Targeting Endoplasmic Reticulum Stress Research Articles

Total ginsenosides extend healthspan of aging Drosophila by suppressing imbalances in intestinal stem cells and microbiota

BackgroundDisruption of stem cell and microbial homeostasis accelerates the aging process. Hence, maintaining these balances effectively delays aging and alleviates the symptoms of age-related diseases. Recent research indicates that targeting endoplasmic reticulum (ER) stress and immune deficiency (IMD) signalling may play a positive role in maintaining homeostasis in aging intestinal stem cells (ISC) and microbial equilibrium. Previous research has suggested that total ginsenosides (TG) derived from Panax ginseng C. A. Meyer may exhibit potential anti-aging properties by mitigating ER stress and mediating the IMD pathway. Nevertheless, it remains unclear whether TG improve ISC and microbial homeostasis by modulating ER stress and the IMD pathway to promote healthy aging. PurposeTo elucidate whether TG promotes healthspan in Drosophila and its underlying molecular mechanisms, focusing on its role in regulating ER stress and the IMD pathway to maintain ISC and intestinal microbiota homeostasis. MethodsHigh performance liquid chromatography was performed to detect the main saponin monomer in TG. Survival rate, gut length, barrier function, and feeding/excretion behaviour assays were used to evaluate the effects of TG on the lifespan and gut health of Drosophila. At the stem cell level, “esg-luciferase” reporter system, esg-GFP/delta stem cell fluorescent labelling, and phospho-histone H3+ mitotic activity assays were employed to determine whether TG prevented natural aging or oxidative stress-associated ISC over-proliferation in Drosophila. Immunofluorescence staining was used to detect the effects of TG on ER stress during aging. Overexpression or interference of ER stress target genes and their related c-Jun N-terminal kinase (JNK) gene was manipulated using gene editing technology to verify the molecular mechanism by which TG maintains age-related ISC proliferation homeostasis. Molecular docking and isothermal titration calorimetry were used to verify the direct interactions between TG and ER stress target genes. In addition, at the intestinal flora level, 16S rDNA sequencing was used to analyse the effect of TG on the diversity and abundance of Drosophila intestinal flora and the possible functional pathways involved. RT-qPCR was performed to determine whether TG mediated the expression of target genes in the IMD pathway. A dominant bacterial species-specific mono-association analysis were performed to verify whether the effects of TG on IMD target genes and ISC proliferation depended on the direct control of the dominant bacterial species. ResultsOur results suggest that administration of TG delays the decline in gut morphology and function in aging Drosophila. TG prevents age-associated ISC hyperproliferation by inhibiting ER stress IRE1-mediated JNK signaling. Furthermore, oral TG prevented aging-associated ISC and gut microbiota dysbiosis by remodelling the gut microbiota and inhibiting Acetobacter-mediated activation of IMD target genes. ConclusionTG promotes healthy aging by inhibiting the excessive proliferation of ISC and alleviating intestinal microbial imbalance, thereby providing new insights for the research and development of anti-aging TG products.

Endoplasmic reticulum stress: bridging inflammation and obesity-associated adipose tissue.

Obesity presents a significant global health challenge, increasing the susceptibility to chronic conditions such as diabetes, cardiovascular disease, and hypertension. Within the context of obesity, lipid metabolism, adipose tissue formation, and inflammation are intricately linked to endoplasmic reticulum stress (ERS). ERS modulates metabolism, insulin signaling, inflammation, as well as cell proliferation and death through the unfolded protein response (UPR) pathway. Serving as a crucial nexus, ERS bridges the functionality of adipose tissue and the inflammatory response. In this review, we comprehensively elucidate the mechanisms by which ERS impacts adipose tissue function and inflammation in obesity, aiming to offer insights into targeting ERS for ameliorating metabolic dysregulation in obesity-associated chronic diseases such as hyperlipidemia, hypertension, fatty liver, and type 2 diabetes.

