Endoplasmic Reticulum Stress Signaling Pathways Research Articles

Promoting ER stress in a plasmacytoid dendritic cell line drives fibroblast activation

BackgroundFibrosis remains a major complication in several chronic diseases, including systemic sclerosis (SSc). Plasmacytoid dendritic cells (pDCs) are innate immune cells that play a key role in the development of fibrosis in SSc patients, through still poorly defined mechanisms. Interestingly, endoplasmic reticulum (ER) stress signaling pathways are dysregulated in pDCs from patients with SSc, but their contribution to fibrosis remains unclear. Thus, this study aimed to unravel the mechanisms behind the involvement of pDCs and ER stress in fibrosis.MethodsTo address this question, we established an in vitro model designed to study the interactions between pDCs and fibroblasts. More specifically, IMR-90 fibroblasts were co-cultured with CAL-1, a pDC cell line. ER stress was then induced by the bacterial toxin SubAB. Extracellular matrix (ECM) production was assessed using immunoblotting, qPCR and confocal microscopy. The importance of cell-to-cell contact was investigated using conditioned media (CM) and transwell assays.ResultsDirect contact of CAL-1 and IMR-90 cells under ER stress conditions led to increased expression of fibronectin and alpha-smooth muscle actin (α-SMA). This effect required expression of the ER stress signaling sensor protein kinase R-like ER kinase (PERK) in pDCs and was observed only upon direct contact between both cell types.ConclusionsOverall, our data suggest that ER stress induction in pDCs promotes fibroblast activation, which may contribute to the development of fibrosis in SSc.

Docetaxel-induced liver and kidney toxicity in rats can be alleviated by suppressing oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis and autophagy signaling pathways after Silymarin treatment.

Approximately 20 million new cancer cases have occurred worldwide, and dose limitation occurs because of the liver and kidney toxicity of chemotherapeutic agents. Inflammation/apoptosis/ROS pathways appear to be activated in the liver and kidney toxicity of chemotherapeutic agents. This study was conducted to investigate the potential effects of silymarin (SLY) use against docetaxel (DTX)-induced liver and kidney damage in rats. For this purpose, 30mg/kg DTX was administered intraperitoneally to Sprague Dawley rats on the first day of the study, followed by SLY (25 or 50mg/kg/day) orally for 7 days. Then, various analyses were performed on liver and kidney tissues using biochemical, molecular and histological methods. The data obtained showed that DTX administration suppressed antioxidant markers and increased lipid peroxidation in liver and kidney tissues. It was also determined that DTX administration triggered markers of endoplasmic reticulum stress, inflammation, apoptosis and autophagy. On the other hand, SLY treatment increased enzymatic and non-enzymatic antioxidant levels and decreased malondialdehyde levels. Additionally, SLY alleviated DTX-induced endoplasmic reticulum stress, inflammation, apoptosis and autophagy in liver and kidney tissues. Immunohistochemical analyses showed that DTX increased the density of 8-OHdG positive cells in liver and kidney tissues, while oxidative DNA damage decreased after SLY administration. ALT, AST, ALP, Urea and Creatinine levels increased in the DTX group and decreased in the SLY treatment groups. In conclusion, DTX administration caused toxicity in liver and kidney tissues and damaged tissue integrity, while SLY treatment alleviated DTX-induced toxicity.

Pemphigus vulgaris autoantibodies induce an ER stress response.

Desmosomes are intercellular junctions that mediate cell-cell adhesion and are essential for maintaining tissue integrity. Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease caused by autoantibodies (IgG) targeting desmoglein 3 (Dsg3), a desmosomal cadherin. PV autoantibodies cause desmosome disassembly and loss of cell-cell adhesion, but the molecular signaling pathways that regulate these processes are not fully understood. Using high-resolution time-lapse imaging of live keratinocytes, we found that ER tubules make frequent and persistent contacts with internalizing Dsg3 puncta in keratinocytes treated with PV patient IgG. Biochemical experiments demonstrated that PV IgG activated ER stress signaling pathways, including both IRE1⍺ and PERK pathways, in cultured keratinocytes. Further, ER stress transcripts were upregulated in PV patient skin. Pharmacological inhibition of ER stress protected against PV IgG-induced desmosome disruption and loss of keratinocyte cell-cell adhesion, suggesting that ER stress may be an important pathomechanism and a therapeutically targetable pathway for PV treatment. These data support a model in which desmosome adhesion is integrated with ER function to serve as a cell adhesion stress sensor that is activated in blistering skin disease.

