The pro‐inflammatory cytokine interleukin 1 beta (IL‐1β) plays a critical role in osteoarthritis (OA) disease pathogenesis. MicroRNA (miRNA) activity is related to inflammation in OA and some miRNAs ...specifically regulate IL‐mediated degradation of cartilage type II collagen. Previous studies have indicated that miR‐144‐3p is a useful target in the regulation of pro‐inflammatory cytokines in different diseases. However, the role of miR‐144‐3p in OA is unclear. In this study, we observed a negative correlation between miR‐144‐3p and IL‐1β expression in OA. miR‐144‐3p mimic transfection of OA synovial fibroblasts downregulated levels of IL‐1β expression, while blocking the MAPK, PI3K/Akt, and NF‐κB signaling pathways relating to IL‐1β production, and effectively increased miR‐144‐3p expression in OASFs. Findings from an anterior cruciate ligament transection rat model revealed that administration of miR‐144‐3p mimic effectively ameliorated OA progression and reduced the numbers of IL‐1β‐positive cells in synovial tissue. This study suggests that miR‐144‐3p is a useful therapeutic target in OA disease.
In this study, our findings support the targeting of microRNA (miR)‐144‐3p in the treatment of osteoarthritis (OA). This RNA molecule binds directly to interleukin (IL)‐1β and downregulates IL‐1β expression in vitro and in vivo. This study suggests that miR‐144‐3p is a useful therapeutic target in OA disease.
Gut microbiota alterations manifest as intermittent hypoxia and fragmented sleep, thereby mimicking obstructive sleep apnea-hypopnea syndrome (OSAHS). Here, we sought to perform the first direct ...survey of gut microbial dysbiosis over a range of apnea-hypopnea indices (AHI) among patients with OSAHS. We obtained fecal samples from 93 patients with OSAHS 5 < AHI ≤ 15 (
=40), 15 < AHI ≤ 30 (
=23), and AHI ≥ 30 (
=30) and 20 controls (AHI ≤ 5) and determined the microbiome composition via 16S rRNA pyrosequencing and bioinformatics analysis of variable regions 3-4. We measured fasting levels of homocysteine (HCY), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). Results revealed gut microbial dysbiosis in several patients with varying severities of OSAHS, reliably separating them from controls with a receiver operating characteristic-area under the curve (ROC-AUC) of 0.789. Functional analysis in the microbiomes of patients revealed alterations; additionally, decreased in short-chain fatty acid (SCFA)-producing bacteria and increased pathogens, accompanied by elevated levels of IL-6.
levels correlated with HCY levels. Stratification analysis revealed that the
enterotype posed the highest risk for patients with OSAHS. Our results show that the presence of an altered microbiome is associated with HCY among OSAHS patients. These changes in the levels of SCFA affect the levels of pathogens that play a pathophysiological role in OSAHS and related metabolic comorbidities.
Liver fibrosis and cirrhosis are primarily caused by the activation of hepatic stellate cells (HSCs), regardless of their etiology. Collagen type I (collagen I) and connective tissue growth factor ...(CTGF) is produced more readily by activated HSCs. Consequently, identifying the molecular and cellular mechanisms responsible for HSCs activation is essential to better understand its mechanism of action and therapeutic potential. Cell death is caused by iron‐dependent lipid peroxidation during ferroptosis. Ferroptosis plays an important role in the survival of activated HSCs and could contribute to the development of innovative prevention and treatment strategies for liver fibrosis. Danshensu (Dan) is a pure molecule extracted from the Salvia miltiorrhiza herb that protects against liver damage. However, Dan's effect on attenuating HSCs activation by regulating ferroptosis remains unclear. The results of this study indicated that lipopolysaccharide (LPS)‐induced LX‐2 and T6 cells activation occurs through the upregulation of collagen I, CTGF, Gpx4, and SLC7A11. Interestingly, Dan attenuated LPS‐induced liver fibrosis in those cells by upregulating collagen I, CTGF, Gpx4, and SLC7A11 and by increasing lipid reactive oxygen species accumulation. Furthermore, the results also showed that the ferroptosis inhibitor liproxstatin attenuated the overproduction of lipid reactive oxygen species in LPS‐activated LX‐2 cells. We conclude that Dan attenuates LPS‐induced HSC activation during liver fibrosis by regulating ferroptosis in LX‐2 and T6 cells.
