Discovery medicine最新文献

{"title":"Propofol Triggers Cell Death in Lung Cancer Cells by Increasing PANX1 Expression, Activating the Mitochondrial Cell Death Pathway, and Enhancing ROS Levels.","authors":"Jie Zhang, Anqing Chen, Yonggang Song","doi":"10.24976/Discov.Med.202436190.205","DOIUrl":"https://doi.org/10.24976/Discov.Med.202436190.205","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer treatment remains a global challenge due to tumor cell resistance. Propofol, traditionally used as an anesthetic, has demonstrated potential anti-tumor properties. This study seeks to elucidate how propofol induces cell death in lung cancer cells by upregulating Pannexin 1 (PANX1) expression, activating the mitochondrial cell death pathway, and augmenting reactive oxygen species (ROS) production.</p><p><strong>Methods: </strong>In this study, the A549 lung cancer cell line was employed as the experimental model. Cells underwent exposure to varying propofol concentrations and were pre-treated with H₂O₂ and N-acetylcysteine (NAC) to simulate oxidative stress and antioxidant conditions. Various techniques, including 5-Ethynyl-2'-deoxyuridine (EdU), colony formation, Transwell, 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA), Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL), and JC-1 (5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide) probes, were employed to evaluate propofol's effects on lung cancer cell viability, growth, invasion, ROS levels, apoptosis, and mitochondrial membrane potential. Western blot analysis was used to measure PANX1, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, and Cytochrome C (Cyt C) protein levels. Additionally, PANX1's influence on propofol-induced apoptosis was investigated through siRNA interference.</p><p><strong>Results: </strong>The experiment unveiled propofol's dose-dependent inhibition of A549 lung cancer cell growth, coupled with decreased cell proliferation and invasion attributable to heightened ROS production. Notably, propofol treatment significantly elevated mitochondrial membrane potential, signifying activation of the mitochondrial cell death pathway (<i>p</i> < 0.01). Furthermore, propofol upregulated PANX1 expression (<i>p</i> < 0.01), thereby intensifying apoptosis signaling, whereas PANX1 inhibition ameliorated propofol-induced apoptosis (<i>p</i> < 0.01). These findings underscore the pivotal role of PANX1 upregulation and ROS augmentation in propofol-induced apoptosis in lung cancer cells.</p><p><strong>Conclusion: </strong>This study provides evidence that propofol induces cell death in lung cancer cells by upregulating PANX1, activating the mitochondrial apoptosis pathway, and increasing ROS production. These findings suggest that targeting PANX1 and ROS could enhance the anti-cancer efficacy of propofol in lung cancer.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 190","pages":"2231-2243"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>BRIP1</i> Induced Ferroptosis to Inhibit Glioma Cells and was Associated with Increased Oxidative Stress.","authors":"Cheng Chen, Zhong-Hua Wu, Xiao-Jian Lu, Jin-Long Shi","doi":"10.24976/Discov.Med.202436190.208","DOIUrl":"https://doi.org/10.24976/Discov.Med.202436190.208","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Glioma, a malignant brain tumour, poses a significant threat to human life and well-being. Identifying new treatment targets is crucial. This study aimed to explore the impact of &lt;i&gt;BRIP1&lt;/i&gt; (BRCA1 interacting helicase 1) on glioma cell ferroptosis and its underlying mechanisms.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We utilized GEPIA (Gene Expression Profiling Interactive Analysis) to predict the expression of &lt;i&gt;BRIP1&lt;/i&gt; in glioma. The expression of &lt;i&gt;BRIP1&lt;/i&gt; was evaluated in normal brain glial cell lines (HEB) as well as two glioblastoma (GBM) cell lines (U87 and U251) using qRT-PCR (quantitative RT-PCR) and Western blot analyses. U251 cells were specifically chosen to investigate the impact of &lt;i&gt;BRIP1&lt;/i&gt; down-regulation and treatment with erastin (a ferroptosis activator) on cell viability and proliferation. In U251 cells, si-&lt;i&gt;BRIP1&lt;/i&gt; was administered in combination