Discovery medicine最新文献

{"title":"FMO1 Promotes Nonalcoholic Fatty Liver Disease Progression by Regulating PPARα Activation and Inducing Ferroptosis.","authors":"Lin Zou,&nbsp;Qin Shi,&nbsp;Yingxuan Li,&nbsp;Zhen Yuan,&nbsp;Li Peng,&nbsp;Jiancan Lu,&nbsp;Hongling Zhu,&nbsp;Junhua Ma","doi":"10.24976/Discov.Med.202335177.60","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335177.60","url":null,"abstract":"<p><strong>Background: </strong>The function of flavin containing dimethylaniline monooxygenase 1 (FMO1), which is known to play a part in lipid metabolism, remains unclear in the development of nonalcoholic fatty liver disease (NAFLD). This research has the objective of examining the contributions of FMO1 in the progression of NAFLD and the associated mechanisms, particularly the peroxisome proliferator activated receptor alpha (PPARα) and ferroptosis pathways.</p><p><strong>Methods: </strong>An <i>in vitro</i> NAFLD model was established by treating L02 cells with free fatty acids (FFAs). The FMO1 and ferroptosis levels were examined in the cellular NAFLD model. <i>FMO1</i> was knocked down using short-interfering RNA transfection. The effects of <i>FMO1</i> knockdown on lipid accumulation, PPARα expression, and ferroptosis were examined in the cellular NAFLD model. Additionally, the effects of <i>FMO1</i> and/or <i>PPARα</i> overexpression on lipid metabolism and ferroptosis were analyzed. Furthermore, L02 cells were pre-treated with GW7647 (PPARα agonist) or RSL3 (ferroptosis activator) and stimulated with FFAs.</p><p><strong>Results: </strong>The levels of FMO1 and ferroptosis were upregulated in the <i>in vitro</i> NAFLD model. <i>FMO1</i> knockdown suppressed the FFA-induced accumulation of lipids in hepatocytes, downregulation of PPARα expression, and upregulation of ferroptosis. In contrast, <i>FMO1</i> overexpression dysregulated lipid metabolism and downregulated PPARα levels. Meanwhile, <i>PPARα</i> overexpression mitigated the <i>FMO1</i> overexpression-induced upregulation of ferroptosis and lipid accumulation. Treatment with RSL3 suppressed the effects of <i>PPARα</i> overexpression on lipid accumulation and FMO1 expression.</p><p><strong>Conclusions: </strong>FMO1 upregulates ferroptosis by suppressing PPARα in NAFLD, which leads to the dysregulation of lipid metabolism.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 177","pages":"612-622"},"PeriodicalIF":1.4,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10195772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mice, Rats and Guinea Pigs Exhibit Significant Variations in the Plasma, Urine and Tissue Levels of Taurine, Betaine, Sarcosine and Other Osmolyte-Active Amino Acids.","authors":"Lenka Tomasova,&nbsp;Klaudia Maksymiuk,&nbsp;Dawid Chabowski,&nbsp;Emilia Samborowska,&nbsp;Marcin Ufnal","doi":"10.24976/Discov.Med.202335177.50","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335177.50","url":null,"abstract":"<p><strong>Background: </strong>Osmolytes are naturally occurring compounds that protect cells from osmotic stress in high-osmolarity tissues, such as the kidney medulla. Some amino acids, including taurine, betaine, glycine, alanine, and sarcosine, are known to act as osmolytes. This study aimed to establish the levels of these amino acids in body fluids and tissues of laboratory animals used as models for human diseases in biomedical research.</p><p><strong>Methods: </strong>Liquid chromatography coupled with mass spectrometry was used to quantify taurine, glycine, betaine, alanine, beta-alanine, and sarcosine in plasma, urine, and tissues of adult, male mice, rats and guinea pigs.</p><p><strong>Results: </strong>Among the species analyzed, taurine was found to have the highest tissue concentrations across all compounds, with the heart containing the greatest amount. In guinea pigs, betaine levels were higher in the renal medulla than in the renal cortex (<i>p</i> < 0.01), while in rats and mice, there were no significant differences in betaine levels between the kidney cortex and medulla. The urine of guinea pigs had lower levels of sarcosine compared to rats (<i>p</i> < 0.001), while the plasma (<i>p</i> < 0.05; > 0.05), heart (<i>p</i> < 0.05; < 0.05), lungs (<i>p</i> < 0.01; < 0.01), liver (<i>p</i> < 0.001; < 0.05), and kidneys (<i>p</i> < 0.01; < 0.01) of rats exhibited notably higher concentrations of sarcosine compared to both mice and guinea pigs, respectively.