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Hyperinsulinemia and its particular Crucial Function throughout Growing older, Being overweight, Diabetes type 2, Heart disease and Cancer.
Diabetes, a chronic non-communicable disease, has become one of the most serious and critical public health problems with increasing incidence trends. Chronic vascular complications are the major causes of disability and death in diabetic patients with endothelial dysfunction. Diabetes is intimately associated with endothelial mitochondrial dysfunction, indicated by increased oxidative stress, decreased biogenesis, increased DNA damage, and weakened autophagy in mitochondria. All these morphological and functional changes of mitochondria play important roles in diabetic endothelial dysfunction. read more Herein, we reviewed the roles and mechanisms of endothelial mitochondrial dysfunction, particularly mitochondrial dynamics in the vascular complications of diabetes and summarized the potential mitochondria-targeted therapies in diabetic vascular complications.Hyperglycemic milieu in diabetes mellitus stimulates macrophages for exaggerated pro-inflammatory cytokine response, particularly IL-1β, IL-6, and TNF-α. Although hyperglycemia causes macrophages to produce pro-inflammatory cytokines, AGEs (advanced glycation end products) active inflammation, produced as a result of chronic hyperglycemia, inducers cause polarization of macrophages into pro-inflammatory M1 phenotype. AGEs in diabetes accelerate atherosclerotic plaque initiation and progression via promoting macrophages polarization towards pro-inflammatory state. Gliclazide (Glz) is a well known antidiabetic drug with excellent safety profile. Its repurposing in the management of diabetes-associated late complications has tremendous merit. The present study demonstrated that Glz retards diabetic atherosclerotic progression, and cytokines storm in a concentration dependent manner over a concentration range of 1-100 μM than those of AGEs (200 μg/ml)-treated cells through a mechanism that alters macrophage M1 polarization state. Glz exerted these beneficial effects, independent of its antidiabetic effect. Glz pretreatment significantly (P less then 0.05) inhibited the AGEs-induced pro-inflammatory mediators (NO•, reactive oxygen species, i-NOS), and production of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. It also significantly (P less then 0.05) promoted the production of anti-inflammatory cytokines (IL-10 and TGF-β) in RAW 264.7 mouse macrophages. Glz pretreatment also effectively abated the AGEs-induced RAGE (~2-fold decrease), and CD86 surface marker expressions (P less then 0.001 at 100 μM) on macrophages by inhibiting the NF-kβ activation in a concentration dependent manner (1-100 μM) (P less then 0.001). In conclusion, our data demonstrates that Glz alleviates the diabetic atherosclerosis progression by ameliorating the AGEs-mediated M1 pro-inflammatory phenotype via blocking AGE-RAGE/TLR4-reactive oxygen species -activated NF-kβ nexus in macrophages.The neuroprotective effects of some 16-substituted steroidal derivatives against the locomotive impairment and cognitive deficits in the lipopolysaccharide (LPS)-induced neuroinflammation model of rats have been investigated. The in vivo and in vitro evaluations include behavioural tests (actophotometer, block tests, Morris water maize and elevated plus maize), estimation of the biochemical parameters such as acetylcholinesterase, lipid peroxide, reactive oxygen, and nitric oxide species and molecular assays for the key proinflammatory mediators like Tumour Necrosis Factor alpha (TNF-α) and Interleukin 1 beta (IL- 1β) after 21 days of the treatment with the steroids. Behavioural and biochemical studies indicated impairment in the locomotor activity and cognitive dysfunction in rats after LPS treatment. In addition, higher levels of TNF-α and IL-1β in the blood serum of the rats were also noticed. However, significant alleviation of LPS-induced movement and memory disorders was observed in LPS-injected rats after treatment with 16-substituted steroidal derivatives 1-11. Furthermore the biochemical and molecular studies revealed suppression of oxidative and nitrosative stress, decreased acetylcholinesterase activity, and reduction of TNF-α and IL-1β levels after treatment with compounds 1-11. Among all the 16-substituted steroidal derivatives, the compounds 8 and 11 were found to be the most active neuroprotective agents and produced effects marginally better than standard drug dexamethasone.Complex of platelet-derived growth factor (PDGF) isoforms and PDGF receptors have important functions in the regulation of growth and survival of various cell types. Herein, it was found that aberrant PDGFC expression is closely associated with survival rates in triple-negative breast cancer (TNBC) patients. In addition, PDGFC expression was identified to be significantly increased in TNBC cells unlike other subtypes such as PDGFA, PDGFB, and PDGFD. Apparently, the effects of specific PDGF receptor (PDGFR) inhibitors such as sunitinib and ponatinib on HCC1806 and Hs578T TNBC cells were investigated. Both inhibitors decreased cell viability in a dose-dependent manner. In addition, the inhibitors completely inhibited cell growth in both the cell lines and decreased the expression of matrix metalloproteinase-1 (MMP-1), one of the metastasis-related genes. Cell migration was also decreased by the inhibitors. Finally, the combined effects of the inhibitors with doxorubicin (DOX) were investigated. The results showed that the combination of two PDGFR inhibitors with DOX inhibited the growth of cells and enhanced the apoptotic cell death more uniformly than DOX. Consequently, it is demonstrated that PDGFR inhibitors, sunitinib and ponatinib hold the potential for effective treatment of TNBC.Given that neuronal degeneration in Alzheimer's disease (AD) is caused by the combination of multiple neurotoxic insults, current directions in the research of novel therapies to treat this disease attempts to design multitarget strategies that could be more effective than the simply use of acetylcholinesterase