Abstract 380: Co-downregulation of GRP78 and ATR enhances apoptosis in pancreatic ductal adenocarcinoma

Abstract Background: Targeting endoplasmic reticulum (ER) stress is a potential therapeutic strategy in preclinical models of pancreatic duct adenocarcinoma (PDAC). GRP78 is known as the master regulator of the unfolded protein response (UPR) pathway, regulating ER stress by activating the UPR pathway to avoid cell apoptosis and regulates the activation of UPR pathway signals by binding PERK. Overexpression of GRP78 in PDAC results in the retention of misfolded and unassembled proteins, as well as the accumulation of ROS, leading to the promotion of genomic instability. However, there has been limited research on targeting GRP78 as a therapeutic strategy in PDAC. In this study, we aimed to investigate the anticancer effects of BOLD-100, an inhibitor of GRP78, in PDAC. Methods: We used 9 PDAC cell lines (Capan-1, AsPC-1, HPAFII, MIA-PaCa2, Panc-1, Capan-2, SNU-213, SNU-324, SNU-2918). The mouse xenograft model of Capan-1 was established for in vivo study. BOLD-100 (GRP78 inhibitor), AZD6738 (ATR inhibitor), NAC (N-Acetylcysteine; ROS scavenger) and TUDCA (Tauroursodeoxycholic acid; ER stress inhibitor) were used. MTT assay, CFA assay, cell cycle analysis, RT-PCR, western blot, immunoprecipitation, DCF-DA staining and Annexin V assay were used to elucidate the action of BOLD-100. The combination of BOLD-100 with AZD6738 has been evaluated in both in vitro and in vivo model. Results: BOLD-100 suppressed the proliferation of PDAC cells and decreased the mRNA level of GRP78, which in turn disrupted the interaction between GRP78 and PERK. BOLD-100 increased ER stress and ROS, leading to activation of PERK, eIF2a, and CHOP. Activation of UPR pathway induced CHOP-dependent apoptosis and inhibited PDAC cell growth. Moreover, TUDCA reversed the ROS accumulation induced by BOLD-100, confirming that ER stress regulates ROS levels. The accumulation of ROS upregulated the active forms of ATR and CHK1, suggesting the activation of the DNA damage repair pathway. Notably, the treatment of NAC abrogated the activation of ATR-CHK1 axis by BOLD-100-induced ROS accumulation. AZD6738 synergized with BOLD-100 in in vitro and in vivo, by suppressing BOLD-100-induced ATR phosphorylation. Conclusion: GRP78 could serve as one of the potential therapeutic targets in PDAC. The combination of BOLD-100 and AZD6738 demonstrates a synergistic effect suggesting GRP78/ATR dual targeting as a promising therapeutic option for patients with PDAC. Citation Format: Su In Lee, Ah-Rong Nam, Kyoung-Seok Oh, Jae-Min Kim, Ju-Hee Bang, Yoojin Jeong, Sea Young Choo, Hyo Jung Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh. Co-downregulation of GRP78 and ATR enhances apoptosis in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 380.

Abstract 1476: OSBPL3 facilitates endoplasmic reticulum stress and stemness in triple negative breast cancer

