Biomolecules最新文献

{"title":"MiR-92 Controls Synaptic Development Through Glial Vha55 Regulation.","authors":"Simon M Moe, Alicia Taylor, Alan P Robertson, David Van Vactor, Elizabeth M McNeill","doi":"10.3390/biom15091330","DOIUrl":"10.3390/biom15091330","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) have emerged as important biomarkers for complex neurological conditions. Modifications in synaptic morphology characterize several of these disease states, indicating a possible role of miRNA in modulating synaptic formation and plasticity. Within the third-instar larvae of Drosophila melanogaster, we uncovered a functional role for highly human-conserved miR-92 in synaptogenesis of the glutamatergic peripheral nervous system. Loss of miR-92 results in underdeveloped synaptic architecture, coinciding with significantly reduced physiological activity. We demonstrate a novel role for miR-92 glial-specific expression to support synaptic growth function and plasticity. Modifications of miR-92 within glial tissue result in aberrant glial barrier properties, including an increased uptake of external dyes. Within the glia, miR-92 regulates a V-ATPase subunit (Vha55), impairing the glial cells from forming appropriate insulating layers around the nervous system. These modifications may impact how the nervous system adapts to its environment, increasing immature 'ghost bouton' budding and impairing responses to changes in environmental conditions. Our work highlights the importance of glial-specific miR-92 on synaptic development, affecting glial health and function through its downstream target Vha55, and demonstrates a novel mechanism for glia in synaptogenesis and homeostatic plasticity.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Effect of Selenium Nanoparticles, Sorafenib, and Selenium-Sorafenib Nanocomplex in the Lungs and Kidneys of Mice with TAA-Induced HCC.","authors":"Egor A Turovsky, Sergey V Gudkov, Elena G Varlamova","doi":"10.3390/biom15091336","DOIUrl":"10.3390/biom15091336","url":null,"abstract":"<p><p>Hepatocellular carcinoma is a primary malignant tumor of the liver, which is a serious health problem due to its aggressive nature, late diagnosis, and metastasis to other organs. We present, for the first time, the mRNA expression patterns of a wide range of genes involved in inflammation, fibrosis, endoplasmic reticulum stress, various forms of cell death, and signaling cascades in the lungs and kidneys of mice with thioacetamide-induced HCC. It is known that HCC often metastasizes to the lungs, and it is also important to understand which pathological processes occur in the kidneys, since the liver and kidneys are key target organs of toxicity. The main goal of this work was to study the pathological processes in the lungs and kidneys in HCC and the effectiveness of selenium nanocomplexes, as well as the well-known drug sorafenib, in mitigating these pathological consequences. These results present a significant contribution to the study of HCC metastasis to the lungs and kidneys and to the development of drugs that are most effective in the late stages of HCC. In addition, a hierarchy of the distribution of the selenium in the liver, kidneys, and lungs was established after the treatment of mice with HCC with selenium nanoparticles and a selenium-sorafenib nanocomplex. These data are important for developing a treatment protocol and determining optimal dosages of the drugs under study, which allows for achieving the desired therapeutic effect and neutralizing the toxic effect of selenium on healthy tissues and organs.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Skin Microenvironment: A Dynamic Regulator of Hair Follicle Development, Cycling and Disease.","authors":"Weiguo Song, Mingli Peng, Qiqi Ma, Xiaoyu Han, Chunyan Gao, Wenqi Zhang, Dongjun Liu","doi":"10.3390/biom15091335","DOIUrl":"10.3390/biom15091335","url":null,"abstract":"<p><p>As essential skin appendages, hair follicles exhibit complex developmental and regenerative processes shaped by the skin microenvironment. Imbalances in skin microenvironmental homeostasis are often accompanied by follicle miniaturization and even hair loss. In studying the mechanisms of hair follicle development, in addition to focusing on the self-regulation of intrinsic signaling within the follicle, it is also crucial to examine the remodeling of the follicular microenvironment triggered by dynamic changes in the skin microenvironment. Herein, we review the individual and combined roles of various cells, tissues, signaling molecules, and metabolic alterations within the skin microenvironment in hair follicle development. Moreover, we summarize the potential applications of the skin microenvironment in treating hair-related diseases, highlight the existing challenges and limitations in the research field, and provide perspectives on future research directions, aiming to elucidate the critical role of the skin microenvironment in regulating hair follicle development.