Phosphatidylinositol 3 kinase (PI3K) is a key molecule in the initiation of signal transduction pathways after the binding of extracellular signals to cell surface receptors. An intracellular kinase, PI3K activates multiple intracellular signaling pathways that affect cell growth, proliferation, migration, secretion, differentiation, transcription and translation. Dysregulation of PI3K activity, and as aberrant PI3K signaling, lead to a broad range of human diseases, such as cancer, immune disorders, diabetes, and cardiovascular diseases. A growing number of studies have shown that PI3K and its signaling pathways play key roles in the pathophysiological process of atherosclerosis. Furthermore, drugs targeting PI3K and its related signaling pathways are promising treatments for atherosclerosis. Therefore, we have reviewed how PI3K, an important regulatory factor, mediates the development of atherosclerosis and how targeting PI3K can be used to prevent and treat atherosclerosis.
Ferroptosis is characterized by the accumulation of iron and lipid peroxidation products, which regulates physiological and pathological processes in numerous organs and tissues. A growing body of research suggests that ferroptosis is a key causative factor in a variety of skeletal muscle diseases, including sarcopenia, rhabdomyolysis, rhabdomyosarcoma, and exhaustive exercise-induced fatigue. However, the relationship between ferroptosis and various skeletal muscle diseases has not been investigated systematically. This review’s objective is to provide a comprehensive summary of the mechanisms and signaling factors that regulate ferroptosis, including lipid peroxidation, iron/heme, amino acid metabolism, and autophagy. In addition, we tease out the role of ferroptosis in the progression of different skeletal muscle diseases and ferroptosis as a potential target for the treatment of multiple skeletal muscle diseases. This review can provide valuable reference for the research on the pathogenesis of skeletal muscle diseases, as well as for clinical prevention and treatment.
Skimmin, a natural coumarin derivate, has been showed to be protective against experimental diabetic nephropathy; however, its protective effect on diabetic cardiomyopathy (DCM) is not clarified. By using in vitro and in vivo models, we investigated skimmin's protective effect on impaired heart tissues in DCM. DCM was induced by streptozotocin (STZ, 60 mg/kg) using Sprague Dawley rats, and diabetic rats were treated with either skimmin (15 or 30 mg/kg) or the vehicle for 16 weeks, and normal rats were used as a control. Hematoxylin and eosin and Masson's trichrome staining were performed to evaluate the cardiac histopathology, and the oxidative stress and proinflammation cytokines in heart tissues were measured. The protein levels of key mediators in fibrosis, pyroptosis, and autophagy in heart tissues were investigated using western blotting. In vitro, primary neonatal cardiomyocytes were treated with skimmin (2 and 10 μM) under stimulation by high glucose (30 mM) and low glucose (5 mM) respectively, and the molecular mechanisms on pyroptosis and autophagy were studied. Compared to the vehicle‐treated DCM group, skimmin treatment significantly improved the ejection fraction and fractional shortening of the left ventricle and reduced the oxidative stress by increasing the glutathione level and activity of superoxide dismutase and catalase. Skimmin also reduced cardiac fibrosis, and decreased proinflammation cytokines in cardiac tissues. Mechanism studies showed skimmin may enhance the autophagy and ameliorate NLRP3 inflammasome activation to play a protective role in DCM. This study, for the first time, indicates that skimmin might be a promising lead compound for DCM.
Nuclear factor of activated T cells (NFAT) is a transcription factor with a multidirectional regulatory function, that is widely expressed in immune cells, including cells in the cardiovascular system, and non-immune cells. A large number of studies have confirmed that calcineurin/NFAT signal transduction is very important in the development of vascular system and cardiovascular system during embryonic development, and plays some role in the occurrence of vascular diseases such as atherosclerosis, vascular calcification, and hypertension. Recent in vitro and in vivo studies have shown that NFAT proteins and their activation in the nucleus and binding to DNA-related sites can easily ɨnduce the expression of downstream target genes that participate in the proliferation, migration, angiogenesis, and vascular inflammation of vascular wall related cells in various pathophysiological states. NFAT expression is regulated by various signaling pathways, including CD137-CD137L, and OX40-OX40L pathways. As a functionally diverse transcription factor, NFAT interacts with a large number of signaling molecules to modulate intracellular and extracellular signaling pathways. These NFAT-centered signaling pathways play important regulatory roles in the progression of atherosclerosis, such as in vascular smooth muscle cell phenotypic transition and migration, endothelial cell injury, macrophage-derived foam cell formation, and plaque calcification. NFAT and related signaling pathways provide new therapeutic targets for vascular diseases such as atherosclerosis. Hence, further studies of the mechanism of NFAT in the occurrence and evolution of atherosclerosis remain crucial.