Abstract Background: Triple negative breast cancer (TNBC) is a type of aggressive breast cancer with a poor survival. Endoplasmic reticulum (ER) stress, induced by exposed to intrinsic (e.g. oncogenes) and external factors (e.g. chemotherapies), is an important factor in both tumor progression and responses to chemotherapies. Recent studies have demonstrated that the progression of ER stress may result in the emergence of cancer stem cells (CSC), which also arise as a consequence of metastasis. However, the mechanism of targeting ER stress signaling in cancer stem cells remains to be investigated. Aim: (i) To investigate the mechanistic role of Oxysterol binding protein-like 3 (OSBPL3) in TNBC and its links with breast cancer mortality, particularly caused by chemotherapeutic resistance and metastasis; and (ii) to test a hypothesis that OSBPL3 facilitates the abnormal activation of ER stress and cancer stemness, result in the resistance to chemotherapy and metastasis in TNBC. Methods: The expression level of OSBPL3 in TNBC was determined by immunohistochemical staining and the mRNA expression profiles from the TCGA database. Roles of OSBPL3 in cancer cell growth, metastasis, stemness and activation of ER stress were determined by molecular and cell biology methods. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation (ChIP), promoter luciferase reporter assay was included for detecting the transcription of OSBPL3 in TNBC. TNBC xenograft nude mice were used to study the inhibition of tumor development. Results: OSBPL3 is a novel TNBC target, which is overexpressed in TNBC tissues and significantly associated with clinical pathology of advanced TNM stage and poor prognosis of tumor patients. Mechanistically, Increased OSBPL3 induced ER stress and ER stress agonist (tunicamycin) treatment results in the translocation of XBP1, an ER stress sensor, into the nucleus to induce OSBPL3 expression through direct binding to the OSBPL3 promoter. In addition, OSBPL3 facilitates the stemness induced by ER stress via phosphorylating GSK3β and transporting accumulated β-catenin to the nucleus to promote the expression of stemness-related transcriptional factors, ultimately resulting in tumor metastasis and resistance to chemotherapy. Furthermore, OSBPL3-specific siRNAs encapsulated by jetPEI nanocarriers prominently inhibit tumor growth and epirubicin-induced resistance in vivo. Conclusion: We identified an important role of OSBPL3-ER stress-XBP1 feedback loop in the stemness and resistance to chemotherapy, representing a future biomarker and therapeutic target of TNBC. Citation Format: Shengyu Pu, Huimin Zhang, Yu Ren, Jianjun He, Na Hao. OSBPL3 facilitates endoplasmic reticulum stress and stemness in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1476.

Endoplasmic reticulum stress enhances the expression of TLR3-induced TSLP by airway epithelium.

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pleiotropic cytokine that regulates T-helper 2 (Th2) immune responses in the lung and plays a major role in severe uncontrolled asthma. Emerging evidence suggests a role for endoplasmic reticulum (ER) stress in the pathogenesis of asthma. In this study, we determined if ER stress and the unfolded protein response (UPR) signalling are involved in TSLP induction in the airway epithelium. For this, we treated human bronchial epithelial basal cells and differentiated primary bronchial epithelial cells with ER stress inducers and the TSLP mRNA and protein expression was determined. A series of siRNA gene knockdown experiments were conducted to determine the ER stress-induced TSLP signalling pathways. cDNA collected from asthmatic bronchial biopsies was used to determine the gene correlation between ER stress and TSLP. Our results show that ER stress signalling induces TSLP mRNA expression via the PERK-CHOP signalling pathway. AP-1 transcription factor is important in regulating this ER stress-induced TSLP mRNA induction, though ER stress alone cannot induce TSLP protein production. However, ER stress significantly enhances TLR3-induced TSLP protein secretion in the airway epithelium. TSLP and ER stress (PERK) mRNA expression positively correlates in bronchial biopsies from participants with asthma, particularly in neutrophilic asthma. In conclusion, these results suggest that ER stress primes TSLP which is then enhanced further upon TLR3 activation, which may induce severe asthma exacerbations. Targeting ER stress using pharmacological interventions may provide novel therapeutics for severe uncontrolled asthma.

Inhibition of Endoplasmic Reticulum Stress Improves Chronic Ischemic Hippocampal Damage Associated with Suppression of IRE1α/TRAF2/ASK1/JNK-Dependent Apoptosis.