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Reactive Oxygen Species: A Unifying Mechanism in Long COVID and Spike Protein-Associated Injury: A Narrative Review.","authors":"Eunseuk Lee, Adaobi Amelia Ozigbo, Joseph Varon, Mathew Halma, Madison Laezzo, Song Peng Ang, Jose Iglesias","doi":"10.3390/biom15091339","DOIUrl":"10.3390/biom15091339","url":null,"abstract":"<p><p>Post-acute sequelae of SARS-CoV-2 infection (long COVID) present with persistent fatigue, cognitive impairment, and autonomic and multisystem dysfunctions that often go unnoticed by standard diagnostic tests. Increasing evidence suggests that mitochondrial dysfunction and oxidative stress are central drivers of these post-viral sequelae. Viral infections, particularly SARS-CoV-2, disrupt mitochondrial bioenergetics by altering membrane integrity, increasing mitochondrial reactive oxygen species (mtROS), and impairing mitophagy, leading to sustained immune activation and metabolic imbalance. This review synthesizes an understanding of how mitochondrial redox signaling and impaired clearance of damaged mitochondria contribute to chronic inflammation and multisystem organ symptoms in both long COVID and post-vaccine injury. We discuss translational biomarkers and non-invasive techniques, exploring therapeutic strategies that include pharmacological, non-pharmacological, and nutritional approaches, as well as imaging modalities aimed at assessing and restoring mitochondrial health. Recognizing long COVID as a mitochondrial disorder that stems from redox imbalance will open new options for personalized treatment and management guided by biomarkers. Future clinical trials are essential to validate these approaches and translate mitochondrial resuscitation into effective care for patients suffering from long COVID and related post-viral syndromes.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Allosteric Control Overcomes Steric Limitations for Neutralizing Antibodies Targeting Conserved Binding Epitopes of the SARS-CoV-2 Spike Protein: Exploring the Intersection of Binding, Allostery, and Immune Escape with a Multimodal Computational Approach.","authors":"Mohammed Alshahrani, Vedant Parikh, Brandon Foley, Gennady Verkhivker","doi":"10.3390/biom15091340","DOIUrl":"10.3390/biom15091340","url":null,"abstract":"<p><p>Understanding the atomistic basis of multi-layer mechanisms employed by broadly reactive neutralizing antibodies of the SARS-CoV-2 spike protein without directly blocking receptor engagement remains an important challenge in coronavirus immunology. Class 4 antibodies represent an intriguing case: they target a deeply conserved, cryptic epitope on the receptor-binding domain yet exhibit variable neutralization potency across subgroups F1 (CR3022, EY6A, COVA1-16), F2 (DH1047), and F3 (S2X259). The molecular basis for this variability is not fully understood. Here, we employed a multi-modal computational approach integrating atomistic and coarse-grained molecular dynamics simulations, binding free energy calculations, mutational scanning, and dynamic network analysis to elucidate how these antibodies engage the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and influence its function. Our results reveal that neutralization efficacy arises from the interplay of direct interfacial interactions and allosteric effects. Group F1 antibodies (CR3022, EY6A, COVA1-16) primarily operate via classic allostery, modulating flexibility in RBD loop regions to indirectly interfere with the ACE2 receptor binding through long-range effects. Group F2 antibody DH1047 represents an intermediate mechanism, combining partial steric hindrance-through engagement of ACE2-critical residues T376, R408, V503, and Y508-with significant allosteric influence, facilitated by localized communication pathways linking the epitope to the receptor interface. Group F3 antibody S2X259 achieves potent neutralization through a synergistic mechanism involving direct competition with ACE2 and localized allosteric stabilization, albeit with potentially increased escape vulnerability. Dynamic network