Integrated network pharmacology, molecular docking and in vivo experiments to elucidate the extenuative mechanisms of ginseng polysaccharide against Toxoplasma gondii-induced testicular toxicity.

Toxoplasma gondii (T. gondii) causes obvious reproductive toxicity in male by inducing inflammation and apoptosis in testicular tissue. Ginseng polysaccharide (GP) is an active compound in ginseng, known for its remarkable anti-inflammatory and antioxidant properties. This study aimed to investigate the effects of GP against T. gondii-induced testicular injury by integrating network pharmacology and in vivo experiments. Totally 9 core targets were identified, and PI3K/AKT1 signaling pathway were enriched via the network pharmacology analysis of GP against T. gondii-induced testicular injury, and molecular docking indicated that TLR4-related inflammatory pathways and Bax-related apoptotic pathways were also involved. In vivo experiments showed that GP (100 or 200mg/kg) mitigated the histopathology damage, enhanced spermatogenic capacity of the testis, and increased the levels of testosterone, luteinizing hormone and follicular-stimulating hormone in the serum. Proteins related to testosterone biosynthesis, StAR, P450scc and 17β-HSD, were significantly up-regulated. GP also inhibited the levels of inflammatory factors, by inhibiting the TLR4-P2X7R/NLRP3 inflammatory pathway in the testicular tissue. In addition, GP remarkably decreased testicular cell apoptosis rate, activated the PI3K/AKT pathway, and remarkably inhibited the apoptosis-associated PERK/eIF2α/ATF4/CHOP endoplasmic reticulum (ER) stress signaling pathway. In conclusion, the extenuative mechanisms of GP against T. gondii-induced testicular toxicity were comprehensively identified through integrating network pharmacology with in vivo experiments, it suggested that GP alleviates T. gondii-induced testicular toxicity by inhibiting the TLR4-P2X7R/NLRP3 inflammatory and PERK/eIF2α/ATF4/CHOP ER stress signaling pathways. This study provides new evidence for further development of ginseng as healthcare products to improve male reproductive function in T. gondii-infected patients.

Mcl-1 is a Gatekeeper Molecule to Regulate the Crosstalk Between Ferroptotic Agent-Induced ER Stress and TRAIL-Induced Apoptosis.

We previously reported that ferroptosis interplays with apoptosis through the integration of two independent pathways: the endoplasmic reticulum (ER) stress signaling pathway and the mitochondria-dependent apoptotic signaling pathway. In this study, we investigated a potential gatekeeper molecule, Mcl-1, between the two signal transduction pathways. Morphology studies and cell death analyses confirmed that a combination treatment of ferroptotic agent erastin (ERA) and apoptotic agent TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) synergistically enhances TRAIL-induced apoptosis in human pancreatic adenocarcinoma BxPC3 and human colorectal carcinoma HCT116 cells. We further observed that ERA upregulated the proapoptotic proteins PUMA (p53 upregulated modulator of apoptosis) and NOXA, as well as the anti-apoptotic protein Mcl-1 (myeloid cell leukemia sequence 1). These results suggest that ERA upregulates these molecules which results in maintenance of the balance between them. Interestingly, this balance was offset when BxPC3 cells and HCT116 cells were treated with ERA in combination with TRAIL. Our studies suggest that the imbalance between PUMA and NOXA and Mcl-1 during the combined treatment is responsible for ERA-enhanced TRAIL-induced apoptosis. This hypothesis was tested by employing a HCT116 Mcl-1 knock-in of phosphorylation site mutant (S121A/E125A/S159A/T163A) and investigated the synergistic interaction between the ERA and TRAIL. Along with morphology and cell death studies, immunoblotting analyses revealed that HCT116 Mcl-1 knock-in mutant cells effectively inhibited reduction of Mcl-1 and apoptosis promoted by the combination treatment. Moreover, ERA enhanced Mcl-1 inhibitor-induced apoptosis. Collectively, our studies suggest that Mcl-1 is a gatekeeper molecule between the ER stress pathway and the mitochondria-dependent apoptotic pathway.

