Biomolecules

12 pages, 3403 KiB

Open AccessArticle

L-Cysteine Upregulates Testosterone Biosynthesis and Blood–Testis Barrier Genes in Cultured Human Leydig Cells and THP-1 Monocytes and Increases Testosterone Secretion in Human Leydig Cells

by Jeffrey Justin Margret and Sushil K. Jain

Biomolecules 2024, 14(9), 1171; https://doi.org/10.3390/biom14091171 - 18 Sep 2024

Abstract

Leydig cells are the primary source of testosterone or androgen production in male mammals. The blood–testis barrier (BTB) maintains structural integrity and safeguards germ cells from harmful substances by blocking their entry into the seminiferous tubules. L-cysteine is essential to the production of [...] Read more.

Leydig cells are the primary source of testosterone or androgen production in male mammals. The blood–testis barrier (BTB) maintains structural integrity and safeguards germ cells from harmful substances by blocking their entry into the seminiferous tubules. L-cysteine is essential to the production of glutathione, a powerful antioxidant crucial to protecting against oxidative stress-induced damage. Animal studies have demonstrated the protective effect of L-cysteine in preventing testicular damage caused by chemicals or radiation. This study examines whether L-cysteine enhances the expression of testosterone biosynthesis and the BTB genes in human Leydig cells and THP-1 monocytes. The Leydig cells and THP-1 monocytes were treated with L-cysteine for 24 h. RNA was extracted following treatment, and the gene expression was analyzed using quantitative RT-PCR. Testosterone levels in the cell supernatant were measured using an ELISA kit. L-cysteine treatment in Leydig cells significantly upregulated the expression of CYP11A1 (p = 0.03) and the BTB genes CLDN1 (p = 0.03), CLDN11 (p = 0.02), and TJP1 (p = 0.02). Similarly, L-cysteine significantly upregulated the expression of CYP11A1 (p = 0.03) and CYP19A1 (p < 0.01), and the BTB genes CLDN1 (p = 0.04), CLDN2 (p < 0.01), CLDN4 (p < 0.01), CLDN11 (p < 0.01), and TJP1 (p = 0.03) in THP-1 monocytes. Further, L-cysteine supplementation increased the testosterone secretion levels in human Leydig cells. The findings suggest that L-cysteine supplementation could be used as an adjuvant therapy to promote the integrity of the BTB genes, testosterone biosynthesis and secretion, and the maintenance of testicular functions, which in turn mitigates the risk of male infertility. Full article

(This article belongs to the Section Molecular Reproduction)

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28 pages, 3780 KiB

Open AccessArticle

Myco-Biosynthesis of Silver Nanoparticles, Optimization, Characterization, and In Silico Anticancer Activities by Molecular Docking Approach against Hepatic and Breast Cancer

by Noura El-Ahmady El-Naggar, Nada S. Shweqa, Hala M. Abdelmigid, Amal A. Alyamani, Naglaa Elshafey, Hoda M. Soliman and Yasmin M. Heikal

Biomolecules 2024, 14(9), 1170; https://doi.org/10.3390/biom14091170 - 18 Sep 2024

Abstract

This study explored the green synthesis of silver nanoparticles (AgNPs) using the extracellular filtrate of Fusarium oxysporum as a reducing agent and evaluated their antitumor potential through in vitro and in silico approaches. The biosynthesis of AgNPs was monitored by visual observation of [...] Read more.

This study explored the green synthesis of silver nanoparticles (AgNPs) using the extracellular filtrate of Fusarium oxysporum as a reducing agent and evaluated their antitumor potential through in vitro and in silico approaches. The biosynthesis of AgNPs was monitored by visual observation of the color change and confirmed by UV–Vis spectroscopy, revealing a characteristic peak at 418 nm. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses showed spherical nanoparticles ranging from 6.53 to 21.84 nm in size, with stable colloidal behavior and a negative zeta potential of −15.5 mV. Selected area electron diffraction (SAED) confirmed the crystalline nature of the AgNPs, whereas energy-dispersive X-ray (EDX) indicated the presence of elemental silver at 34.35%. A face-centered central composite design (FCCD) was employed to optimize the biosynthesis process, yielding a maximum AgNPs yield of 96.77 µg/mL under the optimized conditions. The antitumor efficacy of AgNPs against MCF-7 and HepG2 cancer cell lines was assessed, with IC₅₀ values of 35.4 µg/mL and 7.6 µg/mL, respectively. Molecular docking revealed interactions between Ag metal and key amino acids of BCL-2 (B-cell lymphoma-2) and FGF19 (fibroblast growth factor 19), consistent with in vitro data. These findings highlight the potential of biologically derived AgNPs as promising therapeutic agents for cancer treatment and demonstrate the utility of these methods for understanding the reaction mechanisms and optimizing nanomaterial synthesis. Full article

20 pages, 8056 KiB

Open AccessArticle

Exploration into Galectin-3 Driven Endocytosis and Lattices

by Massiullah Shafaq-Zadah, Estelle Dransart, Satish Kailasam Mani, Julio Lopes Sampaio, Lydia Bouidghaghen, Ulf J. Nilsson, Hakon Leffler and Ludger Johannes

Biomolecules 2024, 14(9), 1169; https://doi.org/10.3390/biom14091169 - 18 Sep 2024

Abstract

Essentially all plasma membrane proteins are glycosylated, and their activity is regulated by tuning their cell surface dynamics. This is achieved by glycan-binding proteins of the galectin family that either retain glycoproteins within lattices or drive their endocytic uptake via the clathrin-independent glycolipid-lectin [...] Read more.