analysis identified a conserved \"allosteric ring\" within the RBD core that serves as a structural scaffold for long-range signal propagation, with antibody-specific extensions modulating communication to the ACE2 interface. These findings support a model where Class 4 neutralization strategies evolve through the refinement of peripheral allosteric connections rather than epitope redesign. This study establishes a robust computational framework for understanding the atomistic basis of neutralization activity and immune escape for Class 4 antibodies, highlighting how the interplay of binding energetics, conformational dynamics, and allosteric modulation governs their effectiveness against SARS-CoV-2.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetrahydrocannabivarin (THCV) Dose Dependently Blocks or Substitutes for Tetrahydrocannabinol (THC) in a Drug Discrimination Task in Rats.","authors":"Hakan Kayir, Larissa Kouroukis, Iman Aziz, Jibran Younis Khokhar","doi":"10.3390/biom15091329","DOIUrl":"10.3390/biom15091329","url":null,"abstract":"<p><p>Delta-9-Tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid and structural analog of THC, exhibits a dual pharmacological profile as a CB1 receptor agonist/antagonist and a partial CB2 agonist. This study evaluated the effects of THCV in a THC discrimination model in rats. Male Sprague-Dawley rats (<i>n</i> = 16, 300-340 g, PND60) were trained under a fixed ratio 20 (FR20) schedule to discriminate THC (3 mg/kg) from vehicle. Substitution tests were conducted with THC (0.325-3 mg/kg), THCV (0.75-6 mg/kg), and THC-THCV combinations. THCV produced an inverted U-shaped substitution curve, significantly differing from vehicle (<i>p</i> = 0.008). At 3 mg/kg, THCV partially substituted for THC (54.6% ± 17.82, <i>p</i> = 0.003). Response rate significantly increased during the substitution test with 3 mg/kg of THCV (<i>p</i> = 0.042). THCV (6 mg/kg) reversed THC (0.75 mg/kg)-induced responding (<i>p</i> = 0.040), with no significant change in response rate (<i>p</i> = 0.247). However, THCV combined with THC (1.5 mg/kg) affected response rates (<i>p</i> = 0.012), with 6 mg/kg significantly reducing rates vs. 3 mg/kg (<i>p</i> = 0.013). Blood THC and 11-OH-THC levels remained unchanged when THC was combined with THCV. The findings suggest THCV can partially mimic or block THC's discriminative effects in a dose-dependent manner, possibly acting as a partial CB1 agonist.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Convergence in Neurodegeneration: Natural Products, Drug Repurposing, and Biomolecular Targets.","authors":"Caterina Vicidomini, Giovanni N Roviello","doi":"10.3390/biom15091333","DOIUrl":"10.3390/biom15091333","url":null,"abstract":"<p><p>Neurodegenerative diseases pose an escalating global health burden, caused by their intricate pathophysiological mechanisms, and consequently, a persistent lack of curative therapies [...].</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The First Heterozygous <i>TWNK</i> Nonsense Mutation Associated with Progressive External Ophthalmoplegia: Evidence for a New Piece in the Puzzle of Mitochondrial Diseases.","authors":"Diego Lopergolo, Gianna Berti, Gian Nicola Gallus, Silvia Bianchi, Filippo Maria Santorelli, Alessandro Malandrini, Nicola De Stefano","doi":"10.3390/biom15091337","DOIUrl":"10.3390/biom15091337","url":null,"abstract":"<p><strong>Background: </strong>The <i>TWNK</i> gene encodes a protein that colocalizes with mitochondrial DNA (mtDNA) in mitochondrial nucleoids. It acts as mtDNA helicase during replication, thus playing a pivotal role in the replication and maintenance of mtDNA stability. <i>TWNK</i> mutations are associated with a wide spectrum of clinical phenotypes and a marked heterogeneity. However, heterozygous nonsense variants in the gene have never been described in association with disease.</p><p><strong>Methods: </strong>We analyzed a next-generation sequencing (NGS) targeted gene panel in a cohort including 40 patients with high clinical suspicion of mitochondrial disorders. Selected patients underwent a complete neurological examination, electrophysiology tests, and muscle biopsy. Segregation analysis was performed in available family members. The 3D structure of twinkle was visualized and analyzed using Swiss Model and Pymol version 3.1.6.1.</p><p><strong>Results: </strong>We found four <i>TWNK</i>-mutated subjects from two unrelated families. They exhibited a variable clinical spectrum, ranging from asymptomatic individuals to subjects with psychiatric disorder, chronic progressive external ophthalmoplegia (CPEO), and CPEO-plus. All the subjects shared the heterozygous <i>TWNK</i> p.Glu665Ter variant.