Chronic cerebral ischemia is a complex form of stress, of which the most common hemodynamic characteristic is chronic cerebral hypoperfusion (CCH). Lasting endoplasmic reticulum (ER) stress can drive neurological disorders. Targeting ER stress shows potential neuroprotective effects against stroke. However, the role of ER stress in CCH pathological processes and the effects of targeting ER stress on brain ischemia are unclear. Here, a CCH rat model was established by bilateral common carotid artery occlusion. Rats were treated with 4-PBA, URB597, or both for 4weeks. Neuronal morphological damage was detected using hematoxylin-eosin staining. The expression levels of the ER stress-ASK1 cascade-related proteins GRP78, IRE1α, TRAF2, CHOP, Caspase-12, ASK1, p-ASK1, JNK, and p-JNK were assessed by Western blot. The mRNA levels of TNF-α, IL-1β, and iNOS were assessed by RT-PCR. For oxygen-glucose deprivation experiments, mouse hippocampal HT22 neurons were used. Apoptosis of the hippocampus and HT22 cells was detected by TUNEL staining and Annexin V-FITC analysis, respectively. CCH evoked ER stress with increased expression of GRP78, IRE1α, TRAF2, CHOP, and Caspase-12. Co-immunoprecipitation experiments confirmed the interaction between TRAF2 and ASK1. ASK1/JNK signaling, inflammatory cytokines, and neuronal apoptosis were enhanced, accompanied by persistent ER stress; these were reversed by 4-PBA and URB597. Furthermore, the ASK1 inhibitor GS4997 and 4-PBA displayed synergistic anti-apoptotic effects in cells with oxygen-glucose deprivation. In summary, ER stress-induced apoptosis in CCH is associated with the IRE1α/TRAF2/ASK1/JNK signaling pathway. Targeting the ER stress-ASK1 cascade could be a novel therapeutic approach for ischemic cerebrovascular diseases.

ARRB1 downregulates acetaminophen-induced hepatoxicity through binding to p-eIF2α to inhibit ER stress signaling.

Acetaminophen (APAP) stands as the predominant contributor to drug-induced liver injury (DILI), and limited options are available. β-Arrestin1 (ARRB1) is involved in numerous liver diseases. However, the role of ARRB1 in APAP-induced liver injury remained uncertain. Wild-type (WT) and ARRB1 knockout (KO) mice were injected with APAP and sacrificed at the indicated times. The histological changes, inflammation, endoplasmic reticulum (ER) stress, and apoptosis were then evaluated. Hepatic cell lines AML-12 and primary hepatocytes were used for in vitro analyses. Systemic ARRB1-KO mice were susceptible to APAP-induced hepatotoxicity, as indicated by larger areas of centrilobular necrosis area and higher levels of ALT, AST, and inflammation level. Moreover, ARRB1-KO mice exhibited increased ER stress (indicated by phosphorylated α subunit of eukaryotic initiation factor 2 (p-eIF2α)-activating transcription factor 4 (ATF4)-CCAAT-enhancer-binding protein homologous protein (CHOP)) and apoptosis (indicated by cleaved caspase 3). Further rescue experiments demonstrated that the induction of apoptosis was partially mediated by ER stress. Overexpression of ARRB1 alleviated APAP-induced ER stress and apoptosis. Moreover, co-IP analysis revealed that ARRB1 directly bound to p-eIF2α and eIF2α. ARRB1 protected against APAP-induced hepatoxicity through targeting ER stress and apoptosis. ARRB1 is a prospective target for treating APAP-induced DILI.

ER stress mediated inflammation in cancer pathogenesis

Inflammation is a complex process which is associated with the initiation and progression of cancer. Prolonged Endoplasmic Reticulum (ER) stress triggers inflammation which is a key factor associated with cancer pathogenesis. ER stress also contributes to immune suppression in inflammatory and tumor microenvironment. It stimulates the production of pro-inflammatory cytokines by regulating the activation of various transcription factors and inflammatory signalling pathways. Targeting ER stress is an exciting possibility that can be used as a therapeutic strategy for cancer treatment. This mini review focuses on the emerging link between ER stress-induced inflammatory responses in cancer development.

Tangeretin enhances pancreatic beta-TC-6 function by ameliorating tunicamycin-induced cellular perturbations.