</p><p><strong>Conclusions: </strong>There are pronounced differences in the concentrations of taurine, betaine, and other amino acids across the investigated species. It is important to acknowledge these differences when selecting animal models for preclinical studies and to account for variations in amino acid concentrations when selecting amino acids doses for interventional studies.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 177","pages":"492-502"},"PeriodicalIF":1.4,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10493986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory Mediators and GBM Malignancy: Current Scenario and Future Prospective.","authors":"Ilya Ulasov,&nbsp;Vaishali Singh,&nbsp;Anastasia Laevskaya,&nbsp;Peter Timashev,&nbsp;Rajesh Kumar Kharwar","doi":"10.24976/Discov.Med.202335177.47","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335177.47","url":null,"abstract":"<p><p>Glioblastoma multiforme is one of the most widespread and dangerous forms of brain tumor with high inflammation. The tumor microenvironment comprises diverse tumor cells, different types of immune cells, and the extracellular matrix. Inflammatory mediators like chemokines, cytokines, and growth factors possibly serve as a capable therapeutic target to quash their tumor-promoting properties in glioblastoma multiforme (GBM). Cytokines are a heterogeneous group of soluble functional proteins which are also associated with the induction and progression of tumors. These are supposed to have both pro-inflammatory (such as tumor necrosis factor-α (TNF-α), interleukin-17A (IL-17A), interferon-γ (IFN-γ), IL-4, IL-2, IL-6, IL-12, IL-13) and anti-inflammatory (such as transforming growth factor-β (TGF-β), IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF)) actions and are the crucial communications channels in the tumor microenvironment. In the present minireview we discuss the tumor microenvironment and inflammatory mediators and focus on the involvement of cytokines in establishing communication with the tumor microenvironment. The presented data highlight the possible roles of cytokines in communication between glioblastoma cells and tumor microenvironment. Cytokines formed by immune cells protect the host organs while cytokines secreted by tumor cells are used for their advantage. Though the clinical trials with a number of immunotherapeutic agents are going on around the globe, there is still a requirement for thorough investigation of the regulatory mechanism managing GBM growth, recurrence, and tumor response to the therapy.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 177","pages":"458-475"},"PeriodicalIF":1.4,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10493985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Action Mechanisms, Anti-Cancer and Antibiotic-Modulation Potential of <i>Vaccinium myrtillus</i> L. Extract.","authors":"Mikayel Ginovyan,&nbsp;Anush Babayan,&nbsp;Anahit Shirvanyan,&nbsp;Alvard Minasyan,&nbsp;Meri Qocharyan,&nbsp;Barbara Kusznierewicz,&nbsp;Izabela Koss-Mikołajczyk,&nbsp;Nikolay Avtandilyan,&nbsp;Anne Vejux,&nbsp;Agnieszka Bartoszek,&nbsp;Naira Sahakyan","doi":"10.24976/Discov.Med.202335177.59","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335177.59","url":null,"abstract":"<p><strong>Background: </strong>Herbal medicinal products containing <i>Vaccinium myrtillus</i> L. (bilberry) fruits and fruit extracts are widely available in the market. Although bilberry leaves and stems are considered as bio-waste, they contain much higher levels of phenolic compounds than fruits. The study aimed to investigate the antimicrobial and anticancer potential of aerial part extracts from <i>Vaccinium myrtillus</i> L. (<i>V. myrtillus</i>, VM) plants harvested at high altitudes in Armenian landscape and characterize the bioactive phytochemicals.