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OBJECTIVE: We aimed to investigate the role of forkhead box O1 (FoxO1) inhibitor AS1842856 (AS) in nonalcoholic steatohepatitis (NASH) mice and the potential mechanisms. METHODS: Mice were given methionine-choline-sufficient (MCS), or methionine- and choline-deficient (MCD) diet for 5 weeks, along with AS (60 mg/kg) or vehicle gavage treatment (0.2 mL/day). Body and liver weight, serum triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting glucose and insulin levels were measured. Liver macrophage infiltration and ileal ZO-1 protein expression were also detected. Interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α, sterol regulatory element binding protein (SREBP)-1c, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase), α-smooth muscle actin (SMA), recombinant collagen type III α1 (Col3a1), and connective tissue growth factor (Ctgf) expressions were measured. Stool samples were collected for 16S rDNA sequencing. RESULTS: Compared to the MCD group, AS attenuated liver weight, reduced serum TG, ALT, and AST levels, increased HDL-C levels, mitigated hepatic steatosis, decreased macrophage infiltration, and augmented ileal ZO-1 proteins in NASH mice. It also reduced the levels of IL-6, IL-1ß, and TNF-α, alongside with the Srebp-1c mRNA expression. However, no significant effects on Pepck, G6Pase, α-SMA, Col3a1, or Ctgf were observed. Furthermore, AS promoted diversity and altered gut microbiota composition in NASH mice, causing increased beneficial bacteria like Akkermansia muciniphila, Parabacteroides distasonis, and Prevotellamassilia, which were associated with metabolic functions. CONCLUSION: FoxO1 inhibitor AS ameliorated hepatic steatosis, inflammation, and intestinal dysbiosis in NASH mice, making it a potentially promising treatment for NASH.
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Background: Sepsis is a common complication of severe trauma, burns, infection, or major surgery. This disease-related end-organ dysfunction results from systemic inflammatory response syndrome (SIRS). Acute kidney damage (AKI), also known as acute renal failure, is one of the most frequent and serious sequelae of sepsis. Nuclear transcription factor-κB (NF-κB) regulates the transcription of inflammation-related genes and operates as a mediator in the immune system. While parthenolide (PTL) has been reported to prevent harmful inflammatory reactions, its effects on sepsis-associated AKI are unknown. The current study investigates the effects of PTL in sepsis-associated AKI using cell and cecal ligation and puncture (CLP) models. Methods: Lipopolysaccharide (LPS)-stimulated rat glomerular mesangial cells were treated with 10 µM PTL. Inflammatory mediators, including TNF-α, IL-6, and IL-1ß, in the culture supernatants were measured by ELISA, and NF-κB levels were assessed by qPCR. After the generation of the septic CLP model, rats were intraperitoneally injected with 500 g/kg PTL and were euthanized after 72 h. Serum and kidney samples were analyzed. Results: TNF-α, IL-1ß, and IL-6 levels were elevated after LPS treatment of rat glomerular mesangial cells (p=0.004, p=0.002, and p=0.004, respectively) but were significantly reduced in the PTL treatment group (p ≤ 0.001, p=0.01, and p ≤ 0.001). NF-κB p65 levels were also increased after LPS treatment in this group and were reduced in the PTL treatment group. PTL treatment also reduced kidney damage after CLP induction, as shown by histological analysis and reductions in the levels of BUN, Cre, KIM-1, and NAGL. CLP-induced kidney inflammation together with increased levels of proinflammatory cytokines and inflammatory-related proteins. The elevated levels of renal TNF-α, IL-6, and IL-1ß were downregulated after PTL treatment. The PTL treatment also reduced the CLP-induced activation of NF-κB p65 in the damaged kidneys. Conclusion: PTL reduced inflammation induced by CLP-induced AKI in rat models and LPS-induced damage to glomerular mesangial cells by suppressing NF-κB signaling.
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Background: Fecal microbiota transplantation (FMT) has been found to be effective in irritable bowel syndrome with predominant diarrhea (IBS-D). We conducted this study to determine the impact of a low FODMAP diet (LFD) on the gut microbiota and the efficacy of FMT in the treatment of IBS-D. Methods: A retrospective analysis of a single-arm open-label prospective study was conducted to investigate the impact of FMT alone (n = 40) and FMT+LFD (n = 40) in refractory IBS-D. The IBS-quality of life (QOL), IBS-severity scoring system (SSS), gastrointestinal symptom rating scale (GSRS), Hamilton anxiety scale (HAMA), and Hamilton depression scale (HAMD) were used to evaluate the efficacy, and partial 16S rDNA amplicon sequencing was used to profile the microbiota. Results: The response rates were higher in the FMT+LFD group than in the FMT group (1 mo, 3 mo, 6 mo: 70.0% vs. 55.0%, 67.5% vs. 57.5%, 62.5% vs. 27.5%, respectively). The FMT+LFD group showed significantly better improvement in IBS-QOL at 1, 3, and 6 months; IBS-SSS at 6 months; and GSRS at 1 month compared to FMT alone. Changes in HAMA and HAMD were similar in the two groups. The LFD significantly upregulated the FMT-induced microbial diversity (OTUs: 666 vs. 574, Adonis: P = 0.02) and significantly strengthened the upregulation of Bacteroides, Alistipes, and Ruminococcaceae_UCG-002 and the downregulation of Bifidobacterium. Conclusion: An LFD enhanced the efficacy of FMT, increased the gut microbial diversity after FMT, and strengthened the inhibitory effect of FMT on conditional pathogens.