Essentially all plasma membrane proteins are glycosylated, and their activity is regulated by tuning their cell surface dynamics. This is achieved by glycan-binding proteins of the galectin family that either retain glycoproteins within lattices or drive their endocytic uptake via the clathrin-independent glycolipid-lectin (GL-Lect) mechanism. Here, we have used immunofluorescence-based assays to analyze how lattice and GL-Lect mechanisms affect the internalization of the cell adhesion and migration glycoprotein α₅β₁ integrin. In retinal pigment epithelial (RPE-1) cells, internalized α₅β₁ integrin is found in small peripheral endosomes under unperturbed conditions. Pharmacological compounds were used to competitively inhibit one of the galectin family members, galectin-3 (Gal3), or to inhibit the expression of glycosphingolipids, both of which are the fabric of the GL-Lect mechanism. We found that under acute inhibition conditions, endocytic uptake of α₅β₁ integrin was strongly reduced, in agreement with previous studies on the GL-Lect driven internalization of the protein. In contrast, upon prolonged inhibitor treatment, the uptake of α₅β₁ integrin was increased, and the protein was now internalized by alternative pathways into large perinuclear endosomes. Our findings suggest that under these prolonged inhibitor treatment conditions, α₅β₁ integrin containing galectin lattices are dissociated, leading to an altered endocytic compartmentalization. Full article

(This article belongs to the Special Issue Cell Biology and Biomedical Application of Galectins)

13 pages, 2931 KiB

Open AccessArticle

Schild Analysis of the Interaction between Parthenolide and Cocaine Suggests an Allosteric Relationship for Their Effects on Planarian Motility

by Jyothi Kakuturu, Mary O’Brien and Oné R. Pagán

Biomolecules 2024, 14(9), 1168; https://doi.org/10.3390/biom14091168 - 18 Sep 2024

Abstract

The freshwater planarian is an emerging animal model in neuroscience due to its centralized nervous system that closely parallels closely parallels the nervous system of vertebrates. Cocaine, an abused drug, is the ‘founding member’ of the local anesthetic family. Parthenolide, a sesquiterpene lactone, [...] Read more.

The freshwater planarian is an emerging animal model in neuroscience due to its centralized nervous system that closely parallels closely parallels the nervous system of vertebrates. Cocaine, an abused drug, is the ‘founding member’ of the local anesthetic family. Parthenolide, a sesquiterpene lactone, acts as a behavioral and physiological antagonist of cocaine in planarians and rats, respectively. Previous work from our laboratory showed that both parthenolide and cocaine reduced planarian motility and that parthenolide reversed the cocaine-induced motility decrease at concentrations where parthenolide does not affect the movement of the worms. However, the exact mechanism of the cocaine/parthenolide antagonism is unknown. Here, we report the results of a Schild analysis to explore the parthenolide/cocaine relationship in the planarian Girardia tigrina. The Schild slopes of a family of concentration–response curves of parthenolide ± a single concentration of cocaine and vice versa were −0.55 and −0.36, respectively. These slopes were not statistically different from each other. Interestingly, the slope corresponding to the parthenolide ± cocaine (but not the cocaine ± parthenolide) data set was statistically different from −1. Our data suggest an allosteric relationship between cocaine and parthenolide for their effect on planarian motility. To the best of our knowledge, this is the first study about the mechanism of action of the antagonism between cocaine and parthenolide. Further studies are needed to determine the specific nature of the parthenolide/cocaine target(s) in this organism. Full article

(This article belongs to the Section Biological Factors)

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20 pages, 2080 KiB

Open AccessReview

Inhalation Anesthetics Play a Janus-Faced Role in Self-Renewal and Differentiation of Stem Cells

by Xiaotong Hao, Yuan Li, Hairong Gao, Zhilin Wang and Bo Fang

Biomolecules 2024, 14(9), 1167; https://doi.org/10.3390/biom14091167 - 18 Sep 2024

Abstract

Inhalation anesthesia stands as a pivotal modality within clinical anesthesia practices. Beyond its primary anesthetic effects, inhaled anesthetics have non-anesthetic effects, exerting bidirectional influences on the physiological state of the body and disease progression. These effects encompass impaired cognitive function, inhibition of embryonic [...] Read more.