</p><p><strong>Material and methods: </strong>For evaluation of antioxidant properties, chemical-based tests (total phenolic and flavonoid content, and antiradical activity in 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) tests) and cellular antioxidant activity (CAA) assay were applied. Genotoxicity and anticancer properties of the extract alone and in combination with fluorouracil were explored in human cancer and normal cell lines. Antibacterial properties of <i>V.</i> <i>myrtillus</i> extract alone and in combination with antibiotics, as well as their effect on proton-flux rate through cell membrane were explored on bacterial strains. The characterization of active phytochemicals was done using Liquid Chromatography-Quadrupole-Orbitrap High-Resolution Mass Spectrometry (LC-Q-Orbitrap HRMS).</p><p><strong>Results: </strong>The <i>V. myrtillus</i> aerial part extract demonstrated promising antioxidant properties in all tests. The selective cytotoxic activity was documented against various cancer cell lines (human colon adenocarcinoma (HT29), human breast cancer (MCF-7) and human cervical carcinoma (HeLa)), while it did not inhibit the growth of tested human normal primary renal mixed epithelial cells (HREC) even at 10-fold higher concentrations. The extract did not have genotoxic properties in comet assay making it a potential source for the development of anticancer preparations. The investigated extract did not directly inhibit the growth of <i>Escherichia coli</i> (<i>E. coli</i>) and <i>Salmonella typhimurium</i> (<i>S. typhimurium</i>) strains at up to 1 mg/mL concentration. However, <i>V. myrtillus</i> extract enhanced the kanamycin intake and increased its efficiency against <i>E. coli</i> strain. The phytochemical characterization of the extract showed the presence of different groups of phenolics.</p><p><strong>Conclusions: </strong>Based on obtained data, we suggest the aerial parts of the <i>V. myrtillus</i> plant as an alternative source of bioactive natural products for food supplements, nutraceuticals, functional foods and medicine.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 177","pages":"590-611"},"PeriodicalIF":1.4,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10140279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low Dose of 5-Aminolevulinic Acid Hydrochloride Alleviates the Damage in Cardiomyocytes Induced by Lenvatinib via PI3K/AKT Signaling Pathway.","authors":"Yun Shi,&nbsp;Fengying Hu,&nbsp;Hao Fu,&nbsp;Shaojie Li,&nbsp;Chengzhi Lu,&nbsp;Chunxiu Hu","doi":"10.24976/Discov.Med.202335177.49","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335177.49","url":null,"abstract":"<p><strong>Background: </strong>Lenvatinib is an oral tyrosine kinase inhibitor (TKI), and has been applied in the clinical trials for the treatment of hepatocellular carcinoma (HCC). The function of 5-aminolevulinic acid hydrochloride (ALA) treatment in protecting cardiomyocytes under lenvatinib stimulation was investigated.</p><p><strong>Methods: </strong>H9c2 cells were treated with 2 mg/mL lenvatinib for 48 h and 1 mM ALA in the lenvatinib with low dose 5-aminolevulinic acid treatment group (LL) group, 10 mM ALA in the lenvatinib with high-dose 5-aminolevulinic acid treatment group (LH) group and cells without treatment were used as an internal control. C57/BL mice were treated with 10 mg/kg lenvatinib and 200 mg/kg ALA in the LL group and 400 mg/kg ALA in the LH group by gavage once per day for 4 weeks. The proliferation ability of cells was detected using the methyl thiazolyl tetrazolium (MTT) assay. Target gene expression was calculated through real-time quantitative PCR (qPCR), and target protein expression was calculated through Western blotting analysis. The concentrations of cardiovascular protective factors were detected using enzyme linked immunosorbent assay (ELISA).</p><p><strong>Results: </strong>In these experiments, 10 mM ALA significantly increased the viability rate of cardiomyocytes (105.4 ± 8.0%) compared with the single lenvatinib treatment group (73.2 ± 6.5%). We also noticed that activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways were activated after low-dose ALA treatment. 