with the necroptosis inhibitor Necrostain-1 (Nec-1), apoptosis inhibitor Z-VAD-FMK (carbobenzoxy-valyl-alanyl-aspartyl- [O-methyl]-fluoromethylketone), autophagy inhibitor CQ (Chloroquine), pyroptosis inhibitor VX765 (Belnacasan), or ferroptosis inhibitor Fer-1 (ferrostain-1), as well as erastin+Fer-1, to determine the mode of programmed cell death using the CCK-8 (Cell counting kit-8) assay. Malondialdehyde (MDA) and glutathione (GSH) levels were measured using ELISA (Enzyme linked immunosorbent assay). Intracellular Fe&lt;sup&gt;2+&lt;/sup&gt; content was detected using a commercial reagent kit. &lt;i&gt;Gpx4&lt;/i&gt; (Glutathione peroxidase 4) levels were measured using Western blot analysis. The relationship between &lt;i&gt;BRIP1&lt;/i&gt; and &lt;i&gt;SLC7A11&lt;/i&gt; (Solute Carrier Family 7 Member 11) was verified by co-IP (co-immunoprecipitation) experiments. The level of &lt;i&gt;SLC7A11&lt;/i&gt; and &lt;i&gt;SLC3A2&lt;/i&gt; (Solute Carrier Family 3 Member 2) was analyzed through qRT-PCR and Western blot analyses. A rescue experiment was conducted to observe the effects of &lt;i&gt;SLC7A11&lt;/i&gt; overexpression on si-&lt;i&gt;BRIP1&lt;/i&gt;-treated U251 cells.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The GEPIA database predicted that the expression level of &lt;i&gt;BRIP1&lt;/i&gt; was increased in glioma. The expression level of &lt;i&gt;BRIP1&lt;/i&gt; was higher in U251 cells compared to HEB and U87 cells (&lt;i&gt;p&lt;/i&gt; &lt; 0.05). Both down-regulation of &lt;i&gt;BRIP1&lt;/i&gt; and treatment with erastin resulted in inhibited cell viability and proliferation in U251 cells (&lt;i&gt;p&lt;/i&gt; &lt; 0.05). The mode of programmed cell death in si-&lt;i&gt;BRIP1&lt;/i&gt;-treated U251 cells was ferroptosis. Following si-&lt;i&gt;BRIP1&lt;/i&gt; transfection or erastin treatment, there was an increase in the levels of MDA and intracellular Fe&lt;sup&gt;2+&lt;/sup&gt; content, as well as a decrease in the levels of GSH, &lt;i&gt;Gpx4&lt;/i&gt;, and &lt;i&gt;SLC7A11&lt;/i&gt; (&lt;i&gt;p&lt;/i&gt; &lt; 0.05). However, these alterations observed in the si-&lt;i&gt;BRIP1&lt;/i&gt; group were reversed by Fer-1 treatment (&lt;i&gt;p&lt;/i&gt; &lt; 0.05). The co-IP results demonstrated that BRIP1 and SLC7A11 were able to bind to each other. Up-regulation of &lt;i&gt;SLC7A11&lt;/i&gt; reversed the reduction","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 190","pages":"2264-2273"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulating Histone Deacetylases and Carbonic Anhydrases by Metal Complexes: A Potent Strategy for Treating Cancers.","authors":"Yen Thi Nguyen, Namdoo Kim, Hyuck Jin Lee","doi":"10.24976/Discov.Med.202436190.198","DOIUrl":"10.24976/Discov.Med.202436190.198","url":null,"abstract":"<p><p>Utilizing metal complexes to inhibit histone deacetylases (HDACs) and carbonic anhydrases (CAs) highlights their therapeutic potential, particularly in anticancer strategies. The metal complexes, with their unique three-dimensional structures, fit adequately into the active sites of the enzymes, not only improving selectivity but also providing facile coordination with amino acid residues to enhance their inhibitory ability. This review emphasizes the role of metal complexes in the selective inhibition of HDACs and CAs along with details of their mechanism of action. Additionally, we summarize the inhibition ability and cytotoxicity of metal complexes targeting HDACs and CAs, as well as the therapeutic implications that can lead to the invention and development of metal complexes as potent anticancer agents.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 190","pages":"2152-2174"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Risk Factors and Characteristics of Coronary Artery Lesions in Premature Acute Myocardial Infarction Patients.","authors":"Rong Wang, Shiqin Tu, Mingzhuo Tan, Lingyun Gao","doi":"10.24976/Discov.Med.202436190.207","DOIUrl":"https://doi.org/10.24976/Discov.Med.202436190.207","url":null,"abstract":"<p><strong>Background: </strong>The incidence of atherosclerotic cardiovascular disease (ASCVD) is increasing, with individuals experiencing acute myocardial infarction (AMI) at a younger age. Premature AMI is a serious condition with high rates of morbidity and mortality. This study aimed to identify clinical characteristics and risk factors associated with premature AMI and to evaluate the diagnostic value of those risk factors.