Stevia aquatic extract protects the pancreas from streptozocin (STZ) induced damage: A stereological study

299-307In recent years, among antidiabetic medicinal herbs, Stevia received a lot of attention due to its diverse therapeutic applications. Despite extensive reports on the effects of Stevia on the pancreas, its molecular mechanism is not clear yet. In this study, we investigated the protective and preventive effects of oral extracts of Stevia on the pancreas through the stereological methods in streptozocin (STZ) induced diabetic rats. Thus, 66 adult male rats were assigned to six groups (n = 11) viz., healthy control, healthy Stevia (400 mg /kg), diabetic-control, diabetic-metformin (500 mg/kg), diabetic-Stevia and pre-Stevia-diabetic group. Treatment with Stevia significantly reduced fasting blood sugar (FBS) and MDA compared to the diabetic control group (P <0.05). The results indicated that the weight and the volume of the pancreas increased significantly in all our treated groups compared to the diabetic one (P <0.05). The volume density of the pancreatic islands and the number of beta cells increased in healthy and diabetic groups treated with Stevia (P <0.05). However, the pre-treated diabetic rats with Stevia did not show significant preventive effects on the volume and number of beta cells as well as the volume of islets against destructive effects of STZ. More specifically, our results confirmed the protective effects of Stevia through restoring pancreatic cells and repairing the stereological damage induced by STZ

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells.

Glioblastoma (GBM) is the most prevalent malignant primary brain tumor with a very poor survival rate. Temozolomide (TMZ) is the common chemotherapeutic agent used for GBM treatment. We recently demonstrated that simvastatin (Simva) increases TMZ-induced apoptosis via the inhibition of autophagic flux in GBM cells. Considering the role of the unfolded protein response (UPR) pathway in the regulation of autophagy, we investigated the involvement of UPR in Simva-TMZ-induced cell death by utilizing highly selective IRE1 RNase activity inhibitor MKC8866, PERK inhibitor GSK-2606414 (PERKi), and eIF2α inhibitor salubrinal. Simva-TMZ treatment decreased the viability of GBM cells and significantly increased apoptotic cell death when compared to TMZ or Simva alone. Simva-TMZ induced both UPR, as determined by an increase in GRP78, XBP splicing, eukaryote initiation factor 2α (eIF2α) phosphorylation, and inhibited autophagic flux (accumulation of LC3β-II and inhibition of p62 degradation). IRE1 RNase inhibition did not affect Simva-TMZ-induced cell death, but it significantly induced p62 degradation and increased the microtubule-associated proteins light chain 3 (LC3)β-II/LC3β-I ratio in U87 cells, while salubrinal did not affect the Simva-TMZ induced cytotoxicity of GBM cells. In contrast, protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibition significantly increased Simva-TMZ-induced cell death in U87 cells. Interestingly, whereas PERK inhibition induced p62 accumulation in both GBM cell lines, it differentially affected the LC3β-II/LC3β-I ratio in U87 (decrease) and U251 (increase) cells. Simvastatin sensitizes GBM cells to TMZ-induced cell death via a mechanism that involves autophagy and UPR pathways. More specifically, our results imply that the IRE1 and PERK signaling arms of the UPR regulate Simva-TMZ-mediated autophagy flux inhibition in U251 and U87 GBM cells

The ER Stress/UPR Axis in Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis.

Cellular protein homeostasis in the lungs is constantly disrupted by recurrent exposure to various external and internal stressors, which may cause considerable protein secretion pressure on the endoplasmic reticulum (ER), resulting in the survival and differentiation of these cell types to meet the increased functional demands. Cells are able to induce a highly conserved adaptive mechanism, known as the unfolded protein response (UPR), to manage such stresses. UPR dysregulation and ER stress are involved in numerous human illnesses, such as metabolic syndrome, fibrotic diseases, and neurodegeneration, and cancer. Therefore, effective and specific compounds targeting the UPR pathway are being considered as potential therapies. This review focuses on the impact of both external and internal stressors on the ER in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) and discusses the role of the UPR signaling pathway activation in the control of cellular damage and specifically highlights the potential involvement of non-coding RNAs in COPD. Summaries of pathogenic mechanisms associated with the ER stress/UPR axis contributing to IPF and COPD, and promising pharmacological intervention strategies, are also presented

Stevia aquatic extract protects the pancreas from streptozocin (STZ) induced damage: A stereological study

In recent years, among antidiabetic medicinal herbs, Stevia received a lot of attention due to its diverse therapeutic applications. Despite extensive reports on the effects of Stevia on the pancreas, its molecular mechanism is not clear yet. In this study, we investigated the protective and preventive effects of oral extracts of Stevia on the pancreas through the stereological methods in streptozocin (STZ) induced diabetic rats. Thus, 66 adult male rats were assigned to six groups (n = 11) viz., healthy control, healthy Stevia (400 mg /kg), diabetic-control, diabetic-metformin (500 mg/kg), diabetic-Stevia and pre-Stevia-diabetic group. Treatment with Stevia significantly reduced fasting blood sugar (FBS) and MDA compared to the diabetic control group (P &lt;0.05). The results indicated that the weight and the volume of the pancreas increased significantly in all our treated groups compared to the diabetic one (P &lt;0.05). The volume density of the pancreatic islands and the number of beta cells increased in healthy and diabetic groups treated with Stevia (P &lt;0.05). However, the pre-treated diabetic rats with Stevia did not show significant preventive effects on the volume and number of beta cells as well as the volume of islets against destructive effects of STZ. More specifically, our results confirmed the protective effects of Stevia through restoring pancreatic cells and repairing the stereological damage induced by STZ