Inhalation anesthesia stands as a pivotal modality within clinical anesthesia practices. Beyond its primary anesthetic effects, inhaled anesthetics have non-anesthetic effects, exerting bidirectional influences on the physiological state of the body and disease progression. These effects encompass impaired cognitive function, inhibition of embryonic development, influence on tumor progression, and so forth. For many years, inhaled anesthetics were viewed as inhibitors of stem cell fate regulation. However, there is now a growing appreciation that inhaled anesthetics promote stem cell biological functions and thus are now regarded as a double-edged sword affecting stem cell fate. In this review, the effects of inhaled anesthetics on self-renewal and differentiation of neural stem cells (NSCs), embryonic stem cells (ESCs), and cancer stem cells (CSCs) were summarized. The mechanisms of inhaled anesthetics involving cell cycle, metabolism, stemness, and niche of stem cells were also discussed. A comprehensive understanding of these effects will enhance our comprehension of how inhaled anesthetics impact the human body, thus promising breakthroughs in the development of novel strategies for innovative stem cell therapy approaches. Full article

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21 pages, 2421 KiB

Open AccessReview

Deciphering the Potentials of Cardamom in Cancer Prevention and Therapy: From Kitchen to Clinic

by Shabana Bano, Avisek Majumder, Ayush Srivastava and Kasturi Bala Nayak

Biomolecules 2024, 14(9), 1166; https://doi.org/10.3390/biom14091166 - 18 Sep 2024

Abstract

Cardamom (cardamum) is a spice produced from the seeds of several Elettaria and Amomum plants of the Zingiberaceae family. Cardamom has been demonstrated to offer numerous benefits, including its antioxidant, antimicrobial, anti-inflammatory, and other metabolic (anti-diabetic) properties, and its potential to reduce cancer [...] Read more.

Cardamom (cardamum) is a spice produced from the seeds of several Elettaria and Amomum plants of the Zingiberaceae family. Cardamom has been demonstrated to offer numerous benefits, including its antioxidant, antimicrobial, anti-inflammatory, and other metabolic (anti-diabetic) properties, and its potential to reduce cancer risk. Recently, researchers have extracted and tested multiple phytochemicals from cardamom to assess their potential effectiveness against various types of human malignancy. These studies have indicated that cardamom can help overcome drug resistance to standard chemotherapy and protect against chemotherapy-induced toxicity due to its scavenging properties. Furthermore, chemical compounds in cardamom, including limonene, cymene, pinene, linalool, borneol, cardamonin, indole-3-carbinol, and diindolylmethane, primarily target the programmed cell death lignin-1 gene, which is more prevalent in cancer cells than in healthy cells. This review provides the medicinal properties and pharmacological uses of cardamom, its cellular effects, and potential therapeutic uses in cancer prevention and treatment, as well as its use in reducing drug resistance and improving the overall health of cancer patients. Based on previous preclinical studies, cardamom shows significant potential as an anti-cancer agent, but further exploration for clinical use is warranted due to its diverse mechanisms of action. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

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35 pages, 5486 KiB

Open AccessReview

Complex Pathophysiology of Acute Kidney Injury (AKI) in Aging: Epigenetic Regulation, Matrix Remodeling, and the Healing Effects of H₂S

by Shreyasi Gupta, Subhadeep Mandal, Kalyan Banerjee, Hebah Almarshood, Sathnur B. Pushpakumar and Utpal Sen

Biomolecules 2024, 14(9), 1165; https://doi.org/10.3390/biom14091165 - 17 Sep 2024

Abstract

The kidney is an essential excretory organ that works as a filter of toxins and metabolic by-products of the human body and maintains osmotic pressure throughout life. The kidney undergoes several physiological, morphological, and structural changes with age. As life expectancy in humans [...] Read more.

The kidney is an essential excretory organ that works as a filter of toxins and metabolic by-products of the human body and maintains osmotic pressure throughout life. The kidney undergoes several physiological, morphological, and structural changes with age. As life expectancy in humans increases, cell senescence in renal aging is a growing challenge. Identifying age-related kidney disorders and their cause is one of the contemporary public health challenges. While the structural abnormalities to the extracellular matrix (ECM) occur, in part, due to changes in MMPs, EMMPRIN, and Meprin-A, a variety of epigenetic modifiers, such as DNA methylation, histone alterations, changes in small non-coding RNA, and microRNA (miRNA) expressions are proven to play pivotal roles in renal pathology. An aged kidney is vulnerable to acute injury due to ischemia-reperfusion, toxic medications, altered matrix proteins, systemic hemodynamics, etc., non-coding RNA and miRNAs play an important role in renal homeostasis, and alterations of their expressions can be considered as a good marker for AKI. Other epigenetic changes, such as histone modifications and DNA methylation, are also evident in AKI pathophysiology. The endogenous production of gaseous molecule hydrogen sulfide (H₂S) was documented in the early 1980s, but its ameliorative effects, especially on kidney injury, still need further research to understand its molecular mode of action in detail. H₂S donors heal fibrotic kidney tissues, attenuate oxidative stress, apoptosis, inflammation, and GFR, and also modulate the renin–angiotensin–aldosterone system (RAAS). In this review, we discuss the complex pathophysiological interplay in AKI and its available treatments along with future perspectives. The basic role of H₂S in the kidney has been summarized, and recent references and knowledge gaps are also addressed. Finally, the healing effects of H₂S in AKI are described with special emphasis on epigenetic regulation and matrix remodeling. Full article