A Novel PPARγ Modulator Falcarindiol Mediates ER Stress-Mediated Apoptosis by Regulating NOX4 and Overcomes Radioresistance in Breast Cancer.

The extract of the rhizome of Cnidium officinale Makino has potential anti-cancer and anti-inflammatory effects in many diseases, such as cancer. However, the biological functions of falcarindiol (FAD) in breast cancer are not fully understood. This study proved the anti-inflammatory and anti-cancer effects of FAD in breast cancer. Breast cancer models confirmed that FAD reduces cell viability and decreases the tumor volume of xenograft mouse models in a dose-dependent manner. FAD mediated caspase-3-dependent apoptosis in MDA-MB-231 and MCF-7 cells, whereas Z-VAD-FMK in combination with FAD inhibited caspase-3-induced apoptosis. FAD mediates apoptosis through cytosolic reactive oxygen species (ROS) and calcium (Ca2+) production and ER stress signaling pathways. In addition, FAD combined with thapsigargin (TG) exerts a synergistic apoptotic cell death effect. In the loss-of-function experiments, PERK or CHOP ablation suppressed intracellular ROS and Ca2+ release and ER stress-induced apoptosis in FAD-treated breast cancer models. Since there is a relationship between ROS and NADPH Oxidase 4 (NOX4), Nox4 ablation blocked ER stress-mediated apoptotic cell death by inhibiting ROS release in FAD-induced breast cancer models. Radioresistant models, such as MCF-7R and MDA-MB-231R, were developed to address the cellular radioresistance in clinical radiotherapy. FAD combined with radiation (2 Gy) overcame radioresistance via the inhibition of the epithelial-mesenchymal transition (EMT) phenomenon, such as the upregulation of PPARγ, VIM, and CDH2 and the downregulation of CDH1. Consequently, these results show that FAD may be a novel treatment as a breast cancer therapy.

Guilu Erxian glue reduces endoplasmic reticulum stress-mediated apoptosis and restores the balance of extracellular matrix synthesis and degradation in chondrocytes by inhibiting the ATF6/GRP78/CHOP signaling pathway

Knee Osteoarthritis (KOA) is characterized by phenotypic alterations, apoptosis, and the breakdown of the extracellular matrix (ECM) in the superficial articular cartilage cells. The inflammatory response activates the Endoplasmic Reticulum Stress (ERS) signaling pathway, which plays a critical role in the pathophysiology and progression of KOA. Chondrocytes stimulated by thapsigargin(TG)exhibit heightened ERS and significantly increase the expression of ERS-associated proteins. Key mediators of ERS-induced apoptosis include X-box-binding protein 1(XBP1), elevated levels of the protein transport protein Sec61 subunit (SEC61), and C/EBP homologous protein (CHOP).While the precise mechanism of action of Guilu Erxian Glue (GEG), a medication commonly used in the clinical treatment of KOA, remains to be fully elucidated, our research has shown that GEG mitigates the imbalance between ECM synthesis and degradation, as well as chondrocyte apoptosis resulting from ERS. This effect is likely achieved through the suppression of the Activating Transcription Factor 6 (ATF6)/Glucose-Regulatory Protein 78 (GRP78)/CHOP signaling pathway.In summary,our research results indicate that GEG can activate the ATF6/GRP78/CHOP signaling pathway to restore endoplasmic reticulum (ER) homeostasis in chondrocytes, thereby reducing chondrocyte apoptosis and ultimately promoting the balance between ECM synthesis and degradation.