Assuntos
Gastroenteropatias , Síndrome do Intestino Irritável , DNA Ribossômico , Diarreia/terapia , Dieta , Transplante de Microbiota Fecal , Fezes/microbiologia , Humanos , Síndrome do Intestino Irritável/terapia , Estudos Prospectivos , Qualidade de Vida , Estudos RetrospectivosRESUMO
Background: Sepsis is defined as a host inflammatory response to infection that can result in end-organ dysfunction. One of the most common consequences of sepsis is acute kidney injury (AKI). Panax notoginseng powder (PNP) has been previously reported to protect against overactive inflammation process. However, the potential effect of PNP on septic AKI is poorly described. The current study was conducted to investigate the protective effects of PNP in septic AKI rats. Methods: A model of septic AKI was established on male SD rats by using the cecal ligation and puncture procedure. PNP was administrated by gavage after the cecal ligation and puncture (CLP) procedure, and the mice were sacrificed at 6, 12, and 72 h after induction of sepsis. The serum and kidney samples were collected and assayed for biochemical tests, histopathological staining, inflammation, and apoptosis-related gene/protein expression. In addition, 15 rats in each group were used to calculate the 7-day survival rate. Results: CLP-induced kidney injury was observed by the histopathological score, which markedly was attenuated by PNP treatment. Consistently, PNP intervention significantly alleviated the elevated levels of serum creatinine and blood urea nitrogen in CLP-induced sepsis rats. The CLP procedure also triggered proinflammatory cytokine production and increased the expression of various inflammation-related proteins in the kidneys. However, PNP inhibited the renal expression of IL-18, IL-1ß, TNF-α, and IL-6 to substantially improve inflammatory response. Mechanistically, CLP induced the increase of the NF-κB p65 level in the injured kidneys, while PNP notably inhibited the corresponding protein expression. Conclusion: PNP attenuated kidney inflammation to protect against CLP-induced septic AKI in rats via inhibiting the NF-κB signaling pathway.
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Asperger syndrome (AS) is a chronic neurodevelopmental disorder. Although all of the clinically diagnosed cases display normal intelligence and speech functions, barriers in social interaction and communication seriously affect mental health and psychological function. In addition to traditional psychological/behavioral training and symptomatic medication, in-depth studies of intestinal microbiota and mental health have indicated that probiotics (e.g., Lactobacillus rhamnosus) can effectively reduce the occurrence of AS. Fecal microbiota transplantation (FMT) is a type of biological therapy that involves the transplant of intestinal microbiota from healthy donors into the patient's gastrointestinal tract to improve the gut microenvironment. In this case report, we describe the first case of adult AS treated with FMT. The patient suffered from diarrhea-predominant irritable bowel syndrome for 6 years with symptoms of diarrhea and abdominal pain. After three rounds of FMT, the diarrhea and abdominal pain were significantly improved. Moreover, the symptoms of AS were also significantly ameliorated. We found that FMT changed the structure of the intestinal microbiota as well as the patient's serum metabolites, and these changes were consistent with the patient's symptoms. The metabolites may affect signaling pathways, as revealed by Kyoto Encyclopedia of Genes and Genomes enrichment analysis. The changes in microbial metabolites following FMT may affect other regions (e.g., the nervous system) via the circulatory system, such that the bacteria-gut-blood-brain axis may be the means through which FMT mitigates AS.
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Gut dysbacteriosis is closely related to various intestinal and extraintestinal diseases. Fecal microbiota transplantation (FMT) is a biological therapy that entails transferring the gut microbiota from healthy individuals to patients in order to reconstruct the intestinal microflora in the latter. It has been proved to be an effective treatment for recurrent Clostridium difficile infection. Studies show that the gut microbiota plays an important role in the pathophysiology of neurological and psychiatric disorders through the microbiota-gut-brain axis. Therefore, reconstruction of the healthy gut microbiota is a promising new strategy for treating cerebral diseases. We have reviewed the latest research on the role of gut microbiota in different nervous system diseases as well as FMT in the context of its application in neurological, psychiatric, and other nervous system-related diseases (Parkinson's disease, Alzheimer's disease, multiple sclerosis, epilepsy, autism spectrum disorder, bipolar disorder, hepatic encephalopathy, neuropathic pain, etc.).