Danshensu (Dan) attenuates lipopolysaccharide‐induced hepatic stellate cells activation via decreasing expression of collagen І, connective tissue growth factor, glutathione peroxidase 4, cystine/glutamate antiporter xCT, and lipocalin‐2. However, Dan increases lipid reactive oxygen species accumulation.
Highlights • Metabolic parameters are time-dependently disrupted in isolation rearing rats. • IL-1 beta, IL-6, TNF-alpha are elevated in isolation rearing rats. • Correlations between ...pro-inflammatory cytokines and metabolism are sex specific. • Early life experience is crucial for inflammation and metabolism.
Osteoarthritis (OA) is characterized by the infiltration and adhesion of monocytes into the inflamed joint synovium. Interleukin (IL)-17 is a critical inflammatory mediator that participates in the ...progression of OA, although the mechanisms linking IL-17 and monocyte infiltration are not well understood. Our analysis of synovial tissue samples retrieved from the Gene Expression Omnibus (GEO) dataset exhibited higher monocyte marker (CD11b) and vascular cell adhesion molecule 1 (VCAM-1) levels in OA samples than in normal, healthy samples. The stimulation of human OA synovial fibroblasts (OASFs) with IL-17 increased VCAM-1 production and subsequently enhanced monocyte adhesion. IL-17 affected VCAM-1-dependent monocyte adhesion by reducing miR-5701 expression through the protein kinase C (PKC)-α and c-Jun N-terminal kinase (JNK) signaling cascades. Our findings improve our understanding about the effect of IL-17 on OA progression and, in particular, VCAM-1 production and monocyte adhesion, which may help with the design of more effective OA treatments.
Obstructive sleep apnea-hypopnea syndrome (OSAHS) is an independent risk factor for hypertension (HTN). The oral microbiota plays a pathophysiological role in cardiovascular diseases; however, there ...are few reports directly investigating and identifying the organisms involved in OSAHS-related HTN. Therefore, this study aimed to identify those organisms. We obtained 139 oral samples and determined the microbiome composition using pyrosequencing and bioinformatic analyses of the 16S rRNA. We examined the fasting levels of cytokines and homocysteine in all participants and analyzed the correlations between the oral microbiota and homocysteine levels. We determined the molecular mechanism underlying HTN by investigating the genetic composition of the strains in the blood. We detected higher relative abundances of Porphyromonas and Aggregatibacter and elevated proinflammatory cytokines in patients with OSAHS of varying severity compared with individuals without OSAHS; however, the two organisms were not measured in the blood samples from all participants. High levels of specific Porphyromonas bacteria were detected in patients with OSAHS with and without HTN, whereas the relative abundance of Aggregatibacter was negatively correlated with the homocysteine level. The receiver operating characteristic curve analysis of controls and patients with OSAHS resulted in area under the curve values of 0.759 and 0.641 for patients with OSAHS with or without HTN, respectively. We found that the predictive function of oral microbiota was different in patients with OSAHS with and without HTN. However, there was no direct invasion by the two organisms causing endothelial cell injury, leading to speculation regarding the other mechanisms that may lead to HTN. Elucidating the differences in the oral microbiome will help us understand the pathogenesis of OSAHS-related HTN.