</p><p><strong>Discussion and conclusions: </strong>We describe the clinical phenotype and muscle biopsy findings associated with the first reported heterozygous nonsense <i>TWNK</i> variant, thus expanding the current knowledge of Twinkle-related disorders. Our findings are in line with the high intrafamilial clinical variability associated with <i>TWNK</i> mutations. Although PEO and skeletal muscle involvement remain hallmarks of the disease, extra-muscular features should be carefully assessed.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Patterny</i>: A Troupe of Decipherment Helpers for Intrinsic Disorder, Low Complexity and Compositional Bias in Proteins.","authors":"Paul M Harrison","doi":"10.3390/biom15091332","DOIUrl":"10.3390/biom15091332","url":null,"abstract":"<p><p>Intrinsically disordered regions (IDRs) are sometimes considered parts of the 'dark proteomes', i.e., protein parts that have been largely under-appreciated, as are the overlapping phenomena of low-complexity or compositionally biased regions (LCRs/CBRs). Experimentalists and computationalists alike are still learning how to decrypt the functionally meaningful features of such regions. Here, I report the creation of the support troupe <b><i>Patterny</i></b> to aid such protein cryptanalysis. The current troupe members are named <i>Blocky</i>, <i>Bandy</i>, <i>Moduley</i>, <i>Repeaty</i>, and <i>Runny</i>. To discern important features, protein regions are compared to ideal assortments wherein everything is sampled proportionally and dispersed randomly. <i>Blocky</i> discerns the segregation of amino-acids by type, and scores them for it. <i>Bandy</i> is focused on picking out compositional bands and calculating their evenness. <i>Moduley</i> labels the boundaries of optimized compositional modules ('CModules') and other possible boundary sets for compositionally biased regions. <i>Repeaty</i> concisely summarizes repetitiveness using an information entropy of amino-acid interval diversity. <i>Runny</i> enumerates homopeptide content and assesses its significance. Both original whole sequences and CModules from <i>Moduley</i>, are fed into the other <b><i>Patterny</i></b> members. <b><i>Patterny</i></b> is applied to some illustrative sample data from yeast proteome and the DISPROT database. It is available at Github, and might aid those aiming to intensify light-shedding and hypothesis generation for protein regions with function encoded in a distributed manner, such as IDRs and LCRs/CBRs more generally.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inorganic Polyphosphate Modulates Chromosome Transmission Fidelity in the Fission Yeast <i>Schizosaccharomyces pombe</i>.","authors":"Sarune Bollé, Elisa Koc, Adolfo Saiardi, Lisa Juhran, Eva Walla, Ursula Fleig, Abel Alcázar-Román","doi":"10.3390/biom15091331","DOIUrl":"10.3390/biom15091331","url":null,"abstract":"<p><p>Chromosome transmission fidelity is vital for organism fitness. Yet, extrinsic and intrinsic changes can affect this process, leading to aneuploidy, the loss/gain of chromosomes, which is a hallmark of cancer. Here, using a haploid fission yeast <i>Schizosaccharomyces pombe</i> strain with a segmental aneuploidy, we assayed genome stability under different temperatures and altered gene dosage. We find that <i>S. pombe</i> genome stability is temperature-dependent and is unexpectedly modulated by intracellular levels of inorganic polyphosphate polymers (polyP). The <i>vtc4⁺</i> gene, encoding a subunit of the polyP-generating VTC complex, is present twice due to the segmental aneuploidy resulting in a gene-dosage-coupled increase in polyP. Using strains with different amounts of polyP, we find a direct negative correlation between polyP and chromosome segregation fidelity. PolyP modulates the function of the conserved CCAN kinetochore subcomplex, as the abnormal growth phenotype caused by the mutant CCAN protein Fta2-291 was rescued in the absence of polyP, while extra polyP had the opposite effect. Importantly, this appears to occur in part by modulation of the nucleolin Gar2. Gar2 is the functional homolog of the <i>Saccharomyces cerevisiae</i> Nsr1 protein, whose function is modulated by posttranslational polyP-mediated polyphosphorylation. Thus, polyP modulates genome stability, linking cellular metabolism to chromosome transmission fidelity.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}