Activation of Gαq sequesters specific transcripts into Ago2 particles

Hormones and neurotransmitters can activate the Gαq / phospholipase Cβ1 (PLCβ1) signaling system eliciting cellular calcium responses. PLCβ1 also prevents the aggregation of ribosomal and RNA proteins into stress granules, which are halted translation complexes that form in response to cellular stress. Activation of Gαq promotes PLCβ1association releasing bound proteins and promoting the formation of stress granules. However, the cellular impact of stress granules formed from routine Gαq protein signaling is unknown. Here, we have characterized Ago2 stress granules formed in response to Gαq activation in a neuronal-like cell line. We find these stress granule have a distinct protein composition, and unlike stress granules formed under heat stress, contain only two mRNA transcripts, chromogranin B, which is involved in secretory function, and ATP synthase 5f1b, which is required for ATP synthesis. Our studies show an unexpected pathway where Gαq/PLCβ regulates the translation of specific proteins.

EFFECT OF MELANOCORTINS AND EXPERIMENTAL SOCIAL STRESS ON THE LEVEL OF CASPASE-3 AND CASPASE-8

At present the study of stress-generating effects and key mechanisms of regulation of apoptosis remain in the focus of attention of researchers. Stress causes dysfunctions of many body systems which lead to disruption of homeostasis and molecular cell mechanisms of programmed cell death. In this context, the problem of pharmacological regulation and correction of these disorders poses an urgent problem. Neuropeptide compounds such as melanocortins are interesting in this direction as regulators and correctors. Under conditions of experimental social stress activation of apoptotic processes was established due to an increase in the level of caspase-3 and caspase-8. The studied neuropeptides Semax (ACTH (4-7)-Pro-Gly-Pro) and ACTH (6-9)-Pro-Gly-Pro exhibit antiapoptotic effects under conditions of induced social stress in rats. This action of neuropeptides is manifested by a decrease in the activity of the initiating and effector caspases in the blood serum of experimental animals.

The Interplay of Mitochondrial Oxidative Stress and Endoplasmic Reticulum Stress in Cardiovascular Fibrosis in Obese Rats

We have evaluated the role of mitochondrial oxidative stress and its association with endoplasmic reticulum (ER) stress activation in the progression of obesity-related cardiovascular fibrosis. MitoQ (200 µM) was orally administered for 7 weeks to male Wistar rats that were fed a high-fat diet (HFD, 35% fat) or a control diet (CT, 3.5% fat). Obese animals presented cardiovascular fibrosis accompanied by increased levels of extracellular matrix proteins and profibrotic mediators. These alterations were associated with ER stress activation characterized by enhanced levels (in heart and aorta vs. CT group, respectively) of immunoglobulin binding protein (BiP; 2.1-and 2.6-fold, respectively), protein disulfide-isomerase A6 (PDIA6; 1.9-fold) and CCAAT-enhancer-binding homologous protein (CHOP; 1.5- and 1.8-fold, respectively). MitoQ treatment was able to prevent (p < 0.05) these modifications at cardiac and aortic levels. MitoQ (5 nM) and the ER stress inhibitor, 4-phenyl butyric acid (4 µM), were able to block the prooxidant and profibrotic effects of angiotensin II (Ang II, 10−6 M) in cardiac and vascular cells. Therefore, the data show a crosstalk between mitochondrial oxidative stress and ER stress activation, which mediates the development of cardiovascular fibrosis in the context of obesity and in which Ang II can play a relevant role.

Endophytic Streptomyces hygroscopicus OsiSh-2-Mediated Balancing between Growth and Disease Resistance in Host Rice

Under disease stress, activation of defense response in plants often comes with the cost of a reduction in growth and yield, which is referred as the growth-defense trade-off. The microorganisms which can be recruited by plants to mitigate the growth-defense trade-off are of great value in crop breeding.

Corticosterone Can Be an Essential Stress Index in Channel Catfish (Ictalurus punctatus)

Although cortisol is considered the main glucocorticoid involved in regulating stress in fish by elevating the serum glucose, the presence of serum corticosterone and whether its level can be used as an indicator for fish stress activation and reflect the degree of fish stress remains to be determined. To comprehensively and accurately evaluate the performance of two glucocorticoids after stress, in this study, seven of the most common stressors (ammonia nitrogen, high-temperature, acid, alkali, Aeromonas hydrophila, and salinity) in aquaculture were selected. The levels of serum corticosterone, cortisol, and glucose were detected within 48 h, and then the dynamic changes were analyzed. In addition, the kidneys were collected to detect the expression of corresponding proteins involved in corticosterone and cortisol synthesis (3 β-HSD and CYP17A1) for further exploration. From the results obtained, the content of serum corticosterone was about 100 times higher than that of cortisol, and it was found that corticosterone and cortisol showed different dynamic changes within 48 h among the seven kinds of stress. In the subsequent detection of glucose, it was found that the dynamic shift in glucose was not consistent with the dynamic changes of corticosterone or cortisol entirely but seemed to be caused by the combination of the two. In the follow-up protein expression detection, we found that corticosterone seemed to respond to stress earlier. Therefore, it is concluded that the responses of corticosterone and cortisol to stress are independent, corticosterone may be more sensitive in the current seven acute stresses, and then they regulate glucose together to resist stress. The study aimed to fill the vacancy of corticosterone in fish research and provide a reference for the complete evaluation of fish stress degree.

