of these compounds. We further analyzed the dose–response relationship, observing a biphasic, potentially hormetic effect. Two candidate compounds specifically caused a shift in Rab11 vesicles to the cell periphery, without significant impact on Rab5 or Rab7. Drosophila larvae exposed to another candidate compound with predicted oral bioavailability exhibited minimal toxicity, subcellular dispersal of endogenous Rab11, and a decrease in RAB11-dependent nephrocyte function, further supporting an inhibitory role. Taken together, the combination of computational screening and experimental validation allowed the identification of small molecules that modify the function of Rab11. This discovery may further open avenues for treating RAB11-associated disorders. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery, 2nd Edition)
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14 pages, 5764 KiB  
Article
Carotenoid Cleavage Dioxygenase Gene CCD4 Enhances Tanshinone Accumulation and Drought Resistance in Salvia miltiorrhiza
by Qian Tian, Wei Han, Shuai Zhou, Liu Yang, Donghao Wang, Wen Zhou and Zhezhi Wang
Int. J. Mol. Sci. 2024, 25(23), 13223; https://doi.org/10.3390/ijms252313223 - 9 Dec 2024
Viewed by 303
Abstract
Danshen (Salvia miltiorrhiza Bunge) is a perennial herbaceous plant of the Salvia genus in the family Lamiaceae. Its dry root is one of the important traditional Chinese herbal medicines with a long officinal history. The yield and quality of S. miltiorrhiza are [...] Read more.
Danshen (Salvia miltiorrhiza Bunge) is a perennial herbaceous plant of the Salvia genus in the family Lamiaceae. Its dry root is one of the important traditional Chinese herbal medicines with a long officinal history. The yield and quality of S. miltiorrhiza are influenced by various factors, among which drought is one of the most significant types of abiotic stress. Based on the transcriptome database of S. miltiorrhiza, our research group discovered a carotenoid cleavage dioxygenase gene, SmCCD4, belonging to the carotenoid cleavage oxygenase (CCO) gene family which is highly responsive to drought stress on the basis of our preceding work. Here, we identified 26 CCO genes according to the whole-genome database of S. miltiorrhiza. The expression pattern of SmCCD4 showed that this gene is strongly overexpressed in the aboveground tissue of S. miltiorrhiza. And by constructing SmCCD4 overexpression strains, it was shown that the overexpression of SmCCD4 not only promotes the synthesis of abscisic acid and increases plant antioxidant activity but also regulates the synthesis of the secondary metabolites tanshinone and phenolic acids in S. miltiorrhiza. In summary, this study is the first in-depth and systematic identification and investigation of the CCO gene family in S. miltiorrhiza. The results provide useful information for further systematic research on the function of CCO genes and provide a theoretical basis for improving the yield and quality of S. miltiorrhiza. Full article
(This article belongs to the Special Issue Molecular Research in Plant Adaptation to Abiotic Stress)
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26 pages, 6573 KiB  
Article
Semisynthesis and Antitumour Evaluation of Natural Derivatives from ent-Kaurene ent-15α-Angeloyloxykaur-l6-en-3β-ol Isolated from Distichoselinum tenuifolium
by Yass K. Yasser, Daniel Gil, Houda Zentar, María Jesús Durán-Peña, Belen Prados-Lopez, Jorge Juárez-Moreno, José Manuel Botubol-Ares, Ali Haidour, Juan Sainz, Antonio Fernández, Ramón Alvarez-Manzaneda, Rachid Chahboun and Fernando J. Reyes-Zurita
Int. J. Mol. Sci. 2024, 25(23), 13222; https://doi.org/10.3390/ijms252313222 - 9 Dec 2024
Viewed by 339
Abstract
Two natural ent-kaurene diterpenoids, ent-15α-angeloyloxykaur-16-en-3β-ol (7) and ent-15α-angeloyloxykaur-16-en-3β,9-diol (8), were extracted from the aerial parts of Distichoselinum tenuifolium, and six new derivatives were synthesised from compound (7). The antitumour properties of these natural and [...] Read more.
Two natural ent-kaurene diterpenoids, ent-15α-angeloyloxykaur-16-en-3β-ol (7) and ent-15α-angeloyloxykaur-16-en-3β,9-diol (8), were extracted from the aerial parts of Distichoselinum tenuifolium, and six new derivatives were synthesised from compound (7). The antitumour properties of these natural and derivative ent-kaurenes (2, 7, 9–13) were evaluated in three cancer cell lines: HT29 (colon cancer), HepG2 (hepatocellular carcinoma), and B16-F10 (murine melanoma). Among them, the synthesised ent-kaurene (13) containing an exomethylene–cyclopentanone moiety showed the strongest antiproliferative effects in all cell lines tested, with significantly lower IC50 values around 2.5 μM. Compounds 13 and 12, together with their precursor (7), were selected for further comparative cytometric and microscopic analyses. Cell cycle studies revealed that derivatives 12 and 13 exhibited promising cytostatic activity by inducing selective G2/M phase arrest, particularly effective in HT29 and HepG2 cells. Conversely, precursor (7) showed no significant effect on B16-F10 cell cycle distribution. The Annexin V-FITC/PI double staining assay confirmed the robust apoptotic effects of compounds (7), 12 and 13, with compound 13 inducing up to 99% total apoptosis and exhibiting significant apoptotic activity in all cell lines tested. These apoptotic effects were closely linked to mitochondrial dysfunction, as evidenced by a marked loss of mitochondrial membrane potential and reduced Rh123 fluorescence in treated cells, thereby activating the intrinsic apoptotic pathway. These findings highlight the critical role of mitochondrial disruption in the cytotoxic mechanisms of these ent-kaurenes and underscore their potential as promising anticancer agents. Full article
(This article belongs to the Special Issue Small Molecule Drug Design and Research: 3rd Edition)
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21 pages, 4591 KiB  
Article
Impact of the COL1A1 Gene Polymorphisms on Pain Perception in Tennis Elbow Patients: A Two-Year Prospective Cohort Study
by Paweł Niemiec, Alicja Jarosz, Tomasz Nowak, Anna Balcerzyk-Matić, Tomasz Iwanicki, Joanna Iwanicka, Katarzyna Gawron, Marcin Kalita, Sylwia Górczyńska-Kosiorz, Wojciech Kania and Karol Szyluk
Int. J. Mol. Sci. 2024, 25(23), 13221; https://doi.org/10.3390/ijms252313221 - 9 Dec 2024
Viewed by 283
Abstract
The COL1A1 gene encodes the α1 chain of type I collagen, and the data reported so far demonstrate that its polymorphic variants may affect biomechanical properties of bones, muscles, and tendons, and contribute to musculoskeletal disorders. Given, however, limited research on these variants [...] Read more.
