Exploring gut microbiota's role in rheumatic valve disease: insights from a Mendelian randomization study and mediation analysis.

Background: Investigating the relationship between gut microbiota and Rheumatic Valve Disease (RVD) is crucial for understanding the disease's etiology and developing effective interventions. Our study adopts a novel approach to examine the potential causal connections between these factors. Methods: Utilizing a two-sample Mendelian Randomization (MR) framework, we incorporated a multi-variable MR (MVMR) strategy to assess the mediatory mechanisms involved. This approach involved analyzing data from the MiBioGen consortium for gut microbiota and the FinnGen for RVD, among other sources. Instrumental variables (IVs) were carefully selected based on rigorous MR principles, and statistical analysis was conducted using bidirectional two-sample MR, such as inverse variance-weighted (IVW), weighted median, MR-Egger regression and MR Steiger Test methods. The MR-PRESSO strategy was employed for outlier detection, and MVMR was used to untangle the complex relationships between multiple microbiota and RVD. Results: Our analysis highlighted several gut microbiota classes and families with potential protective effects against RVD, including Lentisphaerae, Alphaproteobacteria, and Streptococcaceae. In contrast, certain genera, such as Eubacterium eligens and Odoribacter, were identified as potential risk factors. The MVMR analysis revealed significant mediation effects of various immune cell traits and biomarkers, such as CD4-CD8- T cells, CD3 on Terminally Differentiated CD8+ T cell and Pentraxin-related protein PTX, elucidating the complex pathways linking gut microbiota to RVD. Conclusion: This study underscores the intricate and potentially causal relationship between gut microbiota and RVD, mediated through a range of immune and hormonal factors. The use of MVMR in our methodological approach provides a more comprehensive understanding of these interactions, highlighting the gut microbiota's potential as therapeutic targets in RVD management. Our findings pave the way for further research to explore these complex relationships and develop targeted interventions for RVD.

Glucose Concentration in Regulating Induced Pluripotent Stem Cells Differentiation Toward Insulin-Producing Cells.

The generation of insulin-producing cells from human-induced pluripotent stem cells holds great potential for diabetes modeling and treatment. However, existing protocols typically involve incubating cells with un-physiologically high concentrations of glucose, which often fail to generate fully functional IPCs. Here, we investigated the influence of high (20 mM) versus low (5.5 mM) glucose concentrations on IPCs differentiation in three hiPSC lines. In two hiPSC lines that were unable to differentiate to IPCs sufficiently, we found that high glucose during differentiation leads to a shortage of NKX6.1+ cells that have co-expression with PDX1 due to insufficient NKX6.1 gene activation, thus further reducing differentiation efficiency. Furthermore, high glucose during differentiation weakened mitochondrial respiration ability. In the third iPSC line, which is IPC differentiation amenable, glucose concentrations did not affect the PDX1/NKX6.1 expression and differentiation efficiency. In addition, glucose-stimulated insulin secretion was only seen in the differentiation under a high glucose condition. These IPCs have higher KATP channel activity and were linked to sufficient ABCC8 gene expression under a high glucose condition. These data suggest high glucose concentration during IPC differentiation is necessary to generate functional IPCs. However, in cell lines that were IPC differentiation unamenable, high glucose could worsen the situation.

Investigation of Roles of SLC38A1 in Proliferation and Differentiation of Mouse Tongue Epithelium and Expression in Human Oral Tongue Squamous Cell Carcinoma.

The aerobic glycolytic pathway, boosting lactate formation, and glutamine addiction are two hallmarks of cancer pathophysiology. Consistent with this, several cell membrane glutamine transporters, belonging to different solute carrier (SLC) families, have been shown to be upregulated in a cell-specific manner to furnish the cells with glutamine and glutamine-derived metabolic intermediates. Among them, the system A transporter Slc38a1 has a higher affinity for glutamine compared to other SLC transporters, and it undergoes highly multifaceted regulation at gene and protein levels. The current study aimed to investigate the functional role of Slc38a1 in the proliferation and maturation of the mouse tongue epithelium. Secondly, we aimed to examine the expression of SLC38A1 and its regulation in human tongue oral squamous cell carcinoma (OTSCC). Employing Slc38a1 wild-type and knockout mice, we showed that Slc38a1 was not directly linked to the regulation of the proliferation and differentiation of the mouse tongue epithelium. External transcriptomic datasets and Western blot analyses showed upregulation of SLC38A1 mRNA/protein in human OTSCC and oral cancer cell lines as compared to the corresponding controls. Further, an investigation of external datasets indicated that mechanisms other than the amplification of the SLC38A1 chromosomal locus or hypomethylation of the SLC38A1 promoter region might be important for the upregulation of SLC38A1 in OTSCC.

