A crosstalk between p21 and UPR-induced transcription factor C/EBP homologous protein (chop) linked to type 2 diabetes

Type 2 diabetes (T2D) is a disease that is characterized by raised levels of glucose in the blood combined with insulin resistance and relative insulin deficiency. The pathogenesis of type 2 diabetes is associated with the induction of the unfolded protein response (UPR). While UPR aims to restore tissue homeostasis following stress of the endoplasmic reticulum (ER), prolonged ER stress triggers apoptosis at least in part through the unfolded protein response (UPR)-activated transcription factor C/EBP (CCAAT/enhancer binding protein) homologous protein (CHOP). CHOP has elevated as a critical mediator connecting accumulation and aggregation of unfolded proteins in the ER and oxidative stress and also contributes to the induction of apoptosis in β-cell (beta-cell) – cells under conditions of increased insulin demand. p21 is a cell cycle regulator that is implicated in the regulation of the UPR by various mechanisms involving inhibition of apoptosis and facilitation of the regeneration capacity of the β cells. In this review we summarize the role of ER stress in the pathogenesis of type 2 diabetes which is associated with the induction of the unfolded protein response (UPR). We also review recent evidence associating p21 activity with β cell health and regenerative capacity by mechanisms that may interfere with the effects of p21 in the UPR or operate independently of ER stress. Most likely understanding the molecular details of the pathogenesis of type 2 diabetes will be beneficial for the management of the disease

Chop-dependent regulation of p21/waf1 during ER stress

The transcription factor CHOP/GADD153 is induced during the unfolded protein response (UPR) and is associated to the induction of ER stress-related apoptosis. However, how the transition between the pro-survival and the pro-apoptotic role of ER stress is being orchestrated remains poorly understood. Here we show that tunicamycin, an antibiotic promoting ER stress, suppresses the expression of p21, a tumor suppressor that induces cell cycle arrest and inhibits apoptosis. This suppression of p21 levels was independent of p53 that is the major transcriptional regulator of p21, but could be reproduced by forced expression of CHOP. Consistently with these findings, siRNA-mediated inhibition of p21 levels restored the sensitivity of CHOP-deficient cells to tunicamycin. Our findings are consistent with a CHOP-dependent role for p21 in the shift from the pro-survival to the pro-apoptotic function of UPR

Polyomyositis and myocarditis associated with acquired toxoplasmosis in an immunocompetent girl

BACKGROUND: Acquired toxoplasmosis more frequently goes unrecognized. Immunocompetent adults and adolescents with primary infection are generally asymptomatic, but symptoms may include malaise, fever, and lymphadenopathy. By contrast, immunocompromised patients may experience severe manifestations including encephalitis and multisystem organ failure. CASE PRESENTATION: We report a case of polymyositis and myocarditis in a 13-year old immunocompetent girl with toxoplasmosis. The patient presented with proximal muscle weakness, dysphagia, palms and soles rash and elevated serum levels of muscle enzymes, with liver and myocardial involvement. The diagnosis of toxoplasmosis was confirmed by serology. The patient was treated with prednisolone and had an excellent outcome. During a follow-up period of four years no relapses occurred and antibody levels to the T. gondii significantly decreased. CONCLUSIONS: Although several previous cases of toxoplasmosis occuring in association with polymyositis have been described in the literature such a wide spectrum of acute toxoplasmosis is rather unusual in immunocompetent adolescents. The relationship between T. gondii and polymyositis remains obscure. Appropriate investigation should be performed in every case of polymyositis not only for the appropriate treatment but also for further elucidation of this relationship

Sex differences in arterial hypertension.