Pancreatic beta cell health and its insulin-secreting potential are severely compromised under the diabetic condition. One of the key mediators of beta cell dysfunction is endoplasmic reticulum (ER) stress. Pharmacological intervention of ER stress and associated complications in pancreatic beta cells may be an effective strategy for the management of diabetes. In the present study, we evaluated the efficacy of tangeretin, a citrus pentamethoxyflavone, in the alleviation of ER stress and associated perturbations in pancreatic Beta-TC-6 cell lines. Tunicamycin (pharmacological ER stress inducer) at subtoxic levels was observed to induce beta cell dysfunction by upregulation of intracellular ROS levels, lowering mitochondrial number/biogenesis and membrane potential, elevation of UPR markers, XBP-1, GADD153, and ER resident chaperones. Treatment with tangeretin was successful in improving the beta cell function by lowering the ROS levels and improving the mitochondrial biogenesis and mitochondrial membrane potential. Tangeretin also downregulated the expression levels of XBP-1, GADD153, and ER resident chaperones. GLUT2 expression, however, did not undergo any significant change under ER stress. We also observed altered expression of Pdx-1, TRB3, and p-Akt under the ER stress condition. Tangeretin augmented the expression levels of Pdx-1, and p-Akt while curtailing the expression of TRB3 in beta cells. Tunicamycin treatment suppressed the insulin levels, however, co-treatment with tangeretin could only marginally improve the levels. Targeting ER stress and associated pathways in pancreatic Beta-TC-6 cell lines by tangeretin can be an effective strategy for improving beta cell function.

Suppression of endoplasmic reticulum stress by 4-PBA enhanced atherosclerotic plaque stability via up-regulating CLOCK expression

Endoplasmic reticulum (ER) stress refers to a condition where the normal functioning of the ER is disrupted due to a variety of cellular stress factors. As a result, there is an accumulation of unfolded and misfolded proteins within the ER. Numerous studies have shown that ER stress can exacerbate inflammatory reactions and contribute to the development of various inflammatory diseases. However, the role of ER stress in the stability of atherosclerotic plaques remains poorly understood. In this study, we aimed to explore the potential impact of a specific ER stress inhibitor known as 4-phenyl butyric acid (4-PBA) on atherosclerosis in mice. The mice were fed a high-fat diet, and treatment with 4-PBA significantly improved the stability of the atherosclerotic plaques. This was evidenced by a reduction in oxidative stress and an increase in circadian locomotor output cycles kaput (CLOCK) protein and mRNA expression within the plaques. Additionally, 4-PBA reduced the expression of ER stress-related proteins and decreased apoptosis in the atherosclerotic plaques. In vitro investigation, we observed the effect of 4-PBA on vascular smooth muscle cells (VSMCs) that were exposed to oxidized low-density lipoprotein (ox-LDL), a significant contributor to the development of atherosclerosis. 4-PBA reduced reactive oxygen species (ROS) production and attenuated apoptosis, GRP78 and CHOP protein expression in ox-LDL-Induced VSMCs via up-regulating CLOCK expression. However, when the short hairpin RNA against CLOCK (sh-CLOCK) was introduced to the VSMCs, the protective effect of 4-PBA was abolished. This suggests that the up-regulation of CLOCK expression is crucial for the beneficial effects of 4-PBA on atherosclerotic plaque stability. This finding suggests that targeting ER stress and modulating CLOCK protein levels might be a promising way to enhance the stability of atherosclerotic plaques.

A Review of Oral Fixed-Dose Sodium Phenylbutyrate and Ursodoxicoltaurine in People with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is estimated to affect approximately 300,000 individuals worldwide. From symptom onset, the disease has rapid progression, and typically leads to death in approximately 3 years, though there is wide phenotypic variability. ALS pathophysiology is probably driven by several cellular and molecular mechanisms, including endoplasmic reticulum (ER) dysfunction, apoptosis, oxidative stress, impaired intracellular transport, neuroinflammation, and defective RNA metabolism and protein homeostasis. Several agents that target these pathways are in development, and a few are approved in certain regions. A fixed-dose combination of sodium phenylbutyrate and ursodoxicoltaurine (PB and TURSO, also known as AMX0035) was developed to target ER stress and mitochondrial dysfunction. This combination was approved for the treatment of ALS in the USA and Canada in 2022, following findings from the CENTAUR trial. CENTAUR was a Phase II trial comprising a 24-week randomised placebo-controlled phase and an open-label extension (OLE) phase. Treatment with PB and TURSO significantly slowed the rate of functional decline over 24 weeks compared with placebo, meeting the primary endpoint of the study. Over long-term follow-up, median survival duration was about 4.8 months longer in the group originally randomised to PB and TURSO, compared with the group originally randomised to placebo. PHOENIX, a Phase III trial of PB and TURSO planned to be completed in 2024, includes a 48-week randomised controlled phase, followed by an OLE. The PHOENIX trial is expected to provide additional insights regarding the effects of PB and TURSO in ALS.

