Role Of Endoplasmic Reticulum Stress Research Articles

Pleiotropic role of endoplasmic reticulum stress in the protection of psoralidin against sepsis-associated encephalopathy

Sepsis-associated encephalopathy (SAE) is a severe complication that affects the central nervous system and is a leading cause of increased morbidity and mortality in intensive care units. Psoralidin (PSO), a coumarin compound isolated from the traditional Chinese medicine Psoralea corylifolia L., can penetrate the blood-brain barrier and has various pharmacological activities, including anti-inflammation, anti-oxidation and anti-depression. This study aims to explore whether PSO alleviates SAE and delve into the underlying mechanisms. We found that PSO treatment significantly reduced sepsis scores, aspartate transaminase (AST) and aspartate transaminase (LDH), while increased anal temperature and neurological scores in CLP-injured mice. Moreover, PSO treatment ameliorated sepsis-associated cognitive impairment, mood, anxiety disorders, inhibited inflammatory responses, as well as attenuated endoplasmic reticulum stress (ERS). These results were also validated in vitro experiments, PSO treatment reduced ROS, inflammation response, and attenuated ERS in LPS-injured N2a cells. Importantly, tunicamycin (TUN), as ERS agonist, significantly reversed the protective effect of PSO on LPS-injured N2a cells, as evidenced by increased expression levels of IL-6, NLRP3, CHOP, and ATF6. Likewise, ATF6 overexpression also reversed the protective effect of PSO. In conclusion, these results confirmed that PSO has a protective effect on SAE, which was largely attributed to neuroinflammation and ERS. These findings provide new insights into the neuroprotective role of PSO and suggest that PSO is a new therapeutic intervention of SAE.

Increased ER Stress and Unfolded Protein Response Activation in Epithelial and Inflammatory Cells in Hypersensitivity Pneumonitis.

Several types of cytotoxic insults disrupt endoplasmic reticulum (ER) homeostasis, cause ER stress, and activate the unfolded protein response (UPR). The role of ER stress and UPR activation in hypersensitivity pneumonitis (HP) has not been described. HP is an immune-mediated interstitial lung disease that develops following repeated inhalation of various antigens in susceptible and sensitized individuals. The aim of this study was to investigate the lung expression and localization of the key effectors of the UPR, BiP/GRP78, CHOP, and sXBP1 in HP patients compared with control subjects. Furthermore, we developed a mouse model of HP to determine whether ER stress and UPR pathway are induced during this pathogenesis. In human control lungs, we observed weak positive staining for BiP in some epithelial cells and macrophages, while sXBP1 and CHOP were negative. Conversely, strong BiP, sXBP1- and CHOP-positive alveolar and bronchial epithelial, and inflammatory cells were identified in HP lungs. We also found apoptosis and autophagy markers colocalization with UPR proteins in HP lungs. Similar results were obtained in lungs from an HP mouse model. Our findings suggest that the UPR pathway is associated with the pathogenesis of HP.

Endoplasmic reticulum stress is attenuated by glycolysis in lymphatic malformations.

This study aims to investigate the role of endoplasmic reticulum stress (ER stress) in human dermal lymphatic endothelial cells (HDLECs) and lymphatic malformations (LMs) and its relationship with aerobic glycolysis and inflammation. The proliferation and apoptosis of HDLECs were examined with lipopolysaccharide (LPS) treatment. ER stress-associated proteins and glycolysis-related markers were detected by western blot. Glycolysis indexes were detected by seahorse analysis and lactic acid production assay kits. Immunohistochemistry was used to reveal the ER stress state of lymphatic endothelial cells (LECs) in LMs. LPS induced ER stress in HDLECs but did not trigger detectable apoptosis. Intriguingly, LPS-treated HDLECs also showed increased glycolysis flux. Knockdown of Hexokinase 2, a key enzyme for aerobic glycolysis, significantly inhibited the ability of HDLECs to resist ER stress-induced apoptosis. Moreover, compared to normal skin, glucose-regulated protein 78 (GRP78/BIP), and phosphorylation protein kinase R-like kinase (p-PERK), two key ER stress-associated markers, were upregulated in LECs of LMs, which was correlated with the inflected state. In addition, excessively activated ER stress inhibited the progression of LMs in rat models. These data indicate that glycolysis could rescue activated ER stress in HDLECs, which is required for the accelerated development of LMs. Inflammation enhances both ER stress and glycolysis in LECs while glycolysis is required to attenuate the pro-apoptotic effect of ER stress. Endoplasmic reticulum (ER) stress is activated in lymphatic endothelial cells (LECs) of LMs, especially in inflammatory condition. The expression of ER stress-related proteins is increased in LMs and correlated with Hexokinase 2 expression. Pharmacological activation of ER stress suppresses the formation of LM lesions in the rat model. ER stress may be a promising and effective therapeutic target for the treatment of LMs.