There is strong evidence that sex chromosomes and sex hormones influence blood pressure (BP) regulation, distribution of cardiovascular (CV) risk factors and co-morbidities differentially in females and males with essential arterial hypertension. The risk for CV disease increases at a lower BP level in females than in males, suggesting that sex-specific thresholds for diagnosis of hypertension may be reasonable. However, due to paucity of data, in particularly from specifically designed clinical trials, it is not yet known whether hypertension should be differently managed in females and males, including treatment goals and choice and dosages of antihypertensive drugs. Accordingly, this consensus document was conceived to provide a comprehensive overview of current knowledge on sex differences in essential hypertension including BP development over the life course, development of hypertension, pathophysiologic mechanisms regulating BP, interaction of BP with CV risk factors and co-morbidities, hypertension-mediated organ damage in the heart and the arteries, impact on incident CV disease, and differences in the effect of antihypertensive treatment. The consensus document also highlights areas where focused research is needed to advance sex-specific prevention and management of hypertension

May Measurement Month 2017: an analysis of blood pressure screening results from Australia - South-East Asia and Australasia

Increased blood pressure (BP) is the single biggest contributing risk factor to the global disease burden. May Measurement Month (MMM) is a global initiative of the International Society of Hypertension aimed at raising awareness of high BP. In Australia, hypertension affects around six million adults and continues to remain the greatest attributable cause of cardiovascular mortality and morbidity (48.3%), stroke deaths (28%), and kidney disease (14%). An opportunistic cross-sectional survey was carried out during May 2017 predominantly in capital cities across Australia which included adult volunteers. Blood pressure measurement, the definition of hypertension and statistical analysis followed the standard MMM protocol. Additional information obtained included anthropometric data and responses to questionnaires on demographic, lifestyle, and environmental factors. Data were collected from 3817 individuals. After multiple imputation, of the 3758 individuals for whom a mean of the second and third BP reading was available, 1188 (31.2%) had hypertension. Of 3213 individuals not receiving antihypertensive treatment, 591 (18.4%) were hypertensive, and 239 (40.1%) of the 596 individuals receiving treatment had uncontrolled BP. Adjusted BP was higher in association with antihypertensive medication, cerebrovascular disease, smoking, and alcohol consumption. Blood pressure was higher when measured on the right arm and on Tuesdays. MMM17 was one of the largest BP screening campaigns undertaken in Australia using standardized BP measurements. In line with previous surveys, around one-third of screened adults had hypertension and approximately 40% of treated individuals remained uncontrolled. These results suggest that opportunistic screening can identify significant numbers with raised BP

Definition of ambulatory blood pressure targets for diagnosis and treatment of hypertension in relation to clinic blood pressure: prospective cohort study

Background Twenty-four hour ambulatory blood pressure thresholds have been defined for the diagnosis of mild hypertension but not for its treatment or for other blood pressure thresholds used in the diagnosis of moderate to severe hypertension. We aimed to derive age and sex related ambulatory blood pressure equivalents to clinic blood pressure thresholds for diagnosis and treatment of hypertension

Endoplasmic reticulum unfolded protein response, aging and exercise: an update

9 p.The endoplasmic reticulum (ER) is a dynamic and multifunctional organelle responsible for protein biosynthesis, folding, assembly and modifications. Loss of protein folding regulation, which leads to unfolded or misfolded proteins accumulation inside the ER lumen, drives ER stress (ERS) and unfolded protein response (UPR) activation. During aging, there is a decline in the ability of the cell to handle protein folding, accumulation and aggregation, and the function of UPR is compromised. There is a progressive failure of the chaperoning systems and a decline in many of its components, so that the UPR activation cannot rescue the ERS. Physical activity has been proposed as a powerful tool against aged-related diseases, which are linked to ERS. Interventional studies have demonstrated that regular exercise is able to decrease oxidative stress and inflammation and reverse mitochondrial and ER dysfunctions. Exercise-induced metabolic stress could activate the UPR since muscle contraction is directly involved in its activation, mediating exercise-induced adaptation responses. In fact, regular moderate-intensity exercise-induced ERS acts as a protective mechanism against current and future stressors. However, biological responses vary according to exercise intensity and therefore induce different degrees of ERS and UPR activation. This article reviews the effects of aging and exercise on ERS and UPR, also analyzing possible changes induced by different types of exercise in elderly subjects.S