(This article belongs to the Special Issue Homocysteine and H₂S in Health and Disease)

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13 pages, 718 KiB

Open AccessReview

Are Small Molecules Effective in Treating Inflammatory Pouch Disorders Following Ileal Pouch-Anal Anastomosis for Ulcerative Colitis? Here Is Where We Stand

by Antonietta Gerarda Gravina, Raffaele Pellegrino, Giovanna Palladino, Giuseppe Imperio, Francesco Calabrese, Andrea Pasta, Edoardo Giovanni Giannini, Alessandro Federico and Giorgia Bodini

Biomolecules 2024, 14(9), 1164; https://doi.org/10.3390/biom14091164 - 17 Sep 2024

Abstract

Ulcerative colitis (UC) management encompasses conventional and advanced treatments, including biological therapy and small molecules. Surgery, particularly in the form of ileal pouch-anal anastomosis (IPAA), is indicated in cases of refractory/severe disease. IPAA can lead to acute complications (e.g., acute pouchitis) as well [...] Read more.

Ulcerative colitis (UC) management encompasses conventional and advanced treatments, including biological therapy and small molecules. Surgery, particularly in the form of ileal pouch-anal anastomosis (IPAA), is indicated in cases of refractory/severe disease. IPAA can lead to acute complications (e.g., acute pouchitis) as well as late complications, including chronic inflammatory disorders of the pouch. Chronic pouchitis, including the antibiotic-dependent (CADP) and antibiotic-refractory (CARP) forms, represents a significant and current therapeutic challenge due to the substantial need for evidence regarding viable treatment options. Biological therapies have shown promising results, with infliximab, adalimumab, ustekinumab, and vedolizumab demonstrating some efficacy in chronic pouchitis; however, robust randomized clinical trials are only available for vedolizumab. This narrative review focuses on the evidence concerning small molecules in chronic pouchitis, specifically Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor (S1P-R) modulators. According to the preliminary studies and reports, Tofacitinib shows a potential effectiveness in CARP. Upadacitinib presents variable outcomes from the case series, necessitating further evaluation. Filgotinib and ozanimod demonstrate anecdotal efficacy. This review underscores the need for high-quality studies and real-world registries to develop robust guidelines for advanced therapies in post-IPAA inflammatory disorders, supported by vigilant clinical monitoring and ongoing education from international IBD specialist societies. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Disease)

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17 pages, 8104 KiB

Open AccessArticle

Potential Plasma Proteins (LGALS9, LAMP3, PRSS8 and AGRN) as Predictors of Hospitalisation Risk in COVID-19 Patients

by Thomas McLarnon, Darren McDaid, Seodhna M. Lynch, Eamonn Cooper, Joseph McLaughlin, Victoria E. McGilligan, Steven Watterson, Priyank Shukla, Shu-Dong Zhang, Magda Bucholc, Andrew English, Aaron Peace, Maurice O’Kane, Martin Kelly, Manav Bhavsar, Elaine K. Murray, David S. Gibson, Colum P. Walsh, Anthony J. Bjourson and Taranjit Singh Rai

Biomolecules 2024, 14(9), 1163; https://doi.org/10.3390/biom14091163 - 17 Sep 2024

Abstract

Background: The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has posed unprecedented challenges to healthcare systems worldwide. Here, we have identified proteomic and genetic signatures for improved prognosis which is vital for COVID-19 research. Methods: We investigated the proteomic and genomic profile [...] Read more.

Background: The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has posed unprecedented challenges to healthcare systems worldwide. Here, we have identified proteomic and genetic signatures for improved prognosis which is vital for COVID-19 research. Methods: We investigated the proteomic and genomic profile of COVID-19-positive patients (n = 400 for proteomics, n = 483 for genomics), focusing on differential regulation between hospitalised and non-hospitalised COVID-19 patients. Signatures had their predictive capabilities tested using independent machine learning models such as Support Vector Machine (SVM), Random Forest (RF) and Logistic Regression (LR). Results: This study has identified 224 differentially expressed proteins involved in various inflammatory and immunological pathways in hospitalised COVID-19 patients compared to non-hospitalised COVID-19 patients. LGALS9 (p-value < 0.001), LAMP3 (p-value < 0.001), PRSS8 (p-value < 0.001) and AGRN (p-value < 0.001) were identified as the most statistically significant proteins. Several hundred rsIDs were queried across the top 10 significant signatures, identifying three significant SNPs on the FSTL3 gene showing a correlation with hospitalisation status. Conclusions: Our study has not only identified key signatures of COVID-19 patients with worsened health but has also demonstrated their predictive capabilities as potential biomarkers, which suggests a staple role in the worsened health effects caused by COVID-19. Full article

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33 pages, 2607 KiB

Open AccessReview

Advances in Microbial Exopolysaccharides: Present and Future Applications

by Huu-Thanh Nguyen, Thuy-Trang Pham, Phu-Tho Nguyen, Hélène Le-Buanec, Holy N. Rabetafika and Hary L. Razafindralambo

Biomolecules 2024, 14(9), 1162; https://doi.org/10.3390/biom14091162 - 16 Sep 2024

Abstract

Microbial exopolysaccharides (EPSs) are receiving growing interest today, owing to their diversity in chemical structure and source, multiple functions, and immense potential applications in many food and non-food industries. Their health-promoting benefits for humans deserve particular attention because of their various biological activities [...] Read more.