The Role of Endoplasmic Reticulum Stress in Metabolic Diseases.

The endoplasmic reticulum (ER), the center of protein folding, also controls the cell's life-and-death signaling mechanisms. ER stress caused by unfolded or misfolded proteins leads to the activation of the unfolded protein response (UPR) in the cell. The UPR utilizes three main signaling pathways to restore disrupted ER homeostasis. These signaling pathways are protein kinase R-like endoplasmic reticulum kinase, inositol-requiring enzyme 1, and activating transcription factor 6. Studies have reported that ER stress (ERS) plays a role in the pathogenesis of metabolic disorders such as diabetes, obesity, atherosclerosis, and nonalcoholic liver disease. This review will briefly discuss the ERS response in these metabolic diseases.

Critical role of endoplasmic reticulum stress on bisphenol A‐induced cytotoxicity in human keratinocyte HaCaT cells

AbstractBisphenol A (BPA) is widely used in plastic and paper products, and its exposure can occur through skin contact or oral ingestion. The hazardous effects of BPA absorbed through the skin may be more severe; however, few studies have investigated the skin toxicity of BPA. This study investigated the effects of BPA on human epidermal keratinocyte cell lines, which is relevant for skin exposure. BPA treatment reduced cell viability in a time‐ and concentration‐dependent manner and elevated oxidative and endoplasmic reticulum (ER) stress. N‐acetylcysteine (NAC), an oxidative stress inhibitor, reduced BPA‐induced reactive oxygen species (ROS) levels. However, only 10% of the decreased cell viability was restored at the highest NAC concentration. Treatment with tauroursodeoxycholic acid (TUDCA), which is an ER stress inhibitor, effectively countered the increase in ER stress‐related proteins induced by BPA. Moreover, TUDCA treatment led to a reduction in oxidative stress, as demonstrated by the decrease in ROS levels, maintenance of mitochondrial membrane potential, and modulation of stress signaling proteins. Consequently, TUDCA significantly improved BPA‐induced cytotoxicity in a concentration‐dependent manner. Notably, combined treatment using TUDCA and NAC further reduced the BPA‐induced ROS levels; however, no significant difference in cell viability was observed compared with that for TUDCA treatment alone. These findings indicated that the oxidative stress observed following BPA exposure was exacerbated by ER stress. Moreover, the principal factor driving BPA‐induced cytotoxicity was indeed ER stress, which has potential implications for developing therapeutic strategies for diseases associated with similar stress responses.

The VAMP-associated protein VAP27-1 plays a crucial role in plant resistance to ER stress by modulating ER–PM contact architecture in Arabidopsis

The endoplasmic reticulum (ER) and the plasma membrane (PM) form ER–PM contact sites (EPCSs) that allow the ER and PM to exchange materials and information. Stress-induced disruption of protein folding triggers ER stress, and the cell initiates the unfolded protein response (UPR) to resist the stress. However, whether EPCSs play a role in ER stress in plants remains unclear. VESICLE-ASSOCIATED MEMBRANE PROTEIN (VAMP)-ASSOCIATED PROTEIN 27-1 (VAP27-1) functions in EPCS tethering and is encoded by a family of 10 genes (VAP27-1–10) in Arabidopsis thaliana. Here, we used CRISPR-Cas9-mediated genome editing to obtain a homozygous vap27-1 vap27-3 vap27-4 (vap27-1/3/4) triple mutant lacking three of the key VAP27 family members in Arabidopsis. The vap27-1/3/4 mutant exhibits defects in ER–PM connectivity and EPCS architecture, as well as excessive UPR signaling. We further showed that relocation of VAP27-1 to the PM mediates specific VAP27-1-related EPCS remodeling and expansion under ER stress. Moreover, the spatiotemporal dynamics of VAP27-1 at the PM increase ER–PM connectivity and enhance Arabidopsis resistance to ER stress. In addition, we revealed an important role for intracellular calcium homeostasis in the regulation of UPR signaling. Taken together, these results broaden our understanding of the molecular and cellular mechanisms of ER stress and UPR signaling in plants, providing additional clues for improving plant broad-spectrum resistance to different stresses.