Strategies targeting endoplasmic reticulum stress to improve Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder with motor symptoms, which is caused by the progressive death of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Accumulating evidence shows that endoplasmic reticulum (ER) stress occurring in the SNpc DA neurons is an early event in the development of PD. ER stress triggers the activation of unfolded protein response (UPR) to reduce stress and restore ER function. However, excessive and continuous ER stress and UPR exacerbate the risk of DA neuron death through crosstalk with other PD events. Thus, ER stress is considered a promising therapeutic target for the treatment of PD. Various strategies targeting ER stress through the modulation of UPR signaling, the increase of ER's protein folding ability, and the enhancement of protein degradation are developed to alleviate neuronal death in PD models. In this review, we summarize the pathological role of ER stress in PD and update the strategies targeting ER stress to improve ER protein homeostasis and PD-related events.

Chinese herbal medicine and active ingredients for diabetic cardiomyopathy: molecular mechanisms regulating endoplasmic reticulum stress.

Background: Diabetic cardiomyopathy (DCM) is one of the serious microvascular complications of diabetes mellitus. It is often associated with clinical manifestations such as arrhythmias and heart failure, and significantly reduces the quality of life and years of survival of patients. Endoplasmic reticulum stress (ERS) is the removal of unfolded and misfolded proteins and is an important mechanism for the maintenance of cellular homeostasis. ERS plays an important role in the pathogenesis of DCM by causing cardiomyocyte apoptosis, insulin resistance, calcium imbalance, myocardial hypertrophy and fibrosis. Targeting ERS is a new direction in the treatment of DCM. A large number of studies have shown that Chinese herbal medicine and active ingredients can significantly improve the clinical outcome of DCM patients through intervention in ERS and effects on myocardial structure and function, which has become one of the hot research directions. Purpose: The aim of this review is to elucidate and summarize the roles and mechanisms of Chinese herbal medicine and active ingredients that have the potential to modulate endoplasmic reticulum stress, thereby contributing to better management of DCM. Methods: Databases such as PubMed, Web of Science, China National Knowledge Internet, and Wanfang Data Knowledge Service Platform were used to search, analyze, and collect literature, in order to review the mechanisms by which phytochemicals inhibit the progression of DCM by targeting the ERS and its key signaling pathways. Keywords used included "diabetic cardiomyopathy" and "endoplasmic reticulum stress." Results: This review found that Chinese herbs and their active ingredients can regulate ERS through IRE1, ATF6, and PERK pathways to reduce cardiomyocyte apoptosis, ameliorate myocardial fibrosis, and attenuate myocardial hypertrophy for the treatment of DCM. Conclusion: A comprehensive source of information on potential ERS inhibitors is provided in this review. The analysis of the literature suggests that Chinese herbal medicine and its active ingredients can be used as potential drug candidates for the treatment of DCM. In short, we cannot ignore the role of traditional Chinese medicine in regulating ERS and treating DCM, and look forward to more research and new drugs to come.

Abstract 12477: ER Stress Chop Depletion in Endothelial Cells Protects From Renovascular Hypertension Pathogenesis