Microbial exopolysaccharides (EPSs) are receiving growing interest today, owing to their diversity in chemical structure and source, multiple functions, and immense potential applications in many food and non-food industries. Their health-promoting benefits for humans deserve particular attention because of their various biological activities and physiological functions. The aim of this paper is to provide a comprehensive review of microbial EPSs, covering (1) their chemical and biochemical diversity, including composition, biosynthesis, and bacterial sources belonging mainly to lactic acid bacteria (LAB) or probiotics; (2) their technological and analytical aspects, especially their production mode and characterization; (3) their biological and physiological aspects based on their activities and functions; and (4) their current and future uses in medical and pharmaceutical fields, particularly for their prebiotic, anticancer, and immunobiotic properties, as well as their applications in other industrial and agricultural sectors. Full article

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16 pages, 1220 KiB

Open AccessReview

Research Progress on Dendritic Cells in Hepatocellular Carcinoma Immune Microenvironments

by Wenya Li, Guojie Chen, Hailin Peng, Qingfang Zhang, Dengyun Nie, Ting Guo, Yinxing Zhu, Yuhan Zhang and Mei Lin

Biomolecules 2024, 14(9), 1161; https://doi.org/10.3390/biom14091161 - 16 Sep 2024

Abstract

Dendritic cells (DCs) are antigen-presenting cells that play a crucial role in initiating immune responses by cross-presenting relevant antigens to initial T cells. The activation of DCs is a crucial step in inducing anti-tumor immunity. Upon recognition and uptake of tumor antigens, activated [...] Read more.

Dendritic cells (DCs) are antigen-presenting cells that play a crucial role in initiating immune responses by cross-presenting relevant antigens to initial T cells. The activation of DCs is a crucial step in inducing anti-tumor immunity. Upon recognition and uptake of tumor antigens, activated DCs present these antigens to naive T cells, thereby stimulating T cell-mediated immune responses and enhancing their ability to attack tumors. It is particularly noted that DCs are able to cross-present foreign antigens to major histocompatibility complex class I (MHC-I) molecules, prompting CD8⁺ T cells to proliferate and differentiate into cytotoxic T cells. In the malignant progression of hepatocellular carcinoma (HCC), the inactivation of DCs plays an important role, and the activation of DCs is particularly important in anti-HCC immunotherapy. In this review, we summarize the mechanisms of DC activation in HCC, the involved regulatory factors and strategies to activate DCs in HCC immunotherapy. It provides a basis for the study of HCC immunotherapy through DC activation. Full article

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17 pages, 13879 KiB

Open AccessArticle

Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner

by Alexandra V. Schmidt, Sivakama S. Bharathi, Keaton J. Solo, Joanna Bons, Jacob P. Rose, Birgit Schilling and Eric S. Goetzman

Biomolecules 2024, 14(9), 1160; https://doi.org/10.3390/biom14091160 - 15 Sep 2024

Abstract

Sirtuin-2 (Sirt2), an NAD+-dependent lysine deacylase enzyme, has previously been implicated as a regulator of glucose metabolism, but the specific mechanisms remain poorly defined. Here, we observed that Sirt2−/− males, but not females, have decreased body fat, moderate hypoglycemia upon fasting, and perturbed [...] Read more.

Sirtuin-2 (Sirt2), an NAD+-dependent lysine deacylase enzyme, has previously been implicated as a regulator of glucose metabolism, but the specific mechanisms remain poorly defined. Here, we observed that Sirt2−/− males, but not females, have decreased body fat, moderate hypoglycemia upon fasting, and perturbed glucose handling during exercise compared to wild type controls. Conversion of injected lactate, pyruvate, and glycerol boluses into glucose via gluconeogenesis was impaired, but only in males. Primary Sirt2−/− male hepatocytes exhibited reduced glycolysis and reduced mitochondrial respiration. RNAseq and proteomics were used to interrogate the mechanisms behind this liver phenotype. Loss of Sirt2 did not lead to transcriptional dysregulation, as very few genes were altered in the transcriptome. In keeping with this, there were also negligible changes to protein abundance. Site-specific quantification of the hepatic acetylome, however, showed that 13% of all detected acetylated peptides were significantly increased in Sirt2−/− male liver versus wild type, representing putative Sirt2 target sites. Strikingly, none of these putative target sites were hyperacetylated in Sirt2−/− female liver. The target sites in the male liver were distributed across mitochondria (44%), cytoplasm (32%), nucleus (8%), and other compartments (16%). Despite the high number of putative mitochondrial Sirt2 targets, Sirt2 antigen was not detected in purified wild type liver mitochondria, suggesting that Sirt2’s regulation of mitochondrial function occurs from outside the organelle. We conclude that Sirt2 regulates hepatic protein acetylation and metabolism in a sex-specific manner. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Liver Diseases)