Possible role of endoplasmic reticulum stress in the pathogenesis of chronic adenoiditis and adenoid hypertrophy: A prospective, parallel-group study.

Adenoid tissue is a first-line host defense secondary lymphoid organ, especially in childhood. The endoplasmic reticulum (ER) is required to maintain balanced cellular activity. With impaired ER functions, protein accumulation occurs, resulting in ER stress, which plays a role in the etiopathogenesis of many diseases. We aimed to investigate the relationship between ER stress and adenoid tissue disorders, thereby elucidating the mechanisms of immunity-related diseases. Fifty-four pediatric patients (>3 years old) who underwent adenoidectomy for chronic adenoiditis (CA) or adenoid hypertrophy (AH) were enrolled in this prospective, parallel-group clinical study. Adenoids were divided into two groups (CA or AH) based on their size and evaluated for ER stress pathway and apoptosis pathway markers by Real-time PCR and Western blot analysis. ER stress pathway markers significantly differed between the CA and AH groups. Children with CA had higher ER stress marker levels than the AH group (p < .001 for ATF-4, ATF-6, and GRP78, and p < .05 for EDEM1, CHOP, EIF2AK3, ERNI, and GRP94). Apoptosis pathway marker levels (BAX and BCL-2) were not different between groups. ER stress contributes to the etiopathogenesis of adenoid tissue diseases and the pathogenesis of adenoid tissue disorders, which are part of the immune response. These results may guide the development of new and alternative treatments for immune system disorders.

Abstract 389: The role of endoplasmic reticulum stress in immune surveillance and effectiveness of immunotherapy in renal and ovarian carcinoma

Abstract In complex tumor-host interactions, the immune response has a dual role, with the capacity to both promote and suppress tumor growth, requiring complex interactions of regulatory molecules within the cellular network of the tumor-immune microenvironment (TIME). Various factors in TIME, such as low pH and hypoxia, cause Endoplasmic Reticulum Stress (ERS). Immune cells exposed to ERS lack antigen presentation, exhibit a suppressor phenotype, and can initiate apoptosis. Therefore, relieving ERS can benefit immune surveillance and response to immunotherapy. Our research is focused on tumor-immune cells interaction, specifically in ovarian and renal cancers. We conducted in vitro co-cultures of these cancer cells with peripheral blood mononuclear cells (PBMC) and manipulated ERS using a well-established ERS inducer tunicamycin and a chemical chaperone tauroursodeoxycholic acid (TUDCA). We then employed various techniques such as MTT, RT-qPCR, western blotting, immunofluorescence staining, scratch wound assay, and 3D co-cultures to analyze cellular viability, gene expression, protein levels of ERS markers (e.g., BiP, CHOP, PERK), immune cell activity (e.g., IL-2, INFγ, FoxP3, PD-1), migration, invasiveness, interaction, spheroid formation, and immune cell infiltration. Furthermore, we examined ERS and immune profiles in tumor samples from patients with ovarian and renal cancer who underwent conventional therapy or immunotherapy.Relieving ERS increased the infiltration of PBMC into tumor spheroids and reduced the expression of BiP and PERK in PBMC. In vitro, the viability of ovarian and renal cancer cells increased when cultured alone after ERS alleviation. However, when co-cultured with PBMC, their viability decreased, indicating enhanced immune cell response. Additionally, the growth and migration of ovarian and renal cancer cells were limited in these co-cultures, along with increased expression of BiP and CHOP and an elevated CHOP/BiP ratio. We connected these findings to the molecular background of ERS in patient samples and observed a positive correlation between a favorable clinical outcome, higher lymphocyte infiltration at the tumor site, and increased levels of BiP and CHOP in cancer cells. We further applied these results to OC and RCC in vivo syngeneic mouse models, currently with very promising outcomes.Based on these results we expect ERS alleviation as a suitable approach to improving the survival and effectiveness of immune cell populations within hostile tumor-induced microenvironment with positive effects on anticancer immunotherapy. Supported by Ministry of Health of the Czech Republic, grant nr. NU21-03-00539, and by the Johannes Amos Comenius Programme, project SALVAGE nr. CZ.02.01.01/00/22_008/0004644. All rights reserved. Citation Format: Marek Svoboda, Lukas Moran, Barbora Vavrusakova, Lenka Krejci, Kamila Souckova, Katerina Vasickova, Milos Holanek. The role of endoplasmic reticulum stress in immune surveillance and effectiveness of immunotherapy in renal and ovarian carcinoma [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 389.

