Role Of Unfolded Protein Response Research Articles

Endothelial Unfolded Protein Response-Mediated Cytoskeletal Effects.

The endothelial semipermeable monolayers ensure tissue homeostasis, are subjected to a plethora of stimuli, and their function depends on cytoskeletal integrity and remodeling. The permeability of those membranes can fluctuate to maintain organ homeostasis. In cases of severe injury, inflammation or disease, barrier hyperpermeability can cause irreparable damage of endothelium-dependent issues, and eventually death. Elucidation of the signaling regulating cytoskeletal structure and barrier integrity promotes the development of targeted pharmacotherapies towards disorders related to the impaired endothelium (e.g., acute respiratory distress syndrome, sepsis). Recent reports investigate the role of unfolded protein response in barrier function. Herein we review the cytoskeletal components, the unfolded protein response function; and their interrelations on health and disorder. Moreover, we emphasize on unfolded protein response modulators, since they ameliorate illness related to endothelial leak.

Inhibition of proteasome activity facilitates definitive endodermal specification of pluripotent stem cells by influencing YAP signalling

AimsThe knowledge of the molecular players that regulate the generation of endoderm cells is imperative to obtain homogenous population of pancreatic β-cells from stem cells. The Ubiquitin proteasome system (UPS) has been envisaged as a crucial intracellular protein degradation system, but its role in the generation of β-cells remains elusive. Hence, it would be appropriate to unravel the potential role of UPS in endoderm specification and utilize the understanding to generate β-cells from pluripotent stem cells. Materials and methodsThe pluripotent stem cells (mESCs, miPSCs and hIPSCs) were subjected to differentiation towards pancreatic β-cells and assessed the proteasomal activity during endodermal differentiation. Pharmacologic agents MG132 and IU-1 were employed to inhibit and activate proteasomal activity respectively at the definitive endoderm stage to investigate its impact on the generation of β-cells. The expression of stage-specific genes were analyzed at transcript and protein levels. We also explored the role of unfolded protein response and UPS-regulated signalling pathways in endodermal differentiation. Key findingsWe observed decreased proteasomal activity specifically during endoderm, but not during the generation of other lineages. Extraneous proteasomal inhibition enhanced the expression of endodermal genes while increasing the proteasomal activity hindered definitive endodermal differentiation. Proteasomal inhibition at the definitive endodermal stage culminated in an enriched generation of insulin-positive cells. Elevated endodermal gene expression was consistent in mESCs and hIPSCs upon proteasomal inhibition. Mechanistic insight revealed the proteasome-inhibited enhanced endodermal differentiation to be via modulating the YAP pathway. SignificanceOur study unravels the specific involvement of UPS in endoderm cell generation from pluripotent stem cells and paves the way for obtaining potential definitive endodermal cells for plausible cellular therapy in the future.

Unraveling the unfolded protein response signature: implications for tumor immune microenvironment heterogeneity and clinical prognosis in stomach cancer.

Stomach cancer is a leading cause of cancer-related deaths globally due to its high grade and poor response to treatment. Understanding the molecular network driving the rapid progression of stomach cancer is crucial for improving patient outcomes. This study aimed to investigate the role of unfolded protein response (UPR) related genes in stomach cancer and their potential as prognostic biomarkers. RNA expression data and clinical follow-up information were obtained from the TCGA and GEO databases. An unsupervised clustering algorithm was used to identify UPR genomic subtypes in stomach cancer. Functional enrichment analysis, immune landscape analysis, and chemotherapy benefit prediction were conducted for each subtype. A prognostic model based on UPR-related genes was developed and validated using LASSO-Cox regression, and a multivariate nomogram was created. Key gene expression analyses in pan-cancer and in vitro experiments were performed to further investigate the role of the identified genes in cancer progression. A total of 375 stomach cancer patients were included in this study. Analysis of 113 UPR-related genes revealed their close functional correlation and significant enrichment in protein modification, transport, and RNA degradation pathways. Unsupervised clustering identified two molecular subtypes with significant differences in prognosis and gene expression profiles. Immune landscape analysis showed that UPR may influence the composition of the tumor immune microenvironment. Chemotherapy sensitivity analysis indicated that patients in the C2 molecular subtype were more responsive to chemotherapy compared to those in the C1 molecular subtype. A prognostic signature consisting of seven UPR-related genes was constructed and validated, and an independent prognostic nomogram was developed. The gene IGFBP1, which had the highest weight coefficient in the prognostic signature, was found to promote the malignant phenotype of stomach cancer cells, suggesting its potential as a therapeutic target. The study developed a UPR-related gene classifier and risk signature for predicting survival in stomach cancer, identifying IGFBP1 as a key factor promoting the disease's malignancy and a potential therapeutic target. IGFBP1's role in enhancing cancer cell adaptation to endoplasmic reticulum stress suggests its importance in stomach cancer prognosis and treatment.