</p><p><strong>Methods: </strong>The study collected data from first-time AMI patients who underwent coronary angiography at the hospital between January 2022 and April 2023. They were divided into two groups by age: premature AMI (men <55 years, women <65 years) and non-premature AMI. A control group of similar-aged patients without coronary artery disease was also included.</p><p><strong>Results: </strong>Out of 388 patients with first-time AMI, 313 were male, and 249 had ST-segment elevation myocardial infarction (STEMI). Among 73 control patients, 31 were male. Those with premature AMI had more risk factors like smoking, overweight, obesity, family history of coronary artery disease, and STEMI. They also had shorter hospital stays and higher diastolic blood pressure and faster heart rates. Single-vessel lesions were more frequent in premature AMI patients. After adjusting for confounding factors, smoking status (Odds ratio (OR) 4.454, 95% confidence interval (CI): 1.836-10.806, <i>p</i> = 0.001), glycated hemoglobin (HbA1c) level (OR 2.261, 95% CI: 1.219-4.193, <i>p</i> = 0.010), the non-high-density lipoprotein cholesterol (non-HDL-C)/HDL-C ratio (OR 4.394, 95% CI: 1.204-16.031, <i>p</i> = 0.025), and the monocyte-to-high-density lipoprotein ratio (MHR) (OR 6.164, 95% CI: 1.386-27.417, <i>p</i> = 0.017) were identified as independent risk factors for premature AMI development. The combination of these risk factors provided the greatest predictive value for premature AMI (area under the curve (AUC) = 0.874, 95% CI: 0.826-0.922, <i>p</i> < 0.001, sensitivity = 0.843, specificity = 0.795).</p><p><strong>Conclusions: </strong>Premature AMI is often characterized by STEMI, single-vessel lesions, and a low occurrence of left main coronary artery involvement. Smoking status, HbA1c levels, the non-HDL-C/HDL-C ratio, and the MHR are significantly associated with premature AMI.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 190","pages":"2253-2263"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiotensin-converting Enzyme 2 Suppresses Pulmonary Fibrosis Associated with Wnt and TGF-β1 Signaling Pathways.","authors":"Yanhua Tang, Ju Liu, Ling Liu","doi":"10.24976/Discov.Med.202436190.209","DOIUrl":"https://doi.org/10.24976/Discov.Med.202436190.209","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Pulmonary fibrosis is a severe respiratory condition marked by the formation of scar tissue in the lungs, which makes it distinguishable from atypical fibrosis. The specific mechanisms of angiotensin-converting enzyme 2 (ACE2) in pulmonary fibrosis are still unclear, although it has been demonstrated to have a significant role in this condition. The objective of this study was to examine the impact of ACE2 on lung fibrosis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Both &lt;i&gt;in vivo&lt;/i&gt; and &lt;i&gt;in vitro&lt;/i&gt; experimental approaches were employed in this study to evaluate the function of ACE2. In the &lt;i&gt;in vivo&lt;/i&gt; experiments, an animal model of pulmonary fibrosis was established by injecting 0.1 mL of bleomycin solution into C57BL/6 male mice, and the effects of ACE2 overexpression on pulmonary fibrosis were observed, for the animal group overexpressing ACE2 (Model+ACE2 group), treatments with SB505124 (transforming growth factor-β type I receptor (TGF-βRI) (ALK5) inhibitor) and XAV939 (Wnt Family Member 3a (Wnt3a) inhibitor) were administered, to evaluate the effects of these pathway inhibitors on ACE2 overexpression in the treatment of pulmonary fibrosis. Lung tissue samples were collected from the animals and subjected to pathological examination (hematoxylin and eosin (HE) and Masson's trichrome staining) to assess the degree of pathological inflammation and fibrosis. Concurrently, the expression levels of proteins and genes related to the ACE2, Wnt/glycogen synthase kinase (GSK)-3β/β-catenin, and TGF-β1/Smad2 signaling pathways were measured using Western blotting and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) techniques. In the &lt;i&gt;in vitro&lt;/i&gt; experiments, pulmonary fibrosis was simulated in human lung fibroblasts (HLFs), which were stimulated with TGF-β1. The correlation of ACE2 overexpression to attenuate pulmonary fibrosis with Wnt/GSK-3β/β-catenin and TGF-β1/Smad2 signaling pathways was explored.