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18 pages, 2698 KiB

Open AccessArticle

ANT-Mediated Inhibition of the Permeability Transition Pore Alleviates Palmitate-Induced Mitochondrial Dysfunction and Lipotoxicity

by Natalia V. Belosludtseva, Anna I. Ilzorkina, Dmitriy A. Serov, Mikhail V. Dubinin, Eugeny Yu. Talanov, Maxim N. Karagyaur, Alexandra L. Primak, Jiankang Liu and Konstantin N. Belosludtsev

Biomolecules 2024, 14(9), 1159; https://doi.org/10.3390/biom14091159 - 15 Sep 2024

Abstract

Hyperlipidemia is a major risk factor for vascular lesions in diabetes mellitus and other metabolic disorders, although its basis remains poorly understood. One of the key pathogenetic events in this condition is mitochondrial dysfunction associated with the opening of the mitochondrial permeability transition [...] Read more.

Hyperlipidemia is a major risk factor for vascular lesions in diabetes mellitus and other metabolic disorders, although its basis remains poorly understood. One of the key pathogenetic events in this condition is mitochondrial dysfunction associated with the opening of the mitochondrial permeability transition (MPT) pore, a drop in the membrane potential, and ROS overproduction. Here, we investigated the effects of bongkrekic acid and carboxyatractyloside, a potent blocker and activator of the MPT pore opening, respectively, acting through direct interaction with the adenine nucleotide translocator, on the progression of mitochondrial dysfunction in mouse primary lung endothelial cells exposed to elevated levels of palmitic acid. Palmitate treatment (0.75 mM palmitate/BSA for 6 days) resulted in an 80% decrease in the viability index of endothelial cells, which was accompanied by mitochondrial depolarization, ROS hyperproduction, and increased colocalization of mitochondria with lysosomes. Bongkrekic acid (25 µM) attenuated palmitate-induced lipotoxicity and all the signs of mitochondrial damage, including increased spontaneous formation of the MPT pore. In contrast, carboxyatractyloside (10 μM) stimulated cell death and failed to prevent the progression of mitochondrial dysfunction under hyperlipidemic stress conditions. Silencing of gene expression of the predominate isoform ANT2, similar to the action of carboxyatractyloside, led to increased ROS generation and cell death under conditions of palmitate-induced lipotoxicity in a stably transfected HEK293T cell line. Altogether, these results suggest that targeted manipulation of the permeability transition pore through inhibition of ANT may represent an alternative approach to alleviate mitochondrial dysfunction and cell death in cell culture models of fatty acid overload. Full article

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26 pages, 2177 KiB

Open AccessArticle

Insights into Transient Dimerisation of Carnitine/Acylcarnitine Carrier (SLC25A20) from Sarkosyl/PAGE, Cross-Linking Reagents, and Comparative Modelling Analysis

by Nicola Giangregorio, Annamaria Tonazzi, Ciro Leonardo Pierri and Cesare Indiveri

Biomolecules 2024, 14(9), 1158; https://doi.org/10.3390/biom14091158 - 14 Sep 2024

Abstract

The carnitine/acylcarnitine carrier (CAC) is a crucial protein for cellular energy metabolism, facilitating the exchange of acylcarnitines and free carnitine across the mitochondrial membrane, thereby enabling fatty acid β-oxidation and oxidative phosphorylation (OXPHOS). Although CAC has not been crystallised, structural insights are derived [...] Read more.

The carnitine/acylcarnitine carrier (CAC) is a crucial protein for cellular energy metabolism, facilitating the exchange of acylcarnitines and free carnitine across the mitochondrial membrane, thereby enabling fatty acid β-oxidation and oxidative phosphorylation (OXPHOS). Although CAC has not been crystallised, structural insights are derived from the mitochondrial ADP/ATP carrier (AAC) structures in both cytosolic and matrix conformations. These structures underpin a single binding centre-gated pore mechanism, a common feature among mitochondrial carrier (MC) family members. The functional implications of this mechanism are well-supported, yet the structural organization of the CAC, particularly the formation of dimeric or oligomeric assemblies, remains contentious. Recent investigations employing biochemical techniques on purified and reconstituted CAC, alongside molecular modelling based on crystallographic AAC dimeric structures, suggest that CAC can indeed form dimers. Importantly, this dimerisation does not alter the transport mechanism, a phenomenon observed in various other membrane transporters across different protein families. This observation aligns with the ping–pong kinetic model, where the dimeric form potentially facilitates efficient substrate translocation without necessitating mechanistic alterations. The presented findings thus contribute to a deeper understanding of CAC’s functional dynamics and its structural parallels with other MC family members. Full article