The COL1A1 gene encodes the α1 chain of type I collagen, and the data reported so far demonstrate that its polymorphic variants may affect biomechanical properties of bones, muscles, and tendons, and contribute to musculoskeletal disorders. Given, however, limited research on these variants in tendon pathology, we analyzed the impact of COL1A1 polymorphisms on the tendinopathy phenotype and the effectiveness of platelet-rich plasma (PRP) treatment for tennis elbow. Pain perception and therapy outcomes were analyzed from baseline, i.e., before PRP injection to two years post-PRP injection in a cohort of 107 patients. The study focused on seven COL1A1 variants: rs2249492 (C/T), rs2586488 (A/G), rs2075558 (A/C), rs2253369 (C/T), rs35231764 (A/G), rs1800012 (C/A), and rs9898186 (C/T). We demonstrated that carriers of the TT/CT (rs2249492), AA/AC (rs1800012), and TT/CT (rs9898186) genotypes reported pain related to injury more frequently than subjects with other COL1A1 variants, also in the context of performing specific activities and other pain characteristics. These polymorphisms did not significantly influence therapy effectiveness, although rs35231764 showed a moderate effect. In conclusion, the T (rs2249492), A (rs1800012), and T (rs9898186) alleles of COL1A1 gene are risk factors for pain perception in tennis elbow patients, but do not appear to substantially impact PRP treatment outcomes. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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10 pages, 2179 KiB  
Article
The Probiotics Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, and Limosilactobacillus fermentum Enhance Spermatozoa Motility Through Mitochondrial Function-Related Factors
by Eun Hye Lee, Yu Jin Kim, Il Seon Jung, Dae Keun Kim and Jae Ho Lee
Int. J. Mol. Sci. 2024, 25(23), 13220; https://doi.org/10.3390/ijms252313220 - 9 Dec 2024
Viewed by 307
Abstract
Idiopathic male infertility is characterized by increased mortality or reduced motility and vitality of sperm. There are several reports on probiotics in the male reproductive tract, but the effects of these probiotics on sperm motility remain to be elucidated. In this study, we [...] Read more.
Idiopathic male infertility is characterized by increased mortality or reduced motility and vitality of sperm. There are several reports on probiotics in the male reproductive tract, but the effects of these probiotics on sperm motility remain to be elucidated. In this study, we investigated the impact and mechanism of probiotics on the vitality and motility of mouse sperm. We collected mature sperm from the caudal vas deferens of mice and prepared three probiotics donated by HEM Pharma Inc.: Lacticaseibacillus rhamnosus, Limosilactobacillus fermentum, and Lacticaseibacillus paracasei. We analyzed the vitality and motility of sperm according to the concentration and duration of probiotic treatment. The probiotics increased the motility and vitality of sperm. Specifically, they enhanced sperm motility by 30–40% compared with untreated sperms. The probiotics enhanced mitochondrial activity in sperm through specific factors like AMPK and SIRT1. All three probiotics enhanced the activities of mitochondrial function-related proteins in sperm. In conclusion, we found that the probiotics improved the vitality and motility of mouse sperm and increased mitochondrial function in mature sperm. These findings suggest that probiotics can be utilized to enhance sperm motility and treat male infertility. Full article
(This article belongs to the Special Issue Microbiome Modulation through Probiotics: Molecular Insights and Therapeutic Applications)
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16 pages, 4662 KiB  
Article
Modulating Amyloid-β Toxicity: In Vitro Analysis of Aβ42(G37V) Variant Impact on Aβ42 Aggregation and Cytotoxicity
by Shu-Hsiang Huang, Shang-Ting Fang, Chin-Hao Yang, Je-Wen Liou and Yi-Cheng Chen
Int. J. Mol. Sci. 2024, 25(23), 13219; https://doi.org/10.3390/ijms252313219 - 9 Dec 2024
Viewed by 299
Abstract
Alzheimer’s disease (AD) is primarily driven by the formation of toxic amyloid-β (Aβ) aggregates, with Aβ42 being a pivotal contributor to disease pathology. This study investigates a novel agent to mitigate Aβ42-induced toxicity by co-assembling Aβ42 with its G37V variant (Aβ42(G37V)), where Gly [...] Read more.
Alzheimer’s disease (AD) is primarily driven by the formation of toxic amyloid-β (Aβ) aggregates, with Aβ42 being a pivotal contributor to disease pathology. This study investigates a novel agent to mitigate Aβ42-induced toxicity by co-assembling Aβ42 with its G37V variant (Aβ42(G37V)), where Gly at position 37 is substituted with valine. Using a combination of Thioflavin-T (Th-T) fluorescence assays, Western blot analysis, atomic force microscopy (AFM)/transmission electron microscopy (TEM), and biochemical assays, we demonstrated that adding Aβ42(G37V) significantly accelerates Aβ42 aggregation rate and mass while altering the morphology of the resulting aggregates. Consequently, adding Aβ42(G37V) reduces the Aβ42 aggregates-induced cytotoxicity, as evidenced by improved cell viability assays. The possible mechanism for this effect is that adding Aβ42(G37V) reduces the production of reactive oxygen species (ROS) and lipid peroxidation, typically elevated in response to Aβ42, indicating its protective effects against oxidative stress. These findings suggest that Aβ42(G37V) could be a promising candidate for modulating Aβ42 aggregation dynamics and reducing its neurotoxic effects, providing a new avenue for potential therapeutic interventions in AD. Full article
(This article belongs to the Section Biochemistry)
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16 pages, 3208 KiB  
Article
OCTN1 (SLC22A4) as a Target of Heavy Metals: Its Possible Role in Microplastic Threats
by Luana S. Brunetti, Mariafrancesca Scalise, Raffaella Scanga, Lara Console, Michele Galluccio, Mauro F. La Russa, Lorena Pochini and Cesare Indiveri
Int. J. Mol. Sci. 2024, 25(23), 13218; https://doi.org/10.3390/ijms252313218 - 9 Dec 2024
Viewed by 286
Abstract
Microplastics represent a threat due to their ability to enter the food chain, with harmful consequences for living organisms. The riskiness of these particles is also linked to the release of other contaminants, such as heavy metals. Solute Carriers (SLCs) represent eminent examples [...] Read more.