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The ACE2 overexpression could effectively reduce pulmonary fibrosis and inflammation in mice and HLFs by modulating signaling pathways (&lt;i&gt;p&lt;/i&gt; &lt; 0.01). In mice, ACE2 reduced inflammation and collagen accumulation, decreasing levels of α-smooth muscle actin (α-SMA) and fibronectin (&lt;i&gt;p&lt;/i&gt; &lt; 0.01). Compared to the Model+ACE2 group, the Model+ACE2+SB505124 underwent a greater reduction in inflammation and fibrosis, as well as decreased levels of α-SMA and fibronectin (&lt;i&gt;p&lt;/i&gt; &lt; 0.05). Overexpression of ACE2, XAV939, and SB505124 all significantly reduced the expression levels of Wnt3a, β-catenin, p-GSK-3β, TGF-β1, and p-Smad2 proteins in mice with pulmonary fibrosis (&lt;i&gt;p&lt;/i&gt; &lt; 0.05). In HLFs, ACE2 counteracted TGF-β1 effects, reducing cell proliferation and levels of fibrosis markers such as collagen, α-SMA and fibronectin (&lt;i&gt;p&lt;/i&gt; &lt; 0.01). It also inhibited the TGF-β1-induced epithelial-mesenchymal transition (EMT), showcasing its therapeutic potential against l","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 190","pages":"2274-2286"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Daphnetin Modulates Immune Balance and Enhances Pregnancy Viability in a Mouse Model of Unexplained Recurrent Abortion.","authors":"Sheng-Gen Long, Zhi-Qin Zhang, Jun Tan","doi":"10.24976/Discov.Med.202436190.199","DOIUrl":"https://doi.org/10.24976/Discov.Med.202436190.199","url":null,"abstract":"<p><strong>Background: </strong>Our previous research revealed that daphnetin (7,8-dihydroxycou-marin) positively influences the balance between forked transcription factor P3 (<i>Foxp3</i>+) regulatory T cells (Treg) and T helper 17 (Th17) cells in the peripheral blood mononuclear cells of individuals with unexplained recurrent pregnancy loss. However, the specific mechanism remains unclear. This research aims to further examine how daphnetin regulates the Th17 cell/<i>Foxp3</i>+ Treg cell imbalance in a mouse model with unexplained recurrent spontaneous abortion (URSA).</p><p><strong>Methods: </strong>Mice (n = 40) were allocated into the following groups: daphnetin high dose (4 mg/kg·day), daphnetin low dose (1 mg/kg·day), URSA model, and normal pregnancy (control). We used flow cytometry for assessing the Th17/Treg cell ratio in peripheral blood mononuclear cells, quantitative real-time polymerase chain reaction for measuring cytokine expression levels, and transmission electron microscopy for observing ultrastructural changes in decidual tissues and calculating the embryo absorption rate.</p><p><strong>Results: </strong>Compared to the URSA model group, daphnetin significantly reduced the T17cell/<i>Foxp3</i>+ Treg cell ratio in peripheral blood mononuclear cells. Daphnetin also decreased the expression of Th17 cell-related cytokines, including orphan nuclear receptor γt (<i>RORγt</i>) and signal transduction and transcriptional activator 3 (STAT3), as well as increase the expression of <i>Foxp3</i>+ Treg cells-related cytokines, including STAT5 and <i>Foxp3</i>+. Furthermore, daphnetin reduced the embryo absorption rate and improved the decidual tissue ultrastructure of URSA model mice.</p><p><strong>Conclusion: </strong>Daphnetin improves the Th17 cell/<i>Foxp3</i>+ Treg cell imbalance in URSA model mice, thereby contributing to the repair of decidual tissue damage and reducing the embryo absorption rate. These findings suggest that daphnetin may offer a new method for treating URSA.