Estradiol-mediated small GTP-binding protein GDP dissociation stimulator induction contributes to sex differences in resilience to ferroptosis in takotsubo syndrome.

BACKGROUND: Declining beneficial cardiovascular actions of estradiol (E2) have been associated with disproportionate susceptibility to takotsubo syndrome (TTS) in postmenopausal women. However, the underlying mechanisms between E2 and this marked disproportion remain unclear. SmgGDS (small GTP-binding protein GDP dissociation stimulator), as a key modulator of cardiovascular disease, plays protective roles in reducing oxidative stress and exerts pleiotropic effects of statins. Whether SmgGDS levels are influenced by E2 status and the effect of SmgGDS on sex differences in TTS are poorly understood. METHODS: Clinical data were reviewed from TTS inpatients. Echocardiography, immunofluorescence, and immunohistochemistry were performed together with expression analysis to uncover phenotypic and mechanism changes in sex differences in TTS-like wild-type (WT) and SmgGDS± mice. HL-1 cardiomyocytes were used to further examine and validate molecular mechanisms. RESULTS: In 14 TTS inpatients, TTS had a higher incidence in postmenopausal women as compared to premenopausal women and men. In murine TTS, female WT mice exhibited higher cardiac SmgGDS levels than male WT mice. Ovariectomy reduced SmgGDS expression in female WT mice similar to that observed in male mice, whereas E2 replacement in these ovariectomized (OVX) female mice reversed this effect. The physiological importance of this sex-specific E2-mediated SmgGDS response is underscored by the disparity in cardiac adaptation to isoproterenol (ISO) stimulation between both sexes of WT mice. E2-mediated SmgGDS induction conferred female protection against TTS-like acute cardiac injury involving ferritinophagy-mediated ferroptosis. No such cardioprotection was observed in male WT mice and OVX female. A causal role for SmgGDS in this sex-specific cardioprotective adaptation was indicated, inasmuch as SmgGDS deficiency abolished E2-modulated cardioprotection against ferritinophagy and aggravates TTS progression in both sexes. Consistently, knockdown of SmgGDS in HL-1 cardiomyocytes exacerbated ferroptosis in a ferritinophagy-dependent manner and abrogated the protective role of E2 against ferritinophagy. Mechanistically, our findings revealed that SmgGDS regulated E2-dependent cardioprotective effects via AMPK/mTOR signaling pathway. SmgGDS deficiency abolished E2-conferred protection against ferritinophagy through activating AMPK/mTOR pathway, while treatment with recombinant SmgGDS in HL-1 cells significantly mitigated this pathway-associated ferritinophagy activity. CONCLUSIONS: These results demonstrate that SmgGDS is a central mediator of E2-conferred female cardioprotection against ferritinophagy-mediated ferroptosis in TTS.

Recurrent spontaneous coronary artery dissection.

Spontaneous coronary artery dissection (SCAD) is a significant cause of myocardial infarction (MI) and is more prevalent in pregnancy. The disease is being increasingly appreciated and diagnosed with the development and application of coronary angiography and intravascular imaging. Recurrent spontaneous coronary artery dissection (R-SCAD) is relatively common, with recurrence rates ranging from 8 to 27%. R-SCAD usually involves anatomical sites different from the original SCAD lesion and can cause MI, ventricular arrhythmias, and cardiogenic shock. This study aims to conduct a comprehensive review of R-SCAD to identify early risk factors and guide prevention policies and interventions. In addition, the risk of R-SCAD in subsequent pregnancies in women with a history of SCAD is discussed.

Metabolic remodeling in takotsubo syndrome.