Microplastics represent a threat due to their ability to enter the food chain, with harmful consequences for living organisms. The riskiness of these particles is also linked to the release of other contaminants, such as heavy metals. Solute Carriers (SLCs) represent eminent examples of first-level targets of heavy metals due to their localization on the cell surface. Putative targets of heavy metals are the organic cation transporters that form a sub-clade of the SLC22 family. Besides the physiological role in the absorption/release of endogenous organic cations, these transporters are crucial in drug disposition and their interaction with xenobiotics. In this work, the human SLC22A4, commonly known as OCTN1, was used as a benchmark to test interactions with heavy metals released by microplastics, exploiting the proteoliposome tool. The potency of metals to interfere with the OCTN1 function has been evaluated by measuring IC50 values calculated in the micromolar range. The molecular mechanism of interaction has been defined using site-directed mutagenesis and computational analyses. Finally, some chemical and physiological thiol-reacting compounds show the capacity to rescue the metal-inhibited OCTN1 function. The conclusions drawn on OCTN1 can be extended to other members of the SLC22 family and orthologous transporters in fish. Full article
(This article belongs to the Special Issue Transport of Nutrients and Ions Relevant to Human Pathophysiology)
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16 pages, 4631 KiB  
Article
Role of Annexin 7 (ANXA7) as a Tumor Suppressor and a Regulator of Drug Resistance in Thyroid Cancer
by Alakesh Bera, Surya Radhakrishnan, Narayanan Puthillathu, Madhan Subramanian, Nahbuma Gana, Eric Russ, Harvey B. Pollard and Meera Srivastava
Int. J. Mol. Sci. 2024, 25(23), 13217; https://doi.org/10.3390/ijms252313217 - 9 Dec 2024
Viewed by 242
Abstract
Thyroid cancer is the most common endocrine malignancy in the United States, with an overall favorable prognosis. However, some patients experience poor outcomes due to the development of resistance to conventional therapies. Genetic alterations, including mutations in BRAF, Met, and p53, play critical [...] Read more.
Thyroid cancer is the most common endocrine malignancy in the United States, with an overall favorable prognosis. However, some patients experience poor outcomes due to the development of resistance to conventional therapies. Genetic alterations, including mutations in BRAF, Met, and p53, play critical roles in thyroid cancer progression, with the BRAF V600E mutation detected in over 60% of cases. This study investigates the tumor-suppressive role of Annexin A7 (ANXA7) in thyroid cancer, focusing on its potential impact on tumor behavior and therapeutic response. Our analysis, which included RNA sequencing and protein profiling, revealed reduced ANXA7 expression in thyroid cancer cells, particularly in those harboring the BRAF V600E mutation. Upon treatment with inhibitors targeting BRAF and MEK, ANXA7 expression increased, leading to reduced phosphorylation of ERK and activation of apoptotic pathways. Additionally, we identified the cyclin-dependent kinase inhibitor p21 as a key player in modulating resistance to BRAF inhibitors. Combination therapies aimed at concurrently increasing p21 and ANXA7 levels resulted in a marked enhancement of apoptosis. These findings suggest a previously uncharacterized regulatory network involving the ANXA7/p21/BRAF/MAPK/p53 axis, which may contribute to drug resistance in thyroid cancer. This study provides new insights into overcoming resistance to BRAF and MAPK inhibitors, with implications for treating thyroid cancer and potentially other BRAF-mutant tumors. Future efforts will focus on high-throughput screening approaches to explore ANXA7-targeted therapeutic strategies for thyroid cancer. Full article
(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)
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16 pages, 2783 KiB  
Article
Functional Analysis of TAAR1 Expression in the Intestine Wall and the Effect of Its Gene Knockout on the Gut Microbiota in Mice
by Anastasia N. Vaganova, Ilya S. Zhukov, Taisiia S. Shemiakova, Konstantin A. Rozhkov, Lyubov S. Alferova, Alena B. Karaseva, Elena I. Ermolenko and Raul R. Gainetdinov
Int. J. Mol. Sci. 2024, 25(23), 13216; https://doi.org/10.3390/ijms252313216 - 9 Dec 2024
Viewed by 299
Abstract
Currently, the TAAR1 receptor has been identified in various cell groups in the intestinal wall. It recognizes biogenic amine compounds like phenylethylamine or tyramine, which are products of decarboxylation of phenylalanine and tyrosine by endogenous or bacterial decarboxylases. Since several gut bacteria produce [...] Read more.
Currently, the TAAR1 receptor has been identified in various cell groups in the intestinal wall. It recognizes biogenic amine compounds like phenylethylamine or tyramine, which are products of decarboxylation of phenylalanine and tyrosine by endogenous or bacterial decarboxylases. Since several gut bacteria produce these amines, TAAR1 is suggested to be involved in the interaction between the host and gut microbiota. The purpose of this present study was to clarify the TAAR1 function in the intestinal wall and estimate the TAAR1 gene knockout effect on gut microbiota composition. By analyzing public transcriptomic data of the GEO repository, we identified TAAR1 expression in enterocytes, enteroendocrine cells, tuft cells, and myenteric neurons in mice. The analysis of genes co-expressed with TAAR1 in enteroendocrine cells allows us to suggest the TAAR1 involvement in enteroendocrine cell maturation. Also, in myenteric neurons, we identified the co-expression of TAAR1 with calbindin, which is specific for sensory neurons. The 16S rRNA gene-based analysis of fecal microbiota revealed a slight but significant impact of TAAR1 gene knockout in mice on the gut microbial community, which manifests in the higher diversity, accompanied by low between-sample variability and reorganization of the microbial co-occurrence network. Full article
(This article belongs to the Special Issue Molecular Advances in Gut Microbiota and Its Interaction with Immune System)
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14 pages, 4450 KiB  
Article
Integrated Transcriptomic and Proteomic Analyses of Antler Growth and Ossification Mechanisms
by Ruijia Liu, Pan Zhang, Jiade Bai, Zhenyu Zhong, Yunfang Shan, Zhibin Cheng, Qingxun Zhang, Qingyun Guo, Hao Zhang and Bo Zhang
Int. J. Mol. Sci. 2024, 25(23), 13215; https://doi.org/10.3390/ijms252313215 - 9 Dec 2024
Viewed by 326
Abstract
Antlers are the sole mammalian organs capable of continuous regeneration. This distinctive feature has evolved into various biomedical models. Research on mechanisms of antler growth, development, and ossification provides valuable insights for limb regeneration, cartilage-related diseases, and cancer mechanisms. Here, ribonucleic acid sequencing [...] Read more.
