Discovery medicine最新文献

{"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":null,"pages":null},"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":null,"pages":null},"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":"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":null,"pages":null},"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":null,"pages":null},"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":"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":null,"pages":null},"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":"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":null,"pages":null},"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":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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 (<i>glucose-related protein 78</i> (<i>GRP78</i>), <i>GRP94</i> and <i>C/EBP homologous protein</i> (<i>CHOP</i>)), and hematoxylin-eosin (HE) staining of rat cardiac tissue was carried out to observe the pathological state of myocardial tissue.</p><p><strong>Results: </strong>The moderate group showed higher levels of iNOS, NO, <i>GRP78</i>, <i>GRP94</i> and <i>CHOP</i> than the mild group and lower levels of them than the severe group (all <i>p</i> < 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, <i>GRP78</i>, <i>GRP94</i> and <i>CHOP</i> in TS patients. In addition, the intervention group had lower levels of iNOS, NO, inflammatory factors, <i>GRP78</i>, <i>GRP94</i>, and <i>CHOP</i> 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.</p><p><strong>Conclusions: </strong>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.<","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":null,"pages":null},"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}

{"title":"Mutation Characteristics of Phenylalanine Hydroxylase Gene in Children with Phenylketonuria in Yinchuan City.","authors":"Xinyou Yu,&nbsp;Fang Liu,&nbsp;Bo Wei,&nbsp;Meijuan Li,&nbsp;Ruiping Lu,&nbsp;Lihua Pan","doi":"10.24976/Discov.Med.202335177.54","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335177.54","url":null,"abstract":"<p><strong>Background: </strong>Phenylalanine hydroxylase deficiency (PAHD) is an autosomal recessive disorder affecting phenylalanine (Phe) metabolism caused by mutations in the phenylalanine hydroxylase (<i>PAH</i>) gene. It has a complex phenotype with many variants and genotypes in various populations. This study sets out to analyze the screening results of children with phenylketonuria (PKU) in Yinchuan City and characterize the mutation variants of the <i>PAH</i> gene.</p><p><strong>Methods: </strong>Phenylketonuria screening results were retrospectively analyzed in 398,605 neonates (207,361 males and 191,244 females) born in different maternity hospitals in Yinchuan City between January 2017 and December 2021. Screening for genetic metabolic diseases was performed with parental consent at their own expense. A comprehensive diagnosis was performed by integrating tandem mass spectrometry (MS/MS) findings with clinical presentations. High-throughput sequencing (HTS) was used to detect genetic and metabolic disease-associated genes in children with PKU who were clinically diagnosed and voluntarily tested. The identified loci were validated through Sanger sequencing and parental verification.</p><p><strong>Results: </strong>Among the screened newborns, 45 (11.3/100,000) PKU cases were diagnosed. In the 38 cases that underwent self-financed <i>PAH</i> sequencing, 56 mutations were detected in 76 chromosomes, with an overall detection rate of 73.7%. All patients harbored mutant genes, and the 56 mutations detected identified represented 14 variants, including 8 missense mutations, 2 splicing mutations, 2 nonsense mutations, and 2 silent mutations. The mutations were primarily distributed in <i>exons 2</i>, <i>3</i>, <i>6</i>, <i>7</i>, <i>9</i>, <i>11</i>, and <i>intron 4</i>, with the highest frequency observed in <i>exon 7</i> (25 [44.7%]), followed by <i>exon 11</i> (15 [26.7%]). The most prevalent mutations were <i>exon 7</i>-p.R252W (10 [17.9%]) and <i>exon 7</i>-p.R261Q (8 [14.3%]).</p><p><strong>Conclusions: </strong>The <i>PAH</i> gene mutations in children with PKU in Yinchuan City are predominantly concentrated in <i>exons 6</i>, <i>7</i>, and <i>11</i>, with the highest detection rates observed for p.R252W and p.R261Q mutations.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10195766","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":"Predictive Model for the Diagnosis of Benign/Malignant Complex Cystic and Solid Breast Nodules.","authors":"Han Liu,&nbsp;Chun-Jie Hou,&nbsp;Jing-Lan Tang,&nbsp;An-Ning Liu,&nbsp;Ke-Feng Lu,&nbsp;Ying Liu,&nbsp;Pei Du","doi":"10.24976/Discov.Med.202335176.23","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335176.23","url":null,"abstract":"<p><strong>Purpose: </strong>To develop an ultrasound predictive model to differentiate between benign and malignant complex cystic and solid nodules (C-SNs).