The heart requires a large and constant supply of energy that is mainly the result of an efficient metabolic machinery that converges on mitochondrial oxidative metabolism to maintain its continuous mechanical work. Perturbations in these metabolic processes may therefore affect energy generation and contractile function directly. Metabolism characteristics in takotsubo syndrome (TTS) reveals several metabolic alterations called metabolic remodeling, including the hyperactivity of sympathetic metabolism, derangements of substrate utilization, effector subcellular dysfunction and systemic metabolic disorders, ultimately contributing to the progression of the disease and the development of a persistent and long-term heart failure (HF) phenotype. In this review, we explore the current literature investigating the pathological metabolic alterations in TTS. Although the metabolic dysfunction in takotsubo hearts is initially recognized as a myocardial metabolic inflexibility, we suggest that the widespread alterations of systemic metabolism with complex interplay between the heart and peripheral tissues rather than just cardiometabolic disorders per se account for long-term maladaptive metabolic, functional and structural impairment under this condition. Therapeutic strategies with the recent evidence from small clinical and animal researches, especially for targeting substrate utilization and/or oxidative stress, might be promising tools to improve the outcome of patients with TTS beyond that achieved with traditional sympathetic inhibition and symptomatic therapies.

Construction of a predictive model and prognosis of left ventricular systolic dysfunction in patients with sepsis based on the diagnosis using left ventricular global longitudinal strain.

BACKGROUND: Cardiac dysfunction, a common complication of sepsis, is associated with increased mortality. However, its risk factors are poorly understood, and a predictive model might help in the management of cardiac dysfunction. METHODS: A monocentric prospective study of patients with sepsis was performed. Left ventricular global longitudinal strain (LV GLS) was measured using echocardiography within 72 h of the patients diagnosed with sepsis, and the patients were categorized into two groups: LV GLS > -17%, left ventricular systolic dysfunction group (LVSD group); and LV GLS ≤ -17%, non-left ventricular systolic dysfunction group (Non-LVSD group). The baseline characteristics and prognosis of the two groups were analyzed. Based on the results of the multivariate logistic regression analysis, a predictive model of LVSD was established and a nomogram was drawn. RESULTS: Fifty-one left ventricular systolic dysfunction in patients with sepsis and 73 non-LVSD sepsis patients were included. Prognostic analysis showed that patients with LVSD had higher ICU mortality, in-hospital mortality, the incidence of atrial fibrillation (P < 0.05), and risk of death (HR = 3.104, 95% CI = 1.617-5.957, P < 0.001) compared to patients with non-LVSD. There were no significant differences in the rate of tracheal intubation, the incidence of acute kidney injury (AKI), the proportion of continuous renal replacement therapy (CRRT), length of ICU stay, and length of hospital stay between the 2 groups (P > 0.05). High sensitive troponin I (Hs-TnI) ≥ 0.131 ng/ml, procalcitonin (PCT) ≥ 40 ng/ml, lactate (Lac) ≥ 4.2 mmol/L, and N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥ 3270 pg/ml were found to be the best cut-off values for the prediction of LVSD. CONCLUSION: Sepsis patients with left ventricular systolic dysfunction had a higher risk of death and atrial fibrillation. Hs-TnI, PCT, Lac, and NT-proBNP were independent risk factors of LVSD, and the LVSD predictive model constructed using these factors showed good diagnostic performance. TRIAL REGISTRATION: Chinese Clinical Trial Registry No: ChiCTR2000032128. Registered on 20 April 2020, http://www.chictr.org.cn/showproj.aspx ?proj=52531.

Analysis of Cardiac Adverse Reactions Caused by Different Doses of Adriamycin Chemotherapy in Patients with Breast Cancer.