5-ALA treatment led to the downregulation of intercellular cell adhesion molecule-1 (ICAM-1) (0.81- and 0.71-fold), vascular cell adhesion molecule (VCAM) (0.63- and 0.66-fold), angiotensin I (ANGI) (0.88- and 0.66-fold), ANGII (0.66- and 0.48-fold) and upregulation of endothelial nitric oxide synthases (eNOS) (1.25- and 1.89-fold) compared with non 5-ALA treatment group.</p><p><strong>Conclusions: </strong>With more experiments on animal models, low-dose of ALA treatment might be a therapeutic strategy to alleviate the damage to cardiomyocytes induced by lenvatinib.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 177","pages":"483-491"},"PeriodicalIF":1.4,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10195765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gentiopicroside Ameliorates Cerebrovascular Angiogenesis, Neuronal Injury and Immune Disorder in Rats with Cerebral Ischemia/Reperfusion Injury via VEGF and Phosphorylated Nrf2 Elevation.","authors":"Lin Zhang,&nbsp;Xiuli Chu,&nbsp;Chen Xu,&nbsp;Gang Cui","doi":"10.24976/Discov.Med.202335177.57","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335177.57","url":null,"abstract":"BACKGROUND\u0000Cerebral ischemia-reperfusion (CI/R) injury is induction of blood flow restoration after an ischemic stroke. Gentiopicroside (GPC) is the principal active secoiridoid glycoside of Gentiana Manshurica Kitagawa. This research aimed to illuminate the function of GPC and its mechanism in CI/R injury.\u0000\u0000\u0000METHODS\u0000After CI/R injury models were constructed, GPC (25, 50 or 100 mg/kg) was then administered by gavage to rats. Rats were grouped into Sham, CI/R, CI/R+25 mg/kg GPC, CI/R+50 mg/kg GPC, and CI/R+100 mg/kg GPC. Neuronal cells were exposed to oxygen-glucose deprivation and reperfusion (OGD/R) injury to establish ischemic-like conditions in vitro, and cells were further treated with 25, 50, or 100 μM GPC. Cells were grouped into control, OGD/R, OGD/R+25 μM GPC, OGD/R+50 μM GPC, and OGD/R+100 μM GPC. GPC's function on rat cerebral injury, angiogenesis, oxidative stress, neuronal injury and immune dysfunction in vivo was estimated using hematoxylin-eosin staining, Western blot, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, commercial kits and enzyme linked-immunosorbent assay. Meanwhile, GPC's mechanism in CI/R injury was examined via Western blot. GPC's function in vitro was estimated via Cell Counting Kit-8 assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, flow cytometry.\u0000\u0000\u0000RESULTS\u0000GPC alleviated cerebral injury through decreasing cerebral infarction volume, cerebral indexes, brain water contents (p < 0.05). GPC reduced oxidative stress and boosted cerebral angiogenesis in CI/R rats (p < 0.05). Meanwhile, GPC weakened neuronal cell apoptosis, and decreased neuron-specific enolase and S100beta protein levels in CI/R rats. GPC reduced inflammatory cytokines contents in serum and brain tissues of CI/R rats (p < 0.05). Moreover, GPC increased the viability and proliferation in OGD/R-treated neuronal cells, but decreased cell apoptosis (p < 0.05). Mechanistically, GPC upregulated vascular endothelial growth factor (VEGF) and phosphorylated nuclear factor E2-related factor 2 (p-Nrf2) levels in CI/R rat brain tissues (p < 0.05).\u0000\u0000\u0000CONCLUSIONS\u0000GPC reduced cerebrovascular angiogenesis, neuronal injury and immune disorder in CI/R injury through elevating VEGF and p-Nrf2.","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 177","pages":"565-575"},"PeriodicalIF":1.4,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10195770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using Machine Learning to Identify Risk Factors and Establishing a Clinical Prediction Model to Predict Atherosclerosis Complications in Idiopathic Membranous Nephropathy.","authors":"Yipeng Chen,&nbsp;Ying He,&nbsp;Guangqun Xing","doi":"10.24976/Discov.Med.202335177.52","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335177.52","url":null,"abstract":"<p><strong>Background: </strong>Clinically, it has been observed that patients with idiopathic membranous nephropathy (IMN) have a higher probability of coronary heart disease. We aim to investigate the risk factors associated with coronary heart disease in IMN patients using a mechanomics approach and establish a clinical diagnosis model.