Biomolecules最新文献

{"title":"Ischemic Postconditioning Regulates New Cell Death Mechanisms in Stroke: Disulfidptosis.","authors":"Shanpeng Liu, Qike Wu, Can Xu, Liping Wang, Jialing Wang, Cuiying Liu, Heng Zhao","doi":"10.3390/biom14111390","DOIUrl":"10.3390/biom14111390","url":null,"abstract":"<p><strong>Background and objective: </strong>Stroke poses a critical health issue without effective neuroprotection. We explore ischemic postconditioning's (IPostC) potential to mitigate stroke-induced brain injury, focusing on its interaction with disulfidptosis, a novel cell death pathway marked by protein disulfide accumulation. We aim to clarify IPostC's protective mechanisms against stroke through gene sequencing and experimental analysis in mice.</p><p><strong>Methods: </strong>Through our initial investigation, we identified 27 disulfidptosis-related genes (DRGs) and uncovered their interactions. Additionally, differential gene analysis revealed 11 potential candidate genes that are linked to disulfidptosis, stroke, and IPostC. Our comprehensive study employed various analytical approaches, including machine learning, functional enrichment analysis, immune analysis, drug sensitivity analysis, and qPCR experiments, to gain insights into the molecular mechanisms underlying these processes.</p><p><strong>Results: </strong>Our study identified and expanded the list of disulfidptosis-related genes (DRGs) critical to stroke, revealing key genes and their interactions. Through bioinformatics analyses, including PCA, UMAP, and differential gene expression, we were able to differentiate the effects of stroke from those of postconditioning, identifying <i>Peroxiredoxin 1</i> (<i>PRDX1</i>) as a key gene of interest. GSEA highlighted <i>PRDX1</i>'s involvement in protective pathways against ischemic damage, while its correlations with various proteins suggest a broad impact on stroke pathology. Constructing a ceRNA network and analyzing drug sensitivities, we explored <i>PRDX1</i>'s regulatory mechanisms, proposing novel therapeutic avenues. Additionally, our immune infiltration analysis linked <i>PRDX1</i> to key immune cells, underscoring its dual role in stroke progression and recovery. <i>PRDX1</i> is identified as a key target in ischemic stroke based on colocalization analysis, which revealed that <i>PRDX1</i> and ischemic stroke share the causal variant rs17522918. The causal relationship between <i>PRDX1</i>-related methylation sites (cg02631906 and cg08483560) and the risk of ischemic stroke further validates <i>PRDX1</i> as a crucial target.</p><p><strong>Conclusions: </strong>These results suggest that the DRGs are interconnected with various cell death pathways and immune processes, potentially contributing to IPostC regulating cell death mechanisms in stroke.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725874","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 Dual Burden: Exploring Cardiovascular Complications in Chronic Kidney Disease.","authors":"Alfredo Caturano, Raffaele Galiero, Maria Rocco, Giuseppina Tagliaferri, Alessia Piacevole, Davide Nilo, Giovanni Di Lorenzo, Celestino Sardu, Vincenzo Russo, Erica Vetrano, Marcellino Monda, Raffaele Marfella, Luca Rinaldi, Ferdinando Carlo Sasso","doi":"10.3390/biom14111393","DOIUrl":"10.3390/biom14111393","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) represents a significant global health challenge, affecting millions of individuals and leading to substantial morbidity and mortality. This review aims to explore the epidemiology, cardiovascular complications, and management strategies associated with CKD, emphasizing the importance of preventing cardiovascular disease and early intervention. CKD is primarily driven by conditions such as diabetes mellitus, hypertension, and cardiovascular diseases, which often coexist and exacerbate renal impairment. Effective management requires a multifaceted approach, including lifestyle modifications, pharmacological interventions, and regular monitoring. Dietary changes, such as sodium restriction and a controlled intake of phosphorus and potassium, play a vital role in preserving renal function. Pharmacological therapies, particularly angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and emerging agents like SGLT2 inhibitors, have shown efficacy in slowing disease progression and improving patient outcomes. Furthermore, patients undergoing dialysis face increased cardiovascular risk, necessitating comprehensive management strategies to address both renal and cardiac health. As the landscape of CKD treatment evolves, ongoing research into novel therapeutic options and personalized medical approaches are essential. This review underscores the urgent need for awareness, education, and effective preventive measures to mitigate the burden of CKD and enhance the quality of life for affected individuals.