Introduction: Renovascular hypertension poses a significant risk for cardiovascular diseases, with endoplasmic reticulum (ER) stress playing a critical role in their development. However, the specific impact of ER stress-induced C/EBP homologous protein (CHOP) expression in endothelial cells on renovascular hypertension-induced cardiovascular complications remains unexplored. This study investigates the effects of disrupting ER stress CHOP in endothelial cells on microvascular dysfunction associated with renovascular hypertension. Hypothesis: We hypothesize that deleting ER stress CHOP in endothelial cells (EC) can mitigate renovascular hypertension-induced vascular endothelial dysfunction. Methods: Eight-week-old male and female mice (CHOP flx/flx and EC CHOP-/- ) were divided into eight groups: control groups undergoing a sham operation for 4 weeks and renovascular hypertension groups subjected to 2-kidney-1-clip (2K1C) surgery for 4 weeks. Body weight, blood pressure, running performance, cardiac hypertrophy and fibrosis, lung edema, inflammation, vascular endothelial function, and signaling were assessed. Results: Male and female CHOP flx/flx mice subjected to 2K1C for four weeks exhibited hypertension, cardiac hypertrophy and fibrosis, lung edema, impaired running performance, and endothelium-dependent vascular relaxation dysfunction. In contrast, male and female EC CHOP-/- mice subjected to 2K1C for four weeks were protected against the pathogenesis of renovascular hypertension. Furthermore, mesenteric resistance arteries from CHOP flx/flx mice displayed reduced endothelial nitric oxide synthase (eNOS) phosphorylation, while EC HOP-/- mice showed no such effect. Conclusions: These findings emphasize the significance of targeting ER stress CHOP in endothelial cells of male and female mice to protect against the development and pathogenesis of renovascular hypertension.

Sleep Deprivation Impairs Intestinal Mucosal Barrier by Activating Endoplasmic Reticulum Stress in Goblet Cells

Sleep deficiency is associated with intestinal inflammatory conditions and is increasingly recognized as a public health concern worldwide. However, the effects of sleep deficiency on intestinal goblet cells (GCs), which play a major role in intestinal barrier formation, remain elusive. Herein, the effects of sleep deprivation on intestinal GCs were determined using a sleep-deprivation mouse model. Sleep deprivation impaired the intestinal mucosal barrier and decreased the expression of tight junction proteins. According to single-cell RNA sequencing and histologic assessments, sleep deprivation significantly reduced GC numbers and mucin protein levels in intestinal tissues. Furthermore, sleep deprivation initiated endoplasmic reticulum stress by activating transcription factor 6 and binding Ig protein. Treatment with melatonin, an endoplasmic reticulum stress regulator, significantly alleviated endoplasmic reticulum stress responses in intestinal GCs. In addition, melatonin increased the villus length, reduced the crypt depth, and restored intestinal barrier function in mice with sleep deprivation. Overall, the findings revealed that sleep deprivation could impair intestinal mucosal barrier integrity and GC function. Targeting endoplasmic reticulum stress could represent an ideal strategy for treating sleep deficiency-induced gastrointestinal disorders.

Targeting endoplasmic reticulum stress signaling in ovarian cancer therapy.

The endoplasmic reticulum (ER), an organelle present in various eukaryotic cells, is responsible for intracellular protein synthesis, post-translational modification, and folding and transport, as well as the regulation of lipid and steroid metabolism and Ca2+ homeostasis. Hypoxia, nutrient deficiency, and a low pH tumor microenvironment lead to the accumulation of misfolded or unfolded proteins in the ER, thus activating ER stress (ERS) and the unfolded protein response, and resulting in either restoration of cellular homeostasis or cell death. ERS plays a crucial role in cancer oncogenesis, progression, and response to therapies. This article reviews current studies relating ERS to ovarian cancer, the most lethal gynecologic malignancy among women globally, and discusses pharmacological agents and possible targets for therapeutic intervention.

Lipotoxicity, ER Stress, and Cardiovascular Disease: Current Understanding and Future Directions.

The endoplasmic reticulum (ER) is a sub-cellular organelle that is responsible for the correct folding of proteins, lipid biosynthesis, calcium storage, and various post-translational modifications. In the disturbance of ER functioning, unfolded or misfolded proteins accumulate inside the ER lumen and initiate downstream signaling called unfolded protein response (UPR). The UPR signaling pathway is involved in lipolysis, triacylglycerol synthesis, lipogenesis, the mevalonate pathway, and low-density lipoprotein receptor recycling. ER stress also affects lipid metabolism by changing the levels of enzymes that are involved in the synthesis or modifications of lipids and causing lipotoxicity. Lipid metabolism and cardiac diseases are in close association as the deregulation of lipid metabolism leads to the development of various cardiovascular diseases (CVDs). Several studies have suggested that lipotoxicity is one of the important factors for cardiovascular disorders. In this review, we will discuss how ER stress affects lipid metabolism and their interplay in the development of cardiovascular disorders. Further, the current therapeutics available to target ER stress and lipid metabolism in various CVDs will be summarized.