</p><p><strong>Methods: </strong>We collected sixty-nine clinical data points from patients undergoing phospholipase A2 receptor (anti-PLA2R) tests at the Affiliated Hospital of Qingdao University between July 9, 2019 and March 15, 2021. We excluded patients with cancer, hepatitis B, recent injuries or surgeries, and those under 18. Finally, 162 patients were considered for our study, which included 73 patients with coronary heart disease. The patients were split into test and validation groups at a 7:3 ratio. We utilized the Mann-Whitney U test for initial factor screening and the least absolute shrinkage and selection operator (LASSO) regression for further index screening. Eventually, the effectiveness of the clinical model was evaluated through visual statistical methods.</p><p><strong>Results: </strong>Age, lymphocyte count, the sum of high-density lipoprotein (HDL) and low-density lipoprotein (LDL), serum creatinine, and antithrombin III were risk factors for coronary heart disease in patients with idiopathic membranous nephropathy in a multivariate regression (<i>p</i> < 0.1). In the training group, 14 clinical features were finally screened by the LASSO regression, and the area under the curve (AUC) of the training group was 0.90 (95% CI 0.877-0.959), accuracy (ACC) was 0.85, sensitivity was 0.76, specificity was 0.91, and precision was 0.85. F1 scored 0.80. In the verification group, AUC was 0.84 (0.743-0.927), ACC was 0.80, sensitivity was 0.67, specificity was 0.87, precision was 0.75, and F1 scored 0.71. We then visualized them using a nomogram based on multivariate regression. The C index and clinical decision curve evaluated them. The C index was 83.8%, and the clinical decision curve was also excellent.</p><p><strong>Conclusions: </strong>We've established an effective clinical prediction model for patients with IMN who also have coronary heart disease. This model holds significant potential for enhancing clinical decision-making.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 177","pages":"517-524"},"PeriodicalIF":1.4,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10195767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macula Densa Nitric Oxide Synthase 1 Controls Renin Release and Renin-Dependent Blood Pressure Changes.","authors":"Catherine Liu, Ximing Wang, Colby Parris, Qi Pang, Muhammad Usman Naeem, Lei Wang","doi":"10.24976/Discov.Med.202335177.53","DOIUrl":"10.24976/Discov.Med.202335177.53","url":null,"abstract":"<p><strong>Background: </strong>The function of macula densa nitric oxide synthase 1 (NOS1) in the regulation of renin release is controversial. This study was conducted to further elucidate the role of macula densa NOS1 in renin release and blood pressure regulation in response to salt challenges and hemorrhagic shock.</p><p><strong>Methods: </strong>To investigate the specific role of NOS1 in the macula densa within the kidney in response to varying sodium concentrations in the diet, tissue macula densa-specific NOS1 knockout (MD-NOS1KO) and wild type (WT) mice were subjected to sequential low (0.1% NaCl) and high (1.4% NaCl) sodium diets. Separate groups of mice, consisting of both MD-NOS1KO subgroup and WT subgroup, were induced hemorrhagic shock by retro-orbital bleeding of 12 mL blood/kg body weight. Mean arterial pressure (MAP) was measured by a radio-telemetry system. Plasma renin concentration (PRC) was measured with the radioimmunoassay for both sodium diet and hemorrhagic shock experiments.