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Background Endothelial–mesenchymal transition (EndMT) plays a crucial role in promoting myocardial fibrosis and exacerbating cardiac dysfunction. Dapagliflozin (DAPA) is a sodium–glucose-linked transporter 2 (SGLT-2) inhibitor that has been shown to improve cardiac function in non-diabetic patients with heart failure (HF). However, the precise mechanisms by which DAPA exerts its beneficial effects are yet to be fully elucidated. Methods Isoproterenol (ISO) was used to generate a HF model in mice. For in vitro experiments, we used TGF-β1-stimulated human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs). Results Both our in vivo and in vitro results showed that EndMT occurred with decreased SIRT1 (NAD + -dependent deacetylase) protein expression, which could be reversed by DAPA therapy. We found that the protective effect of DAPA was significantly impaired upon SIRT1 inhibition. Mechanistically, we observed that SIRT1 phosphorylation, a required modification for its ubiquitination and degradation, was reduced by DAPA treatment, which induces the nucleus translocation of SIRT1 and promotes its binding to the active intracellular domain of Notch1 (NICD). This interaction led to the deacetylation and degradation of NICD, and the subsequent inactivation of the Notch1 signaling pathway which contributes to ameliorating EndMT. Conclusions Our study revealed that DAPA can attenuate EndMT induced by ISO in non-diabetic HF mice. This beneficial effect is achieved through SIRT1-mediated deacetylation and degradation of NICD. Our findings provide greater insight into the underlying mechanisms of the therapeutic effects of DAPA in non-diabetic HF. Graphical Abstract

The development of unstable carotid atherosclerotic plaques is associated with the induction of neutrophil extracellular traps (NETs) via the activation of diverse inflammatory mediators in the circulating bloodstream. However, the underlying mechanisms through which NETs influence the microenvironment of atherosclerotic plaques and contribute to the development of unstable carotid plaques remain largely elusive. The objective of this study was to elucidate the role of myeloid differentiation protein 1 (MD-1, LY86 )-induced NETs underlying the crosstalk between unstable plaque formation and the plaque microenvironment. We employed bioinformatics analysis to identify key genes associated with carotid-unstable plaque, followed by comprehensive validation using various experimental approaches on tissue specimens and plasma samples classified based on pathological characteristics. Patients with carotid-unstable plaques exhibited elevated plasma concentrations of MD-1 ( LY86 ), while patients with stable plaques demonstrated comparatively lower levels. Furthermore, soluble MD-1 was found to induce the formation of NETs through activation of Toll-like receptor signaling pathway. The proliferative and immature vascularization effects of NETs on endothelial cells, as well as their inhibitory impact on cell migration, are directly correlated with the concentration of NETs. Additionally, NETs were found to activate the NF-κB signaling pathway, thereby upregulating ICAM1, VCAM1, MMP14, VEGFA, and IL6 expression in both Human umbilical vein endothelial cells (HUVECs) and HAECs. Subsequently, a significant increase in intraplaque neovascularization by NETs results in poor carotid plaque stability, and NETs in turn stimulate macrophages to produce more MD-1, generating a harmful positive feedback loop. Our findings suggest that soluble MD-1 in the bloodstream triggers the production of NETs through activation of the Toll-like receptor signaling pathway and further indicate NETs mediate a crosstalk between the microenvironment of the carotid plaque and the neovascularization of the intraplaque region. Inhibiting NETs formation or MD-1 secretion may represent a promising strategy to effectively suppress the development of unstable carotid plaques. NETs influence carotid plaque microenvironment and neovascularization Atherosclerosis, a disease where arteries get blocked with fat, is a main cause of heart disease and stroke. Predicting which atherosclerotic plaques will cause heart attacks is hard. Researchers analyzed gene data from unstable and stable carotid plaques, focusing on neutrophils and a protein called MD-1. The study involved 30 patients and 10 healthy volunteers to understand how MD-1 and neutrophils contribute to plaque instability. The main finding is that MD-1 could be a biomarker for unstable plaques, offering a new target for therapies to prevent major heart events. This progress in understanding the molecular mechanisms behind plaque instability could lead to better prevention strategies for heart disease. Future research may focus on developing treatments that target MD-1 and neutrophils to stabilize plaques and reduce the risk of heart attacks. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Background Heart failure (HF) after myocardial infarction (MI) is a prevalent disease with a poor prognosis. Relieving pathological cardiac remodeling and preserving cardiac function is a critical link in the treatment of post-MI HF. Thus, more new therapeutic targets are urgently needed. The expression of ADAM17 is increased in patients with acute MI, but its functional role in post-MI HF remains unclear. Methods To address this question, we examined the effects of ADAM17 on the severity and prognosis of HF within 1 year of MI in 152 MI patients with or without HF. In mechanistic studies, the effects of ADAM17 on ventricular remodeling and systolic function were extensively assessed at the tissue and cellular levels by establishing animal model of post-MI HF and in vitro hypoxic cell model. Results High levels of ADAM17 predicted a higher incidence of post-MI HF, poorer cardiac function and higher mortality. Animal studies demonstrated that ADAM17 promoted the occurrence of post-MI HF, as indicated by increased infarct size, cardiomyocyte hypertrophy, myocardial interstitial collagen deposition and cardiac failure. ADAM17 knock down significantly improved pathological cardiac remodeling and cardiac function in mice with MI. Mechanistically, activated ADAM17 inhibited the cardioprotective effects of ACE2 by promoting hydrolytic shedding of the transmembrane protein ACE2 in cardiomyocytes, which subsequently mediated the occurrence of cardiac remodeling and the progression of heart failure. Moreover, the activation of ADAM17 in hypoxic cardiomyocytes was dependent on p38 MAPK phosphorylation at threonine 735. Conclusions These data highlight a novel and important mechanism for ADAM17 to cause post-MI HF, which will hopefully be a new potential target for early prediction or intervention of post-MI HF. 1TH-7ttE8r63zZ3UeeV3ZM Video abstract