PURPOSE: This paper is aimed at studying the adverse reactions of breast cancer patients after chemotherapy with different doses of adriamycin. METHODS: 122 breast cancer patients undergoing mastectomy in the Haining Central Hospital from June 2018 to June 2020 were selected as the research objects. Patients were divided into control group and study group according to the different dose of adriamycin given to patients during chemotherapy. Patients in the control group received intravenous drip of adriamycin at 50 mg/m2. Patients in the study group were given intravenous drip at 75 mg/m2. Patients in both the groups started intravenous drip of cyclophosphamide 500 mg/m2 on the first day of chemotherapy, and chemotherapy for 21 days was a cycle. A total of 6 cycles were carried out. Abnormal electrocardiograph (ECG) is compared between the two groups. Myocardial enzyme and oxidative stress indicators were tested, and Doppler ultrasound examination was conducted. RESULTS: After chemotherapy, the abnormal rate of ECG in the study group was 56.46%, which was significantly higher than that in the control group (46.67%). After chemotherapy, the indexes of myocardial enzymes and oxidative stress increased, while superoxide dismutase (SOD) decreased significantly, and the differences were statistically significant. At the end of chemotherapy, the differences of serum myocardial enzymes and oxidative stress indexes in the study group were higher than those in the control group. After chemotherapy, there was no significant difference between left ventricular ejection fraction (LVEF) and Sa in the study group and the control group, but Ea in the study group was higher than that in the control group and E/Ea was lower than that in the control group. CONCLUSION: High-dose adriamycin chemotherapy is more likely to cause accumulation of cardiotoxicity, resulting in decreased cardiac function and cardiac injury in breast cancer patients.

Atorvastatin treatment ameliorates cardiac function and remodeling induced by isoproterenol attack through mitigation of ferroptosis.

Ferroptosis has been identified as an important role in damaged heart. Meanwhile, statin therapy has been reported to be beneficial for the treatment of heart failure(HF) under different conditions. However, the beneficial effects of statin treatment on regulation of ferroptosis in failing heart is unveiled. The aim of this study is to explore the protective efficacy of atorvastatin against the ferroptosis related signaling pathway in isoproterenol(ISO)-induced HF. We found that ATV and ferrostatin-1(Fer-1,as a positive control) significantly improved ISO-decreased cell viability and cell survival by reducing oxidative stress and Fe2+-dependent lipid peroxidation in H9C2 cells. Additionally, ISO triggered marked ferritinophagy accompanied by up-regulating protein levels of LC3BII,NCOA4 and Beclin1 and down-regulating protein levels of P62 and FTH1 in damaged cells, which nevertheless was significantly blocked by administration of ATV and these results were in parallel with the results obtained after 3-methyadenine(3-MA) treatment. Consistently, C57BL/6J mice were used in used in this study and administered 5 mg/kg/day ISO for 2 weeks to simulate cardiac injury. 20 mg/kg/day ATV treatment for 2 weeks simultaneously markedly improved cardiac dysfunction and remodeling induced by ISO attack. ATV showed significantly protective effects through suppressing the activation of ferroptosis related signaling, as evidenced by decreasing the mRNA levels of PTGS2(a marker of ferroptosis), contents of malonaldehyde and protein levels of NOX4 and increasing the contents of glutathione(GSH), the ratio of GSH/GSSG and protein levels of GPX4 and SLC7A11. Moreover, ISO evidently triggered degradation of FTH1 in failing heart. However, ATV significantly prevented these changes in damaged heart. Overall, these results reveal atorvastatin suppresses ferroptosis and exhibits protective effect on failing myocardium of mice after ISO insult though inhibiting ferritinophagy-mediated ferroptosis, which might be a potential therapeutic strategy in the prevention of ISO-associated cardiomyopathy.

DRD4 (Dopamine D4 Receptor) Mitigate Abdominal Aortic Aneurysm via Decreasing P38 MAPK (mitogen-activated protein kinase)/NOX4 (NADPH Oxidase 4) Axis-Associated Oxidative Stress.

[Figure: see text].

Tempol prevents isoprenaline-induced takotsubo syndrome via the reactive oxygen species/mitochondrial/anti-apoptosis /p38 MAPK pathway.