Comprehensive Analysis of the Clinical and Biological Significances of Endoplasmic Reticulum Stress in Diffuse Gliomas

BackgroundAs a critical organelle for protein and lipid synthesis, the dysfunction of endoplasmic reticulum has a significant impact on multiple biological processes of cells. Thus, in this study, we constructed an ER stress-related risk signature to investigate the functional roles of ER stress in gliomas.MethodsA total of 626 samples from TCGA RNA-seq dataset (training cohort) and 310 samples from CGGA RNA-seq dataset (validation cohort) were enrolled in this study. Clinical information and genomic profiles were also obtained. The ER stress signature was developed by the LASSO regression model. The prognostic value of the risk signature was evaluated by Cox regression, Kaplan-Meier and ROC Curve analyses. Bioinformatics analysis and experiment in vitro were performed to explore the biological implication of this signature.ResultsWe found that the ER stress-related signature was tightly associated with major clinicopathological features and genomic alterations of gliomas. Kaplan-Meier curve and Cox regression analysis indicated that ER stress activation was an independent prognostic factor for patients with glioma. Besides, we also constructed an individualized prognosis prediction model through Nomogram and ROC Curve analysis. Bioinformatics analysis suggested that ER stress activation also promoted the malignant progression of glioma and participated in the regulation of tumor immune microenvironment, especially the infiltration of macrophages in M2 phase. These results were further validated in IHC analysis and cell biology experiments.ConclusionThe ER stress activation had a high prognostic value and could serve as a promising target for developing individualized treatment of glioma.

Neutrophil extracellular traps impair intestinal barrier functions in sepsis by regulating TLR9-mediated endoplasmic reticulum stress pathway

Increased neutrophil extracellular traps (NETs) formation has been found to be associated with intestinal inflammation, and it has been reported that NETs may drive the progression of gut dysregulation in sepsis. However, the biological function and regulation of NETs in sepsis-induced intestinal barrier dysfunction are not yet fully understood. First, we found that both circulating biomarkers of NETs and local NETs infiltration in the intestine were significantly increased and had positive correlations with markers of enterocyte injury in abdominal sepsis patients. Moreover, the levels of local citrullinated histone 3 (Cit H3) expression were associated with the levels of BIP expression. To further confirm the role of NETs in sepsis-induced intestinal injury, we compared peptidylarginine deiminase 4 (PAD4)-deficient mice and wild-type (WT) mice in a lethal septic shock model. In WT mice, the Cit H3-DNA complex was markedly increased, and elevated intestinal inflammation and endoplasmic reticulum (ER) stress activation were also found. Furthermore, PAD4 deficiency alleviated intestinal barrier disruption and decreased ER stress activation. Notably, NETs treatment induced intestinal epithelial monolayer barrier disruption and ER stress activation in a dose-dependent manner in vitro, and ER stress inhibition markedly attenuated intestinal apoptosis and tight junction injury. Finally, TLR9 antagonist administration significantly abrogated NETs-induced intestinal epithelial cell death through ER stress inhibition. Our results indicated that NETs could contribute to sepsis-induced intestinal barrier dysfunction by promoting inflammation and apoptosis. Suppression of the TLR9–ER stress signaling pathway can ameliorate NETs-induced intestinal epithelial cell death.

Oxidative Stress in SLE T Cells, Is NRF2 Really the Target to Treat?

Oxidative stress is a major component of cellular damage in T cells from patients with systemic lupus erythematosus (SLE) resulting amongst others in the generation of pathogenic Th17 cells. The NRF2/Keap1 pathway is the most important antioxidant system protecting cells from damage due to oxidative stress. Activation of NRF2 therefore seems to represent a putative therapeutic target in SLE, which is nevertheless challenged by several findings suggesting tissue and cell specific differences in the effect of NRF2 expression. This review focusses on the current understanding of oxidative stress in SLE T cells and its pathophysiologic and therapeutic implications.

Mechanistic Insights into the Link between Obesity and Prostate Cancer

Obesity is a pandemic of increasing worldwide prevalence. There is evidence of an association between obesity and the risk of prostate cancer from observational studies, and different biologic mechanisms have been proposed. The chronic low-level inflammation within the adipose tissue in obesity results in oxidative stress, activation of inflammatory cytokines, deregulation of adipokines signaling, and increased circulating levels of insulin and insulin-like growth factors (IGF). These mechanisms may be involved in epithelial to mesenchymal transformation into a malignant phenotype that promotes invasiveness, aggressiveness, and metastatic potential of prostate cancer. A thorough understanding of these mechanisms may be valuable in the development of effective prostate cancer prevention strategies and treatments. This review provides an overview of these mechanisms.

Modulation of SARS-CoV-2 Spike-induced Unfolded Protein Response (UPR) in HEK293T cells by selected small chemical molecules

Coronaviruses (CoV) exploits the endoplasmic reticulum (ER) of the host cells for replication and in doing so, increases ER stress. evokes Unfolded Protein Response (UPR) and possibly autophagy, which could all attribute to the pathophysiology of the viral infections. To date, little is known about the roles of ER stress, UPR, and autophagy in SARS-CoV-2 infection. Here we over-expressed the viral Spike (S) protein in cultured HEK293T cells, as it has been shown that such protein is largely responsible for UPR activation in other CoV-infected cells. We noticed, in the transfected cells, heightened ER stress, activation of the PERK-eIF2α arm of the UPR, induction of autophagy and cell death. When we treated the transfected cells with Tauroursodeoxycholic acid (TUDCA), 4-phenyl butyric acid (PBA), Salubrinal, Trazadone hydrochloride, and Dibenzoylmethane (DBM), we saw reduced the BiP/GRP78 levels, but only PBA and TUDCA could significantly diminish the levels of peIF2α and autophagy expression.