Ghrelin Alleviates Intestinal Dysfunction in Sepsis Through the KLF4/MMP2 Regulatory Axis by Activating SIRT1.
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ABSTRACT:
SUBMITTER: Li B
PROVIDER: S-EPMC8102724 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cholesterol crystal- (CC-) induced endothelial cell inflammation and pyroptosis play an important role in the development of cardiovascular diseases, especially in atherosclerosis (AS). Increasing evidence suggests that cholesterol crystals are known to be a pivotal pathological marker of atherosclerotic plaque vulnerability. As a classical nonspecific anti-inflammatory drug, colchicine has been widely used in the treatment of acute gout. However, whether colchicine could alleviate CC-induced endothelial cell injury and the related mechanisms remains to be addressed. In this study, the protective effect of colchicine on human umbilical vein endothelial cells (HUVECs) was confirmed. Our results revealed that after cotreatment with colchicine and cholesterol crystals in endothelial cells, the uptake of cholesterol crystals was significantly decreased, the cell viability was obviously increased, and the release of lactate dehydrogenase (LDH) and the number of pyroptotic cells decreased significantly; then, the expression of NLRP3 inflammasome-related proteins and various inflammatory factors was also visibly suppressed; moreover, as a potent activator of NLRP3 inflammasome, the intracellular ROS level was clearly reduced, while mitochondrial membrane potential improved significantly. In addition, the expression levels of AMP-dependent kinase (AMPK) pathway-related proteins as well as various antioxidant enzymes were elevated notably in varying degrees. However, the above effects of colchicine were completely offset by the treatment of siRNA targeting AMPK? and Sirtuin1 (SIRT1). Therefore, we conclude that colchicine plays a crucial role in alleviating the intracellular inflammatory response and NLRP3 inflammation activation, attenuating the levels of cellular oxidative stress and pyroptosis in endothelial cells via regulating AMPK/SIRT1 signaling, which may be a concrete mechanism for the secondary prevention of cardiovascular diseases.
| S-EPMC7378601 | biostudies-literature
Project description:Multi-organ failure caused by the inflammatory cytokine storm induced by severe infection is the major cause of death for sepsis. Sj-Cys is a cysteine protease inhibitor secreted by Schistosoma japonicum with strong immunomodulatory functions on host immune system. Our previous studies have shown that treatment with Sj-Cys recombinant protein (rSj-Cys) attenuated inflammation caused by sepsis. However, the immunological mechanism underlying the immunomodulation of Sj-Cys for regulating inflammatory diseases is not yet known. In this study, we investigated the effect of Sj-Cys on the macrophage M2 polarization and subsequent therapeutic effect on sepsis. The rSj-Cys was expressed in yeast Pichia pastoris. Incubation of mouse bone marrow-derived macrophages (BMDMs) with yeast-expressed rSj-Cys significantly activated the polarization of macrophages to M2 subtype characterized by the expression of F4/80+ CD206+ with the elated secretion of IL-10 and TGF-?. Adoptive transfer of rSj-Cys treated BMDMs to mice with sepsis induced by cecal ligation and puncture (CLP) significantly improved their survival rates and the systemic clinical manifestations of sepsis compared with mice receiving non-treated normal BMDMs. The therapeutic effect of Sj-Cys-induced M2 macrophages on sepsis was also reflected by the reduced pathological damages in organs of heart, lung, liver and kidney and reduced serological levels of tissue damage-related ALT, AST, BUN and Cr, associated with downregulated pro-inflammatory cytokines (IFN-gamma and IL-6) and upregulated regulatory anti-inflammatory cytokines (IL-10 and TGF-?). Our results demonstrated that Sj-Cys is a strong immunomodulatory protein with anti-inflammatory features through activating M2 macrophage polarization. The findings of this study suggested that Sj-Cys itself or Sj-Cys-induced M2 macrophages could be used as therapeutic agents in the treatment of sepsis or other inflammatory diseases.