Regulation of chondrocyte apoptosis in osteoarthritis by endoplasmic reticulum stress.

Osteoarthritis(OA), a common degenerative joint disease, is characterized by the apoptosis of chondrocytes as a primary pathophysiological change, with endoplasmic reticulum stress(ERS) playing a crucial role. It has been demonstrated that an imbalance in endoplasmic reticulum(ER) homeostasis can lead to ERS, activating three cellular adaptive response pathways through the unfolded protein responseto restore ER homeostasis. Mild ERS exerts a protective effect on cells, while prolonged ERS that disrupts the self-regulatory balance of the ER activates apoptotic signaling pathways, leading to chondrocyte apoptosis and hastening OA progression. Hence, controlling the ERS signaling pathway and its apoptotic factors has become a critical focus for preventing and treating OA. This review aims to elucidate the key mechanisms of ERS pathway-induced apoptosis, associated targets, and regulatory pathways, offering valuable insights to enhance the mechanistic understanding of OA. It also reviews the mechanisms studied for ERS-related drugs or compounds for the treatment of OA.

Isoliquiritigenin induced hepatotoxicity and endoplasmic reticulum stress in zebrafish embryos

Isoliquiritigenin (ISL), a naturally occurring flavonoid derived from licorice root, exhibits antioxidant, anticancer, anti-inflammatory, and anti-allergic properties, and is frequently detected in both environmental and human samples. Previous studies from our lab have demonstrated that ISL exposure can lead to developmental deformities and aberrant immune responses. However, the molecular mechanisms underlying ISL toxicity in zebrafish embryos remain incompletely elucidated. Therefore, this study aimed to elucidate the effects of ISL exposure on endoplasmic reticulum (ER) stress in zebrafish embryos by assessing the expression levels of ER stress markers HSPA5 and CHOP, along with associated apoptosis factors, under various ISL concentrations, with tunicamycin (TM) serving as a positive control. Furthermore, targeted analyses of ER stress-related pathways were conducted using RNA transcriptome sequencing, and the up-regulated gene was verified by western blot. The results revealed that ISL exposure significantly elevated the expression levels of HSPA5 and CHOP, concomitantly activating ER stress pathways, including pPERK-eIF2α-ATF4 and ATF6 pathways in zebrafish embryos. These findings suggest that the activation of endoplasmic reticulum stress signaling pathways may contribute to the developmental deformities observed in zebrafish embryos following ISL exposure, thereby highlighting the potential ecological risks associated with ISL usage.

Jingfang Granules alleviates OVA-induced allergic rhinitis through regulating endoplasmic reticulum stress signaling pathway

Ethnopharmacological relevanceJingfang Granules (JF) is a modified herbal compound preparation that is empirically used in clinical practice for the treatment of allergic diseases. Nevertheless, the role of JF in allergic rhinitis (AR) has yet to be demonstrated, and its potential mechanisms of action remain to be fully evaluated. Aim of studyThe objective of this research is to examine the underlying mechanisms by which JF can be used to treat AR. This will be achieved through the use of an ovalbumin (OVA)/aluminum hydroxide AR model in mice. Materials and methodsICR mice were administered an intraperitoneal (i.p.) injection of OVA/aluminium hydroxide in order to permit the establishment of an AR model. Following the intragastric administration of JF to the mice, testing nose scratching and sneezing behavior in mice to determine modeling status, and stained transverse sections of the mouse nose using the Hematoxylin and Eosin (H&E) method were in vitro evaluated to assess the histological effects of JF on mice with AR. The regulatory network was subjected to proteomic and metabolomic investigation. The expression of serum cytokines as well as histamine (HIS) was detected using ELISA kits. Protein expression in nasal mucosal tissues was identified through the use of a Western blot. ResultsJF demonstrated a notable reduction in nose-scratching and sneezing in AR mice. Concurrently, JF markedly reduced IgE, IL-4, IL-6, IL-13, TNF-α and HIS levels while elevating IFN-γ levels in the serum of AR mice. This was achieved by inhibiting the endoplasmic reticulum (ER) stress-related protein associated proteins including GADD and ATF4, p-eIF2α, p-IRE1α, XBP1s and p-PERK. Proteomics, metabolomics, Western blotting and Quantitative Real-time polymerase chain reaction (qPCR) results confirmed that JF inhibits the glycolysis/arginine biosynthesis pathway by suppressing the ER stress (ERs) signaling pathway, which in turn inhibits the inflammatory response. ConclusionFindings from the present study indicate that JF is an efficacious treatment for OVA/aluminum hydroxide-induced nasal mucosal injury and inflammation in mice. Furthermore, the study demonstrated that JF exhibited anti-AR clinic pharmacological effects by modulating the ERs signaling pathway and inhibiting glycolysis as well as arginine biosynthesis.