Antlers are the sole mammalian organs capable of continuous regeneration. This distinctive feature has evolved into various biomedical models. Research on mechanisms of antler growth, development, and ossification provides valuable insights for limb regeneration, cartilage-related diseases, and cancer mechanisms. Here, ribonucleic acid sequencing (RNA-seq) and four-dimensional data-independent acquisition (4D DIA) technologies were employed to examine gene and protein expression differences among four tissue layers of the Chinese milu deer antler: reserve mesenchyme (RM), precartilage (PC), transition zone (TZ), cartilage (CA). Overall, 4611 differentially expressed genes (DEGs) and 2388 differentially expressed proteins (DEPs) were identified in the transcriptome and proteome, respectively. Among the 828 DEGs common to both omics approaches, genes from the collagen, integrin, and solute carrier families, and signaling molecules were emphasized for their roles in the regulation of antler growth, development, and ossification. Bioinformatics analysis revealed that in addition to being regulated by vascular and nerve regeneration pathways, antler growth and development are significantly influenced by numerous cancer-related signaling pathways. This indicates that antler growth mechanisms may be similar to those of cancer cell proliferation and development. This study lays a foundation for future research on the mechanisms underlying the rapid growth and ossification of antlers. Full article
(This article belongs to the Section Molecular Informatics)
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17 pages, 4230 KiB  
Review
Sugar Transport and Signaling in Shoot Branching
by Joan Doidy, Yuhui Wang, Léo Gouaille, Ingrid Goma-Louamba, Zhengrong Jiang, Nathalie Pourtau, José Le Gourrierec and Soulaiman Sakr
Int. J. Mol. Sci. 2024, 25(23), 13214; https://doi.org/10.3390/ijms252313214 - 9 Dec 2024
Viewed by 249
Abstract
The source–sink relationship is critical for proper plant growth and development, particularly for vegetative axillary buds, whose activity shapes the branching pattern and ultimately the plant architecture. Once formed from axillary meristems, axillary buds remain dormant or become active to grow into new [...] Read more.
The source–sink relationship is critical for proper plant growth and development, particularly for vegetative axillary buds, whose activity shapes the branching pattern and ultimately the plant architecture. Once formed from axillary meristems, axillary buds remain dormant or become active to grow into new branches. This transition is notably driven by the regulation of the bud sink strength, which is reflected in the ability to unload, metabolize and store photoassimilates. Plants have so far developed two main mechanisms for unloading sugars (sucrose) towards sink organs, a symplasmic pathway and an apoplasmic pathway, but so far limited investigations have been reported about the modes of sugar uptake during the transition from the dormant to the active outgrowth state of the bud. The available data indicate that the switch from dormant bud to active outgrowing state, requires sugar and is shortly preceded by an increase in bud metabolic activity and a remobilization of the stem starch reserves in favor of growing buds. This activation of the bud sink strength is accompanied by an up-regulation of the main markers of apoplasmic unloading, such as sugar transporters (sucrose transporters—SUTs; sugar will eventually be exported transporters—SWEETs), sucrose hydrolyzing enzymes (cell wall invertase—CWINV) and sugar metabolic pathways (glycolysis/tricarboxylic cycle—TCA; oxidative pentose phosphate pathway—OPPP). As these results are limited to a few species, they are not sufficient to provide a complete and accurate picture of the mode(s) of sugar unloading toward axillary buds and deserve to be complemented by additional studies in a wide variety of plants using systems integration, combining genetic, molecular and immunolocalization approaches. Altogether, we discuss here how sugar is a systemic regulator of shoot branching, acting both as an energy-rich molecule and a signaling entity in the establishment of the bud sink strength. Full article
(This article belongs to the Special Issue Sugar Signaling in Plants and Its Interaction with Phytohormones)
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16 pages, 343 KiB  
Review
A Diagnostic Approach in Large B-Cell Lymphomas According to the Fifth World Health Organization and International Consensus Classifications and a Practical Algorithm in Routine Practice
by Magda Zanelli, Francesca Sanguedolce, Maurizio Zizzo, Stefano Ricci, Alessandra Bisagni, Andrea Palicelli, Valentina Fragliasso, Benedetta Donati, Giuseppe Broggi, Ioannis Boutas, Nektarios Koufopoulos, Moira Foroni, Francesca Coppa, Andrea Morini, Paola Parente, Valeria Zuccalà, Rosario Caltabiano, Massimiliano Fabozzi, Luca Cimino, Antonino Neri and Stefano Ascaniadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2024, 25(23), 13213; https://doi.org/10.3390/ijms252313213 - 9 Dec 2024
Viewed by 250
Abstract
In this article, we provide a review of large B-cell lymphomas (LBCLs), comparing the recently published fifth edition of the WHO classification and the International Consensus Classification (ICC) on hematolymphoid tumors. We focus on updates in the classification of LBCL, an heterogeneous group [...] Read more.
In this article, we provide a review of large B-cell lymphomas (LBCLs), comparing the recently published fifth edition of the WHO classification and the International Consensus Classification (ICC) on hematolymphoid tumors. We focus on updates in the classification of LBCL, an heterogeneous group of malignancies with varying clinical behaviors and different pathological and molecular features, providing a comparison between the two classifications. Besides the well-recognized diagnostic role of clinical, morphological and immunohistochemical data, both classifications recognize the ever-growing impact of molecular data in the diagnostic work-up of some entities. The main aim is to offer a guide for clinicians and pathologists on how the new classifications can be applied to LBCL diagnosis in routine practice. In the first part of the paper, we review the following categories: LBLs transformed from indolent B-cell lymphomas, diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), double-hit/triple-hit lymphomas (DH/TH), high-grade large B-cell lymphoma, not otherwise specified (HGBCL, NOS), LBCL with IRF4 rearrangement, Burkitt lymphoma (BL) and HGBCL/LBCL with 11q aberration, focusing on the differences between the two classifications. In the second part of the paper, we provide a practical diagnostic algorithm when facing LBCLs in routine daily practice. Full article
(This article belongs to the Special Issue From Diagnosis to Treatment of Haematological Neoplasms)
16 pages, 2198 KiB  
Article
Inhibitory Effects of Gliadin Hydrolysates on BACE1 Expression and APP Processing to Prevent Aβ Aggregation
by Chin-Yu Lin, Cheng-Hong Hsieh, Pei-Yu Lai, Ching-Wei Huang, Yung-Hui Chung, Shang-Ming Huang and Kuo-Chiang Hsu
Int. J. Mol. Sci. 2024, 25(23), 13212; https://doi.org/10.3390/ijms252313212 - 9 Dec 2024
Viewed by 288
Abstract
Alzheimer’s disease (AD), a leading neurodegenerative disorder, is closely associated with the accumulation of amyloid-beta (Aβ) peptides in the brain. The enzyme β-secretase (BACE1), pivotal in Aβ production, represents a promising therapeutic target for AD. While bioactive peptides derived from food protein hydrolysates [...] Read more.