</p><p><strong>Methods: </strong>A total of 211 patients with complex C-SNs rated as American College of Radiology Breast Imaging Reporting and Data System (ACR BI-RADS) category 4 or 5 on the ultrasound reports were included in the study, from June 2018-2021. Multivariate stepwise logistic regression analysis was used to establish a predictive model, based on clinical and ultrasound features. The diagnostic performance of the model was evaluated by the area under the curve (AUC) of the receiver operating characteristic curve.</p><p><strong>Results: </strong>A total of 109 breast nodules, including 74 benign nodules (67.89%) and 35 malignant nodules (32.11%), were detected by surgical pathology or puncture biopsy. Multivariate analysis showed that the blood flow (BF) of complex C-SNs (<i>p</i> = 0.03), cystic fluid transmission (<i>p</i> = 0.02), longitudinal diameter (<i>p</i> < 0.001), and age (<i>p</i> = 0.03) were independent risk factors for malignant complex cystic and solid breast nodules. The ultrasound model equation was Z=-12.14+2.24×X12+1.97×X20+0.40×X7+0.11×X0; M=ez1+ez (<i>M</i> is the malignancy score, <i>e</i> = 2.72). The area under the curve (AUC) was 0.89, which indicated good predictive utility for the model.</p><p><strong>Conclusions: </strong>A prediction model incorporating major risk factors can predict the malignant C-SNs with accuracy.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9599843","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":"Amonafide Induces HUVEC Senescence by Inhibiting Autophagy.","authors":"Jing Xia,&nbsp;Yu Zhou,&nbsp;Siyue He,&nbsp;Manoj Kumar Vashisth,&nbsp;Huijie Jia,&nbsp;Qianlong Dai,&nbsp;Yufen He,&nbsp;Xiaobo Wang","doi":"10.24976/Discov.Med.202335176.27","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335176.27","url":null,"abstract":"<p><strong>Background: </strong>Amonafide (Amo), due to hematotoxicity and digestive tract symptoms, the clinical application of which is limited. Several studies have reported that chemotherapy side effects are closely related to cellular senescence accumulation. Our study aims to examine whether amonafide causes senescence in human umbilical vein endothelial cell (HUVEC) lines and investigate its mechanisms associated with senescence.</p><p><strong>Methods: </strong>The experiments of expression of genes and proteins associated with aging were carried out with HUVEC cell lines. The experiments were divided into a control group and an amonafide group with different days. The HUVEC senescence cells were detected by SA-β-Gal staining, Western blotting detected the protein levels of p16, p53, AMPK (Adenosine 5'-Monophosphate (AMP)-Activated Protein Kinase), mTOR (mechanistic Target of Rapamycin), p62, and LC3 (microtubule-associated protein1 light chain 3, MAP1LC3). Fluorescence detected the expression of mRFP (monomeric Red Fluorescent Protein)-GFP (Green Fluorescent Protein)-LC3 and LC3 puncta of HUVEC cells. RT-qPCR (Real-Time Quantitative Polymerase Chain Reaction) tested the expressions of <i>p53</i>, <i>p21</i>, <i>IL</i> (Interleukin)<i>-1β</i>, <i>IL-6</i> (Interleukin-6), <i>IL-8</i> (Interleukin-8), and <i>MCP-1</i> (Monocyte Chemoattractant Protein-1). CCK-8 (Cell Counting Kit-8) assessed the HUVEC cell viability.</p><p><strong>Results: </strong>Here, we reported that amonafide resulted in an increased proportion of SA-β-Gal positive cells, high expression of aging-related proteins (p53 <i>p</i> < 0.05; p16 <i>p</i> < 0.05), and aging-related genes (<i>p53 p</i> < 0.05; <i>p21 p</i> < 0.05; <i>IL-1β p</i> < 0.05; <i>IL-6 p</i> < 0.05; <i>IL-8 p</i> < 0.05; <i>MCP-1 p</i> < 0.05) on the 3rd day. Mechanistically, amonafide could cause an increase in the levels of the mTOR (<i>p</i> < 0.05) on days 1 and 3, and p62 protein (<i>p</i> < 0.05) on day 1, and a decline in LC3II (microtubule-associated protein1 light chain 3Ⅱ)/LC3I levels (<i>p</i> < 0.05) on day 3, which is associated with the regulation of senescence. Additionally, the viability of HUVECs (human umbilical vein endothelial cells) was significantly inhibited by amonafide starting with a concentration of 0.8 μm (<i>p</i> < 0.05).</p><p><strong>Conclusions: </strong>We first discovered that amonafide caused normal cellular senescence in our experiments. Amonafide-induced cellular aging by inhibiting autophagy and activating the mTOR pathway. The findings may offer new strategies for managing adverse reactions to amonafide.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9607573","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}