Inhibition of Endoplasmic Reticulum Stress Improves Acetylcholine-Mediated Relaxation in the Aorta of Type-2 Diabetic Rats.

Endoplasmic reticulum (ER) stress contributes to insulin resistance and macro- and microvascular complications associated with diabetes. This study aimed to evaluate the effect of ER stress inhibition on endothelial function in the aorta of type-2 diabetic rats. Type-2 diabetes was developed in male Sprague-Dawley rats using a high-fat diet and low-dose streptozotocin. Rat aortic tissues were harvested to study endothelial-dependent relaxation. The mechanisms for acetylcholine-mediated relaxation were investigated using pharmacological blockers, Western blotting, oxidative stress, and inflammatory markers. Acetylcholine-mediated relaxation was diminished in the aorta of diabetic rats compared to control rats; supplementation with TUDCA improved relaxation. In the aortas of control and diabetic rats receiving TUDCA, the relaxation was mediated via eNOS/PI3K/Akt, NAD(P)H, and the KATP channel. In diabetic rats, acetylcholine-mediated relaxation involved eNOS/PI3K/Akt and NAD(P)H, but not the KATP channel. The expression of ER stress markers was upregulated in the aorta of diabetic rats and reduced with TUDCA supplementation. The expression of eNOS and Akt were lower in diabetic rats but were upregulated after supplementation with TUDCA. The levels of MDA, IL-6, and SOD activity were higher in the aorta of the diabetic rats compared to control rats. This study demonstrated that endothelial function was impaired in diabetes, however, supplementation with TUDCA improved the function via eNOS/Akt/PI3K, NAD(P)H, and the KATP channel. The improvement of endothelial function was associated with increased expressions of eNOS and Akt. Thus, ER stress plays a crucial role in the impairment of endothelial-dependent relaxation. Mitigating ER stress could be a potential strategy for improving endothelial dysfunction in type-2 diabetes.

Current Status of Endoplasmic Reticulum Stress in Type II Diabetes.

The endoplasmic reticulum (ER) plays a multifunctional role in lipid biosynthesis, calcium storage, protein folding, and processing. Thus, maintaining ER homeostasis is essential for cellular functions. Several pathophysiological conditions and pharmacological agents are known to disrupt ER homeostasis, thereby, causing ER stress. The cells react to ER stress by initiating an adaptive signaling process called the unfolded protein response (UPR). However, the ER initiates death signaling pathways when ER stress persists. ER stress is linked to several diseases, such as cancer, obesity, and diabetes. Thus, its regulation can provide possible therapeutic targets for these. Current evidence suggests that chronic hyperglycemia and hyperlipidemia linked to type II diabetes disrupt ER homeostasis, thereby, resulting in irreversible UPR activation and cell death. Despite progress in understanding the pathophysiology of the UPR and ER stress, to date, the mechanisms of ER stress in relation to type II diabetes remain unclear. This review provides up-to-date information regarding the UPR, ER stress mechanisms, insulin dysfunction, oxidative stress, and the therapeutic potential of targeting specific ER stress pathways.

Sub-acute toxicity study on hydromethanolic leaves extract of Combretum hypopilinum (Combretaceae) Diels in Wistar rats.

The plant Combretum hypopilinum Diels (Combretaceae) has been utilized in Nigeria and other African nations to treat many diseases including liver, inflammatory, gastrointestinal, respiratory, infectious diseases, epilepsy and many more. Pharmacological investigations have shown that the plant possesses anti-infective, antidiarrhoeal, hepatoprotective, anti-inflammatory, anticancer, sedative, antioxidant, and antiepileptic potentials. However, information on its toxicity profile is unavailable despite the plant's therapeutic potential. As such, this work aimed to determine the acute and sub-acute oral toxic effects of the hydromethanolic leaves extract of C. hypopilinum. The preliminary phytochemical evaluation was carried out based on standard procedures. The acute toxicity evaluation was conducted by oral administration of the extract at the dose of 5000 mg/kg based on the guideline of the Organization of Economic Co-operation and Development (OECD) 423. To investigate the sub-acute toxicity effects, the extract was administered orally to the animals daily for 28-consecutive days at the doses of 250, 500, and 1000 mg/kg. Mortality, body weight and relative organ weight were observed. The hepatic, renal, haematological, and lipid profile parameters were investigated. The liver, kidney, heart, lung, small intestine, and stomach were checked for any histopathological alterations. The results of the phytochemical investigation showed cardiac glycosides, tannins, steroids, flavonoids, alkaloids, saponins, and triterpenes. Based on the acute toxicity investigation outcome, no death and signs of toxic effects were observed. The result showed that the oral median lethal dose (LD50) of the extract was more than the 5000 mg/kg. The extract remarkably reduced the weekly body weight of the animals at 500 mg/kg in the first and second weeks. It also significantly decreased the relative kidney weight, alkaline phosphatase, glucose, potassium, and low-density lipoprotein. There was a remarkable elevation in the percentage of eosinophils, basophils, monocytes, and granulocyte. There were histopathological abnormalities on the kidney, lung, stomach, and small intestine. The extract is relatively safe on acute exposure but moderately toxic at higher doses on sub-acute administration, particularly to the kidney.