</p><p><strong>Results: </strong>PRCs were 371 ± 95 and 411 ± 68 ng/mL/hr in WT and MD-NOS1KO mice fed a normal sodium diet, respectively. Low salt intake stimulated an increase in the renin release by about 260% in WT mice (PRC = 1364 ± 217 ng/mL/hr, <i>p</i> < 0.0001) compared to the PRC under normal salt diet. However, the stimulation was significantly blunted in MD-NOS1KO mice (PRC = 678 ± 104 ng/mL/hr, <i>p</i> < 0.001). High salt intake suppressed the PRC to about 61% of the PRC level under a normal salt diet (<i>p</i> < 0.0001). Deletion of macula densa NOS1 further inhibited renin release to 33% of the levels of a normal salt diet. Hemorrhagic shock induced about a 3-fold increase in PRC in WT mice, but only about a 54% increase in the MD-NOS1KO mice (<i>p</i> < 0.0001). The MAP values were substantially greater in WT mice than in MD-NOS1KO mice within the first 6 hours following hemorrhagic shock (<i>p</i> < 0.001). Thus, WT mice showed a much quicker recovery in MAP than MD-NOS1KO mice.</p><p><strong>Conclusions: </strong>Our study demonstrated that macula densa NOS1 plays an important role in mediating renin release. This mechanism is essential in maintaining blood pressure under hypovolemic situations such as hemorrhagic shock.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 177","pages":"525-532"},"PeriodicalIF":1.4,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10921921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10195768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"H₂S Alleviates Propofol-Induced Impaired Learning and Memory by Promoting Nuclear Translocation of <i>Nrf2</i> and Inhibiting Apoptosis and Pyroptosis in Hippocampal Neurons.","authors":"Zhenyu Li,&nbsp;Yanfang Wang,&nbsp;Man Feng,&nbsp;Xue Wang,&nbsp;Baofeng Gao","doi":"10.24976/Discov.Med.202335177.58","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335177.58","url":null,"abstract":"<p><strong>Background: </strong>Repeated exposure to propofol can affect their learning and memory functions, but the mechanism remains unclear. The current study aimed to investigate the mechanism underlying the effect of hydrogen sulfide (H₂S) on the alleviation of propofol-induced learning and memory impairment, mediated by promoting nuclear translocation of the nuclear factor erythroid 2-related factor 2 (<i>Nrf2</i>) and inhibiting apoptosis and pyroptosis in hippocampal neurons.</p><p><strong>Methods: </strong>Rats used in this study were successively exposed to 200 mg/kg propofol for 8 consecutive weeks, followed by inhalation of 10, 40 or 80 ppm H₂S. Subsequently, the effects of different concentrations of H₂S on learning and memory were assessed using the water maze assay. Additionally, the effects of H₂S on cell apoptosis and pyroptosis and nuclear translocation of <i>Nrf2</i> in hippocampal neurons were also determined. Furthermore, NaHS (200 μmol/L) was used as an <i>in vitro</i> donor for H₂S, and rescue experiments were carried out following <i>Nrf2</i> knockdown in H19-7 cells. Moreover, <i>Nrf2</i> function was inhibited following treatment with an intraperitoneal injection of ML385 (30 mg/kg) in the rats. The effects of H₂S on reactive oxygen species (ROS) generation, cell apoptosis, and pyroptosis in propofol-treated and <i>Nrf2</i>-deficient H19-7 cells were also investigated.</p><p><strong>Results: </strong>Exposure to propofol for 8 weeks affected the ability of the rats to find underwater platforms (<i>p</i> < 0.01). Further, the exposure induced cell apoptosis and NLR family pyrin domain containing 3 (NLRP3)-related pyroptosis (<i>p</i> < 0.01). Although inhalation of 10 ppm H₂S did not attenuate the aforementioned effects (<i>p</i> > 0.05), exposure to 40 and 80 ppm H₂S significantly alleviated propofol-induced injury in the hippocampal neurons (<i>p</i> < 0.01). However, the protective effect of 80 ppm H₂S was more obvious as compared to that of the other two doses (<i>p</i> < 0.01). In addition, <i>Nrf2</i> knockdown aggravated the propofol-induced cell pyroptosis and apoptosis as well as reversed the protective effect of H₂S against these processes (<i>p</i> < 0.01). <i>In vivo</i> experiments in this study demonstrated that <i>Nrf2</i> inhibition abrogated the protective effects of H₂S inhalation against learning and memory impairment as well as propofol-induced cell apoptosis and pyroptosis in rats (<i>p</i> < 0.01).