Prognostic Role of Unfolded Protein Response-Related Genes in Hepatocellular Carcinoma.

To reveal the prognostic role of unfolded protein response (UPR) -related genes in hepatocellular carcinoma (HCC). Hepatocellular carcinoma is a genetically heterogeneous tumor, and the prediction of its prognosis remains a challenge. Studies elucidating the molecular mechanisms of UPR have rapidly increased. However, the UPR molecular subtype characteristics of the related genes in HCC progression have yet to be thoroughly studied. Conducting a comprehensive assessment of the prognostic signature of genes related to the UPR in patients with HCC can advance our understanding of the cellular processes contributing to the progression of HCC and offer innovative strategies in precise therapy. Based on the gene expression profiles associated with UPR in HCC, we explored the molecular subtypes mediated by UPR-related genes and constructed a UPR-related genes signature that could precisely predict the prognosis for HCC. Using microarray data of HCC patients, differentially expressed UPR-related genes (DEGs) were discovered in malignancies and normal tissues. The HCC was classified into two molecular subtypes by the NMF algorithm based on DEGs modification of the UPR. Moreover, we developed a UPR-related model for predicting HCC patients' prognosis. The robustness of the UPR-related model was confirmed in external validation. Moreover, we analyzed immune responses in different risk groups. Analysis of immune functions revealed that Treg, Macrophages, aDCs, and MHC class-I were significantly up-regulated in high-risk HCC. At the same time, cytolytic activity and type I and II INF response were higher in a low-risk subgroup. This study identified two UPR molecular subtypes of HCC and developed a ten-gene HCC prognostic signature model (EXTL3, PPP2R5B, ZBTB17, CCT3, CCT4, CCT5, GRPEL2, HSP90AA1, PDRG1, and STC2), which can robustly forecast the progression of HCC.

Endoplasmic reticulum stress: a vital process and potential therapeutic target in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD), a chronic and progressive disease characterized by persistent respiratory symptoms and progressive airflow obstruction, has attracted extensive attention due to its high morbidity and mortality. Although the understanding of the pathogenesis of COPD has gradually increased because of increasing evidence, many questions regarding the mechanisms involved in COPD progression and its deleterious effects remain unanswered. Recent advances have shown the potential functions of endoplasmic reticulum (ER) stress in causing airway inflammation, emphasizing the vital role of unfolded protein response (UPR) pathways in the development of COPD. A comprehensive search of major databases including PubMed, Scopus, and Web of Science was conducted to retrieve original research articles and reviews related to ER stress, UPR, and COPD. The common causes of COPD, namely cigarette smoke(CS)and air pollutants, induce ERstress through the generation of reactive oxygen species (ROS). UPR promotes mucus secretion and further plays a dual role in the cell apoptosis-autophagy axis in the development of COPD. Existing drug research has indicated the potential of UPR as a therapeutic target for COPD. ER stress and UPR activation play significant roles in the etiology, pathogenesis, and treatment of COPD and discuss whether related genes can be used as biomarkers and therapeutic targets.

Role of unfolded protein response and ER-associated degradation under freezing, anoxia, and dehydration stresses in the freeze-tolerant wood frogs.