Alzheimer’s disease (AD), a leading neurodegenerative disorder, is closely associated with the accumulation of amyloid-beta (Aβ) peptides in the brain. The enzyme β-secretase (BACE1), pivotal in Aβ production, represents a promising therapeutic target for AD. While bioactive peptides derived from food protein hydrolysates have neuroprotective properties, their inhibitory effects on BACE1 remain largely unexplored. In this study, we evaluated the inhibitory potential of protein hydrolysates from gliadin, whey, and casein proteins prepared using bromelain, papain, and thermolysin. Through in vitro and cellular assays, bromelain-hydrolyzed gliadin (G-Bro) emerged as the most potent BACE1 inhibitor, with an IC50 of 0.408 mg/mL. G-Bro significantly reduced BACE1 expression and amyloid precursor protein (APP) processing in N2a/PS/APP cell cultures, suggesting its potential to attenuate Aβ aggregation. The unique peptide profile of G-Bro likely contributes to its inhibitory effect, with proline residues disrupting β-sheets, lysine residues introducing positive charges that hinder aggregation, hydrophobic residues stabilizing binding interactions, and glutamine residues enhancing solubility and stability. These findings highlight gliadin hydrolysates, particularly G-Bro, as potential natural BACE1 inhibitors with applications in dietary interventions for AD prevention. However, further studies are warranted to elucidate specific peptide interactions and their bioactivity in neural pathways to better understand their therapeutic potential. Full article
(This article belongs to the Special Issue New Insights into Bioactive Peptides: Design, Synthesis, Structure-Activity Relationship (2nd Edition))
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11 pages, 1321 KiB  
Article
Possible Impact of Peripheral Inflammatory Factors and Interleukin-1β (IL-1β) on Cognitive Functioning in Progressive Supranuclear Palsy–Richardson Syndrome (PSP-RS) and Progressive Supranuclear Palsy–Predominant Parkinsonism (PSP-P)
by Patryk Chunowski, Dagmara Otto-Ślusarczyk, Karolina Duszyńska-Wąs, Agnieszka Drzewińska, Andrzej Załęski, Natalia Madetko-Alster, Alicja Wiercińska-Drapało, Marta Struga and Piotr Alster
Int. J. Mol. Sci. 2024, 25(23), 13211; https://doi.org/10.3390/ijms252313211 - 9 Dec 2024
Viewed by 247
Abstract
Progressive supranuclear palsy (PSP) is a tauopathic atypical parkinsonian syndrome. Recent studies suggest that inflammation may play a role in PSP pathogenesis, highlighting markers like the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and cytokines such as IL-1β and IL-6. This study aimed to [...] Read more.
Progressive supranuclear palsy (PSP) is a tauopathic atypical parkinsonian syndrome. Recent studies suggest that inflammation may play a role in PSP pathogenesis, highlighting markers like the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and cytokines such as IL-1β and IL-6. This study aimed to assess the relationship between peripheral inflammatory markers and psychological abnormalities in PSP-RS and PSP-P patients. The study included 24 participants: 12 with PSP-RS, 12 with PSP-P, and 12 controls. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA); however, the executive functions were evaluated using the Frontal Assessment Battery (FAB), while inflammatory markers such as IL-1β, IL6, NLR, and PLR were measured. The parameter correlation was executed using Spearman’s correlation (rs). The analysis revealed significant negative correlations between NLR and MoCA (rs = −0.48), as well as between PLR and MoCA (rs = −0.60). The negative correlation between IL-1β and MoCA was statistically significant but relatively weak. This study highlights the relevance of inflammatory markers such as NLR and PLR in reflecting cognitive decline in PSP patients, with IL-1β potentially playing a protective role in cognitive function. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 3rd Edition)
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13 pages, 6090 KiB  
Article
Mitigation of Atherosclerotic Vascular Damage and Cognitive Improvement Through Mesenchymal Stem Cells in an Alzheimer’s Disease Mouse Model
by Woong Jin Lee, Kyoung Joo Cho and Gyung Whan Kim
Int. J. Mol. Sci. 2024, 25(23), 13210; https://doi.org/10.3390/ijms252313210 - 9 Dec 2024
Viewed by 314
Abstract
Alzheimer’s disease (AD) is a neurodegenerative condition characterized by progressive memory loss and other cognitive disturbances. Patients with AD can be vulnerable to vascular damage, and damaged vessels can lead to cognitive impairment. Mesenchymal stem cell (MSC) treatment has shown potential in ameliorating [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative condition characterized by progressive memory loss and other cognitive disturbances. Patients with AD can be vulnerable to vascular damage, and damaged vessels can lead to cognitive impairment. Mesenchymal stem cell (MSC) treatment has shown potential in ameliorating AD pathogenesis, but its effect on vascular function remains unclear. This study aimed to improve cognitive function by alleviating atherosclerosis-induced vessel damage using MSCs in mice with a genetic AD background. In this study, a 5xFAD mouse model of AD was used, and atherosclerotic vessel damage was induced by high-fat diets (HFDs). MSCs were injected into the tail vein along with mannitol in 5xFAD mice on an HFD. MSCs were detected in the brain, and vascular damage was improved following MSC treatment. Behavioral tests showed that MSCs enhanced cognitive function, as measured by the Y-maze and passive avoidance tests. Additionally, muscle strength measured by the rotarod test was also increased by MSCs in AD mice with vessel damage induced by HFDs. Overall, our results suggest that stem cells can alleviate vascular damage caused by metabolic diseases, including HFDs, and vascular disease in individuals carrying the AD gene. Consequently, this alleviates cognitive decline related to vascular dementia symptoms. Full article
(This article belongs to the Special Issue New Trends in Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics: 2nd Edition)
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27 pages, 2322 KiB  
Review
The Emerging Role of p21 in Diabetes and Related Metabolic Disorders
by Omar Elmitwalli, Radwan Darwish, Lana Al-Jabery, Ahmed Algahiny, Sornali Roy, Alexandra E. Butler and Ammar S. Hasan
Int. J. Mol. Sci. 2024, 25(23), 13209; https://doi.org/10.3390/ijms252313209 - 9 Dec 2024
Viewed by 307
Abstract
In the context of cell cycle inhibition, anti-proliferation, and the dysregulation observed in certain cancer pathologies, the protein p21 assumes a pivotal role. p21 links DNA damage responses to cellular processes such as apoptosis, senescence, and cell cycle arrest, primarily functioning as a [...] Read more.
