Arterial calcification is common in vascular diseases and involves conversion of vascular smooth muscle cells (VSMCs) to an osteoblast phenotype. Clinical studies suggest that the development of atherosclerosis can be promoted by homocysteine (HCY), but the mechanisms remain unclear. Here, we determined whether increases in HCY levels lead to an increase in VSMC calcification and differentiation, and examined the role of an extracellular matrix remodeler, matrix metalloproteinase-2 (MMP-2). Rat VSMCs were exposed to calcification medium in the absence or presence of HCY (10, 100 or 200 μmol/L) or an MMP-2 inhibitor (10(-6) or 10(-5) mol/L). MTT assays were performed to determine the cytotoxicity of the MMP-2 inhibitor in calcification medium containing 200 μmol/L HCY. Calcification was assessed by measurements of calcium deposition and alkaline phosphatase (ALP) activity as well as von Kossa staining. Expression of osteocalcin, bone morphogenetic protein (BMP)-2, and osteopontin, and MMP-2 was determined by immunoblotting. Calcification medium induced osteogenic differentiation of VSMCs. HCY promoted calcification, increased osteocalcin and BMP-2 expression, and decreased expression of osteopontin. MMP-2 expression was increased by HCY in a dose-dependent manner in VSMCs exposed to both control and calcification medium. The MMP-2 inhibitor decreased the calcium content and ALP activity, and attenuated the osteoblastic phenotype of VSMCs. Vascular calcification and osteogenic differentiation of VSMCs were positively regulated by HCY through increased/restored MMP-2 expression, increased expression of calcification proteins, and decreased anti-calcification protein levels. In summary, MMP-2 inhibition may be a protective strategy against VSMC calcification.
Transient receptor potential melastatin 7 (TRPM7) plays a key role in the pathophysiological response of multiple cell types. However, the role of TRPM7 channels in ox-LDL-induced proliferation and migration of VSMC remains unclear. This study used the thoracic aorta VSMCs to explore the effects of ox-LDL on cell proliferation and migration and to investigate the underlying molecular mechanisms and signaling pathways. Data demonstrated that ox-LDL significantly increased TRPM7 activity, and induced VSMC proliferation and migration. VSMC proliferation and migration were inhibited by nonspecific TRPM7 blocker 2-APB or synthetic siRNA targeting TRPM7. Furthermore, the phosphorylation of ERK1/2 and MEK1/2 associated with cell proliferation and migration decreased in TRPM7-deficient VSMC. Therefore, TRPM7 may constitute a useful target for the treatment of atherosclerosis.Keywords: MEK-ERK pathways; migration; proliferation; TRPM7; VSMCs Migration and excess proliferation of vascular smooth muscle cells (VSMCs) are involved in the pathogenesis of various vascular diseases, such as atherosclerosis [1]. Oxidized low-density lipoprotein (Ox-LDL) contributes to the atherosclerotic plaque formation and progression by several mechanisms, including the induction of endothelial cell activation and dysfunction, macrophage foam cell formation, and smooth muscle cell migration and proliferation [2]. Ox-LDL significantly increases VSMC migration and proliferation through the ERK1/2 signaling pathway [3]. However, the mechanisms underlying the effect of ox-LDL on atherosclerosis are not fully understood.Ion channels participate in cell proliferation in diverse types of cells, including vascular endothelial cells [4], cancer cells [5], smooth muscle cells [6], and mesenchymal stem cells [7]. Transient receptor potential melastatin 7 (TRPM7) channel, a member of TRP channel superfamily [8], is a widely expressed nonselective divalent cation (Ca 2+ and Mg 2+ ) channel with protein serine/threonine kinase activity that regulates diverse physiological/pathological processes, such as Mg 2+ homeostasis [9,10], hypoxic neuronal injury [11], and tumor cell growth/proliferation [12]. Activating TRPM7 channels may also contribute to the physiology/pathophysiology of cardiovascular and cerebrovascular diseases, including arterial calcification [13], atrial fibrillation [14], and hypertension [6,15]. However, little is known about the role of TRPM7 channels in atherosclerosis-related vasculopathy.Studies have shown that TRPM7 channels greatly participate in growth/proliferation and nitric oxide production of vascular endothelial cells [4], angiotensin IIinduced phenotype switching, and VSMC proliferation through the ERK pathway [6]. Although the presence and potential function of TRPM7 channels have been Abbreviations 2-APB, 2-aminoethoxydiphenyl borate; ang II, angiotensin II; DMSO, dimethyl sulfoxide; MAPK, mitogen-activated protein kinase; Ox-LDL, oxidized low-density lipoprotein; PDGF, platelet-derived growth factor; PLC, phospholipase C;...
In the potentially resectable cases of stage III-N2 non-small-cell lung cancer (NSCLC), the optimal post-operative treatment regimen for these patients is uncertain and post-operative radiation therapy (PORT) with chemotherapy is typically recommended. Our aim was to reassess the data of PORT on overall survival (OS) and disease-free survival (DFS) in stage III-N2 NSCLC, in order to figure out whether PORT might lead to a moderate improvement in local control and survival besides resection and adjuvant chemotherapy. A comprehensive search strategy was performed in EMBASE, PubMed, and Cochrane Library for relevant studies comparing PORT combined with adjuvant chemotherapy or adjuvant chemotherapy alone on OS and DFS in resectable stage III-N2 NSCLC. Data were extracted to estimate the effects of PORT on OS and DFS. Eleven studies with 8,928 patients were included. This meta-analysis demonstrated a trend in improving OS associated with the use of PORT (HR=0.88; 95% CI, 0.76 to 1.03; p=0.11) and a significantly difference of effect on DFS associated with the use of PORT (HR=0.78; 95% CI, 0.66 to 0.92; p=0.003). In a subgroup analysis on Caucasian patients, there was a statistically significant benefit (HR=0.88; 95% CI, 0.81 to 0.96; p=0.003) on OS for PORT. Our findings demonstrate that in the postoperative treatment for patients with stage III-N2 NSCLC, PORT is associated with improved OS and leads to a significantly increased DFS.
There is increasing evidence indicating that inflammation represents a key pathological component of Alzheimer’s disease (AD). A possible factor that may contribute to this process is netrin-1, a neuronal guidance molecule. This molecule has been shown to exert an unexpected immunomodulatory function. However, the potential changes and correlations of netrin-1 with T helper 17/regulatory T cells (Th17/Tregs) as related to inflammation in AD has yet to be examined. In this study, netrin-1 and Th17/Tregs balance were investigated, and the relationship among netrin-1, Th17/Tregs and cognitive function were analyzed in a rat model of AD. In this model, a bilateral intracerebroventricular administration of Amyloid β 1-42 (Aβ 1–42 ) was used to produce spatial learning and memory deficits, as well as increased neuronal apoptosis, which were detected 7 days after injection for AD7d group and 14 days for AD14d group. Netrin-1 concentrations were significantly down regulated in both serum and cerebrospinal fluid (CSF) of these AD rats, effects which were strongly correlated with cognitive deficits. Increased levels of interleukin (IL)-17 and deceased IL-10 were observed in both the circulation and CSF and were also correlated with the percent of time spent in the target quadrant of AD in these rats. These changes resulted in netrin-1 concentrations being negatively correlated with IL-17 but positively correlated with IL-10 concentrations in the serum and CSF. We also found that the Th17/Tregs balance was disrupted in these AD rats. Collectively, these findings reveal that the reduction in netrin-1 and the correlated disruption of Th17/Tregs balance in AD rats may diminish the immunosuppressive effect of netrin-1 on Th17/Tregs in AD pathogenesis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.