inhibitors; currently, the most used therapy for AD. One option, explored recently, is the synthesis of new analogues of cannabinoids that could competitively inhibit the acetylcholinesterase (AChE) enzyme and showing the classic neuroprotective profile of cannabinoid compounds. In this work, molecular docking has been used to design some cannabinoid analogues with such multitarget properties, based on the similarities of donepezil and Δ9-tetrahydrocannabinol. The analogues synthesized, compounds 1 and 2, demonstrated to have two interesting characteristics in different in vitro assays competitive inhibition of AChE and competitive antagonism at the CB1/CB2 receptors. They are highly lipophilic, highlighting that they could easily reach the CNS, and apparently presented a low toxicity. These results open the door to the synthesis of new compounds for a more effective treatment of AD.Neuronal survival and axonal renewal following central nervous system damage and in neurodegenerative illnesses, such as Alzheimer's disease (AD), can be enhanced by fast clearance of neuronal apoptotic debris, as well as the removal of amyloid beta (Aβ) by phagocytic cells through the process of efferocytosis. This process quickly inhibits the release of proinflammatory and antigenic autoimmune constituents, enhancing the formation of a microenvironment vital for neuronal survival and axonal regeneration. Therefore, the detrimental features associated with microglial phagocytosis uncoupling, such as the accumulation of apoptotic cells, inflammation and phagoptosis, could exacerbate the pathology in brain disease. Some mechanisms of efferocytosis could be targeted by several promising agents, such as curcumin, URMC-099 and Y-P30, which have emerged as potential treatments for AD. This review aims to investigate and update the current research regarding the signaling molecules and pathways involved in efferocytosis and how these could be targeted as a potential therapy in AD.Nanog is a major transcription factor related to cellular multipotency that plays important roles in the development of tumor cells, drug resistance, migration, and stemness; indicating its great potential as a therapeutic target for various malignancies including colorectal cancer (CRC). Therefore, this study was aimed to evaluate the Nanog suppression effect using small interference RNA (siRNA) combined with 5-fluorouracil (5-FU) on CRC cells. Nanog-overexpressing SW-480 cells were transfected with Nanog si-RNA and treated with 5-FU, in combination or separately. Subsequently, it was observed that Nanog expression was significantly reduced after transfection of SW-480 cells using Nanog siRNA in mRNA and protein levels. Furthermore, Nanog knockdown significantly increased CRC cell sensitivity to 5-FU drug via modulating Bax and Bcl-2 mRNA expression. Also, Nanog knockdown and 5-FU treatment cooperatively decreased the migration and self-renewal ability of SW-480 cells by regulating the expression of relevant genes. Moreover, combination therapy led to cell cycle arrest at the sub-G1 phase in CRC cells. In conclusion, our results indicated that Nanog may play an important role in the drug sensitivity, migration, and self-renewal of CRC cells; suggesting Nanog as a promising target in combination with 5-FU for the development of new therapeutic approaches for CRC.It is unknown whether endovascular intervention (EVI) is associated with superior outcomes when compared with surgical revascularization in octogenarian. National Inpatient Sample (NIS) database was used to compare the outcomes of limb revascularization in octogenarians who had surgical revascularization versus EVI. The NIS database's information on PAD patients ≥80-year-old who underwent limb revascularization between 2002 and 2014 included 394,504 octogenarian patients, of which 184,926 underwent surgical revascularization (46.9%) and 209,578 underwent EVI (53.1%). Multivariate analysis was performed to examine in-hospital outcomes. Trend over time in limb revascularization utilization was examined using Cochrane-Armitage test. EVI group had lower odds of in-hospital mortality (adjusted odds ratio [aOR] 0.61 [95% CI 0.58 to 0.63], myocardial infarction (aOR 0.84 [95% CI 0.81 to 0.87]), stroke (aOR 0.93 [95% CI 0.89 to 0.96]), acute kidney injury (aOR 0.79 [95% CI 0.77 to 0.81]), and limb amputation (aOR 0.77 [95% CI 0.74 to 0.79]) compared with surgical group (p less then 0.001 for all). EVI group had higher risk of bleeding (aOR 1.20 [95% CI 1.18 to 1.23]) and vascular complications (3.2% vs 2.7%, aOR 1.25 [95% CI 1.19 to 1.30]) compared with surgical group (p less then 0.001 for all). Within study period, EVI utilization increased in octogenarian patients from 2.6% to 8.9% (ptrend less then 0.001); whereas use of surgical revascularization decreased from 11.6% to 5.2% (ptrend less then 0.001). In conclusion, the utilization of EVI in octogenarians is increasing, and associated with lower risk of in-hospital mortality and adverse cardiovascular and limb outcomes as compared with surgical revascularization.Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) classically initially present with ventricular arrhythmias or, less commonly, heart failure. Myocardial inflammation has been implicated in pathogenesis, but clinical myocarditis in ARVC is less described. We therefore studied clinical myocarditis as an initial ARVC presentation, and hypothesized that these patients have distinct clinical and genetic characteristics. Using the Johns Hopkins ARVC Registry, we identified 12 patients (all female, median age 20) referred between 2014 and 2019 diagnosed with myocarditis at presentation who were subsequently diagnosed with ARVC by Task Force Criteria. Majority presented with chest pain (n = 7, 58%) or ventricular arrhythmia (n = 3, 25%). All patients had troponin elevations and left ventricular (LV) function was reduced in 5 (42%). Magnetic resonance imaging demonstrated LV delayed gadolinium enhancement and/or pericardial enhancement in 10 (83%); only 3 (25%) patients had right ventricular abnormalities.
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