Acute myocardial infarction (AMI), as the first manifestation of ischemic heart disease, is the most common cause of death in developed countries. A recent study showed that metastasis associated lung adenocarcinoma transcript 1 (MALAT1), a prognostic marker for lung cancer metastasis, could promote myocardial ischemia-reperfusion injury by regulating the levels of microRNA (miR)-145. In order to elucidate the biological function of MALAT1 in the pathogenesis of AMI and to explore the mechanisms underlying its action, an AMI rat model was established by ligation of the left anterior descending coronary artery. Downregulation of MALAT1 by siRNA transfection attenuated heart damage in an AMI model rat. The mouse cardiomyocyte cell line HL-1 was used to show that downregulation of nucleotide binding and oligomerization domain-like receptor C5 (NLRC5) and upregulation of miR-125b-5p were the results of MALAT1 silencing. TargetScan and a dual-luciferase reporter assay indicated that NLRC5 is a direct target of miR-125b-5p. Overexpression of miR-125b-5p significantly reduced hypoxia/reperfusion-induced apoptosis of HL-1 cells, an effect that could be blocked by NLCR5 overexpression. Taken together, these results suggest that MALAT1 reduced the protective effect of miR-125b-5p on injured cells through upregulation of NLCR5. This study highlights the role of MALAT1 in the pathogenesis of AMI and may guide future genetic therapeutic strategies for AMI treatment.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Since most patients with HCC are diagnosed at the intermediate or advanced stage and because HCC has a high incidence of metastasis and recurrence, it is one of the leading causes of cancer death. Exosomes are a subtype of extracellular vesicles and are typically 30–150 nm in diameter. Originating from endosomes, they can be secreted by almost all living cells. They are widely present in various body fluids and serve as an important medium for the interactions between cells. A series of studies have revealed that exosomes-mediated intercellular transfer of proteins, nucleic acids, and metabolites plays a crucial role in the initiation and progression of HCC, hypoxia and angiogenesis, chemotherapy sensitivity, and cell death mode and regulates the immune microenvironment. In this paper, we reviewed the recent researches on the multiple roles of tumor-associated exosomes in the progression of HCC. We laid particular focus on those researches that reveal how exosomes regulate the tumor immune microenvironment (TIME) and how exosomal cargos affect the progression of HCC. Besides, we emphasize some prospective directions to achieve a more accurate and complete analysis of the HCC immune microenvironment.
Autophagy has been shown to maintain neural system homeostasis during stroke. However, the molecular mechanisms underlying neuronal autophagy in ischemic stroke remain poorly understood. This study aims to investigate the regulatory mechanisms of the pathway consisting of maternally expressed gene 3 (MEG3), microRNA-378 (miR-378), and growth factor receptor-bound protein 2 (GRB2) in neuronal autophagy and neurological functional impairment in ischemic stroke. A mouse model of the middle cerebral artery occluded (MCAO)-induced ischemic stroke and an in vitro model of oxygen-glucose deprivation (OGD)-induced neuronal injury were developed. To understand the role of the MEG3/miR-378/GRB2 axis in the neuronal regulation, the expression of proteins associated with autophagy in neurons was measured by Western blot analysis and neuron death was evaluated using LDH leakage rate test. Firstly, it was found that the GRB2 gene, up-regulated in MCAO-operated mice and OGD-exposed neurons, was a target gene of miR-378. Next, miR-378 inhibited neuronal loss and neurological functional impairment in mice as well as neuronal autophagy and neuronal death by silencing of GRB2. Confirmatory in vitro experiments showed that MEG3 could specifically bind to miR-378 and subsequently up-regulate the expression of GRB2, which in turn suppressed the activation of Akt/mTOR pathway. Taken together, these findings suggested that miR-378 might protect against neuronal autophagy and neurological functional impairment, and proposed that a MEG3/miR-378/GRB2 regulatory axis contributed to better understanding of the pathophysiology of ischemic stroke.
Fatty liver disease (FLD) is a growing health issue with burdening unmet clinical needs. FLD has a genetic component but, despite the common variants already identified, there is still a missing heritability component. Using a candidate gene approach, we identify a locus (rs71519934) at the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene resulting in a leucine to threonine substitution at position 186 of the protein (L186T) that reduces susceptibility to the entire spectrum of FLD in individuals at risk. PSD3 downregulation by short interfering RNA reduces intracellular lipid content in primary human hepatocytes cultured in two and three dimensions, and in human and rodent hepatoma cells. Consistent with this, Psd3 downregulation by antisense oligonucleotides in vivo protects against FLD in mice fed a non-alcoholic steatohepatitis-inducing diet. Thus, translating these results to humans, PSD3 downregulation might be a future therapeutic option for treating FLD.