In the context of cell cycle inhibition, anti-proliferation, and the dysregulation observed in certain cancer pathologies, the protein p21 assumes a pivotal role. p21 links DNA damage responses to cellular processes such as apoptosis, senescence, and cell cycle arrest, primarily functioning as a regulator of the cell cycle. However, accumulating empirical evidence suggests that p21 is both directly and indirectly linked to a number of different metabolic processes. Intriguingly, recent investigations indicate that p21 significantly contributes to the pathogenesis of diabetes. In this review, we present a comprehensive evaluation of the scientific literature regarding the involvement of p21 in metabolic processes, diabetes etiology, pancreatic function, glucose homeostasis, and insulin resistance. Furthermore, we provide an encapsulated overview of therapies that target p21 to alleviate metabolic disorders. A deeper understanding of the complex interrelationship between p21 and diabetes holds promise for informing current and future therapeutic strategies to address this rapidly escalating health crisis. Full article
(This article belongs to the Special Issue Diabetes: Advances of Molecular Research)
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14 pages, 1164 KiB  
Review
Microbiome-Based Therapeutics for Insomnia
by Chenyu Li, Sizhe Chen, Yun Wang and Qi Su
Int. J. Mol. Sci. 2024, 25(23), 13208; https://doi.org/10.3390/ijms252313208 - 9 Dec 2024
Viewed by 534
Abstract
Insomnia poses considerable risks to both physical and mental health, leading to cognitive impairment, weakened immune function, metabolic dysfunction, cardiovascular issues, and reduced quality of life. Given the significant global increase in insomnia and the growing scientific evidence connecting gut microbiota to this [...] Read more.
Insomnia poses considerable risks to both physical and mental health, leading to cognitive impairment, weakened immune function, metabolic dysfunction, cardiovascular issues, and reduced quality of life. Given the significant global increase in insomnia and the growing scientific evidence connecting gut microbiota to this disorder, targeting gut microbiota as an intervention for insomnia has gained popularity. In this review, we summarize current microbiome-based therapeutics for insomnia, including dietary modifications; probiotic, prebiotic, postbiotic, and synbiotic interventions; and fecal microbiota transplantation. Moreover, we assess the capabilities and weaknesses of these technologies to offer valuable insights for future studies. Full article
(This article belongs to the Special Issue Current Research on the Role of the Gut Microbiota in Human Diseases and Health)
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17 pages, 4210 KiB  
Review
Diacylglycerol Kinases and Its Role in Lipid Metabolism and Related Diseases
by Yishi Liu, Zehui Yang, Xiaoman Zhou, Zijie Li and Nakanishi Hideki
Int. J. Mol. Sci. 2024, 25(23), 13207; https://doi.org/10.3390/ijms252313207 - 9 Dec 2024
Viewed by 651
Abstract
Lipids are essential components of eukaryotic membranes, playing crucial roles in membrane structure, energy storage, and signaling. They are predominantly synthesized in the endoplasmic reticulum (ER) and subsequently transported to other organelles. Diacylglycerol kinases (DGKs) are a conserved enzyme family that phosphorylate diacylglycerol [...] Read more.
Lipids are essential components of eukaryotic membranes, playing crucial roles in membrane structure, energy storage, and signaling. They are predominantly synthesized in the endoplasmic reticulum (ER) and subsequently transported to other organelles. Diacylglycerol kinases (DGKs) are a conserved enzyme family that phosphorylate diacylglycerol (DAG) to produce phosphatidic acid (PA), both of which are key intermediates in lipid metabolism and second messengers involved in numerous cellular processes. Dysregulation of DGK activity is associated with several diseases, including cancer and metabolic disorders. In this review, we provide a comprehensive overview of DGK types, functions, cellular localization, and their potential as therapeutic targets. We also discuss DGKs’ roles in lipid metabolism and their physiological functions and related diseases. Full article
(This article belongs to the Section Biochemistry)
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18 pages, 2146 KiB  
Article
Maternal Metal Ion Status Along Pregnancy and Perinatal Outcomes in a Group of Mexican Women
by Johana Vásquez-Procopio, Johnatan Torres-Torres, Elodia Rojas-Lima, Salvador Espino-y-Sosa, Juan Mario Solis-Paredes, Maribel Sánchez-Martínez, Mari-Cruz Tolentino-Dolores, Otilia Perichart-Perera, Fanis Missirlis and Guadalupe Estrada-Gutierrez
Int. J. Mol. Sci. 2024, 25(23), 13206; https://doi.org/10.3390/ijms252313206 - 8 Dec 2024
Viewed by 824
Abstract
Pregnancy increases the demand for essential metal ions to support fetal development, making the maternal metal ion status a critical determinant of perinatal outcomes. This prospective cohort study examined changes in metal ion levels across the three trimesters, evaluated the influence of preexisting [...] Read more.
Pregnancy increases the demand for essential metal ions to support fetal development, making the maternal metal ion status a critical determinant of perinatal outcomes. This prospective cohort study examined changes in metal ion levels across the three trimesters, evaluated the influence of preexisting metabolic conditions on the metal ion status, and assessed the associations between maternal metal ion levels and perinatal outcomes in 206 pregnant women from the Biochemical and Epigenetic Origin of Overweight and Obesity (OBESO) cohort receiving care at the Instituto Nacional de Perinatología in Mexico City from 2017 to 2020. Six essential metal ions (iron, zinc, copper, calcium, magnesium, and phosphorus) were measured in blood samples using inductively coupled plasma optic emission spectrometry. Significant variations in the metal ion levels were observed across the trimesters, with notable decreases in iron and magnesium and increases in copper as pregnancies progressed. Maternal hypothyroidism was associated with significantly low levels of zinc and magnesium during pregnancy. Regression analyses revealed robust associations between maternal metal ion levels and perinatal outcomes. For instance, declining magnesium levels as pregnancies progressed were positively associated with gestational diabetes (OR: 2.92, p = 0.04; OR: 2.72, p = 0.03). The maternal metal ion status significantly influences perinatal outcomes. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Nutrition and Health)
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17 pages, 14804 KiB  
Article
A Role for Periostin Pathological Variants and Their Interaction with HSP70-1a in Promoting Pancreatic Cancer Progression and Chemoresistance
by Yasuo Tsunetoshi, Fumihiro Sanada, Yuko Kanemoto, Kana Shibata, Atsushi Masamune, Yoshiaki Taniyama, Koichi Yamamoto and Ryuichi Morishita
Int. J. Mol. Sci. 2024, 25(23), 13205; https://doi.org/10.3390/ijms252313205 - 8 Dec 2024
Viewed by 469
Abstract