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.

Exploring the Role of Endoplasmic Reticulum Stress in Various Diseases: Implications and Potential Therapeutic Strategies

This study examines prospective therapeutic approaches to modulate Endoplasmic reticulum stress (ER stress) for disease intervention and emphasizes the significant role of ER stress in the pathophysiology of numerous diseases. ER stress is an intracellular stress response when the ER fails to properly fold and repair proteins. This cellular stress response holds crucial relevance in developing many diseases, such as metabolic-related diseases, neurodegenerative diseases, and cardiovascular diseases. This work reviews the underlying mechanisms of ER stress and summarizes its association with various diseases. ER stress can lead to the disordered accumulation of intracellular proteins and the abnormality of cell function, impairing the normal physiological function of cells. These abnormal processes are closely related to disease development.Furthermore, several potential therapeutic options have been described, aiming to modulate ER stress and alleviate symptoms of associated diseases. These therapeutic options include small molecules, chemical chaperones, modulation of the UPR signaling pathway, gene therapy, and more. By modulating ER stress, researchers can intervene in disease development and provide new ideas and methods for preventing and treating these diseases.

Endoplasmic reticulum stress in breast cancer: a predictive model for prognosis and therapy selection.

Breast cancer (BC) is a leading cause of mortality among women, underscoring the urgent need for improved therapeutic predictio. Developing a precise prognostic model is crucial. The role of Endoplasmic Reticulum Stress (ERS) in cancer suggests its potential as a critical factor in BC development and progression, highlighting the importance of precise prognostic models for tailored treatment strategies. Through comprehensive analysis of ERS-related gene expression in BC, utilizing both single-cell and bulk sequencing data from varied BC subtypes, we identified eight key ERS-related genes. LASSO regression and machine learning techniques were employed to construct a prognostic model, validated across multiple datasets and compared with existing models for its predictive accuracy. The developed ERS-model categorizes BC patients into distinct risk groups with significant differences in clinical prognosis, confirmed by robust ROC, DCA, and KM analyses. The model forecasts survival rates with high precision, revealing distinct immune infiltration patterns and treatment responsiveness between risk groups. Notably, we discovered six druggable targets and validated Methotrexate and Gemcitabine as effective agents for high-risk BC treatment, based on their sensitivity profiles and potential for addressing the lack of active targets in BC. Our study advances BC research by establishing a significant link between ERS and BC prognosis at both the molecular and cellular levels. By stratifying patients into risk-defined groups, we unveil disparities in immune cell infiltration and drug response, guiding personalized treatment. The identification of potential drug targets and therapeutic agents opens new avenues for targeted interventions, promising to enhance outcomes for high-risk BC patients and paving the way for personalized cancer therapy.

Loss of mitogen-activated protein kinase phosphate-5 aggravates islet dysfunction in mice with type 1 and type 2 diabetes.

Impaired functionality and loss of islet β-cells are the primary abnormalities underlying the pathogenesis of both type 1 and 2 diabetes (T1DM and T2DM). However, specific therapeutic and preventive mechanisms underlying these conditions remain unclear. Mitogen-activated protein kinase phosphatase-5 (MKP-5) has been implicated in carcinogenesis, lipid metabolism regulation, and immune cell activation. In a previous study, we demonstrated the involvement of exogenous MKP-5 in the regulation of obesity-induced T2DM. However, the role of endogenous MKP-5 in the T1DM and T2DM processes is unclear. Thus, mice with MKP-5 knockout (KO) were generated and used to establish mouse models of both T1DM and T2DM. Our results showed that MKP-5 KO exacerbated diabetes-related symptoms in mice with both T1DM and T2DM. Given that most phenotypic studies on islet dysfunction have focused on mice with T2DM rather than T1DM, we specifically aimed to investigate the role of endoplasmic reticulum stress (ERS) and autophagy in T2DM KO islets. To accomplish this, we performed RNA sequence analysis to gain comprehensive insight into the molecular mechanisms associated with ERS and autophagy in T2DM KO islets. The results showed that the islets from mice with MKP-5 KO triggered 5' adenosine monophosphate-activated protein kinase (AMPK)-mediated autophagy inhibition and glucose-regulated protein 78 (GRP-78)-dominated ERS. Hence, we concluded that the autophagy impairment, resulting in islet dysfunction in mice with MKP-5 KO, is mediated through GRP-78 involvement. These findings provide valuable insights into the molecular pathogenesis of diabetes and highlight the significant role of MKP-5. Moreover, this knowledge holds promise for novel therapeutic strategies targeting MKP-5 for diabetes management.