Evidence is mounting that the gut microbiome is related to the underlying pathogenesis of schizophrenia. However, effects of amisulpride on gut microbiota are poorly defined. This study was aimed at ...analyzing cytokines and fecal microbiota in patients with exacerbated symptoms of schizophrenia treated with amisulpride during four weeks of their hospital stay. In the present study, feces collected from patients with schizophrenia were analyzed using 16S rRNA pyrosequencing and bioinformatic analyses to ascertain gut microbiome composition and fasting peripheral blood cytokines. We found that patients undergoing treatment of schizophrenia with amisulpride had distinct changes in gut microbial composition at the genus level, increased levels of short-chain fatty acid-producing bacteria (Dorea and Butyricicoccus), and reduced levels of pathogenic bacteria (Actinomyces and Porphyromonas), but the level of Desulfovibrio was still high. We also found a significant downregulation of butanoate metabolism based on functional analysis of the microbiome. After treatment, elevated levels of interleukin- (IL-) 4 and decreased levels of IL-6 were found. Our findings extend prior work and suggest a possible pharmacological mechanism of amisulpride treatment for schizophrenia, which acts via mediation of the gut microbiome.
Purpose
Migraine, a severely debilitating condition, may be effectively managed with topiramate, known for its migraine prevention and weight loss properties due to changes in body muscle and fat ...composition and improved insulin sensitivity. However, the mechanism of topiramate in modulating insulin response in adipocytes and myocytes remains elusive. This study aims to elucidate these molecular mechanisms, offering insights into its role in weight management for migraine sufferers and underpinning its clinical application.
Methods
Insulin resistance improvements were evaluated through glucose uptake measurements in C2C12 muscle cells and 3T3L-1 adipocytes, with Oil red O staining conducted on adipocytes. RNA-seq transcriptome analysis was used to identify the regulatory target genes of topiramate in these cells. The involvement of key genes and pathways was further validated through western blot analysis.
Results
Topiramate effectively reduced insulin resistance in C2C12 and 3T3L-1 cells. In C2C12 cells, it significantly lowered
SORBS1
gene and protein levels. In 3T3L-1 cells, topiramate upregulated
CTGF
and downregulated
MAPK8
and
KPNA1
genes. Changes were notable in nuclear cytoplasmic transport and circadian signaling pathways. Furthermore, it caused downregulation of MKK7, pJNK1/ JNK1, BMAL1, and CLOCK proteins compared to the insulin-resistant model.
Conclusion
This study provides preliminary insights into the mechanisms through which topiramate modulates insulin resistance in C2C12 myocytes and 3T3L-1 adipocytes, enhancing our understanding of its therapeutic potential in managing weight and insulin sensitivity in migraine patients.
Intermittent hypoxia and sleep fragmentation are pathophysiological processes involved in obstructive sleep apnea (OSA) which affect gut microbiota, sleep architecture, and mTOR signaling pathway. ...However, the involvement of these elements in the pathogenesis mechanism of OSA-associated hypertension remains unclear. Therefore, this study investigated whether the OSA-associated hypertension mechanism is regulated by the gut microbiota and mTOR signaling pathway. Patients were diagnosed by polysomnography; their fecal samples were obtained and analyzed for their microbiome composition by 16S ribosomal RNA pyrosequencing and bioinformatics analysis. Transcript genes on fasting peripheral blood mononuclear cells (PBMCs) were examined using Illumina RNA-sequencing analysis. Totally, we enrolled 60 patients with severe OSA without hypertension (n = 27) and with hypertension (n = 33) and 12 controls (neither OSA nor hypertension). Results revealed that severe-OSA patients with hypertension had an altered gut microbiome, decreased short-chain fatty acid-producing bacteria P<0.05, and reduced arginine and proline metabolism pathways P=0.001, compared with controls; also, they had increased stage N1 sleep and reduced stages N2 and N3 sleep accompanied by repeated arousals P<0.05. Analysis of PBMCs using the Kyoto Encyclopedia of Genes and Genomes database showed that the mTOR signaling pathway P=0.006 was the most important differential gene-enriched pathway in severe-OSA patients with hypertension. Our findings extend prior work and suggest a possibility that the regulation of the mTOR signaling pathway is involved in developing OSA-associated hypertension through its interaction with the disturbance of the gut microbiome and sleep architecture.
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