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Project description:High morbidity and mortality are the most typical characteristics of septic cardiomyopathy. We aimed to reveal the role of miR-22 in septic cardiomyopathy and to explore the underlying mechanisms. miR-22 cardiac-specific knockout (miR-22cKO) mice and miR-22 cardiac-specific transgenic (miR-22cOE) mice were subjected to a cecal ligation and puncture (CLP) operation, while a sham operation was used in the control group. The echocardiogram results suggested that miR-22cKO CLP mice cardiac dysfunction was alleviated. The serum LDH and CK-MB were reduced in the miR-22cKO CLP mice. As expected, there was reduced apoptosis, increased autophagy and alleviated mitochondrial dysfunction in the miR-22cKO CLP mice, while it had contrary role in the miR-22cOE group. Inhibiting miR-22 promoted autophagy by increasing the LC3II/GAPDH ratio and decreasing the p62 level. Additionally, culturing primary cardiomyocytes with lipopolysaccharide (LPS) simulated sepsis-induced cardiomyopathy in vitro. Inhibiting miR-22 promoted autophagic flux confirmed by an increased LC3II/GAPDH ratio and reduced p62 protein level under bafilomycin A1 conditions. Knocking out miR-22 may exert a cardioprotective effect on sepsis by increasing autophagy and decreasing apoptosis via sirt1. Our results revealed that targeting miR-22 may become a new strategy for septic cardiomyopathy treatment.
| S-EPMC8047209 | biostudies-literature
Project description:Atherosclerosis (AS) is the main aetiology of coronary heart disease, cerebral infarction and peripheral vascular disease in humans. Long-noncoding RNA (LincRNA)-p21 has been reported to participate in the development of AS. Therefore, this study was designed to investigate the mechanism of LincRNA-p21 on suppressing the development of AS. We fed ApoE-/- mice with a high-fat diet to induce an AS mouse model where the lesion area of AS and the extent of lipid deposition were measured. The binding of LincRNA-p21 and miR-221 or miR-221 and SIRT1 was measured using a dual luciferase reporter gene assay and RIP. Following loss- and gain- function assays, CCK8, EdU, Transwell assay and scratch test were performed to determine the biological processes of human aortic endothelial cells (HAECs). miR-221 was highly expressed while SIRT1 was poorly expressed in AS. LincRNA-p21 acted as a sponge for miR-221. miR-221 targeted and negatively regulated the expression of SIRT1. LincRNA-p21 promoted the deacetylation of Pcsk9 by SIRT1 by competitively binding to miR-221, whereby promoting HAEC proliferation, migration and tube formation. In conclusion, LincRNA-p21 acted as a molecular sponge for miR-221 to promote deacetylation of the promoter region of Pcsk9 by SIRT1, therefore preventing the development of AS.
| S-EPMC8500963 | biostudies-literature
Project description:Sepsis is a severe disease, which results from the excessive inflammatory response to the infection. Dysfunction of intestinal barrier is a crucial problem in various pathological conditions. Meanwhile, microRNAs exhibit significant roles in the modulation of many diseases, including sepsis. Multiple investigations indicate that miR-199a-5p participates in different human diseases. Nevertheless, little is known on the roles of miR-199a-5p in sepsis. Herein, we evaluated the mechanism of miR-199a-5p on the intestinal barrier dysfunction in sepsis. Intestinal mucosa permeability indicators including D-lactic acid, DAO, and FD-40 levels were determined, and they were greatly increased in sepsis. Then, we proved that miR-199a-5p was induced in sepsis mice tissues and isolated intestinal epithelial cells. Moreover, miR-199a-5p increased D-lactic acid, DAO, and FD-40 while inhibition of miR-199a-5p exhibited a reversed process. Additionally, we observed that miR-199a-5p affected the oxidative damage and inflammation in the intestine tissues from sepsis mice. The content of MDA was elevated whereas SOD was remarkably repressed in the miR-199a-5p mimic group. IL-6, IL-1?, and TNF-? were induced by miR-199a-5p overexpression while IL-10 was reduced by miR-199a-5p. Subsequently, surfactant protein D (SP-D) was predicted as the target of miR-199a-5p. The activation of NF-?B has been identified in sepsis. Herein, we demonstrated that inhibitor of miR-199a-5p contributed to IEC injury via targeting SP-D and inactivating the NF-?B pathway. These revealed miR-199a-5p exacerbated the intestinal barrier dysfunction via inhibiting SP-D and activating the NF-?B pathway in sepsis.