A novel VCP modulator, KUS121, attenuates atherosclerosis progression by maintaining intracellular ATP and mitigating ER stress in endothelial cells

Abstract Back ground: Endoplasmic reticulum (ER) stress signaling pathways have pivotal roles in atherosclerosis progression. Recently, we have developed Kyoto University Substance (KUS) 121, which selectively inhibits ATPase activities of valosin-containing protein (VCP) and consequently saves intracellular ATP consumption and mitigates ER stress. KUS121 are known to have protective effects on several disease models including ischemic heart disease and heart failure. However, the efficacy of KUS121 against atherosclerosis was still unclear. Purpose To elucidate the effect of KUS121 on atherosclerosis and its mechanisms. Methods and Results The daily treatment of KUS121 reduced atherosclerosis progression by approximately 40% and macrophage burden in the plaques were also significantly decreased in ApoE knockout mice on high fat diet. Interestingly, we found that C/EBP homologous protein (CHOP), an established ER stress marker, was mainly expressed in plaque endothelium. Therefore, we assessed the action of KUS 121 in endothelial cells using the EA.hy926 cell line. Consequently, it was demonstrated that KUS121 attenuated ER stress-induced apoptosis and downregulated the IRE1α-associated inflammatory pathways. Consistent with these in vitro findings, KUS121 treatment also significantly reduced endothelial apoptosis assessed by TUNEL staining and inflammation examined by immunostaining of NF-κB and ICAM1 in atherosclerotic plaques. Moreover, KUS121 treatment attenuated the recruitment of inflammatory Ly6C high monocytes assessed by bead-labeling technique, which could be due to the reduction of endothelial ICAM1 expression. Furthermore, we also demonstrated that maintenance of intracellular ATP levels mitigates ER stress and prevents pathological states in endothelial cells. Conclusion KUS121 can be a new therapeutic option for atherosclerotic diseases by maintaining intracellular ATP levels and attenuating ER stress-induced apoptosis and inflammation in plaque endothelium.

4-Phenylbutyric acid suppresses psoralen-induced hepatotoxicity by inhibiting ERS and reestablishing mitochondrial fusion-fission balance in mice

Psoralen is a main active molecule of the traditional Chinese herb medicine Fructus Psoraleae. Our previous studies have shown that psoralen induced liver injury through the endoplasmic reticulum stress (ERS) signaling pathways. In this article, we studied whether the ERS inhibitor, 4-phenylbutyrate acid (4-PBA) could inhibit the liver toxicity caused by psoralen, and explored the underlying mechanisms. Mice were given the solvent, 20 mg/kg, 40 mg/kg, 80 mg/kg of psoralen, or 80 mg/kg of psoralen plus 4-PBA for 14 days. We found that 4-PBA significantly reduced the serum LDH and liver tissue MDA level, increased the activities of SOD and CAT, reduced liver weight and coefficient, repaired histopathological damage, and inhibited hepatocytes apoptosis induced by psoralen. RNA-seq transcriptomics found that except for the endoplasmic reticulum, the mitochondria was severely affected by psoralen. And genes involved in mitochondrial fusion, apoptosis, protein folding, and autophagy were found differently expressed in the psoralen group. Further studies found that 4-PBA inhibited the overexpression of GRP78 and CHOP, increased the Bcl-2/Bax ratio, and reduced the expression of Caspase-3. Moreover, 4-PBA reduced the overexpression of mitochondrial fission protein DRP1, increased the expression of fusion proteins Mfn-2 and OPA1, but has no inhibitory effects on autophagy proteins Atg5 or LC3A/B. In conclusion, 4-PBA inhibited ERS and reestablished mitochondrial fusion-fission balance, thereby blocking cell apoptosis, oxidative stress, and mitochondrial dysfunction, thus prevented against psoralen-induced hepatotoxicity.