Potential Role of Endoplasmic Reticulum Stress in Modulating Protein Homeostasis in Oligodendrocytes to Improve White Matter Injury in Preterm Infants.

Preterm white matter injury (WMI) is a demyelinating disease with high incidence and mortality in premature infants. Oligodendrocyte cells (OLs) are a specialized glial cell that produces myelin proteins and adheres to the axons providing energy and metabolic support which susceptible to endoplasmic reticulum protein quality control. Disruption of cellular protein homeostasis led to OLs dysfunction and cell death, immediately, the unfolded protein response (UPR) activated to attempt to restore the protein homeostasis via IRE1/XBP1s, PERK/eIF2α and ATF6 pathway that reduced protein translation, strengthen protein-folding capacity, and degraded unfolding/misfolded protein. Moreover, recent works have revealed the conspicuousness function of ER signaling pathways in regulating influenced factors such as calcium homeostasis, mitochondrial reactive oxygen generation, and autophagy activation to regulate protein hemostasis and improve the myelination function of OLs. Each of the regulation modes and their corresponding molecular mechanisms provides unique opportunities and distinct perspectives to obtain a deep understanding of different actions of ER stress in maintaining OLs' health and function. Therefore, our review focuses on summarizing the current understanding of ER stress on OLs' protein homeostasis micro-environment in myelination during white matter development, as well as the pathophysiology of WMI, and discussing the further potential experimental therapeutics targeting these factors that restore the function of the UPR in OLs myelination function. Potential Role of ER Stress in Modulating Protein Homeostasis in OLs. OLs, produce myelin proteins and provide energy and metabolic support which are susceptible to cellular protein homeostasis and ER protein quality control. 1) UPR plays a different role in activating IRE1/XBP1s, PERK/eIF2α, and ATF6 pathways not only in attempting to restore protein homeostasis to promote cell survival but also aggravating disruption of cellular protein homeostasis to accelerate cell death. 2) PERK pathway facilitated the protein secretion, amino acid metabolism, and stress response to promote cell survival via phosphorylating eIF2α level and strengthening ATF4 expression; Nevertheless, the prolonged activating of the PERK pathway could up-regulate CHOP, GADD34, and other pro-apoptotic factors to further aggravates cell injury. 3) IRE1 and ATF6 pathways enhanced various gene transcription associated with protein folding, secreting, EARD, and ERQC to prompt cell protein homeostasis micro-environment; However, sustained IRE1 and/or ATF6 activity could prompt cell survival toward apoptosis via the pro-apoptotic pathway, inflammation, and other patterns.

Integrated multi-omic analysis and experiment reveals the role of endoplasmic reticulum stress in lung adenocarcinoma

BackgroundLung cancer is a highly prevalent malignancy worldwide and is associated with high mortality rates. While the involvement of endoplasmic reticulum (ER) stress in the development of lung adenocarcinoma (LUAD) has been established, the underlying mechanism remains unclear.MethodsIn this study, we utilized data from The Cancer Genome Atlas (TCGA) to identify differentially expressed endoplasmic reticulum stress-related genes (ERSRGs) between LUAD and normal tissues. We performed various bioinformatics analyses to investigate the biological functions of these ERSRGs. Using LASSO analysis and multivariate stepwise regression, we constructed a novel prognostic model based on the ERSRGs. We further validated the performance of the model using two independent datasets from the Gene Expression Omnibus (GEO). Additionally, we conducted functional enrichment analysis, immune checkpoint analysis, and immune infiltration analysis and drug sensitivity analysis of LUAD patients to explore the potential biological function of the model. Furthermore, we conducted a battery of experiments to verify the expression of ERSRGs in a real-world cohort.ResultsWe identified 106 ERSRGs associated with LUAD, which allowed us to classify LUAD patients into two subtypes based on gene expression differences. Using six prognostic genes (NUPR1, RHBDD2, VCP, BAK1, EIF2AK3, MBTPS2), we constructed a prognostic model that exhibited excellent predictive performance in the training dataset and was successfully validated in two independent external datasets. The risk score derived from this model emerged as an independent prognostic factor for LUAD. Confirmation of the linkage between this risk model and immune infiltration was affirmed through the utilization of Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The q-PCR results verified significant differences in the expression of prognostic genes between cancer and paracancer tissues. Notably, the protein expression of NUPR1, as determined by immunohistochemistry (IHC), exhibited an opposite pattern compared to the mRNA expression patterns.ConclusionThis study establishes a novel prognostic model for LUAD based on six ER stress-related genes, facilitating the prediction of LUAD prognosis. Additionally, NUPR1 was identified as a potential regulator of stress in LUAD.