ERX-41; Promising compound by targeting LIPA is a new Achilles heel therapeutic strategy for hard-to-treat solid tumors by induction of endoplasmic reticulum stress

Recently there has been an incredible shift in cancer treatment, from broad-spectrum cytotoxic drugs to targeted drugs known as small molecules and macromolecules. Although traditional therapies have been effective in cancer treatment, they often have adverse side effects due to their nonspecific action on both normal and tumor cells. The endoplasmic reticulum (ER), is known to control a variety of vital cellular processes, including protein production, folding/misfolding, and unfolding. The ER affects cell survival and death by activating the unfolded protein response (UPR) if the balance is not preserved. Dysregulation of these pathways' homeostasis in the ER is consequently linked to the emergence and development of cancer's pathological states. Therefore, targeting ER stress and ER stress-mediated apoptosis in cancer cells by small-molecule emerged as an intriguing unconventional approach that may be an effective strategy for treating cancers. This review attempts to introduce one of the newest small molecules known as ERX-41 for cancer has a poor clinical outcome strategy for solid tumors, including breast, brain, pancreatic and ovarian cancer. ERX-41 induces ER stress resulting in cell death through specific LIPA targeting. Importantly, demonstrated that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding and induce ER stress. This molecules targeted approach has a large therapeutic window, with no adverse effects either on normal cells and leading of new Achilles heel discovery in the therapeutics development for multiple hard-to-treat solid tumors.

Crosstalk between endoplasmic reticulum stress and multidrug-resistant cancers: hope or frustration.

Endoplasmic reticulum stress (ERS) is a kind of cell response for coping with hypoxia and other stresses. Pieces of evidence show that continuous stress can promote the occurrence, development, and drug resistance of tumors through the unfolded protein response. Therefore, the abnormal ac-tivation of ERS and its downstream signaling pathways not only can regulate tumor growth and metastasis but also profoundly affect the efficacy of antitumor therapy. Therefore, revealing the molecular mechanism of ERS may be expected to solve the problem of tumor multidrug resistance (MDR) and become a novel strategy for the treatment of refractory and recurrent tumors. This re-view summarized the mechanism of ERS and tumor MDR, reviewed the relationship between ERS and tumor MDR, introduced the research status of tumor tissue and ERS, and previewed the prospect of targeting ERS to improve the therapeutic effect of tumor MDR. This article aims to provide researchers and clinicians with new ideas and inspiration for basic antitumor treatment.

ERX-41; Promising compound by targeting LIPA is a new Achilles heel therapeutic strategy for hard-to-treat solid tumors by induction of endoplasmic reticulum stress

Recently there has been an incredible shift in cancer treatment, from broad-spectrum cytotoxic drugs to targeted drugs known as small molecules and macromolecules. Although traditional therapies have been effective in cancer treatment, they often have adverse side effects due to their nonspecific action on both normal and tumor cells. The endoplasmic reticulum (ER), is known to control a variety of vital cellular processes, including protein production, folding/misfolding, and unfolding. The ER affects cell survival and death by activating the unfolded protein response (UPR) if the balance is not preserved. Dysregulation of these pathways' homeostasis in the ER is consequently linked to the emergence and development of cancer's pathological states. Therefore, targeting ER stress and ER stress-mediated apoptosis in cancer cells by small-molecule emerged as an intriguing unconventional approach that may be an effective strategy for treating cancers. This review attempts to introduce one of the newest small molecules known as ERX-41 for cancer has a poor clinical outcome strategy for solid tumors, including breast, brain, pancreatic and ovarian cancer. ERX-41 induces ER stress resulting in cell death through specific LIPA targeting. Importantly, demonstrated that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding and induce ER stress. This molecules targeted approach has a large therapeutic window, with no adverse effects either on normal cells and leading of new Achilles heel discovery in the therapeutics development for multiple hard-to-treat solid tumors.