Background. Long noncoding RNA (lncRNA) is involved in the occurrence and development of diabetic kidney disease (DKD). It is necessary to identify the expression of lncRNA from DKD patients through systematic reviews, and then carry out silico analyses to recognize the dysregulated lncRNA and their associated pathways. Methods. The study searched Pubmed, Embase, Cochrane Library, WanFang, VIP, CNKI, and CBM to find lncRNA studies on DKD published before March 1, 2021. Systematic review of the literature on this topic was conducted to determine the expression of lncRNA in DKD and non-DKD controls. For the dysregulated lncRNA in DKD patients, silico analysis was performed, and lncRNA2Target v2.0 and starBase were used to search for potential target genes of lncRNA. The Encyclopedia of Genomics (KEGG) pathway enrichment analysis was performed to better identify dysregulated lncRNAs in DKD and determine the associated signal pathways. Results. According to the inclusion and exclusion criteria, 28 publications meeting the eligibility criteria were included in the systematic evaluation. A total of 3,394 patients were enrolled in this study, including 1,238 patients in DKD group, and 1,223 diabetic patients, and 933 healthy adults in control group. Compared with the control, there were eight lncRNA disorders in DKD patients (MALAT1, GAS5, MIAT, CASC2, NEAT1, NR_033515, ARAP1-AS2, and ARAP1-AS1). In addition, five lncRNAs (MALAT1, GAS5, MIAT, CASC2, and NEAT1) participated in disease-related signal pathways, indicating their role in DKD. Discussion. This study showed that there were eight lncRNAs in DKD that were persistently dysregulated, especially five lncRNAs which were closely related to the disease. Although systematic review included 28 studies that analyzed the expression of lncRNA in DKD-related tissues, the potential of these dysregulated lncRNAs as biomarkers or therapeutic targets for DKD remains to be further explored. Trial registration. PROSPERO (CRD42021248634).
Vascular calcification is a pathological process characterized by ectopic calcification of the vascular wall. Medial calcifications are most often associated with kidney disease, diabetes, hypertension, and advanced age. Intimal calcifications are associated with atherosclerosis. Collagen can regulate mineralization by binding to apatite minerals and promoting their deposition, binding to collagen receptors to initiate signal transduction, and inducing cell transdifferentiation. In the process of vascular calcification, type I collagen is not only the scaffold for mineral deposition but also a signal entity, guiding the distribution, aggregation, and nucleation of vesicles and promoting the transformation of vascular smooth muscle cells into osteochondral-like cells. In recent years, collagen has been shown to affect vascular calcification through collagen disc-domain receptors, matrix vesicles, and transdifferentiation of vascular smooth muscle cells.
Given the rise of morbidity and mortality caused by Klebsiella pneumoniae (KP), the increasing number of strains resistant to antibiotics, and the emergence of hypervirulent Klebsiella pneumonia, treatment of KP infection becomes difficult; thus, novel drugs are necessary for treatment. Anthocyanins, or natural flavonoids, have an extensive effect against bacterial infection. However, few studies on anti-KP are identified. Here, we evaluated the therapeutic effect of purple sweet potato anthocyanins (PSPAs) on KP, containing 98.7% delphinidin 3-sambubioside. Results showed that KP-infected mice after PSPAs treatment manifested decreased mortality, weakened lung injury, dampened inflammatory responses, and reduced bacterial systemic dissemination in vivo. In Vitro, PSPAs significantly suppressed pyroptosis and restricted NLRP3 inflammasome activation in alveolar macrophages infected with KP. As for the mechanism, PSPAs promote mitophagy by recruiting Parkin to the mitochondria. PSPAs-conferred mitophagy increased mitochondrial membrane potential and decreased mitochondrial reactive oxygen species and mitochondrial DNA, resulting in impaired NLRP3 inflammasome activation. In addition, the promotion of mitophagy by PSPAs required the Nrf2 signaling pathway. Collectively, these findings suggest that PSPAs are a potential option for the treatment of KP infection.
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