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725948","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":"Efficient Access to New Thienobenzo-1,2,3-Triazolium Salts as Preferred Dual Cholinesterase Inhibitors.","authors":"Milena Mlakić, Maja Sviben, Ana Ratković, Anamarija Raspudić, Danijela Barić, Ivana Šagud, Zlata Lasić, Ilijana Odak, Irena Škorić","doi":"10.3390/biom14111391","DOIUrl":"10.3390/biom14111391","url":null,"abstract":"<p><p>In previous research, 1,2,3-triazolium salts showed significant biological activity as potential inhibitors of cholinesterase enzymes (ChEs), which are crucial for neurotransmission. In this research, pairs of uncharged thienobenzo-triazoles and their charged salts were prepared in order to further examine the role of the positive charge on the nitrogen of the triazole ring in interactions within the active site of the enzymes, and to compare the selectivity of 1,2,3-triazolium salts in relation to their uncharged analogs obtained by photochemical cyclization. Neutral thienobenzo-triazoles showed very good selective activity toward butyrylcholinesterase (BChE), while their salts showed excellent non-selective inhibition toward both BChE (the most active <b>23</b>: IC₅₀ 0.47 μM) and acetylcholinesterase (AChE) enzymes (the most active <b>23</b>: IC₅₀ 4.4 μM). These new structures with incorporated 1,2,3-triazolium salts present the new scaffold for drug development as it is known that the current therapy in Alzheimer's disease (AD) comprises selective AChE inhibitors, while in Parkinson's and all stages of AD, non-selective inhibitors of ChEs are preferred. Molecular docking of the selected compounds and their corresponding salts into the active sites of ChEs was conducted to identify the interactions responsible for the stability of the non-covalent cholinesterase-ligand complexes. As genotoxicity studies are crucial when developing new active substances and finished drug forms, in silico studies for all the synthesized compounds have shown that compound <b>18</b> is the most promising candidate for genotoxic safety.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725686","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 Pivotal Role of One-Carbon Metabolism in Neoplastic Progression During the Aging Process.","authors":"Avisek Majumder, Shabana Bano, Kasturi Bala Nayak","doi":"10.3390/biom14111387","DOIUrl":"10.3390/biom14111387","url":null,"abstract":"<p><p>One-carbon (1C) metabolism is a complex network of metabolic reactions closely related to producing 1C units (as methyl groups) and utilizing them for different anabolic processes, including nucleotide synthesis, methylation, protein synthesis, and reductive metabolism. These pathways support the high proliferative rate of cancer cells. While drugs that target 1C metabolism (like methotrexate) have been used for cancer treatment, they often have significant side effects. Therefore, developing new drugs with minimal side effects is necessary for effective cancer treatment. Methionine, glycine, and serine are the main three precursors of 1C metabolism. One-carbon metabolism is vital not only for proliferative cells but also for non-proliferative cells in regulating energy homeostasis and the aging process. Understanding the potential role of 1C metabolism in aging is crucial for advancing our knowledge of neoplastic progression. This review provides a comprehensive understanding of the molecular complexities of 1C metabolism in the context of cancer and aging, paving the way for researchers to explore new avenues for developing advanced therapeutic interventions for cancer.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725953","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":"Role of Sex and Early Life Stress Experience on Porcine Cardiac and Brain Tissue Expression of the Oxytocin and H₂S Systems.","authors":"Franziska Münz, Nadja Abele, Fabian Zink, Eva-Maria Wolfschmitt, Melanie Hogg, Claus Barck, Josef Anetzberger, Andrea Hoffmann, Michael Gröger, Enrico Calzia, Christiane Waller, Peter Radermacher, Tamara Merz","doi":"10.3390/biom14111385","DOIUrl":"10.3390/biom14111385","url":null,"abstract":"<p><p>Early life stress (ELS) significantly increases the risk of chronic cardiovascular diseases and may cause neuroinflammation. This post hoc study, based on the material available from a previous study showing elevated \"serum brain injury markers\" in male control animals, examines the effect of sex and/or ELS on the cerebral and cardiac expression of the H₂S and oxytocin systems. Following approval by the Regional Council of Tübingen, a randomized controlled study was conducted on 12 sexually mature, uncastrated German Large White swine