Pancreatic ductal adenocarcinoma (PDAC) characterized by an abundant cancer stroma is an aggressive malignancy with a poor prognosis. Periostin (Pn) is a key extracellular matrix (ECM) protein in various tumor progression. Previously, we described the role of Pn alternative splicing variants (ASVs) with [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) characterized by an abundant cancer stroma is an aggressive malignancy with a poor prognosis. Periostin (Pn) is a key extracellular matrix (ECM) protein in various tumor progression. Previously, we described the role of Pn alternative splicing variants (ASVs) with specific functional features in breast cancer. Pn is known to associate with a chemoresistance of PDAC, but the functions of the Pn-ASVs remain largely unknown. In this study, we focused on physiological and pathological Pn-ASVs, and examined the characteristics of Pn-expressing cells and the difference in function of each ASV. We found that cancer-associated fibroblasts (CAFs) are a main source of Pn synthesis, which selectively secrete pathological Pn-ASVs with exon 21 both in mouse and human samples. RNA sequencing identified a gene signature of Pn-positive CAFs associated with ECM-related genes and chemokines, factors that shape the chemoresistance tumor microenvironment (TME). Additionally, only pathological Pn-ASVs interacted with heat shock protein 70-1a (HSP70-1a), leading to significant rescue of gemcitabine-induced PDAC apoptosis. In silico analysis revealed that the presence or absence of exon 21 changes the tertiary structure of Pn and the binding sites for HSP70-1a. Altogether, Pn-ASVs with exon 21 secreted from CAFs play a key role in supporting tumor growth by interacting with cancer cell-derived HSP70-1a, indicating that Pn-ASVs with exon 21 might be a potential therapeutic and diagnostic target in PDAC patients with rich stroma. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Targets for Treatment and Drug Delivery in Tumors)
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16 pages, 6319 KiB  
Article
Application of a Screen-Printed Ion-Selective Electrode Based on Hydrophobic Ti3C2/AuNPs for K+ Determination Across Variable Temperatures
by Zhixue Yu, Hui Wang, Yue He, Dongfei Chen, Ruipeng Chen, Xiangfang Tang, Mengting Zhou, Junhu Yao and Benhai Xiong
Int. J. Mol. Sci. 2024, 25(23), 13204; https://doi.org/10.3390/ijms252313204 - 8 Dec 2024
Viewed by 548
Abstract
Monitoring potassium ion (K+) concentration is essential in veterinary medicine, particularly for preventing hypokalemia in dairy cows, which can severely impact their health and productivity. While traditional laboratory methods like atomic absorption spectrometry are accurate, they are also time-consuming and require [...] Read more.
Monitoring potassium ion (K+) concentration is essential in veterinary medicine, particularly for preventing hypokalemia in dairy cows, which can severely impact their health and productivity. While traditional laboratory methods like atomic absorption spectrometry are accurate, they are also time-consuming and require complex sample preparation. Ion-selective electrodes (ISEs) provide an alternative that is faster and more suitable for field measurements, but their performance is often compromised under variable temperature conditions, leading to inaccuracies. To address this, we developed a novel screen-printed ion-selective electrode (SPE) with hydrophobic Ti3C2 Mxene and gold nanoparticles (AuNPs), integrated with a temperature sensor. This design improves stability and accuracy across fluctuating temperatures by preventing water layer formation and enhancing conductivity. The sensor was validated across temperatures from 5 °C to 45 °C, achieving a linear detection range of 10−⁵ to 10−1 M and a response time of approximately 15 s. It also demonstrated excellent repeatability, selectivity, and stability, making it a robust tool for K+ monitoring in complex environments. This advancement could lead to broader applications in other temperature-sensitive analytical fields. Full article
(This article belongs to the Special Issue Advances in Electrochemistry of Metal Nanomaterials)
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13 pages, 2635 KiB  
Article
Development of a Multiplex RT–qPCR Method for the Identification and Lineage Typing of Porcine Reproductive and Respiratory Syndrome Virus
by Chunhao Tao, Xizhou Zhu, Ying Huang, Weifeng Yuan, Zhen Wang, Hongfei Zhu and Hong Jia
Int. J. Mol. Sci. 2024, 25(23), 13203; https://doi.org/10.3390/ijms252313203 - 8 Dec 2024
Viewed by 423
Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) is the pathogen that causes porcine reproductive and respiratory syndrome (PRRS), leading to abortion of sows and the manifestation of respiratory diseases in piglets. PRRSV strains are categorized into two distinct genotypes: PRRSV–1 and PRRSV–2. PRRSV–2 [...] Read more.
Porcine reproductive and respiratory syndrome virus (PRRSV) is the pathogen that causes porcine reproductive and respiratory syndrome (PRRS), leading to abortion of sows and the manifestation of respiratory diseases in piglets. PRRSV strains are categorized into two distinct genotypes: PRRSV–1 and PRRSV–2. PRRSV–2 can be further classified into several lineages, including sub–lineage 1.8 (NADC30–like), sub–lineage 1.5 (NADC34–like), lineage 8 (HP–PRRSV–like), lineage 5 (VR–2332–like), and lineage 3 (QYYZ–like), all of which are prevalent in China. In order to identify PRRSV–1 and PRRSV–2, two primer–probe combinations were designed, targeting the M gene. In order to further differentiate the five lineages of PRRSV–2, another five primer–probe combinations were designed, targeting the Nsp2 gene. A TaqMan–based multiplex RT–qPCR assay was subsequently developed, integrating the aforementioned seven sets into two primer pools. Following the optimization of primer concentration and annealing temperature, a comprehensive evaluation was conducted to assess the assay’s amplification efficiency, specificity, repeatability, and sensitivity. The developed multiplex RT–qPCR method exhibited excellent repeatability, with coefficients of variation (CVs) less than 2.12%. The detection limits for all seven targets were found to be less than 5 copies/μL. Ultimately, the method was utilized for the detection of a total of 1009 clinical samples, with a PRRSV–positive rate of 7.63% (77/1009). Specifically, the reference method was utilized to further confirm the status of the 77 PRRSV–positive samples and another 27 samples suspected of PRRSV infection. The sensitivity of the method was 97.40% (75/77), and the specificity was 96.30% (26/27), resulting in an overall coincidence rate of 97.12% (101/104). All the PRRSV–positive samples were typed as NADC30–like strains, and the accuracy of this typing was further confirmed by Sanger sequencing. In conclusion, A one–step multiplex RT–qPCR method was successfully constructed, evaluated, and applied to detect clinical samples. The assay provides an easy–to–operate, time–saving, and highly efficient way for the quick identification of PRRSV and simultaneous detection of five PRRSV–2 lineages prevalent in China. The method could offer guidance for PRRSV prevention and control measures. Full article
(This article belongs to the Special Issue Viral Infections: Physiology, Pathophysiology, Pathogenesis, Diagnosis and Treatment)
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19 pages, 3637 KiB  
Article
Valorization of Hom Thong Banana Peel (Musa sp., AAA Group) as an Anti-Melanogenic Agent Through Inhibition of Pigmentary Genes and Molecular Docking Study
by Pichchapa Linsaenkart, Wipawadee Yooin, Supat Jiranusornkul, Korawan Sringarm, Chaiwat Arjin, Pornchai Rachtanapun, Kittisak Jantanasakulwong, Juan M. Castagnini and Warintorn Ruksiriwanich
Int. J. Mol. Sci. 2024, 25(23), 13202; https://doi.org/10.3390/ijms252313202 - 8 Dec 2024
Viewed by 493
Abstract
Prolonged and unprotected exposure to the environment explicitly influences the development of hyperpigmented lesions. The enzyme tyrosinase (TYR) is a key target for regulating melanin synthesis. Several bioactive compounds derived from plant extracts have been found to possess potent anti-melanogenesis properties against TYR. [...] Read more.