| S-EPMC7251462 | biostudies-literature
Project description:BackgroundGut integrity is compromised in abdominal sepsis with increased cellular apoptosis and altered barrier permeability. Intestinal epithelial cells (IEC) form a physiochemical barrier that separates the intestinal lumen from the host's internal milieu and is strongly involved in the mucosal inflammatory response and immune response. Recent research indicates the involvement of the stimulator of interferons genes (STING) pathway in uncontrolled inflammation and gut mucosal immune response.MethodsWe investigated the role of STING signaling in sepsis and intestinal barrier function using intestinal biopsies from human patients with abdominal sepsis and with an established model of abdominal sepsis in mice.FindingsIn human abdominal sepsis, STING expression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared with healthy controls, and the degree of STING expression in the human intestinal lamina propria correlated with the intestinal inflammation in septic patients. Moreover, elevated STING expression was associated with high levels of serum intestinal fatty acid binding protein that served as a marker of enterocyte damage. In mice, the intestinal STING signaling pathway was markedly activated following the induction of sepsis induced by cecal ligation perforation (CLP). STING knockout mice showed an alleviated inflammatory response, attenuated gut permeability, and decreased bacterial translocation. Whereas mice treated with a STING agonist (DMXAA) following CLP developed greater intestinal apoptosis and a more severe systemic inflammatory response. We demonstrated that mitochondrial DNA (mtDNA) was released during sepsis, inducing the intestinal inflammatory response through activating the STING pathway. We finally investigated DNase I administration at 5 hours post CLP surgery, showing that it reduced systemic mtDNA and inflammatory cytokines levels, organ damage, and bacterial translocation, suggesting that inhibition of mtDNA-STING signaling pathway protects against CLP-induced intestinal barrier dysfunction.InterpretationOur results indicate that the STING signaling pathway can contribute to lethal sepsis by promoting IEC apoptosis and through disrupting the intestinal barrier. Our findings suggest that regulation of the mtDNA-STING pathway may be a promising therapeutic strategy to promote mucosal healing and protect the intestinal barrier in septic patients. FUND: National Natural Science Foundation of China.
| S-EPMC6443583 | biostudies-literature
Project description:We previously demonstrated that low biosynthesis of ?-3 fatty acid-derived proresolution mediators, termed protectins, is associated with an impaired global resolution capacity, inflammation and insulin resistance in obese high-fat diet-fed mice. These findings prompted a more direct study of the therapeutic potential of protectins for the treatment of metabolic disorders. Herein we show that protectin DX (PDX) exerts an unanticipated glucoregulatory activity that is distinct from its anti-inflammatory actions. We found that PDX selectively stimulated the release of the prototypic myokine interleukin-6 (IL-6) from skeletal muscle and thereby initiated a myokine-liver signaling axis, which blunted hepatic glucose production via signal transducer and activator of transcription 3 (STAT3)-mediated transcriptional suppression of the gluconeogenic program. These effects of PDX were abrogated in Il6-null mice. PDX also activated AMP-activated protein kinase (AMPK); however, it did so in an IL-6-independent manner. Notably, we demonstrated that administration of PDX to obese diabetic db/db mice raises skeletal muscle IL-6 levels and substantially improves their insulin sensitivity without any impact on adipose tissue inflammation. Our findings thus support the development of PDX-based selective muscle IL-6 secretagogues as a new class of therapy for the treatment of insulin resistance and type 2 diabetes.