Mitochondria dysfunction contributes to acute liver injuries, and mitochondrial regulators, such as PGC-1α and MCJ, affect liver regeneration. Therefore, identification of mitochondrial modulators may pave the way for developing therapeutic strategies. Here, ZHX2 is identified as a mitochondrial regulator during acute liver injury. ZHX2 both transcriptionally inhibits expression of several mitochondrial electron transport chain genes and decreases PGC-1α stability, leading to reduction of mitochondrial mass and OXPHOS. Loss of Zhx2 promotes liver recovery by increasing mitochondrial OXPHOS in mice with partial hepatectomy or CCl4-induced liver injury, and inhibition of PGC-1α or electron transport chain abolishes these effects. Notably, ZHX2 expression is higher in liver tissues from patients with drug-induced liver injury and is negatively correlated with mitochondrial mass marker TOM20. Delivery of shRNA targeting Zhx2 effectively protects mice from CCl4-induced liver injury. Together, our data clarify ZHX2 as a negative regulator of mitochondrial OXPHOS and a potential target for developing strategies for improving liver recovery after acute injuries. Mitochondria dysfunction contributes to acute liver injuries. Zhang et al. find that Zhx2 deletion enhances mitochondrial function by promoting electron transport chain gene expression via PGC-1α dependent and independent manner.

Background The role of the scavenger receptor CD36 in cell metabolism and the immune response has been investigated mainly in macrophages, dendritic cells, and T cells. However, its involvement in B cells has not been comprehensively examined. Methods To investigate the function of CD36 in B cells, we exposed Cd36 fl/fl MB1 cre mice, which lack CD36 specifically in B cells, to apoptotic cells to trigger an autoimmune response. To validate the proteins that interact with CD36 in primary B cells, we conducted mass spectrometry analysis following anti-CD36 immunoprecipitation. Immunofluorescence and co-immunoprecipitation were used to confirm the protein interactions. Results The data revealed that mice lacking CD36 in B cells exhibited a reduction in germinal center B cells and anti-DNA antibodies in vivo. Mass spectrometry analysis identified 30 potential candidates that potentially interact with CD36. Furthermore, the interaction between CD36 and the inhibitory Fc receptor FcγRIIb was first discovered by mass spectrometry and confirmed through immunofluorescence and co-immunoprecipitation techniques. Finally, deletion of FcγRIIb in mice led to decreased expression of CD36 in marginal zone B cells, germinal center B cells, and plasma cells. Conclusions Our data indicate that CD36 in B cells is a critical regulator of autoimmunity. The interaction of CD36-FcγRIIb has the potential to serve as a therapeutic target for the treatment of autoimmune disorders.