Takotsubo Syndrome (TS) is a kind of acute cardiac syndrome with a complex pathophysiological mechanism that remains to be elucidated. The relationship between TS and reactive oxygen species has received increasing attention over in recent years. Therefore, the relationship between TS and reactive oxygen species was investigated in vivo and in vitro. Isoprenaline (ISO) was used to induce TS and tempol (quercetin) was selected as a scavenger to eliminate reactive oxygen species in animal experiments, and echocardiography was used to determine the incidence of TS. The H9C2 cells were cultured with different reagents to investigate the detailed mechanism; Reactive oxygen species levels and mitochondrial function were evaluated. Cell apoptosis rate was analyzed by TUNEL staining and the proteins involved in the signaling pathways were examined by Western blotting. It was found that a high dose of tempol almost eliminated TS and protected the cardiac function. Moreover, tempol also decreased the reactive oxygen species levels and reduced lipid droplet deposition in myocardial tissue. In terms of the cultured cells, tempol preconditioning decreased reactive oxygen species production as well as lipid droplet deposition, and protected the mitochondrial function by reducing mitochondrial swelling, thereby maintaining the mitochondrial membrane potential (ΔΨm) at a level that was higher than that of controls. Furthermore, tempol could reduce cells apoptosis after ISO treatment and decrease the protein level of p38, which is a member of the MAPK family, which and thus plays an important role in regulating cells apoptosis. This antiapoptotic effect of tempol was similar to that of a control reagent, SB203580, which is a specific inhibitor of phospha-p38 (p-p38). This study demonstrated, for the first time, a sudden increase in reactive oxygen species and effects of the downstream cascades play core roles in the development of TS.

NF-κB-mediated miR-650 plays oncogenic roles and activates AKT/ERK/NF-κB pathways by targeting RERG in glioma cells.

PURPOSE: Glioma is the most common cancer in the central nervous system and has a high mortality rate. Despite advances that have been made in the treatment of glioma, its prognosis still remains poor. Dysregulation of miRNAs has been reported in many cancers, including glioma. Here, we set out to assess the role of miR-650 in glioma, including its diagnostic and therapeutic potential. METHODS: miR-650 and RAS-like estrogen-regulated growth inhibitor (RERG) expression levels were analyzed using qRT-PCR in primary glioma tissues and cell lines. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, colony formation, Western blotting, scratch wound healing, Transwell, adhesion, autophagy, immunofluorescence, luciferase reporter, electrophoretic mobility shift, tumor xenograft and flow cytometry assays were employed to investigate the mechanisms underlying the effect of miR-650 and RERG on glioma development. RESULTS: miR-650 was found to be up-regulated in glioma tissues and cell lines compared to non-cancerous brain tissues and neural progenitor cells, respectively. We also found that miR-650 promoted cell proliferation, migration and invasion in glioma cells, and enhanced glioma tumor formation and growth in vivo. We identified and validated RERG as a direct target of miR-650. RERG was shown to act as a tumor suppressor in glioma cells, and its suppressor roles were rescued by miR-650. We found that nuclear factor (NF)-κB bound to the promoter of miR-650 and enhanced its expression. PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2), as a co-factor of the RERG/PHLPP2 complex, mediated miR-650-induced activation of the protein kinase B/extracellular-signal-regulated kinase/NF-κB signaling pathways. CONCLUSIONS: Our data revealed novel functional roles for miR-650 in glioma development and may provide new avenues for future clinical applications.

MiR-489 aggravates H2O2-induced apoptosis of cardiomyocytes via inhibiting IGF1.

Myocardial infarction (MI) is a major type of cardiovascular disorder worldwide. In the present study, we established a new microRNA (miRNA)-mRNA cross-talk network by integrating data obtained from The National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO). In addition, functional assays, including Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analyses, were conducted using the Database for Annotation, Visualization, and Integration Discovery (DAVID). In our study, we generated a new differentially expressed miRNA (DEmiRNA)-differentially expressed gene (DEG) cross-talk network of MI composed of three miRNA (miR-489, miR-375, and miR-142-3p) nodes and 163 mRNA nodes. In vitro experiments demonstrated that miR-489 expression was increased in H2O2-treated H9c2 cardiomyocytes in vitro, mimicking myocardial injury. We observed that down-regulation of miR-489 reduced H2O2-induced apoptosis, while overexpression of miR-489 had the opposite effects, as revealed by flow cytometry and Western blot analyses. Furthermore, we confirmed the relationship between miR-489 and IGF1 through double luciferase reporter gene assays, which partly explains the antiapoptotic mechanism of miR-489. In conclusion, the experimental results of the present study could provide important clues for investigating the mechanism of MI.