of both sexes. The control animals were separated from their mothers at 28-35 days, while the ELS group was separated at day 21. At 20-24 weeks, animals underwent anesthesia, ventilation, and surgical instrumentation. An immunohistochemical analysis of oxytocin, its receptor, and the H₂S-producing enzymes cystathionine-β-synthase and cystathionine-γ-lyase was performed on hypothalamic, prefrontal cortex, and myocardial tissue samples. Data are expressed as the % of positive tissue staining, and differences between groups were tested using a two-way ANOVA. The results showed no significant differences in the oxytocin and H₂S systems between groups; however, sex influenced the oxytocin system, and ELS affected the oxytocin and H₂S systems in a sex-specific manner. No immunohistochemical correlate to the elevated \"serum brain injury markers\" in male controls was identified.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725811","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":"Familial Pancreatic Cancer Research: Bridging Gaps in Basic Research and Clinical Application.","authors":"Suyakarn Archasappawat, Fatimah Al-Musawi, Peiyi Liu, EunJung Lee, Chang-Il Hwang","doi":"10.3390/biom14111381","DOIUrl":"10.3390/biom14111381","url":null,"abstract":"<p><p>Familial pancreatic cancer (FPC) represents a significant yet underexplored area in pancreatic cancer research. Basic research efforts are notably limited, and when present, they are predominantly centered on the <i>BRCA1</i> and <i>BRCA2</i> mutations due to the scarcity of other genetic variants associated with FPC, leading to a limited understanding of the broader genetic landscape of FPC. This review examines the current state of FPC research, focusing on the molecular mechanisms driving pancreatic ductal adenocarcinoma (PDAC) progression. It highlights the role of homologous recombination (HR) and its therapeutic exploitation via synthetic lethality with PARP inhibitors in BRCA1/2-deficient tumors. The review discusses various pre-clinical models of FPC, including conventional two-dimensional (2D) cell lines, patient-derived organoids (PDOs), patient-derived xenografts (PDXs), and genetically engineered mouse models (GEMMs), as well as new advancements in FPC research.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725805","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":"α-Mangostin: A Xanthone Derivative in Mangosteen with Potent Anti-Cancer Properties.","authors":"Amin F Majdalawieh, Tala M Terro, Sogand H Ahari, Imad A Abu-Yousef","doi":"10.3390/biom14111382","DOIUrl":"10.3390/biom14111382","url":null,"abstract":"<p><p>α-Mangostin, a xanthone derivative extracted from the pericarp of the mangosteen fruit (<i>Garcinia mangostana</i> L.), has garnered significant attention for its potential as a natural anti-cancer agent. This review provides a comprehensive analysis of the current literature on the anti-cancer properties of α-mangostin across various cancer types. Through an extensive analysis of in vitro and in vivo studies, this review elucidates the multifaceted mechanisms underlying α-mangostin's cytotoxicity, apoptosis induction through both intrinsic and extrinsic pathways, and modulation of key cellular processes implicated in cancer progression in a diverse array of cancer cells. It causes mitochondrial dysfunction, activates caspases, and regulates autophagy, endoplasmic reticulum stress, and oxidative stress, enhancing its anti-cancer efficacy. Moreover, α-mangostin exhibits synergistic effects with conventional chemotherapeutic agents, suggesting its utility in combination therapies. The ability of α-mangostin to inhibit cell proliferation, modulate cell cycle progression, and induce apoptosis is linked to its effects on key signaling pathways, including Akt, NF-κB, and p53. Preclinical studies highlight the therapeutic potential and safety profile of α-mangostin, demonstrating significant tumor growth inhibition without adverse effects on normal cells. In summary, understanding the molecular targets and mechanisms of action of α-mangostin is crucial for its development as a novel chemotherapeutic agent, and future clinical investigations are warranted to explore its clinical utility and efficacy in cancer prevention and therapy.