The North American amphibian, wood frogs, Rana sylvatica are the most studied anuran to comprehend vertebrate freeze tolerance. Multiple adaptations support their survival in frigid temperatures during winters, particularly their ability to produce glucose as natural cryoprotectant. Freezing and its component consequences (anoxia and dehydration) induce multiple stresses on cells. Among these is endoplasmic reticulum (ER) stress, a condition spawned by buildup of unfolded or misfolded proteins in the ER. The ER stress causes the unfolded protein response (UPR) and the ER-associated degradation (ERAD) pathway that potentially could lead to apoptosis. Immunoblotting was used to assess the responses of major proteins of the UPR and ERAD under freezing, anoxia, and dehydration stresses in the liver and skeletal muscle of the wood frogs. Targets analyzed included activating transcription factors (ATF3, ATF4, ATF6), the growth arrest and DNA damage proteins (GADD34, GADD153), and EDEM (ERAD enhancing α-mannosidase-like proteins) and XBP1 (X-box binding protein 1) proteins. UPR signaling was triggered under all three stresses (freezing, anoxia, dehydration) in liver and skeletal muscle of wood frogs with most tissue/stress responses consistent with an upregulation of the primary targets of all three UPR pathways (ATF4, ATF6, and XBP-1) to enhance the protein folding/refolding capacity under these stress conditions. Only frozen muscle showed preference for proteasomal degradation of misfolded proteins via upregulation of EDEM (ERAD). The ERAD response of liver was downregulated across three stresses suggesting preference for more refolding of misfolded/unfolded proteins. Overall, we conclude that wood frog organs activate the UPR as a means of stabilizing and repairing cellular proteins to best survive freezing exposures.

New-targeted therapy for leukemia based on Endoplasmic Reticulum Stress

The unfolded protein response (UPR) is an evolutionarily conserved adaptive pathway, which is activated by the stress of the endoplasmic reticulum (ER). ER stress often occurs due to the high protein demand in cells and protein folding errors in several diseases, such as different cancers and autoimmune diseases. UPR is mediated by three primary arms called inositol-requiring enzyme-1α (IRE1α), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6α (ATF6α). Given that homeostasis in protein synthesis is frequently deregulated in cancers, UPR plays a critical role in controlling survival and cell death. In addition,, resistance to apoptosis is mediated by the pro-survival mechanism of ER stress in cancer cells. Recent evidence highlighted the deregulation of UPR signaling in hematopoietic stem cells (HSCs) and leukemic cells, so that targeting UPR-driven pro-survival pathways may present new therapeutic benefits in leukemia. In this review article, we aim to provide an updated knowledge on the role of UPR as a novel therapeutic target in leukemia. We first define the different types of leukemia and their challenges with current treatments, and then explore the contribution of UPR to leukemia pathogenesis and treatment. Finally, UPR targeting strategies in pre-clinical and clinical trials of patients with leukemia will be presented.

Combination of Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos improves cardiac function of diabetic cardiomyopathy mice by regulating the unfolded protein response signaling pathway.

Diabetic cardiomyopathy (DCM) is a unique clinical entity elicited by diabetes independent of other cardiovascular risk factors, of which the pathological mechanisms and treatment strategies remain largely undefined. This study aimed to clarify the role of unfolded protein response (UPR) signaling pathway in the pathogenesis of DCM, and to explore the effect of aqueous extract of Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos (DH) on DCM mice. Cardiac function of DCM mice was evaluated by echocardiography, and lipid profile of left ventricular was analyzed by untargeted lipidomics. The results showed that DH significantly improved the diabetic symptoms, cardiac dyslipidemia, and systolic dysfunction of DCM mice. UPR signaling pathway was significantly down-regulated in the left ventricular of DCM mice. DH significantly up-regulated the transcriptions of key transducers in UPR signaling pathway. Conditional knockout of Xbp1 in cardiomyocyte (a key regulator in UPR signaling pathway) eliminated the protective effect of DH on cardiac systolic function of DCM mice, which suggested that UPR signaling pathway, especially the Xbp1, was required for DH protection against DCM. In conclusion, DH improved cardiac function of DCM mice, and this effect was dependent on its regulation of UPR signaling pathway.

MEDB-09. Unraveling the role of unfolded protein response in medulloblastoma cancer stem cells

Medulloblastoma (MB) is the most common malignant childhood brain tumor. The current clinical approach consists of multimodal strategies with debilitating long-term effects and risk of tumor recurrence. Medulloblastoma stem cells (MBSCs) are a fraction of tumor cells with high proliferation potential and the capability to adapt to adverse/restrictive conditions in tumor milieu thus driving the refractoriness to conventional therapies. Recently, high basal levels of Unfolded Protein Response (UPR) molecules have been found in tumors of different tissue-origin and are correlated with poor prognosis and low patient survival. However, little is known about the role of UPR in MB. We investigated the expression and activation of UPR players in MBSCs. Human group 3 MB (G3MB) cell lines, specifically CHLA-01, D283- and D341-Med, were grown in Vitamin A and/or FBS or in stem selective medium (B27™) for 72 h before collection. Cells were fixed, stained with proper primary antibodies and images were acquired by confocal microscopy. The analysis of the transcription factors ATF-4 and CHOP revealed their elevated nuclear expression and co-localization, which resulted to be more marked in G3MB stem-like cells than in the differentiated ones. Also the ATF-6 branch was investigated, in differentiating conditions D283 and D341-Med showed a greater activation of ATF-6, represented by its nuclear localization, in respect to stem cells, while CHLA-01 did not show differences. Conversely XBP1, the transcription factor downstream IRE1 signaling, was not expressed in the three cell lines. Lastly, a Kaplan-Meier analysis on MB patients showed a worse prognosis with a shorter survival rate of patients expressing high ATF4 transcript levels. Our results reveal, even in resting conditions, preferential activation of the PERK branch in G3MB cells grown in stem-like condition suggesting that ATF-4 might be a promising therapeutic and prognostic factor to specifically target the stem compartment in aggressive MB.

Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology.

X-box binding protein 1 (XBP1) is a member of the CREB/ATF basic region leucine zipper family transcribed as the unspliced isoform (XBP1-u), which, upon exposure to endoplasmic reticulum stress, is spliced into its spliced isoform (XBP1-s). XBP1-s interacts with the cAMP response element of major histocompatibility complex class II gene and plays critical role in unfolded protein response (UPR) by regulating the transcriptional activity of genes involved in UPR. XBP1-s is also involved in other physiological pathways, including lipid metabolism, insulin metabolism, and differentiation of immune cells. Its aberrant expression is closely related to inflammation, neurodegenerative disease, viral infection, and is crucial for promoting tumor progression and drug resistance. Meanwhile, recent studies reported that the function of XBP1-u has been underestimated, as it is not merely a precursor of XBP1-s. Instead, XBP-1u is a critical factor involved in various biological pathways including autophagy and tumorigenesis through post-translational regulation. Herein, we summarize recent research on the biological functions of both XBP1-u and XBP1-s, as well as their relation to diseases.

The role of unfolded protein responses in hematopoiesis

Protein production is tightly regulated in cells because the accumulation of un-/misfolded proteins triggers cellular responses, particularly in the endoplasmic reticulum (ER). Recently, several studies have reported the implications of unfolded protein response (UPR) and ER stress in hematopoiesis, particularly in hematopoietic stem cells (HSCs). The majority of HSCs are maintained in a dormant state under physiological conditions in the adult body, and their protein synthesis rate is also maintained at a low level. Once HSC proliferation is activated, the protein synthesis rate is elevated, and therefore, newly synthesized peptides have to be efficiently folded to prevent the induction of UPR. Importantly, UPR can expand the ER capacity that enables increased protein production and eliminates cells accumulating abnormal proteins; thus, blocking the UPR signal could rather be hazardous for the cells. Thus, understanding how protein quality control is properly controlled and developing methods to manipulate the regulatory mechanisms are imperative to maximize the potential role of HSC.

Unfolded protein response activated by endoplasmic reticulum stress in pancreatic cancer: potential therapeutical target.

Pancreatic cancer is still one of the most perilous malignant tumors with a very poor prognosis. Despite the progress in the diagnosis and treatment of pancreatic cancer, the overall 5-year survival rate after diagnosis is less than 10%. The pathogenesis of pancreatic cancer has not been fully clarified, but multiple factors are involved. The poor efficacy of traditional therapies for pancreatic cancer is mainly related to complex tumor microenvironment. In recent years, accumulating studies have demonstrated the role of autophagy and apoptosis triggered by endoplasmic reticulum stress in pancreatic cancer. In particular, unfolded protein response is activated by endoplasmic reticulum stress and plays an important role in the modulation of complex pancreatic tumor microenvironment. Here we summarize recent progress in our understanding of the role of unfolded protein response activated by endoplasmic reticulum stress in tumorigenesis of pancreatic cancer, and highlight the potential of the cascade of unfolded protein response as therapeutic target for pancreatic cancer.