The role of endoplasmic reticulum stress in metabolic diseases and mammary epithelial cell homeostasis in dairy cows.

High-yielding dairy cows undergo various physiological stresses during the transitional phase of the calving cycle. In this period, they experience negative energy balance, subjecting the liver to significant metabolic stress from an influx of nonesterified fatty acids. This metabolic stress not only impairs liver function but also diminishes milk production. Early lactation dairy cows may develop endoplasmic reticulum (ER) stress in the liver, potentially leading to liver-related diseases and contributing to ER stress in mammary epithelial cells, resulting in decreased milk production. Natural products that alleviate ER stress have been identified, and if further in vivo studies confirm their efficacy, they have potential as feed additives to prevent disease and reduce milk yield. Conversely, physiological levels of ER stress play a role in mammary gland development and positively influence protein synthesis in milk. Understanding the threshold level of ER stress in mammary tissue and its detailed mechanisms will be crucial in dairy farming.

Connexin 36 Mediated Intercellular Endoplasmic Reticulum Stress Transmission Induces SSTA Resistance in Growth Hormone Pituitary Adenoma.

Somatostatin analogues (SSTA) are first-line pharmacological treatment choice for acromegaly, which received satisfying tumor shrinkage and normalization of growth hormone. However, there are still patients unresponsive to SSTA, and the underline mechanism remains unknown. Besides, there is no evidence regarding the role of endoplasmic reticulum stress (ERS) and its transmission in SSTA resistance, which also require investigation. Primary growth hormone adenoma cells and cell lines were treated with SSTA; autophagy double-labeled LC3 (mRFP-GFP) adenovirus transfection, flow cytometry sorting, western blotting, calcium imaging as well as immunofluorescence staining were used to determine ERS and autophagy signal transmission; xenograft and syngeneic tumor in vivo model were exploited to confirm the ERS signal transmission mediated effect. Our results revealed that SSTA induces ERS in pituitary growth hormone (GH) adenoma cells. The ERS signals can be intercellularly transmitted, leading to less responsible to SSTA treatment. Moreover, SSTA stimulates inositol triphosphate (IP3) elevation, mediating ERS intercellular transfer. In addition, connexin 36 tunnels ERS transmission, and its blocker, Quinine, exhibits a synergistic effect with SSTA treating GH adenoma. Our study provided insight into ERS intercellular transmission mediated SSTA resistance, which could be translated into clinical usage to improve SSTA efficiency in GH adenoma treatment.

Integrated analysis of TCGA data identifies endoplasmic reticulum stress-related lncRNA signature in stomach adenocarcinoma

Abstract Objectives To investigaed the role of endoplasmic reticulum stress (ERS)-related long non-coding RNAs (lncRNAs) in stomach adenocarcinoma (STAD) using TCGA data. Methods This study integrated clinical, transcriptomic, and tumor data from the Cancer Genome Atlas (TCGA). The expression of ERS genes was evaluated, alongside their association with identified lncRNAs. Gene set enrichment analysis and immune cell infiltration analysis were performed to elucidate the biological pathways influenced by these lncRNAs. Results The study identified five lncRNAs – AC012055.1, LINC01235, LINC00571, LINC02073, and CFAP61-AS1 – strongly correlated with ERS pathways and cancer prognosis. A prognostic model based on these lncRNAs was developed and validated across low- and high-risk groups. Potential biological pathways associated with these lncRNAs were uncovered through immune cell infiltration and GSEA. Additionally, screening identified drugs potentially effective against STAD, highlighting co-expressed genes as probable therapeutic targets. Conclusions This research offers detailed insights into the molecular mechanisms of STAD, enhancing understanding of potential therapeutic targets and showing promise for clinical applications.