Impaired wound healing is a common complication of diabetes. In diabetic wounds, macrophages present dysfunctional efferocytosis and abnormal phenotypes, which could result in excessive neutrophil accumulation and prolonged inflammation, thereby eventually hindering wound repair. ANXA1 N‐terminal peptide Ac2‐26 exhibits a high potential in mitigating inflammation and improving repair; however, its efficacy in diabetic wound repair remains unclear. In this study, a cutaneous excisional wound model was built in genetically diabetic mice. Ac2‐26 or a vehicle solution was employed locally in wound sites. Subsequently, wound zones were measured and sampled at different time intervals post‐wounding. Using hematoxylin‐eosin and Masson's trichrome staining, we observed the histopathological variations and collagen deposition in wound samples. Based on immunohistochemistry and immunofluorescence, the numbers of neutrophils, macrophages, and CD206‐positive macrophages in the wound samples were determined. Cytokine expression in wound samples was studied by immunoblot assay. Results showed that Ac2‐26 treatment could facilitate diabetic wound closure, down‐regulate the number of neutrophils, and improve angiogenesis and collagen deposition. In addition, Ac2‐26 application expedited macrophage recruitment and up‐regulated the percentage of macrophages expressing CD206, which is a marker for M2 macrophages. Moreover, Ac2‐26 inhibited the expressions of TNF‐α and IL‐6 and up‐regulated the expressions of IL‐10, TGF‐β, and VEGFA during diabetic wound healing. Hence, based on the aforementioned findings, Ac2‐26 application in diabetic wounds could exert anti‐inflammatory and pro‐repair effects by reducing neutrophil accumulation and facilitating M2 macrophage development.
Polymyositis (PM) is an autoimmune disease characterized by chronic inflammation in skeletal muscle. Mean platelet volume (MPV), a marker in the assessment of systemic inflammation, is easily measured by automatic blood count equipment. However, to our knowledge, there are no data in the literature with respect to MPV levels in PM patients. Therefore, in this study we aimed to investigate MPV levels in patients with PM. This study included 92 newly diagnosed PM patients and 100 healthy individuals. MPV levels were found to be significantly lower compared with healthy controls (10.3±1.23 vs 11.5±0.74 fL, P<0.001). Interestingly, MPV was found to be positively correlated with manual muscle test (MMT) score and negatively correlated with erythrocyte sedimentation rate (ESR) in patients with PM (r=0.239, P=0.022; r=−0.268, P=0.010, respectively). In addition, MPV was significantly lower in active PM patients compared with inactive PM patients (9.9±1.39 vs 10.6±0.92 fL, P=0.010). MPV was independently associated with PM in multivariate regression analyses, when controlling for hemoglobin and ESR (OR=0.312, P=0.031, 95%CI=0.108 to 0.899). The ROC curve analysis for MPV in estimating PM patients resulted in an area under the curve of 0.800, with sensitivity of 75.0% and specificity of 67.4%. Our results suggest that MPV is inversely correlated with disease activity in patients with PM. MPV might be a useful tool for rapid assessment of disease severity in PM patients.
Aim. To investigate the expressions of glutathione peroxidase 1 (GPX1) and caudal-related homeodomain transcription factor (CDX2) in GAC and their correlation with clinicopathological features and tumor cell proliferation. Methods. The expressions of GPX1, CDX2, and Ki67 were immunohistochemically evaluated in 172 GAC specimens. The association of GPX1 and CDX2 with patient's clinicopathological features and Ki67 positive rate was analyzed statistically. Results. In 172 cases of GAC, the expression of GPX1 was weaker than that in adjacent normal mucosa, and the expression of CDX2 was higher than that in adjacent normal mucosa. High expression GPX1 strong-expression was associated with differentiation, Lauren type, WHO type and extensive lymph node metastasis of GAC. High expression of CDX2 was associated with differentiation, Lauren type, WHO type, extensive lymph node metastasis, and TNM of GAC. Survival curves showed that expressions of GPX1 and CDX2 were factors of good outcome (P = .03 and .02, resp.). According to multivariate analysis, only lymph node metastasis, TNM stage, and CDX2 expression were independently associated with survival. In addition, a strong association of GPX1 expression was noted with Ki67 and CDX2. Conclusions. The expression of GPX1 and CDX2 may play a role in the carcinogenesis, differentiation, and progression of GAC, and CDX2 may be an independent prognostic factor.
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