Additional file 1 of Resveratrol promotes liver cell survival in mice liver-induced ischemia-reperfusion through unfolded protein response: a possible approach in liver transplantation

Additional file 1: Figure 1S. The effect of resveratrol on the serum ALT and AST levels after I/R. Resveratrol was injected into the tail vein of the mouse 5 minutes before reperfusion. The mice’s underwent 1 hour of ischemia and were sacrificed after 3 hours of reperfusion (I/R). Data are expressed as mean ± SD. According to the Tukey post-hoc test used for the comparison between groups, the groups with the same superscript letters did not have significant differences when α = 0.05 (p ≥ .05). Thus, various letters show considerable differences (p <0.05). Figure 2S. The impact of resveratrol on the expression levels of GRP78, PERK, ATF6α, CHOP and XBP1 after I/R. Sham-operated group, I/R, DMSO, 0.02, 0.2 and 2. The mice’s were sacrificed after 1 hour of ischemia and reperfusion (I/R) for 3 hours. Data are expressed as mean ± SD. One-way analysis of variance is used to compare the groups with the same superscript letters, which are not significantly different when α = 0.05 (p ≥ 0.05). However, various letters show considerable differences (p <0.05). Figure 4S. Evaluation of the effect of resveratrol on the liver injury after I/R by histopathological analysis. Sham-operated group with normal liver architecture (A). In mice’s in the IR and IR + DMSO groups (B and C), obvious sinusoidal congestion, vacuolation of the hepatocytes (thin arrow), and focal parenchyma inflammation (thick arrow) were obvious. Mice’s with mild sinusoidal dilation received resveratrol at 0.02 and 0.2 mg/kg. Abnormal histopathological changes in the resveratrol group (D and E) were significantly improved. A higher dose (2 mg / kg) of resveratrol did not have a significant protective effect on the treatment of I / R injury in mice’s (F)

Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses

The COVID-19 pandemic is caused by the 2019–nCoV/SARS-CoV-2 virus. This severe acute respiratory syndrome is currently a global health emergency and needs much effort to generate an urgent practical treatment to reduce COVID-19 complications and mortality in humans. Viral infection activates various cellular responses in infected cells, including cellular stress responses such as unfolded protein response (UPR) and autophagy, following the inhibition of mTOR. Both UPR and autophagy mechanisms are involved in cellular and tissue homeostasis, apoptosis, innate immunity modulation, and clearance of pathogens such as viral particles. However, during an evolutionary arms race, viruses gain the ability to subvert autophagy and UPR for their benefit. SARS-CoV-2 can enter host cells through binding to cell surface receptors, including angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1). ACE2 blockage increases autophagy through mTOR inhibition, leading to gastrointestinal complications during SARS-CoV-2 virus infection. NRP1 is also regulated by the mTOR pathway. An increased NRP1 can enhance the susceptibility of immune system dendritic cells (DCs) to SARS-CoV-2 and induce cytokine storm, which is related to high COVID-19 mortality. Therefore, signaling pathways such as mTOR, UPR, and autophagy may be potential therapeutic targets for COVID-19. Hence, extensive investigations are required to confirm these potentials. Since there is currently no specific treatment for COVID-19 infection, we sought to review and discuss the important roles of autophagy, UPR, and mTOR mechanisms in the regulation of cellular responses to coronavirus infection to help identify new antiviral modalities against SARS-CoV-2 virus

Statins in patients with COVID-19: a retrospective cohort study in Iranian COVID-19 patients.

Background: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has profoundly affected the lives of millions of people. To date, there is no approved vaccine or specific drug to prevent or treat COVID-19, while the infection is globally spreading at an alarming rate. Because the development of effective vaccines or novel drugs could take several months (if not years), repurposing existing drugs is considered a more efficient strategy that could save lives now. Statins constitute a class of lipid-lowering drugs with proven safety profiles and various known beneficial pleiotropic effects. Our previous investigations showed that statins have antiviral effects and are involved in the process of wound healing in the lung. This triggered us to evaluate if statin use reduces mortality in COVID-19 patients. Results: After initial recruitment of 459 patients with COVID-19 (Shiraz province, Iran) and careful consideration of the exclusion criteria, a total of 150 patients, of which 75 received statins, were included in our retrospective study. Cox proportional-hazards regression models were used to estimate the association between statin use and rate of death. After propensity score matching, we found that statin use appeared to be associated with a lower risk of morbidity [HR = 0.85, 95% CI = (0.02, 3.93), P = 0.762] and lower risk of death [(HR = 0.76; 95% CI = (0.16, 3.72), P = 0.735)]; however, these associations did not reach statistical significance. Furthermore, statin use reduced the chance of being subjected to mechanical ventilation [OR = 0.96, 95% CI = (0.61-2.99), P = 0.942] and patients on statins showed a more normal computed tomography (CT) scan result [OR = 0.41, 95% CI = (0.07-2.33), P = 0.312]. Conclusions: Although we could not demonstrate a significant association between statin use and a reduction in mortality in patients with COVID19, we do feel that our results are promising and of clinical relevance and warrant the need for prospective randomized controlled trials and extensive retrospective studies to further evaluate and validate the potential beneficial effects of statin treatment on clinical symptoms and mortality rates associated with COVID-19