Impact of endoplasmic reticulum stress on chondrocyte apoptosis in rat model of DDH.

Developmental dysplasia of the hip (DDH) is a developmental disorder characterized by acetabular dysplasia leading to early osteoarthritis. This study examines the role of endoplasmic reticulum stress (ERS) in chondrocyte apoptosis and cartilage degeneration within a DDH model. In the rat model of DDH, created using a swaddling technique, significant deformities in the femoral head and acetabulum were observed, alongside an upregulation of matrix metalloproteinase-13 in acetabular cartilage. We also noted increased levels of apoptosis and ERS-related factors in the acetabular cartilage of DDH models. Additionally, rat chondrocytes exposed to high-magnitude cyclic tensile strain (CTS, 1 Hz, 10% equibiaxial strain) in vitro exhibited elevated ERS and increased apoptosis. Importantly, treatment with the ERS inhibitor 4-phenylbutyric acid effectively suppressed apoptosis induced by CTS in chondrocytes. Our findings suggest that ERS contributes to the upregulation of apoptosis-related factors in chondrocytes within the DDH model, indicating the potential of ERS modulation as a therapeutic approach for DDH-related cartilage degeneration.

Linagliptin in combination with insulin suppresses apoptotic unfolded protein response in ovaries exposed to type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is one of the main causes of ovarian atresia, but its molecular effect on the ovaries is not fully understood. Accumulating evidence suggests that T1DM causes excessive endoplasmic reticulum(ER) stress and insufficient adaptive unfolded protein response that triggers proapoptotic signaling pathways in ovarian tissue. In addition, problems such as amenorrhea and infertility, which are frequently seen in women with T1DM, continue despite the intensification of insulin therapy and improvement of metabolic control. Therefore new, and adjunctive treatments for women with T1DM need to be explored. We aimed to examine how the use of linagliptin, which has blood sugar-lowering effects and high antioxidant activity, together with insulin affects the expression levels of proteins and genes that play a role in ERstress in type 1 diabetic mouse ovaries. Eighty-four Balb/C 6-week-old female mice were randomly divided into seven groups: control, vehicle, diabetes + insulin, diabetes + linagliptin, diabetes + linagliptin + insulin, diabetes + TUDCA, and diabetes + TUDCA + insulin. TUDCA (an inhibitor of ER stress) groups are positive control groups created to compare linagliptin groups in terms of ER stress. Linagliptin and TUDCA were given by oral gavage and 1U insulin was administered subcutaneously for 2 weeks. A significant decrease was observed in the MDA and NOX1 levels and the number of atretic follicles in the ovaries of the diabetes + linagliptin + insulin group compared to the diabetes + insulin group. The use of linagliptin and insulin increased the expression of pro-survival XBP1s transmembrane protein and decreased the expression of proapoptotic ATF4, pJNK1/2, cleaved caspase 12, and cleaved caspase 3 in mouse ovaries. Our study provides new therapeutic evidence that linagliptin administered in addition to insulin induces ER stress mechanism-dependent survival in ovaries with type 1 diabetes.

Modulating endoplasmic reticulum stress attenuates mast cell degranulation

ObjectivesDegranulation of mast cells leads to direct allergic symptoms. The underlying mechanism needs to be explored further. Endoplasmic reticulum (ER) stress is involved in the pathogenesis of allergic conditions. The objective of this study is to gain a better understanding of the mechanism of mast cell degranulation. MethodsBone marrow derived mast cells and mast cells isolated from the airway tissues were prepared. The role of ER stress in mediating the release of mast cells was tested. RNA sequencing (RNAseq) was used to investigate the genetic activities of mast cells. ResultsOur observation showed that sensitization increased ER stress in mast cells. X-box-1 binding protein (XBP1) activity was linked to mast cell degranulation. Modulation of ER stress or XBP1 expression regulates the release of the mast cell mediator. XBP1 promoted the mediator release of mast cells by activating spleen tyrosine kinase (Syk). Activation of eukaryotic initiation factor 2a (eIF2a) inhibited XBP1 in mast cells. Semaphorin 3A was effective in preventing experimental allergic rhinitis (AR) due to its ability to suppress the release of mast cell mediators. ConclusionsER stress is associated with the mast cell degranulation. By inhibiting XBP1, the crucial molecule of ER stress, mast cell degranulation can be suppressed and experimental AR can be mitigated.