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 190","pages":"2175-2181"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monkeypox Resurgence: A Global Health Challenge Navigating Zoonotic Spillover, Genomic Evolution, and Strategic Response.","authors":"Abdelazeem Mohamed Algammal, Muhammad Shafiq","doi":"10.24976/Discov.Med.202436190.212","DOIUrl":"https://doi.org/10.24976/Discov.Med.202436190.212","url":null,"abstract":"","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 190","pages":"2309-2312"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of Ankyrin-G on Nav1.5 Channel in Hypoxic HL-1 Cardiac Muscle Cells.","authors":"Shanshan Ma, Shuqin Yang, Peng Xu, Wenshui Li, Yang Wang, Chenyang Wang, Heling Huang, Yang Li, Xuebin Cao","doi":"10.24976/Discov.Med.202436190.201","DOIUrl":"https://doi.org/10.24976/Discov.Med.202436190.201","url":null,"abstract":"<p><strong>Background: </strong>Hypoxia has a major regulatory impact on the electrical activity transmission in the myocardium, and it is involved in the development of tachyarrhythmia disease. Anchor protein G (ankyrin-G, ANK-G) is associated with voltage-gated Na⁺ channels (Nav1.5), but its specific role and mechanism have not been fully defined. In this experiment, we investigated the role and mechanism of hypoxia on cardiomyocyte electrophysiology of voltage-gated Na⁺ channel, as well as the intervention effect of ankyrin-G by simulating the environment of cardiomyocytes during hypoxia through hypoxia-treated murine atrial myocytes (HL-1).</p><p><strong>Methods: </strong>The HL-1 cells were divided into 6 groups: normoxia group (NO), hypoxia group (HO), <i>ANK-G</i>-overexpressing hypoxia-negative group (ANK-G NC), <i>ANK-G</i>-overexpressing hypoxia group (ANK-G), <i>ANK-G</i>-silenced hypoxia-negative group (sh<i>ANK-G</i> NC), and <i>ANK-G</i>-silenced hypoxia group (sh<i>ANK-G</i>). <i>ANK-G</i> overexpression was induced using lentiviral vectors through the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system. The characteristics of sodium ion channel current (I_Na) were observed through the whole-cell patch clamp technique. Western blotting was used to detect the expression of ANK-G and Nav1.5 channel proteins, and the distribution of Nav1.5 channel on HL-1 cells was observed by confocal microscope.</p><p><strong>Results: </strong>Under hypoxic conditions, the I_Na peak current amplitude (<i>p</i> < 0.01) and density (<i>p</i> < 0.01) of HL-1 cells increased. Compared with the normoxia group, the steady-state inactivation curve of the hypoxia group shifted to the right. The protein levels of ANK-G and Nav1.5 channels were increased under hypoxia (<i>p</i> < 0.001). In the ANK-G group, the upregulation of ANK-G protein increased the distribution of Nav1.5 channel in the cell membrane under the hypoxic condition (<i>p</i> < 0.01).</p><p><strong>Conclusions: </strong>Hypoxia increases the I_Na amplitude and density of HL-1 cells, and the gating mechanism of I_Na is related to steady-state inactivation. Hypoxic condition triggers the upregulation of the ANK-G protein expression, which promotes the redistribution of Nav1.5 channel proteins in the cell membrane, thereby augmenting I_Na peak current amplitude and density.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 190","pages":"2191-2201"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bipolar Disorder and Ubiquitin Proteasome System Dysfunction: Peripheral Blood Levels of Molecules Playing a Role in Ubiquitination and Their Relationship to Sleep Quality.","authors":"Ünsal Aydιnoğlu, Ece Yazla, İhsan Çetin, Huseyin Kayadibi","doi":"10.24976/Discov.Med.202436190.206","DOIUrl":"https://doi.org/10.24976/Discov.Med.202436190.206","url":null,"abstract":"<p><strong>Background: </strong>Bipolar disorder (BD) is a serious mood disorder, notable for its morbidity and prevalence. It ranks among the top 10 diseases globally in terms of functional impairment among affected individuals. Studies investigating neurobiological processes in the development of BD also aim to identify biological markers. Ubiquitin is a protein that is abundant in all eukaryotic cells and regulates many processes through the ubiquitin-proteasome system. It has been reported to be associated with circadian rhythm and sleep disorders. Circadian rhythm plays a key role in maintaining mood stability in individuals with BD. In this study, we investigated the peripheral levels of molecules involved in the ubiquitination process and their relationship to sleep quality in individuals with BD.