</p><p><strong>Conclusions: </strong>H₂S could attenuate propofol-induced damage in hippocampal neurons by promoting the nuclear translocation of <i>Nrf2</i> and inhibiting cell apoptosis and pyroptosis.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 177","pages":"576-589"},"PeriodicalIF":1.4,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10140773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Clinical Significance of iNOS/NO Signaling Pathway in Traumatic Shock and the Mechanism under the Promotion on the Development of Traumatic Shock via Endoplasmic Reticulum Stress.","authors":"Aihua Lin,&nbsp;Xun Ni","doi":"10.24976/Discov.Med.202335177.63","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335177.63","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;This study aims to clarify the clinical significance of the inducible nitric oxide synthase (iNOs)/nitric oxide (NO) signaling pathway and endoplasmic reticulum stress (ERS) in traumatic shock (TS) and the mechanism of action, so as to offer a novel direction for the emergency treatment of TS in the future.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The clinical data of 90 patients with TS treated in our hospital between June 2019 and January 2021 were retrospectively analyzed. Patients were divided into mild (n = 30), moderate (n = 30), and severe group (n = 30) based on their disease severity. Furthermore, patients were assigned into Groups A and B for fluid resuscitation based on a pulse index continuous cardiac output (PICCO) monitor and fluid resuscitation based on monitoring results of central venous pressure (CVP) and mean arterial pressure (MAP), respectively. Additionally, the 18 purchased Sprague Dawley (SD) rats were randomized into model (TS model), control (normal rats) and intervention (TS model injected with iNOS inhibitor) groups, with 6 rats each. iNOs and NO levels were measured by colorimetry, and the concentrations of inflammatory factors were quantified using enzyme-linked immunosorbent assays (ELISAs). Polymerase chain reaction (PCR) and western blot were adopted for the quantification of ERS markers (&lt;i&gt;glucose-related protein 78&lt;/i&gt; (&lt;i&gt;GRP78&lt;/i&gt;), &lt;i&gt;GRP94&lt;/i&gt; and &lt;i&gt;C/EBP homologous protein&lt;/i&gt; (&lt;i&gt;CHOP&lt;/i&gt;)), and hematoxylin-eosin (HE) staining of rat cardiac tissue was carried out to observe the pathological state of myocardial tissue.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The moderate group showed higher levels of iNOS, NO, &lt;i&gt;GRP78&lt;/i&gt;, &lt;i&gt;GRP94&lt;/i&gt; and &lt;i&gt;CHOP&lt;/i&gt; than the mild group and lower levels of them than the severe group (all &lt;i&gt;p&lt;/i&gt; &lt; 0.05). MAP, extravascular lung water index (EVLWI), pulmonary vascular permeability index (PVPI), and locus control region (LCR) increased in both Groups A and B after resuscitation, with more significant increases of these parameters in Group A. The application of PICCO technique lowered the levels of iNOS, NO, inflammatory factors, &lt;i&gt;GRP78&lt;/i&gt;, &lt;i&gt;GRP94&lt;/i&gt; and &lt;i&gt;CHOP&lt;/i&gt; in TS patients. In addition, the intervention group had lower levels of iNOS, NO, inflammatory factors, &lt;i&gt;GRP78&lt;/i&gt;, &lt;i&gt;GRP94&lt;/i&gt;, and &lt;i&gt;CHOP&lt;/i&gt; than the model group and higher levels of them than the control group. According to the results of HE staining of myocardial tissue, the intervention group had significantly alleviated myocardial necrosis than the model group, with slightly stained cytoplasm, visible contraction bands in most myocardium, and significantly reduced neutrophil infiltration.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;iNOS/NO and ERS increase with the severity of TS, and PICCO can effectively lower their levels. The results of animal experiments suggest that the inhibition of iNOS/NO can relieve inflammation and ERS intensification, thus alleviating the progression of TS.&lt;","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 177","pages":"642-652"},"PeriodicalIF":1.4,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10140777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}