(This article belongs to the Special Issue The Structure and Function of Proteins, Lipids and Nucleic Acids)

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15 pages, 2485 KiB

Open AccessArticle

Functional Role of Piezo1 in the Human Eosinophil Cell Line AML14.3D10: Implications for the Immune and Sensory Nervous Systems

by Sung-Min Hwang, Ji-Min Song, Jung Ju Choi, YunJae Jung, Chul-Kyu Park and Yong Ho Kim

Biomolecules 2024, 14(9), 1157; https://doi.org/10.3390/biom14091157 - 14 Sep 2024

Abstract

Mechanosensitive ion channels, particularly Piezo channels, are widely expressed in various tissues. However, their role in immune cells remains underexplored. Therefore, this study aimed to investigate the functional role of Piezo1 in the human eosinophil cell line AML14.3D10. We detected Piezo1 mRNA expression, [...] Read more.

Mechanosensitive ion channels, particularly Piezo channels, are widely expressed in various tissues. However, their role in immune cells remains underexplored. Therefore, this study aimed to investigate the functional role of Piezo1 in the human eosinophil cell line AML14.3D10. We detected Piezo1 mRNA expression, but not Piezo2 expression, in these cells, confirming the presence of the Piezo1 protein. Activation of Piezo1 with Yoda1, its specific agonist, resulted in a significant calcium influx, which was inhibited by the Piezo1-specific inhibitor Dooku1, as well as other nonspecific inhibitors (Ruthenium Red, Gd³⁺, and GsMTx-4). Further analysis revealed that Piezo1 activation modulated the expression and secretion of both pro-inflammatory and anti-inflammatory cytokines in AML14.3D10 cells. Notably, supernatants from Piezo1-activated AML14.3D10 cells enhanced capsaicin and ATP-induced calcium responses in the dorsal root ganglion neurons of mice. These findings elucidate the physiological role of Piezo1 in AML14.3D10 cells and suggest that factors secreted by these cells can modulate the activity of transient receptor potential 1 (TRPV1) and purinergic receptors, which are associated with pain and itch signaling. The results of this study significantly advance our understanding of the function of Piezo1 channels in the immune and sensory nervous systems. Full article

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11 pages, 258 KiB

Open AccessArticle

Co-Occurrence of Fusarium and Alternaria Metabolites in Brewing Barley Monitored during Two Consecutive Years (2019–2020)

by Kristina Habschied, Krešimir Mastanjević, Jurislav Babić, Rudolf Krska, Michael Sulyok, Alojzije Lalić, Gordana Šimić and Tihomir Kovač

Biomolecules 2024, 14(9), 1156; https://doi.org/10.3390/biom14091156 - 14 Sep 2024

Abstract

Known mycotoxins have been investigated for years. They have been included in legislation and are meticulously controlled in most cereals, cereal-related products, and raw materials of animal origin. However, there are still mycotoxins that need to be addressed by regulations and subsequently are [...] Read more.

Known mycotoxins have been investigated for years. They have been included in legislation and are meticulously controlled in most cereals, cereal-related products, and raw materials of animal origin. However, there are still mycotoxins that need to be addressed by regulations and subsequently are not monitored but can still occur in relatively high concentrations. This research aimed to assess the occurrence of common Fusarium mycotoxins in hulled barley. Samples of hulled barley were treated in the field with two protective treatments, alongside a control sample sans treatment. Furthermore, we aimed to assess the occurrence of Alternaria mycotoxins in the chosen samples. The results have shown that Fusarium mycotoxins were mostly determined by climatic conditions (no mycotoxins in 2020, except siccanol). Most interesting was the appearance of infectopyron, an Alternaria toxin that was detected in all samples in 2019 and in the majority of samples in 2020. The highest concentration was detected in 2019 in hulled barley with 536 µg/kg, while in 2020, the highest concentration of this mycotoxin reached 350 µg/kg. These findings depict the need for further research on food safety regarding mycotoxins, and the need for additional changes in legislation. This investigation shows that fungicide application in rainy years cannot efficiently suppress mycotoxin production. Additionally, even in dry years, some of the mycotoxins not involved in legislation, such as infectopyron and siccanol, do not respond to the application of fungicides. Full article

(This article belongs to the Special Issue Biochemistry of Wine and Beer, 3rd Edition)

20 pages, 3266 KiB

Open AccessArticle

Impact of Multi-Factor Features on Protein Secondary Structure Prediction

by Benzhi Dong, Zheng Liu, Dali Xu, Chang Hou, Na Niu and Guohua Wang

Biomolecules 2024, 14(9), 1155; https://doi.org/10.3390/biom14091155 - 13 Sep 2024

Abstract

Protein secondary structure prediction (PSSP) plays a crucial role in resolving protein functions and properties. Significant progress has been made in this field in recent years, and the use of a variety of protein-related features, including amino acid sequences, position-specific score matrices (PSSM), [...] Read more.

