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In the context of functional determinants of cardiovascular risk, a simple excess in body weight, as indexed by a rise in body mass index (BMI), plays a significant, well-recognized causal role. Conversely, BMI reductions toward normal result in an improvement of risk. Obesity is associated with impaired cardiac autonomic regulation (CAR), through either vagal or sympathetic mechanisms, which could favor the tendency to foster hypertension. Here we study the changing properties of the relationship between increasing grades of BMI and CAR in a population of 756 healthy subjects (age 35.9 ± 12.41 years, 37.4% males, 21.6% overweight, and 16% obese). Evaluation of CAR is based on autoregressive spectral analysis of short-term RR interval and systolic arterial pressure variability, from which a multitude of indices, treated overall as autonomic nervous system (ANS) proxies, is derived. Inspection of the study hypothesis that elevated BMI conditions associate significantly with alterations of CAR, independently ofors corresponding to pressure, pulse, baroreflex, and ANSI is skewed toward the unfavorable abscissa extremity, particularly in the obese group. The significant association of increased BMI with progressive impairments of CAR regarding specifically the pressure domain and the overall ANS performance might underscore the strong hypertensive tendency observed in obesity.Autophagy is a host machinery that controls cellular health. Dysfunction of autophagy is responsible for the pathogenesis of many human diseases that include atherosclerosis obliterans (ASO). Physiologically, host autophagy removes aging organelles and delays the formation of atherosclerotic plaque. However, in ischemia event, dysregulated autophagy can be induced to trigger autosis, leading to an inevitable cellular death. Grb2-associated binder 1 (GAB1) is a docking/scaffolding adaptor protein that regulates many cell processes including autophagy. Our study first reported that the protein expression of GAB1 significantly decreased in ASO. Mechanically, our results showed that inhibition of Akt (protein kinase B), the upstream of mTOR (mechanistic target of rapamycin), significantly enhanced autophagy by demonstrating the downregulation of p62/Sequestosome 1 expression and the upregulation of the ratio of LC3II/LC3I. Conversely, we found that the inhibition of ERK1/2 (extracellular signal-regulated kinases1/2), p38, and JNK (c-Jun N-terminal kinase) signaling pathway, respectively, significantly inhibited autophagy by demonstrating the upregulation of p62 expression and the downregulation of the ratio of LC3II/LC3I. Further, we demonstrated that knockdown of GAB1 significantly increased autophagy in HUVECs (human umbilical vein endothelial cells) via activation of MAPK (mitogen-activated protein kinase) pathways that include ERK1/2, p38, and JNK. Moreover, we found that knockdown of GAB1 profoundly inhibited HUVEC proliferation, migration, and tube formation. Taken together, this study first suggests that GAB1 is a key regulator of autophagy in HUVECs. Targeting GAB1 may serve as a potential strategy for the atherosclerosis treatment.Bone remodeling is the continual process to renew the adult skeleton through the sequential action of osteoblasts and osteoclasts. Nuclear factor RANK, an osteoclast receptor, and its ligand RANKL, expressed on the surface of osteoblasts, result in coordinated control of bone remodeling. Inflammation, a feature of illness and injury, plays a distinct role in skewing this process toward resorption. It does so via the interaction of inflammatory mediators and their related peptides with osteoblasts and osteoclasts, as well as other immune cells, to alter the expression of RANK and RANKL. Such chemical mediators include TNFα, glucocorticoids, histamine, bradykinin, PGE2, systemic RANKL from immune cells, and interleukins 1 and 6. Conditions, such as periodontal disease and alveolar bone erosion, aseptic prosthetic loosening, rheumatoid arthritis, and some sports related injuries are characterized by the result of this process. A thorough understanding of bone response to injury and disease, and ability to detect such biomarkers, as well as imaging to identify early structural and mechanical property changes in bone architecture, is important in improving management and outcomes of bone related pathology. While gut health and vitamin and mineral availability appear vitally important, nutraceuticals also have an impact on bone health. To date most pharmaceutical intervention targets inflammatory cytokines, although strategies to favorably alter inflammation induced bone pathology are currently limited. Further research is required in this field to advance early detection and treatments.G-protein-coupled-receptor (GPCR) signaling is exquisitely controlled to achieve spatial and temporal specificity. read more The endogenous protein kinase inhibitor peptide (PKI) confines the spatial and temporal spread of the activity of protein kinase A (PKA), which integrates inputs from three major types of GPCRs. Despite its wide usage as a pharmaceutical inhibitor of PKA, it was unclear whether PKI only inhibits PKA activity. Here, the effects of PKI on 55 mouse kinases were tested in in vitro assays. We found that in addition to inhibiting PKA activity, both PKI (6-22) amide and full-length PKIα facilitated the activation of multiple isoforms of protein kinase C (PKC), albeit at much higher concentrations than necessary to inhibit PKA. Thus, our results call for appropriate interpretation of experimental results using PKI as a pharmaceutical agent. Furthermore, our study lays the foundation to explore the potential functions of PKI in regulating PKC activity and in coordinating PKC and PKA activities.It has become widely accepted that inflammation is a driving force behind a variety of chronic diseases, such as cardiovascular disease, diabetes, kidney disease, cancer, neurodegenerative disorders, etc. However, the existing nonsteroidal anti-inflammatory drugs show a limited utility in clinical patients. Therefore, the novel agents with different inflammation-inhibitory mechanisms are worth pursuing. Metformin, a synthetic derivative of guanidine, has a history of more than 50 years of clinical experience in treating patients with type 2 diabetes. Intense research efforts have been dedicated to proving metformin’s inflammation-inhibitory effects in cells, animal models, patient records, and randomized clinical trials. The emerging evidence also indicates its therapeutic potential in clinical domains other than type 2 diabetes. Herein, this article appraises current pre-clinical and clinical findings, emphasizing metformin’s anti-inflammatory properties under individual pathophysiological scenarios. In summary, the anti-inflammatory effects of metformin are evident in pre-clinical models.