Endoplasmic reticulum stress is involved in mycotoxin zearalenone induced inflammatory response, proliferation, and apoptosis in goat endometrial stromal cells

Zearalenone (ZEA) is an estrogen-like mycotoxin and is considered a secondary metabolite produced by Fusarium fungi, which are widely found in the surrounding environment. ZEA has been found to cause reproductive dysfunction in female and male animals, but the underlying mechanism remains unclear. Therefore, this study examined cell proliferation, cell apoptosis, autophagy protein expression, and some inflammatory cytokines such as IL-1β and IL-8 of goat endometrial stromal cells (ESCs) induced by different concentrations (0, 15, 30, 60, and 90 µM) of ZEA. The apoptosis rate was detected by flow cytometry. Western Blot and ELISA assay were used to identify the ER stress signaling pathway and some inflammatory cytokines. Our results revealed that ZEA induced cell proliferation and inhibited cell apoptosis at low and middle concentrations, while at high concentrations of ZEA, cell apoptosis was induced in ESCs. Additionally, ZEA induced the ER stress protein markers such as ATF6, IRE1α, EIF2α, and ATF4. LC3 as a marker of autophagy was up-regulated at all concentrations of ZEA. Moreover, IL-1β and IL-8 showed down-regulation at a low concentration of ZEA, but middle and high concentrations showed up-regulation. In the present study, Knockdown ERN1 can inhibit autophagy and the main markers of ER stress. These results suggest that the IRE1 pathway can reduce apoptosis protein markers, down activate IRE1, and unfolded protein response branches such as ATF6 and LC3 in ESCs. Additionally, IL-1β and IL-8 achieve up-regulation under knockdown IRE1, which can block ER stress markers.

TROP2 promotes the proliferation of triple-negative breast cancer cells via calcium ion-dependent ER stress signaling pathway.

To explore the molecular mechanisms of tumor-associated calcium signal transduction factor 2 (TROP2) affecting the occurrence and development of triple-negative breast cancer (TNBC). The TCGA database, immunohistochemical staining, and qRT-PCR were used to analyze the expression of TROP2 in TNBC tissues and cells. The protein expressions of TROP2 and inositol 1,4,5-trisphosphate receptor (IP3R) after TROP2 knockdown were detected by western blot (WB). Cell proliferation was detected by CCK8 and colony formation assay, Annexin V-APC/PI flow cytometry was used to detect apoptosis, and intracellular calcium ion (Ca2+) was detected by flow cytometry with Fura 2-AM fluorescent probe. Finally, the morphological changes of the endoplasmic reticulum (ER) were observed by transmission electron microscopy, and the expression of ER stress (ERS)-related proteins was detected by WB and immunofluorescence staining. TROP2 was up-regulated in TNBC tumor tissues and cells. Silencing TROP2 decreased the proliferation rate and clone formation number, and increased the apoptosis rate and the Ca2+ level in TNBC cells. These phenomena were reversed after the addition of 2-APB. In addition, after TROP2 knockdown, the expressions of IP3R and ERS-related proteins were up-regulated, the ER was cystic dilated, and ERS was activated. And the addition of 2-APB significantly inhibited the activation of ERS induced by TROP2 knockdown. TROP2 regulated the proliferation and apoptosis of TNBC cells through a Ca2+-dependent ERS signaling pathway.

Perfluorooctane sulfonate causes damage to L-02 cells via Wnt/β-catenin signal path and endoplasmic reticulum stress pathway.