Prolonged and unprotected exposure to the environment explicitly influences the development of hyperpigmented lesions. The enzyme tyrosinase (TYR) is a key target for regulating melanin synthesis. Several bioactive compounds derived from plant extracts have been found to possess potent anti-melanogenesis properties against TYR. In particular, the potential of banana peels from various varieties has garnered interest due to their application in skin hyperpigmentation treatment. A molecular docking study demonstrated interactions between rosmarinic acid, which is predominantly found in all Hom Thong peel extracts, and the active site of TYR (PDB ID: 2Y9X) at residues HIS263, VAL283, SER282, and MET280, with the lowest binding energy of −5.05 kcal/mol, showing the strongest interaction. Additionally, Hom Thong banana peels are rich in phenolic compounds that could inhibit melanin content and tyrosinase activity in both human and mouse melanoma cells. These effects may be attributed to the suppression of gene expression related to melanogenesis, including the regulator gene MITF and pigmentary genes TYR, TRP-1, and DCT, indicating effects comparable to those of the standard treatment groups with arbutin and kojic acid. Our findings indicated the potential of Hom Thong peel extracts as anti-melanogenic agents. Full article
(This article belongs to the Special Issue Molecular Studies of Natural Compounds and Plant Extracts—2nd Edition)
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36 pages, 15053 KiB  
Article
Network Pharmacology, Molecular Docking, and In Vitro Insights into the Potential of Mitragyna speciosa for Alzheimer’s Disease
by Rahni Hossain, Kunwadee Noonong, Manit Nuinoon, Hideyuki J. Majima, Komgrit Eawsakul, Pradoldej Sompol, Md. Atiar Rahman and Jitbanjong Tangpong
Int. J. Mol. Sci. 2024, 25(23), 13201; https://doi.org/10.3390/ijms252313201 - 8 Dec 2024
Viewed by 453
Abstract
Mitragyna speciosa Korth. Havil (MS) has a traditional use in relieving pain, managing hypertension, treating cough, and diarrhea, and as a morphine substitute in addiction recovery. Its potential in addressing Alzheimer’s disease (AD), a neurodegenerative condition with no effective treatments, is under investigation. [...] Read more.
Mitragyna speciosa Korth. Havil (MS) has a traditional use in relieving pain, managing hypertension, treating cough, and diarrhea, and as a morphine substitute in addiction recovery. Its potential in addressing Alzheimer’s disease (AD), a neurodegenerative condition with no effective treatments, is under investigation. This study aims to explore MS mechanisms in treating AD through network pharmacology, molecular docking, and in vitro studies. Using network pharmacology, we identified 19 MS components that may affect 60 AD-related targets. The compound–target network highlighted significant interactions among 60 nodes and 470 edges, with an average node degree of 15.7. The KEGG enrichment analysis revealed Alzheimer’s disease (hsa05010) as a relevant pathway. We connected 20 targets to tau and β-amyloid proteins through gene expression data from the AlzData database. Docking studies demonstrated high binding affinities of MS compounds like acetylursolic acid, beta-sitosterol, isomitraphylline, and speciophylline to AD-related proteins, such as AKT1, GSK3B, NFκB1, and BACE1. In vitro studies showed that ethanolic (EE), distilled water (DWE), and pressurized hot water (PHWE) extracts of MS-treated 100 μM H2O2-induced SH-SY5Y cells significantly reduced oxidative damage. This research underscores the multi-component, multi-target, and multi-pathway effects of MS on AD, providing insights for future research and potential clinical applications. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Herbal Compounds in Neuroprotection)
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Article
Biochip-Based Identification of Mycobacterial Species in Russia
by Danila Zimenkov, Vyacheslav Zhuravlev, Anastasia Ushtanit, Marina Filippova, Uliana Semenova, Natalia Solovieva, Maria Sviridenko, Anastasia Khakhalina, Svetlana Safonova, Marina Makarova, Elizaveta Gordeeva, Elena Guselnikova, Yakov Schwartz, Natalia Stavitskaya and Peter Yablonsky
Int. J. Mol. Sci. 2024, 25(23), 13200; https://doi.org/10.3390/ijms252313200 - 8 Dec 2024
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Abstract
Infections caused by nontuberculous mycobacteria (NTM) are rising globally throughout the world. The number of species isolated from clinical samples is steadily growing, which demands the implementation of a robust diagnostic method with wide specificity. This study was carried out in in 2022–2024 [...] Read more.
Infections caused by nontuberculous mycobacteria (NTM) are rising globally throughout the world. The number of species isolated from clinical samples is steadily growing, which demands the implementation of a robust diagnostic method with wide specificity. This study was carried out in in 2022–2024 in three clinical antituberculosis centers in the biggest cities of Russia: Moscow, Saint Petersburg, and Novosibirsk. We developed the DNA hybridization assay ‘Myco-biochip’ that allows the identification of 79 mycobacterial species and analyzed 3119 samples from 2221 patients. Sixty-eight mycobacterial species were identified in clinics, including the three novel species phylogenetically related to M. duvalii, M. lentiflavum, and M. talmoniae. The identification of a close relative of M. talmoniae adds to the existence of separate clade between M. terrae, M. triviale complexes and other slow-growing Mycobacteria, which supports the thesis against the splitting of Mycobacteria into five separate genera. Adding to the list of potentially pathogenic species, we identified M. adipatum and M. terramassiliense, which were previously described as natural habitats. The diversity of acid-fast bacilli identified in TB-suspected persons was not limited to the Mycobacteria genus and also includes species from genera Nocardia, Gordonia, Corynebacterium, Tsukamurella, and Rhodococcus of the order Mycobacteriales. The revealed bacterial diversity in patients with suspected NTM-diseases requires the implementation of relevant species identification assays as the first step in the laboratory diagnostic pipeline. Full article
(This article belongs to the Special Issue Advances in Molecular Biology on Mycobacteria)
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