ER stress and UPR in Alzheimer's disease : mechanisms, pathogenesis, treatments

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by gradual loss of memory and cognitive function, which constitutes a heavy burden on the healthcare system globally. Current therapeutics to interfere with the underlying disease process in AD is still under development. Although many efforts have centered on the toxic forms of A beta to effectively tackle AD, considering the unsatisfactory results so far it is vital to examine other targets and therapeutic approaches as well. The endoplasmic reticulum (ER) stress refers to the build-up of unfolded or misfolded proteins within the ER, thus, perturbing the ER and cellular homeostasis. Emerging evidence indicates that ER stress contributes to the onset and development of AD. A thorough elucidation of ER stress machinery in AD pathology may help to open up new therapeutic avenues in the management of this devastating condition to relieve the cognitive dementia symptoms. Herein, we aim at deciphering the unique role of ER stress in AD pathogenesis, reviewing key findings, and existing controversy in an attempt to summarize plausible therapeutic interventions in the management of AD pathophysiology.Peer reviewe

Deciphering the Role of Autophagy in Heart Failure

Peer reviewe

Ferritinophagy and ferroptosis in the management of metabolic diseases

Ferroptosis is a form of regulated cell death modality associated with disturbed iron-homeostasis and unrestricted lipid peroxidation. Ample evidence has depicted an essential role for ferroptosis as either the cause or consequence for human diseases, denoting the likely therapeutic promises for targeting ferroptosis in the preservation of human health. Ferritinophagy, a selective form of autophagy, contributes to the initiation of ferroptosis through degradation of ferritin, which triggers labile iron overload (IO), lipid peroxidation, membrane damage, and cell death. In this review, we will delineate the role of ferritinophagy in ferroptosis, and its underlying regulatory mechanisms, to unveil the therapeutic value of ferritinophagy as a target in the combat of ferroptosis to manage metabolic diseases.Peer reviewe

Inflammasome Signaling in Atrial Fibrillation: JACC State-of-the-Art Review.

As the most prevalent form of arrhythmia, atrial fibrillation (AF) increases the risk of heart failure, thromboembolism, and stroke, contributing to the raising mortality and morbidity in patients with cardiovascular diseases. Despite the multifaceted nature of AF pathogenesis and complexity of AF pathophysiology, a growing body of evidence indicates that the NLRP3 inflammasome activation contributes to onset and progression of AF. Herein, the authors aim at reviewing the current literature on the role of inflammasome signaling in AF pathogenesis, and novel therapeutic options in the management of AF

Diagnostic Potential of Autophagy-5 Protein, Apolipoprotein B-48, and Oxidative Stress Markers in Serum of Patients with Early-Stage Ischemic Stroke

-OBJECTIVE: Strokes are among the leading causes of death worldwide and have different characteristics. Different physiopathological mechanisms characterize the -umerous subtypes of ischemic stroke (IS). In this study, we investigated the relationship between serum levels of autophagy-5 protein, apolipoprotein B-48, and oxidative stress markers in patients with ischemic stroke.-METHODS: For this study, 100 participants were recruited, of which 50 were patients with IS and 50 were healthy individuals. We conducted a case-control study at Imam Reza Hospital from March 2019 to April 2020. Serum levels of ATG5, apo B-48, and oxidative stress markers were determined in both groups. Our Receiver Operating Characteristic Analysis evaluated the additional diagnostic value of these factors in both groups. -RESULTS: Diabetes, smoking, age, sex, alcohol con-sumption, weight, and height did not differ significantly between the 2 groups (P > 0.05). However, the 2 groups had significant differences in hypertension and body mass in-dex (P 0.05). Fifty-four percent (27 patients) of patients with IS had an ischemic stroke in large vessels, while 46% (23 patients) had an ischemic stroke in small vessels. Serum levels of ATG5, apo B-48, and oxidative stress markers were higher in the case group than in the control group (P 0.0001).-CONCLUSIONS: In patients with IS, serum levels of ATG5, apoB-48, malonaldehyde, total oxidative stress, and total antioxidant capacity can be used as novel biomarkers to predict or treat the disease.This work was supported by a grant from the Vice Chancellor for Research, Tabriz University of Medical Sciences, Tabriz, IRAN. The grant number is IR.TBZMED.REC.1399.879.Tabriz University of Medical Sciences, Tabriz, IRAN [IR.TBZMED.REC.1399.879

FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner

Introduction: Liver fibrosis is a life-threatening pathological anomaly which usually evolves into advanced liver cirrhosis and hepatocellular carcinoma although limited therapeutic option is readily available. FUN14 domain containing 1 (FUNDC1) is a mitophagy receptor with little information in liver fibrosis. Objective: This study was designed to examine the role for FUNDC1 in carbon tetrachloride (CCl4)-induced liver injury. Methods: GEO database analysis and subsequent validation of biological processes including western blot, immunofluorescence, and co-immunoprecipitation were applied to clarify the regulatory role of FUNDC1 on mitophagy and ferroptosis. Results: Our data revealed elevated FUNDC1 levels in liver tissues of patients with liver fibrotic injury and CCl4-challenged mice. FUNDC1 deletion protected against CCl4-induced hepatic anomalies in mice. Moreover, FUNDC1 deletion ameliorated CCl4-induced ferroptosis in vivo and in vitro. Mechanically, FUNDC1 interacted with glutathione peroxidase (GPx4), a selenoenzyme to neutralize lipid hydroperoxides and ferroptosis, via its 96–133 amino acid domain to facilitate GPx4 recruitment into mitochondria from cytoplasm. GPx4 entered mitochondria through mitochondrial protein import system-the translocase of outer membrane/translocase of inner membrane (TOM/TIM) complex, prior to degradation of GPx4 mainly through mitophagy along with ROS-induced damaged mitochondria, resulting in hepatocyte ferroptosis. Conclusion: Taken together, our data favored that FUNDC1 promoted hepatocyte injury through GPx4 binding to facilitate its mitochondrial translocation through TOM/TIM complex, where GPx4 was degraded by mitophagy to trigger ferroptosis. Targeting FUNDC1 may be a promising therapeutic approach for liver fibrosis

ER Stress in Cardiometabolic Diseases: From Molecular Mechanisms to Therapeutics

The endoplasmic reticulum (ER) hosts linear polypeptides and fosters natural folding of proteins through ER-residing chaperones and enzymes. Failure of the ER to align and compose proper protein architecture leads to accumulation of misfolded/unfolded proteins in the ER lumen, which disturbs ER homeostasis to provoke ER stress. Presence of ER stress initiates the cytoprotective unfolded protein response (UPR) to restore ER homeostasis or instigates a rather maladaptive UPR to promote cell death. Although a wide array of cellular processes such as persistent autophagy, dysregulated mitophagy, and secretion of proinflammatory cytokines may contribute to the onset and progression of cardiometabolic diseases, it is well perceived that ER stress also evokes the onset and development of cardiometabolic diseases, particularly cardiovascular diseases (CVDs), diabetes mellitus, obesity, and chronic kidney disease (CKD). Meanwhile, these pathological conditions further aggravate ER stress, creating a rather vicious cycle. Here in this review, we aimed at summarizing and updating the available information on ER stress in CVDs, diabetes mellitus, obesity, and CKD, hoping to offer novel insights for the management of these cardiometabolic comorbidities through regulation of ER stress