Protein secondary structure prediction (PSSP) plays a crucial role in resolving protein functions and properties. Significant progress has been made in this field in recent years, and the use of a variety of protein-related features, including amino acid sequences, position-specific score matrices (PSSM), amino acid properties, and secondary structure trend factors, to improve prediction accuracy is an important technical route for it. However, a comprehensive evaluation of the impact of these factor features in secondary structure prediction is lacking in the current work. This study quantitatively analyzes the impact of several major factors on secondary structure prediction models using a more explanatory four-class machine learning approach. The applicability of each factor in the different types of methods, the extent to which the different methods work on each factor, and the evaluation of the effect of multi-factor combinations are explored in detail. Through experiments and analyses, it was found that PSSM performs best in methods with strong high-dimensional features and complex feature extraction capabilities, while amino acid sequences, although performing poorly overall, perform relatively well in methods with strong linear processing capabilities. Also, the combination of amino acid properties and trend factors significantly improved the prediction performance. This study provides empirical evidence for future researchers to optimize multi-factor feature combinations and apply them to protein secondary structure prediction models, which is beneficial in further optimizing the use of these factors to enhance the performance of protein secondary structure prediction models. Full article

(This article belongs to the Special Issue Protein Structure Prediction with AlphaFold)

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12 pages, 2705 KiB

Open AccessArticle

3D-Cultured MC3T3-E1-Derived Exosomes Promote Endothelial Cell Biological Function under the Effect of LIPUS

by Xiaohan Liu, Rui Cheng, Hongjuan Cao and Lin Wu

Biomolecules 2024, 14(9), 1154; https://doi.org/10.3390/biom14091154 - 13 Sep 2024

Abstract

Porous Ti-6Al-4V scaffold materials can be used to heal massive bone defects because they can provide space for vascularisation and bone formation. During new bone tissue development, rapid vascular ingrowth into scaffold materials is very important. Osteoblast-derived exosomes are capable of facilitating angiogenesis–osteogenesis [...] Read more.

Porous Ti-6Al-4V scaffold materials can be used to heal massive bone defects because they can provide space for vascularisation and bone formation. During new bone tissue development, rapid vascular ingrowth into scaffold materials is very important. Osteoblast-derived exosomes are capable of facilitating angiogenesis–osteogenesis coupling. Low-intensity pulsed ultrasound (LIPUS) is a physical therapy modality widely utilised in the field of bone regeneration and has been proven to enhance the production and functionality of exosomes on two-dimensional surfaces. The impact of LIPUS on exosomes derived from osteoblasts cultured in three dimensions remains to be elucidated. In this study, exosomes produced by osteoblasts on porous Ti-6Al-4V scaffold materials under LIPUS and non-ultrasound stimulated conditions were co-cultured with endothelial cells. The findings indicated that the exosomes were consistently and stably taken up by the endothelial cells. Compared to the non-ultrasound group, the LIPUS group facilitated endothelial cell proliferation and angiogenesis. After 24 h of co-culture, the migration ability of endothelial cells in the LIPUS group was 17.30% higher relative to the non-ultrasound group. LIPUS may represent a potentially viable strategy to promote the efficacy of osteoblast-derived exosomes to enhance the angiogenesis of porous Ti-6Al-4V scaffold materials. Full article

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8 pages, 956 KiB

Open AccessPerspective

Diabetic Kidney Disease: Contribution of Phenyl Sulfate Derived from Dietary Tyrosine upon Gut Microbiota Catabolism

by Haoxin Liu, Tram N. Diep, Ying Wang, Yucheng Wang and Liang-Jun Yan

Biomolecules 2024, 14(9), 1153; https://doi.org/10.3390/biom14091153 - 13 Sep 2024

Abstract

Deranged gut microbiota can release increased levels of uremic toxins leading to exacerbated kidney injury. In diabetic kidney disease (DKD), phenyl sulfate (PS) derived from tyrosine catabolism by gut microbiota has been demonstrated to be both an early diagnostic marker and a therapeutic [...] Read more.

Deranged gut microbiota can release increased levels of uremic toxins leading to exacerbated kidney injury. In diabetic kidney disease (DKD), phenyl sulfate (PS) derived from tyrosine catabolism by gut microbiota has been demonstrated to be both an early diagnostic marker and a therapeutic target. In this perspective article, we summarize PS generation pathways and recent findings on PS and kidney injury in DKD. Increasing evidence has shown that the underlying mechanisms of PS-induced kidney injury mainly involve oxidative stress, redox imbalance, and mitochondrial dysfunction, which all may be targeted to attenuate PS-induced kidney injury. For future research directions, we think that a deeper understanding of the pathogenic role of PS in kidney injury using a variety of diabetic animal models should be investigated. Moreover, we also suggest beneficial approaches that could be used to mitigate the deleterious effect of PS on the kidney. These approaches include caloric restriction, tyrosine restriction, and administration of ketogenic drugs, ketogenic diets or natural products; all of which should be conducted under obese and diabetic conditions. Full article

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