Perfluorooctane sulfonate (PFOS) is one of the most widely used perfluorinated compounds, and as an environmental endocrine disruptor and environmental persistent pollutant, the threat of PFOS to human health is of increasing concern. Exposure to PFOS has been shown to be closely associated with liver disease, but the intrinsic molecular targets and mechanisms of PFOS-induced liver damage are not well understood. This study was conducted to explore whether the Wnt/β-Catenin signaling pathway and the endoplasmic reticulum stress signaling pathway are involved in damage of PFOS to the liver. In this study, we used the CCK-8 method to detect cell viability, a microscope and DAPI staining to observe cell morphology, flow cytometry to detect cell ROS and apoptosis levels; and Western blot to detect the expressions of proteins in the WNT/β-Catenin, endoplasmic reticulum stress and apoptosis-related pathways. We found that PFOS activated WNT/β-Catenin and endoplasmic reticulum stress-related pathways in L-02 cells and could lead to the development of oxidative stress and apoptosis. Our findings showed that PFOS could cause damage to L-02 cells, and the WNT/β-Catenin signaling and endoplasmic reticulum stress pathways were involved in the changes caused by PFOS to L-02 cells, which provided a new theoretical basis for studying the hepatotoxicity and mechanism of PFOS. PFOS can lead to increased intracellular ROS levels, causing oxidative stress, endoplasmic reticulum stress and activation of the WNT/β-catenin signaling pathway. Our experimental results showed that PFOS can cause damage to L-02 cells, and the WNT/β-Catenin signaling pathway and endoplasmic reticulum stress pathway are involved in the process of damage caused by PFOS to L-02 cells.

Targeting Endoplasmic Reticulum Stress by Natural and Chemical Compounds Ameliorates Cisplatin-Induced Nephrotoxicity: A Review.

Cisplatin is a chemotherapeutic that dose-dependently causes renal complications such as decreased kidney function and acute kidney injury. The endoplasmic reticulum (ER) is responsible for calcium homeostasis and protein folding and plays a major part in cisplatin's nephrotoxicity. The current article reviews how chemical and natural compounds modulate cisplatin-induced apoptosis, autophagy, and inflammation by inhibiting ER stress signaling pathways. The available evidence indicates that natural compounds (Achyranthes aspera water-soluble extract, morin hydrate, fucoidan, isoliquiritigenin, leonurine, epigallocatechin-3-gallate, grape seed proanthocyanidin, and ginseng polysaccharide) and chemicals (Sal003, NSC228155, TUG891, dorsomorphin (compound C), HC-030031, dexmedetomidine, and recombinant human erythropoietin (rHuEpo)) can alleviate cisplatin nephrotoxicity by suppression of ER stress signaling pathways including IRE1α/ASK1/JNK, PERK-eIF2α-ATF4, and ATF6, as well as PI3K/AKT signaling pathway. Since ER and related signaling pathways are important in cisplatin nephrotoxicity, agents that can inhibit the abovementioned signaling pathways may hold promise in alleviating this untoward adverse effect.

Tubeimoside-I, an inhibitor of HSPD1, enhances cytotoxicity of oxaliplatin by activating ER stress and MAPK signaling pathways in colorectal cancer

Ethnopharmacological relevanceTubeimoside-I (TBM) promotes various cancer cell death by increasing the reactive oxygen species (ROS) production. However, the specific molecular mechanisms of TBM and its impact on oxaliplatin-mediated anti-CRC activity are not yet fully understood. Aim of the studyTo elucidate the therapeutic effect and underlying molecular mechanism of TBM on oxaliplatin-mediated anti-CRC activity. Materials and methods3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing assays and flow cytometry were conducted to investigate the changes in cell phenotypes and ROS generation. Real-time quantitative PCR (qRT-PCR) and western blotting were performed to detect the expressions of related mRNA and proteins. Finally, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with TBM and oxaliplatin. ResultsThe synergistic enhancement of the anti-tumor effects of oxaliplatin in colon cancer cells by TBM involved in the regulation of ROS-mediated endoplasmic reticulum (ER) stress, C-jun-amino-terminal kinase (JNK), and p38 MAPK signaling pathways. Mechanistically, TBM increased ROS generation in colon cancer cells by inhibiting heat shock protein 60 (HSPD1) expression. Knocking down HSPD1 increased TBM-induced antitumor activity and ROS generation in colon cancer cells. The mouse xenograft tumor models further validated that the combination therapy exhibited stronger anti-tumor effects than monotherapy alone. ConclusionsCombined therapy with TBM and oxaliplatin might be an effective therapeutic strategy for some CRC patients.