Abstract 2029: The ER stress protein IRE1a regulates intracellular calcium, ROS, and the UV damage response through the IP3R inhibitor CIB1

Abstract UV induced DNA damage is the primary driver of human skin cancer. UV can also cause endoplasmic reticulum (ER) stress, but the role of unfolded protein response (UPR) in the cellular response to UV exposure is not clear. Inositol-requiring enzyme 1α (IRE1α) is one of the key regulators of the UPR but its function in the UV response has not been resolved. Here we show that IRE1α, is transiently dephosphorylated and its RNase activity downregulated by UVB resulting in reduced XBP1 splicing. Keratinocytes with either IRE1α knockout or knockdown have elevated cytosolic calcium and ROS resulting in increased apoptosis after UV. Pharmacological inhibition of the ER inositol triphosphate receptor (IP3R) or phospholipase C (PLC) restored normal cytosolic calcium and ROS levels to cells lacking IRE1α. While loss of IRE1α did not alter the frequency of cells with UV-induced cyclo-pyrimidine dimers (CPD), it significantly reduced the percent of γH2AX positive keratinocytes 6 hours after UVB irradiation. This percent of CPD positive cells and the level of γH2AX 6 hours after UV suggesting a defect in the DNA repair response. Pharmacological inhibition of IRE1α RNase or Xbp1 knockdown did not phenocopy IRE1α loss, but overexpression of IRE1α in IRE1α knockdown cells restored γH2AX expression and reduced keratinocyte apoptosis. IRE1α overexpression also enhanced the survival of keratinocytes deficient in p53 function after UV irradiation. Additionally, mice with an epidermal deletion of IRE1α showed more rapid loss of UV-induced CPD positive keratinocytes compared to wildtype mice, primarily through accelerated sloughing of UV damaged cells from the skin. Knockdown of Calcium and integrin binding protein 1 (CIB1), which binds and inhibits the IP3R, elevated cytosolic calcium in keratinocytes and suppressed UV-induced γH2AX. Knockdown of Apoptosis signal-regulating kinase 1 (ASK1), which can interact with IRE1α through TRAF2 as well as CIB1, restored normal levels of UV-induced γH2AX to IRE1α knockdown keratinocytes. Together these results show that IRE1α is essential for maintaining normal cellular calcium and ROS levels and the UV-induced repair response, and suggest a model where IRE1a activation state drives CIB1 binding either to the IP3R or ASK1 to regulate ER calcium efflux, ROS and DNA repair responses following UV. Citation Format: Jeongin Son, Saie Mogre, Adam Glick. The ER stress protein IRE1a regulates intracellular calcium, ROS, and the UV damage response through the IP3R inhibitor CIB1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2029.

The Unfolded Protein Response and Autophagy on the Crossroads of Coronaviruses Infections.

The ability to sense and adequately respond to variable environmental conditions is central for cellular and organismal homeostasis. Eukaryotic cells are equipped with highly conserved stress-response mechanisms that support cellular function when homeostasis is compromised, promoting survival. Two such mechanisms – the unfolded protein response (UPR) and autophagy – are involved in the cellular response to perturbations in the endoplasmic reticulum, in calcium homeostasis, in cellular energy or redox status. Each of them operates through conserved signaling pathways to promote cellular adaptations that include re-programming transcription of genes and translation of new proteins and degradation of cellular components. In addition to their specific functions, it is becoming increasingly clear that these pathways intersect in many ways in different contexts of cellular stress. Viral infections are a major cause of cellular stress as many cellular functions are coopted to support viral replication. Both UPR and autophagy are induced upon infection with many different viruses with varying outcomes – in some instances controlling infection while in others supporting viral replication and infection. The role of UPR and autophagy in response to coronavirus infection has been a matter of debate in the last decade. It has been suggested that CoV exploit components of autophagy machinery and UPR to generate double-membrane vesicles where it establishes its replicative niche and to control the balance between cell death and survival during infection. Even though the molecular mechanisms are not fully elucidated, it is clear that UPR and autophagy are intimately associated during CoV infections. The current SARS-CoV-2 pandemic has brought renewed interest to this topic as several drugs known to modulate autophagy – including chloroquine, niclosamide, valinomycin, and spermine – were proposed as therapeutic options. Their efficacy is still debatable, highlighting the need to better understand the molecular interactions between CoV, UPR and autophagy.

At the Crossroads of Survival and Death: The Reactive Oxygen Species-Ethylene-Sugar Triad and the Unfolded Protein Response.

Upon stress, a trade-off between plant growth and defense responses defines the capacity for survival. Stress can result in accumulation of misfolded proteins in the endoplasmic reticulum (ER) and other organelles. To cope with these proteotoxic effects, plants rely on the unfolded protein response (UPR). The involvement of reactive oxygen species (ROS), ethylene (ETH), and sugars, as well as their crosstalk, in general stress responses is well established, yet their role in UPR deserves further scrutiny. Here, a synopsis of current evidence for ROS-ETH-sugar crosstalk in UPR is discussed. We propose that this triad acts as a major signaling hub at the crossroads of survival and death, integrating information from ER, chloroplasts, and mitochondria, thereby facilitating a coordinated stress response.