</p><p><strong>Methods: </strong>Forty-nine patients with BD and 50 healthy volunteers without any psychiatric disorders were included. The Pittsburgh Sleep Quality Index, the Young Mania Rating Scale, and the Hamilton Depression Rating Scale were administered to the participants. Peripheral blood levels of proteins and enzymes that play a role in ubiquitination processes were determined by the immunosorbent assay method.</p><p><strong>Results: </strong>TAR DNA-binding protein-43 (TDP-43) (<i>p</i> < 0.001), ubiquitin C-terminal hydrolase-L1 enzyme (UCH-L1) (<i>p</i> = 0.037), ubiquitin C-terminal hydrolase-L3 enzyme (UCH-L3) (<i>p</i> = 0.007), histone deacetylase I (Histone Dea-1) (<i>p</i> = 0.006), histone deacetylase II (Histone Dea-2) (<i>p</i> = 0.047), and ligase cullin-3 (<i>p</i> = 0.031) levels were found to be significantly lower in the BD group than in the control group, but these parameters were not associated with sleep quality scores in the BD group.</p><p><strong>Conclusions: </strong>Our results support the data in the literature but show that the ubiquitination process can be affected in BD patients without being associated with sleep quality.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 190","pages":"2244-2252"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Irisin Treatment Prevents Isoproterenol-Induced Cardiac Fibrosis in Mice.","authors":"Clelia Suriano, Roberta Zerlotin, Patrizia Pignataro, Manuela Dicarlo, Angela Oranger, Luciana Zanfino, Adriano De Santis, Silvia Tunnera, Silvia Colucci, Maria Grano, Graziana Colaianni","doi":"10.24976/Discov.Med.202436190.202","DOIUrl":"https://doi.org/10.24976/Discov.Med.202436190.202","url":null,"abstract":"<p><strong>Background: </strong>Cardiac fibrosis is a pathophysiological process that occurs as the end stage of cardiovascular diseases. Irisin is a myokine secreted mainly by skeletal muscle exerting pleiotropic effects. Previous studies found altered irisin levels in patients with cardiovascular diseases and irisin has been shown to preserve cardiac function after ischemia-reperfusion injury in mice. This study aimed to explore whether pretreatment with irisin prevents cardiac fibrosis induced in mice through a single injection of the beta-adrenergic agonist isoproterenol at a high dose.</p><p><strong>Methods: </strong>The cardiac fibrosis model was obtained through a single intraperitoneal administration of 160 mg/kg isoproterenol [ISO] in young C57BL/6J mice. Before ISO injection, mice were pretreated with irisin 100 μg/kg/week [irisin-ISO] or saline [veh-ISO] for 4 weeks. A third group of mice received saline for 4 weeks without ISO injection [CTRL].</p><p><strong>Results: </strong>The mice pretreated with irisin recovered faster than vehicle-treated mice after acute ISO stimulation, as measured by behavioral test. Twenty-four hours after ISO treatment, the serum levels of Troponin I were significantly lower in the group of mice pretreated with irisin compared with veh-ISO mice (<i>p</i> = 0.0117). Moreover, the expression of atrial natriuretic peptide (<i>p</i> = 0.0197) and alpha-smooth muscle actin (<i>p</i> = 0.0261) mRNAs in cardiac tissue of veh-ISO mice were 10- and 15-fold higher than CTRL mice, respectively, while pretreatment with irisin maintained their expression at control levels. Interestingly, 7 days after ISO, the expression of alpha-smooth muscle actin mRNA was still significantly lower in the irisin-ISO group than in the veh-ISO group (<i>p</i> = 0.0145). Moreover, we found increased cardiac hypertrophy, measured as heart-weight/tibia-length ratio, in veh-ISO mice versus CTRL mice (<i>p</i> = 0.0312) which was fully prevented in irisin-ISO mice (<i>p</i> = 0.0258). The cardiac fibrosis score assessed by Masson's trichrome staining was significantly lower in irisin-ISO mice versus veh-ISO mice (<i>p</i> = 0.0261). Notably, some mitochondrial genes, previously identified as controlled by irisin, were markedly increased in the early phase following ISO, whereas irisin maintained their expression similar to controls.</p><p><strong>Conclusion: </strong>Our results demonstrate the beneficial effect of irisin in preventing isoproterenol-induced cardiac hypertrophy and fibrosis.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 190","pages":"2202-2213"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}