Risk Factors Associated with Mortality Among Patients with Novel Coronavirus Disease (COVID-19) in Africa.

BACKGROUND: The novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in China and later spread rapidly to other parts of the world, including Africa. Africa was projected to be devastated by COVID-19. There is currently limited data regarding regional predictors of mortality among patients with COVID-19. This study aimed to evaluate the independent risk factors associated with mortality among patients with COVID-19 in Africa. METHODS: A total of 1028 confirmed cases of COVID-19 from Africa with definite survival outcomes were identified retrospectively from an open-access individual-level worldwide COVID-19 database. The live version of the dataset is available at https://github.com/beoutbreakprepared/nCoV2019 . Multivariable logistic regression was conducted to determine the risk factors that independently predict mortality among patients with COVID-19 in Africa. RESULTS: Of the 1028 cases included in study, 432 (42.0%) were females with a median (interquartile range, IQR) age of 50 (24) years. Older age (adjusted odds ratio {aOR} 1.06; [95% confidence intervals {95% CI}, 1.04-1.08]), presence of chronic disease (aOR 9.63; [95% CI, 3.84-24.15]), travel history (aOR 2.44; [95% CI, 1.26-4.72]), as well as locations of Central Africa (aOR 0.14; [95% CI, 0.03-0.72]) and West Africa (aOR 0.12; [95% CI, 0.04-0.32]) were identified as the independent risk factors significantly associated with increased mortality among the patients with COVID-19. CONCLUSIONS: The COVID-19 pandemic is evolving gradually in Africa. Among patients with COVID-19 in Africa, older age, presence of chronic disease, travel history, and the locations of Central Africa and West Africa were associated with increased mortality. A regional response should prioritize strategies that will protect these populations. Also, conducting a further in-depth study could provide more insights into additional factors predictive of mortality in COVID-19 patients.

Potential Roles of Endoplasmic Reticulum Stress and Cellular Proteins Implicated in Diabesity.

The role of the endoplasmic reticulum (ER) has evolved from protein synthesis, processing, and other secretory pathways to forming a foundation for lipid biosynthesis and other metabolic functions. Maintaining ER homeostasis is essential for normal cellular function and survival. An imbalance in the ER implied stressful conditions such as metabolic distress, which activates a protective process called unfolded protein response (UPR). This response is activated through some canonical branches of ER stress, i.e., the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6). Therefore, chronic hyperglycemia, hyperinsulinemia, increased proinflammatory cytokines, and free fatty acids (FFAs) found in diabesity (a pathophysiological link between obesity and diabetes) could lead to ER stress. However, limited data exist regarding ER stress and its association with diabesity, particularly the implicated proteins and molecular mechanisms. Thus, this review highlights the role of ER stress in relation to some proteins involved in diabesity pathogenesis and provides insight into possible pathways that could serve as novel targets for therapeutic intervention.

Factors associated with acceptance of COVID-19 vaccine among University health sciences students in Northwest Nigeria.

Students of the health sciences are the future frontliners to fight pandemics. The students' participation in COVID-19 response varies across countries and are mostly for educational purposes. Understanding the determinants of COVID-19 vaccine acceptability is necessary for a successful vaccination program. This study aimed to investigate the factors associated with COVID-19 vaccine acceptance among health sciences students in Northwest Nigeria. The study was an online self-administered cross-sectional study involving a survey among students of health sciences in some selected universities in Northwest Nigeria. The survey collected pertinent data from the students, including socio-demographic characteristics, risk perception for COVID-19, and willingness to accept the COVID-19 vaccine. Multiple logistic regression was used to determine the predictors of COVID-19 vaccine acceptance. A total of 440 responses with a median (interquartile range) age of 23 (4.0) years were included in the study. The prevalence of COVID-19 vaccine acceptance was 40.0%. Factors that independently predict acceptance of the vaccine were age of 25 years and above (adjusted odds ratio, aOR, 2.72; 95% confidence interval, CI, 1.44-5.16; p = 0.002), instructions from heads of institutions (aOR, 11.71; 95% CI, 5.91-23.20; p<0.001), trust in the government (aOR, 20.52; 95% CI, 8.18-51.51; p<0.001) and willingness to pay for the vaccine (aOR, 7.92; 95% CI, 2.63-23.85; p<0.001). The prevalence of COVID-19 vaccine acceptance among students of health sciences was low. Older age, mandate by heads of the institution, trust in the government and readiness to pay for the vaccine were associated with acceptance of the vaccine. Therefore, stakeholders should prioritize strategies that would maximize the vaccination uptake.