Seasonal influenza continues to be a global health problem. Current existing vaccines and antivirals against influenza have limited effectiveness, and typically do not stay ahead of the viral evolutionary curve. Broad-spectrum antiviral agents that are effective therapeutically and prophylactically are much needed. We have created a promising new broad-spectrum anti-influenza agent using molecular engineering of a lectin from bananas, H84T, which is well-tolerated and protective in small animal models. However, the potency and effect of H84T on human immune cells and influenza-specific immune responses are undetermined. We found that H84T efficiently inhibited influenza A virus (IAV) replication in primary human dendritic cells (DCs) isolated from blood and tonsil, preserved DC viability and allowed acquisition and presentation of viral antigen. Excitingly, H84T-treated DCs subsequently initiated effective expansion of IAV-specific CD8 T cells. Furthermore, H84T preserved the capacity of IAV-exposed DCs to present a second non-IAV antigen and induce robust antigen-specific CD8 T cell expansion. Our data support H84T as a potent antiviral in humans as it not only effectively inhibits IAV infection, but also preserves induction of robust pathogen-specific adaptive immune responses against diverse antigens, which likely is clinically beneficial.

Background Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor receptor 2 (VEGFR2) inhibition have been investigated as an alternative glioblastoma treatment. However, little is known about the effect of VEGFR2 blockade on glioblastoma cells per se. Methods VEGFR2 expression data in glioma patients were retrieved from the public database TCGA. VEGFR2 intervention was implemented by using its selective inhibitor Ki8751 or shRNA. Mitochondrial biogenesis of glioblastoma cells was assessed by immunofluorescence imaging, mass spectrometry, and western blot analysis. Results VEGFR2 expression was higher in glioma patients with higher malignancy (grade III and IV). VEGFR2 inhibition hampered glioblastoma cell proliferation and induced cell apoptosis. Mass spectrometry and immunofluorescence imaging showed that the anti-glioblastoma effects of VEGFR2 blockade involved mitochondrial biogenesis, as evidenced by the increases of mitochondrial protein expression, mitochondria mass, mitochondrial oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production, all of which play important roles in tumor cell apoptosis, growth inhibition, cell cycle arrest and cell senescence. Furthermore, VEGFR2 inhibition exaggerated mitochondrial biogenesis by decreased phosphorylation of AKT and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which mobilized PGC1α into the nucleus, increased mitochondrial transcription factor A (TFAM) expression, and subsequently enhanced mitochondrial biogenesis. Conclusions VEGFR2 blockade inhibits glioblastoma progression via AKT-PGC1α-TFAM-mitochondria biogenesis signaling cascade, suggesting that VEGFR2 intervention might bring additive therapeutic values to anti-glioblastoma therapy.

Diabetic cardiomyopathy (DCM), a severe complication of diabetes, is characterized by mitochondrial dysfunction, oxidative stress, and DNA damage. Despite its severity, the intrinsic factors governing cardiomyocyte damage in DCM remain unclear. It is hypothesized that impaired iron–sulfur (Fe–S) cluster synthesis plays a crucial role in the pathogenesis of DCM. Reduced S‐sulfhydration of cysteine desulfurase (NFS1) is a novel mechanism that contributes to mitochondrial dysfunction and PARthanatos in DCM. Mechanistically, hydrogen sulfide (H2S) supplementation restores NFS1 S‐sulfhydration at cysteine 383 residue, thereby enhancing Fe–S cluster synthesis, improving mitochondrial function, increasing cardiomyocyte viability, and alleviating cardiac damage. This study provides novel insights into the interplay between Fe–S clusters, mitochondrial dysfunction, and PARthanatos, highlighting a promising therapeutic target for DCM and paving the way for potential clinical interventions to improve patient outcomes. A reduction in mitochondrial iron‐sulfur (Fe–S) cluster synthesis in diabetic cardiomyocytes decreases mitochondrial respiratory chain function, leading to oxidative stress and DNA damage. Supplementing with hydrogen sulfide (H2S) enhances Fe–S cluster synthesis via S‐sulfhydration of cysteine desulfurase (NFS1) at C383, preserving mitochondrial and nuclear DNA integrity and ameliorating diabetic cardiomyopathy (DCM).