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

Dastghaib, Sanaz; Shojaei, Shahla; Mostafavi‐Pour, Zohreh; Sharma, Pawan; Patterson, John B.; Samali, Afshin; Mokarram, Pooneh; Ghavami, Saeid

doi:10.3390/cells9112339

Cited by 60 publications

(63 citation statements)

References 86 publications

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“…Statins are conventionally used as cholesterol-lowering drugs, via inhibition of the mevalonate pathway, for first-line therapeutic prevention of atherosclerotic cardiovascular diseases [ 15 , 16 ]. The discovery of their pleiotropic effects, independent of the cholesterol pathway, further attracted attention to this class of drugs [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Macroautophagy (hereafter autophagy) is the major form of autophagy in the cells [ 63 ]. Autophagy is also induced by starvation [ 64 ]. In this way, autophagy is important for cells by providing them with essential nutrients [ 65 , 66 ].…”

Section: Autophagy and Admentioning

confidence: 99%

Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

Eshraghi

Adlimoghaddam

Mahmoodzadeh

et al. 2021

IJMS

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Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including am-yloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflammation interact in a bidirectional manner. In the current review, we briefly discussed an overview on autophagy and mitophagy in AD and then provided a comprehensive discussion on the role of these pathways in microglia and their involvement in AD pathogenesis.

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“…Two main models for UPR activation have been discussed most frequently. The first model is similar to that of the heat shock response pathway and relies on the availability and regulated binding of the chaperone BiP [ 2 , 3 , 12 , 13 ]. BiP homeostatically binds to UPR sensor proteins to prevent their oligomerization, which is interrupted during ER stress.…”

Section: Unfolded Protein Responsementioning

confidence: 99%

“…Under conditions where the UPR is hindered and the load of unfolded proteins becomes higher, the UPR can initiate apoptosis [ 81 ], autophagy [ 2 , 36 , 82 , 83 ], or cell death [ 33 , 44 , 45 ]. Although the ER is quite robust and resilient, often, cells are operating at the limits of their capacity [ 84 ].…”

Section: Unfolded Protein Responsementioning

confidence: 99%

“…In cells that have developed an ER, including those residing in the lungs, the balance between synthesis and protein secretion sometimes fails, or proteins cannot be properly degraded or reduced by proteases. A disturbance in the synthesis, secretion, or destruction of proteins may lead to the accumulation of non-folded or mis-folded proteins within the ER, disrupting its normal function [ 1 , 2 ]. Such an impairment of ER homeostasis is referred to as ER stress, which plays a significant role in cellular survival and function [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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

Aghaei

Dastghaib

Aftabi

et al. 2020

Life

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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.

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

Cited by 60 publications

References 86 publications

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

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

Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

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

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