Pemphigus vulgaris autoantibodies induce an ER stress response.

Desmosomes are intercellular junctions that mediate cell-cell adhesion and are essential for maintaining tissue integrity. Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease caused by autoantibodies (IgG) targeting desmoglein 3 (Dsg3), a desmosomal cadherin. PV autoantibodies cause desmosome disassembly and loss of cell-cell adhesion, but the molecular signaling pathways that regulate these processes are not fully understood. Using high-resolution time-lapse imaging of live keratinocytes, we found that ER tubules make frequent and persistent contacts with internalizing Dsg3 puncta in keratinocytes treated with PV patient IgG. Biochemical experiments demonstrated that PV IgG activated ER stress signaling pathways, including both IRE1⍺ and PERK pathways, in cultured keratinocytes. Further, ER stress transcripts were upregulated in PV patient skin. Pharmacological inhibition of ER stress protected against PV IgG-induced desmosome disruption and loss of keratinocyte cell-cell adhesion, suggesting that ER stress may be an important pathomechanism and therapeutically targetable pathway for PV treatment. These data support a model in which desmosome adhesion is integrated with ER function to serve as a cell adhesion stress sensor that is activated in blistering skin disease.

TUDCA inhibits EV71 replication by regulating ER stress signaling pathway and suppressing autophagy

Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that alleviates endoplasmic reticulum (ER) stress and inhibits apoptosis, thereby protecting cells. Previous studies have shown that enterovirus 71 (EV71) infection modulates ER stress and induces autophagy to assist viral replication. This study observed the effects of TUDCA pretreatment on HeLa and Vero cells infected with EV71, finding that TUDCA inhibits EV71 replication in TUDCA pretreated HeLa and Vero cells in a dose-dependent manner. We found that TUDCA pretreatment inhibited EV71 replication by regulating three branches of UPR, that is up-regulated ATF6, down-regulated both PERK and IRE1. The results also indicated that autophagy which is downstream of UPR, was inhibited either. The results indicate that TUDCA inhibits EV71 replication by regulating UPR sensor proteins and autophagy following ER stress.

Discovery of PRMT3 Degrader for the Treatment of Acute Leukemia.

Protein arginine methyltransferase 3 (PRMT3) plays an important role in gene regulation and a variety of cellular functions, thus, being a long sought-after therapeutic target for human cancers. Although a few PRMT3 inhibitors are developed to prevent the catalytic activity of PRMT3, there is little success in removing the cellular levels of PRMT3-deposited ω-NG,NG-asymmetric dimethylarginine (ADMA) with small molecules. Moreover, the non-enzymatic functions of PRMT3 remain required to be clarified. Here, the development of a first-in-class MDM2-based PRMT3-targeted Proteolysis Targeting Chimeras (PROTACs) 11 that selectively reduced both PRMT3 protein and ADMA is reported. Importantly, 11 inhibited acute leukemia cell growth and is more effective than PRMT3 inhibitor SGC707. Mechanism study shows that 11 induced global gene expression changes, including the activation of intrinsic apoptosis and endoplasmic reticulum stress signaling pathways, and the downregulation of E2F, MYC, oxidative phosphorylation pathways. Significantly, the combination of 11 and glycolysis inhibitor 2-DG has a notable synergistic antiproliferative effect by further reducing ATP production and inducing intrinsic apoptosis, thus further highlighting the potential therapeutic value of targeted PRMT3 degradation. These data clearly demonstrated that degrader 11 is a powerful chemical tool for investigating PRMT3 protein functions.