| S-EPMC4978533 | biostudies-literature
Project description:BackgroundDiabetic cardiomyopathy (DCM) is a major threat for diabetic patients. Silent information regulator 1 (SIRT1) has a regulatory effect on mitochondrial dynamics, which is associated with DCM pathological changes. Our study aims to investigate whether resveratrol, a SRIT1 activator, could exert a protective effect against DCM.Methods and resultsCardiac-specific SIRT1 knockout (SIRT1KO) mice were generated using Cre-loxP system. SIRT1KO mice displayed symptoms of DCM, including cardiac hypertrophy and dysfunction, insulin resistance, and abnormal glucose metabolism. DCM and SIRT1KO hearts showed impaired mitochondrial biogenesis and function, while SIRT1 activation by resveratrol reversed this in DCM mice. High glucose caused increased apoptosis, impaired mitochondrial biogenesis, and function in cardiomyocytes, which was alleviated by resveratrol. SIRT1 deletion by both SIRT1KO and shRNA abolished the beneficial effects of resveratrol. Furthermore, the function of SIRT1 is mediated via the deacetylation effect on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1?), thus inducing increased expression of nuclear respiratory factor 1 (NRF-1), NRF-2, estrogen-related receptor-? (ERR-?), and mitochondrial transcription factor A (TFAM).ConclusionsCardiac deletion of SIRT1 caused phenotypes resembling DCM. Activation of SIRT1 by resveratrol ameliorated cardiac injuries in DCM through PGC-1?-mediated mitochondrial regulation. Collectively, SIRT1 may serve as a potential therapeutic target for DCM.
| S-EPMC5572590 | biostudies-literature
Project description:AbstractSepsis-induced immunosuppression involves both innate and adaptive immunity and is associated with the increased expression of checkpoint inhibitors, such as programmed cell-death protein 1 (PD-1). The expression of PD-1 is associated with poor outcomes in septic patients, and in models of sepsis, blocking PD-1 or its ligands with antibodies increased survival and alleviated immune suppression. While inhibitory antibodies are effective, they can lead to immune-related adverse events (irAEs), in part due to continual blockade of the PD-1 pathway, resulting in hyperactivation of the immune response. Peptide-based therapeutics are an alternative drug modality that provide a rapid pharmacokinetic profile, reducing the incidence of precipitating irAEs. We recently reported that the potent, peptide-based PD-1 checkpoint antagonist, LD01, improves T-cell responses. The goal of the current study was to determine whether LD01 treatment improved survival, bacterial clearance, and host immunity in the cecal-ligation and puncture (CLP)-induced murine polymicrobial sepsis model. LD01 treatment of CLP-induced sepsis significantly enhanced survival and decreased bacterial burden. Altered survival was associated with improved macrophage phagocytic activity and T-cell production of interferon-γ. Further, myeloperoxidase levels and esterase-positive cells were significantly reduced in LD01-treated mice. Taken together, these data establish that LD01 modulates host immunity and is a viable therapeutic candidate for alleviating immunosuppression that characterizes sepsis and other infectious diseases.
| S-EPMC8284559 | biostudies-literature
Project description:Saturated free fatty acid (FFA)-induced lipotoxicity plays an important role in obesity-induced kidney injury. Exenatide, a Glucagon-like peptide-1 receptor agonist(GLP-1RA), protects against high-fat diet (HFD)-induced kidney injury. The precise mechanism needs to be further explored. This study investigated whether exenatide protects against FFA-induced tubular epithelial cells (TECs) lipotoxicity and elucidated its underlying mechanisms. Here, we show that exenatide treatment reversed HFD induced TECs injuries, including TECs apoptosis and SIRT1 downregulation. The efficacy of exenatide was better than simvastatin. In palmitate (PA)-stimulated HK2 cells, exenatide treatment reversed the downregulation of SIRT1 and prevented an increase in reactive oxygen species (ROS) production, a decrease in mitochondrial membrane potential, and mitochondrial apoptosis. The renal-protective effects of exenatide on the generation of mitochondrial ROS and mitochondrial apoptosis were blocked by inhibiting SIRT1 activation. Collectively, these findings show that exenatide was superior to simvastatin in the treatment of obesity-TECs injuries, the mechanism is partially through SIRT1 restoration, which directly reverses mitochondrial dysfunction and apoptosis.
| S-EPMC8380782 | biostudies-literature