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725962","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":"Cannabidiol Modulates Neuroinflammatory Markers in a PTSD Model Conducted on Female Rats.","authors":"Anna Portugalov, Gaia Peled, Sharon Zorin, Irit Akirav","doi":"10.3390/biom14111384","DOIUrl":"10.3390/biom14111384","url":null,"abstract":"<p><p>Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric condition closely linked to neuroinflammation, with a higher prevalence in women. Cannabidiol (CBD), a non-psychoactive cannabinoid, has shown promise as a potential treatment for PTSD. In this study, we used a PTSD model in which female rats were subjected to a severe foot shock followed by contextual situational reminders (SRs). Testing was conducted one month after exposure. The rats received daily CBD injections for three weeks during the SRs, from days 7 to 28. Two days after the final SR, the rats underwent five extinction trials, followed by the forced swim test (FST). After a five-day rest period, the rats were sacrificed, and brain tissues from the medial prefrontal cortex (mPFC) and ventral subiculum (vSUB) were analyzed for inflammatory markers. Chronic CBD treatment reversed impairments in fear extinction caused by shock and SR. It also reduced learned helplessness in the FST and decreased the upregulation of mPFC-<i>il1β</i> induced by shock and SRs. Additionally, exposure to shock and SRs downregulated mPFC-<i>il6</i> while upregulating vSUB-<i>il6.</i> CBD treatment further downregulated <i>il6</i> expression in the vSUB compared to the vehicle groups. Our findings show that CBD effectively inhibited the development of PTSD-like behaviors and suppressed neuroinflammation in the mPFC.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725876","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":"Slow H₂S-Releasing Donors and 3D Printable Arrays Cellular Models in Osteo-Differentiation of Mesenchymal Stem Cells for Personalized Therapies.","authors":"Ilaria Arciero, Silvia Buonvino, Sonia Melino","doi":"10.3390/biom14111380","DOIUrl":"10.3390/biom14111380","url":null,"abstract":"<p><p>The effects of the hydrogen sulfide (H₂S) slow-releasing donor, named GSGa, a glutathione-conjugate water-soluble garlic extract, on human mesenchymal stem cells (hMSCs) in both bidimensional (2D) and three-dimensional (3D) cultures were investigated, demonstrating increased expression of the antioxidant enzyme HO-1 and decreased expression of the pro-inflammatory cytokine interleukin-6 (IL-6). The administration of the H₂S donor can therefore increase the expression of antioxidant enzymes, which may have potential therapeutic applications in osteoarthritis (OA). Moreover, GSGa was able to promote the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), but not of cardiac mesenchymal stem cells (cMSCs) in a 2D culture system. This result highlights the varying sensitivity of hMSCs to the H₂S donor GSGa, suggesting that the induction of osteogenic differentiation in stem cells by chemical factors is dependent on the tissue of origin. Additionally, a 3D-printable mesenchymal stem cells-bone matrix array (MSCBM), designed to closely mimic the stiffness of bone tissue, was developed to serve as a versatile tool for evaluating the effects of drugs and stem cells on bone repair in chronic diseases, such as OA. We demonstrated that the osteogenic differentiation process in cMSCs can be induced just by simulating bone stiffness in a 3D system. The expression of osteocalcin, RUNX2, and antioxidant enzymes was also assessed after treating MSCs with GSGa and/or increasing the stiffness of the culture environment. The printability of the array may enable better customization of the cavities, enabling an accurate replication of real bone defects. This could optimize the BM array to mimic bone defects not only in terms of stiffness, but also in terms of shape. This culture system may enable a rapid screening of antioxidant and anti-inflammatory compounds, facilitating a more personalized approach to regenerative therapy.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725938","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":"Perceptions of Cancer Through the Ages-From Hippocratic Oncology to Precision Cancer Medicine.","authors":"Spyros Retsas","doi":"10.3390/biom14111383","DOIUrl":"10.3390/biom14111383","url":null,"abstract":"<p><p>The unravelling of the human genome created new perceptions of the origin and evolution of diseases, and for cancer in particular, it established the notion that neoplasia has been a companion of life since its appearance on Earth. It is not surprising that neoplasms, in various forms, develop in numerous species of animals and even in plants. Unmistakable accounts of cancer with clinical features as are understood today begin in the 5th c. B.C. The principles and practice of the Hippocratic and Galenic tradition dominated cancer care virtually into the 20th century. Advanced sequencing technologies at the dawn of the 21st century generated new therapeutic opportunities with immunotherapy, oncolytic virotherapy, and gene transfer, with the latter especially being used in cases of hereditary cancer.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725745","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}