The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic patients is unknown. We evaluated SIRT6 expression and the effect of incretin-based therapies in carotid plaques of asymptomatic diabetic and nondiabetic patients. Plaques were obtained from 52 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Twenty-two diabetic patients were treated with drugs that work on the incretin system, GLP-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors for 26 6 8 months before undergoing the endarterectomy. Compared with nondiabetic plaques, diabetic plaques had more inflammation and oxidative stress, along with a lesser SIRT6 expression and collagen content. Compared with non-GLP-1 therapy-treated plaques, GLP-1 therapy-treated plaques presented greater SIRT6 expression and collagen content, and less inflammation and oxidative stress, indicating a more stable plaque phenotype. These results were supported by in vitro observations on endothelial progenitor cells (EPCs) and endothelial cells (ECs). Indeed, both EPCs and ECs treated with high glucose (25 mmol/L) in the presence of GLP-1 (100 nmol/L liraglutide) presented a greater SIRT6 and lower nuclear factor-kB expression compared with cells treated only with high glucose. These findings establish the involvement of SIRT6 in the inflammatory pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin, the effect of which is associated with morphological and compositional characteristics of a potential stable plaque phenotype.Cardiovascular disease represents the leading cause of death in patients with type 2 diabetes (1). Diabetes leads to increased vulnerability for plaque disruption, and mediates increased incidence and severity of clinical events (2). Inflammation, particularly in diabetes, plays a central role in the cascade of events that result in plaque erosion and fissuring (2). There is now increasing evidence that a number of transcription factors, including the Sir2 family of enzymes, namely sirtuins (SIRTs), regulate multiple genes whose products are putatively involved in the regulation of inflammation and endothelial cell (EC) function (3). The Sir2 family consists of seven enzymes (SIRT1 to SIRT7) that share a conserved core catalytic domain, but differ in their cellular localization and tissue distribution (4). Among the SIRTs, SIRT6, a chromatinassociated deacetylase, is considered to have a leading role in regulating genomic stability, cellular metabolism, stress response, and aging (5-8). A recent study (9) in mice suggested a role for SIRT6 in inflammation. Moreover, the knockdown of SIRT6 resulted in the increased expression of proinflammatory cytokines (interleukin [IL]-1b, IL-6, and IL-8), extracellular matrix remodeling enzymes (matrix metalloproteinase [MMP]-2, MMP-9, and plasminogen activator inhibitor 1), and intracellular adhesion molecule-1 (4). In ECs, the loss of SIRT6 was associated with an increased expression of nuclear factor-kB (NF-kB), whereas o...
The reason of AT is associated to CIU and others allergical and autoimmune diseases is poorly known. The exclusive hormonal therapy reduces the symptoms of CIU and inflammatory response in many chronic diseases associated to AT. We suggest a stimulatory effect of TSH able to produce considerable changes of the immune response and immune tolerance in patients with AT causing target organs damage. The causal mechanism involves immune, nervous and endocrine system, sharing a common set of hormones, cytokines and receptors, in a unique totally integrated loop (the neuro-immuno-endocrine axis).
Our findings suggest a potential role of adiponectin/APPL1 signaling in mediating the effect of incretin in the prevention of atherosclerosis progression or plaque vulnerability in T2DM.
Targeting necroptosis is considered a promising therapeutic strategy in cancer, including Glioblastoma Multiforme (GBM), one of the most lethal brain tumors. Necroptosis is a mechanism of programmed cell death overcoming the apoptosis resistance mechanism underlying GBM tumorigenesis and malignant progression. N6-isopentenyladenosine (iPA), adenosine modified with isoprenoid derivative, displays antitumor activity in different cancer models. In previous studies, we demonstrated that iPA interferes with EGFR signaling reducing glioma cell viability. Here, we show that iPA induces necroptosis in glioblastoma cell lines and in primary cells established from tumor explants, without affecting the viability of non-cancerous brain cell lines, (Normal Human Astrocyte). The activation of RIP1, RIP3, and MLKL and the upregulation of necrosome formation were increased upon iPA treatment while caspase-3, caspase-8, and PARP were not activated in GBM cells. Co-treatment with specific necroptosis inhibitor necrostatin-1 (Nec-1) or Necrosulfonamide (NSA) prevented cell death caused by iPA treatment while the general caspase inhibitor Z-VAD-fluoromethylketone (z-VAD-fmk) did not elicit any effect, suggesting that this molecule induces caspase-independent necroptosis. These results suggest that iPA treatment can be able to bypass the apoptosis resistance mechanism in glioblastoma thereby offering higher therapeutic efficacy.
Background: Vasculogenic mimicry (VM) is a functional microcirculation pattern formed by aggressive tumor cells. Thus far, no effective drugs have been developed to target VM. Glioblastoma (GBM) is the most malignant form of brain cancer and is a highly vascularized tumor. Vasculogenic mimicry represents a means whereby GBM can escape anti-angiogenic therapies. Methods: Here, using an in vitro tube formation assay on Matrigel, we evaluated the ability of N6-isopentenyladenosine (iPA) to interfere with vasculogenic mimicry (VM). RhoA activity was assessed using a pull-down assay, while the modulation of the adherens junctions proteins was analyzed by Western blot analysis. Results: We found that iPA at sublethal doses inhibited the formation of capillary-like structures suppressing cell migration and invasion of U87MG, U343MG, and U251MG cells, of patient-derived human GBM cells and GBM stem cells. iPA reduces the vascular endothelial cadherin (VE-cadherin) expression levels in a dose-dependent manner, impairs the vasculogenic mimicry network by modulation of the Src/p120-catenin pathway and inhibition of RhoA-GTPase activity. Conclusions: Taken together, our results revealed iPA as a promising novel anti-VM drug in GBM clinical therapeutics.
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