Effect of unfolded protein response on the immune infiltration and prognosis of transitional cell bladder cancer

Background: Bladder cancer (BC) is one of the most common human malignancies worldwide. Previous researches have shown that the unfolded protein response (UPR) pathway could contribute to the tumorigenesis of BC. However, the role of UPR in the immune infiltration, progression, and prognosis of BC is unclear. Methods: The GSVA and ssGSEA methods were used for assessing the UPR score and immune cells infiltration score in three BC public datasets, respectively. The relationship between the UPR pathway and clinicopathological characteristics was analyzed by the Kruskal-Wallis, Wilcox test, and log-rank test. The association of the UPR pathway with various tumor-infiltrating immune cells was evaluated with the correlation analysis. Univariate Cox regression analysis was performed to identify risk factors significantly associated with prognosis. The predictive models were built based on risk factors and visualized with nomograms. The performance of our models was evaluated with the calibration curve, Harrell's concordance index (c-index), and receiver operating characteristic (ROC) analysis. Results: We found that the UPR pathway and many UPR-related genes were significantly associated with the pathologic grade, tumor type, and invasive progression of transitional cell bladder cancer (TCBC), and a high UPR score predicted a poor prognosis in patients. The UPR score was positively correlated with the infiltration abundance of many tumor immune cells in TCBC. Besides, we constructed predictive models based on the UPR score, and good performance was observed, with c-indexes ranging from 0.74 to 0.87. Conclusions: Our study proved that the UPR pathway may have an important impact on the progression, prognosis, and tumor immune infiltration in TCBC, and the models we built may provide effective and reliable guides for prognosis assessment and treatment decision-making for TCBC patients.

The role of unfolded protein response in the pathogenesis of endometriosis: contribution of peritoneal fluid

Research questionEndoplasmic reticulum stress (ERS) is caused by the accumulation of the misfolded or unfolded proteins in the endoplasmic reticulum and induces the unfolded protein response (UPR). Peritoneal fluid is important in the pathogenesis of endometriosis. In this study, the role of UPR associated with ERS in endometriosis, and peritoneal fluid, were investigated. DesignNormal, eutopic and ectopic endometrium tissues were divided into menstrual cycle phases, and endometrial stromal cells (ESC) were treated with 10–20% concentration of control peritoneal fluid and peritoneal fluid obtained from women with endometriosis for 10, 30 and 60 min, and 24 and 48 h. The UPR signalling proteins were analysed immunohistochemically and immunocytochemically. Data were compared statistically. Resultsp-IRE1 was increased in ectopic glandular and stromal cells in the early proliferative phase compared with normal and eutopic endometrium. p-PERK increased in ectopic glandular and stromal cells in the late proliferative phase compared with normal endometrium. ATF6 was increased in ectopic glandular epithelium compared with normal endometrium in the proliferative phases, versus eutopic endometrium in the late secretory phase. p-IRE1 and p-PERK were increased in high concentrations of ESC treated with peritoneal fluid obtained from women with endometriosis for 10, 30 and 60 min compared with controls. In ESC treated with peritoneal fluid from women with endometriosis, p-IRE1 decreased at 24–48 h compared with 30 min. ConclusionsIn endometriosis, UPR pathways are activated as highly dependent on cell type and phase. Also, p-PERK and p-IRE1 increased because of exposure to high-dose peritoneal fluid from women with endometriosis in stromal cells. Our findings provide a basis for further studies searching for a potential biomarker for the diagnosis of endometriosis.

Unfolded Protein Response in Lung Health and Disease.

The unfolded protein response (UPR) is a complex element, destined to protect the cells against a diverse variety of extracellular and intracellular challenges. UPR activation devises highly efficient responses to counteract cellular threats. If those activities fail, it will dictate cellular execution. The current work focuses on the role of UPR in pulmonary function, by immersing into the highly interrelated network that operates toward the endothelial barrier function. A highly sophisticated UPR manipulation shall reveal new therapeutic possibilities against inflammatory lung disease, such as acute lung injury and acute respiratory distress syndrome.

Role of unfolded protein response in genital malformation/damage of male mice induced by flutamide.

The unfolded protein response (UPR) is one of a switch of autophagy and apoptosis, and the endoplasmic reticulum stress (ERS) which inducing UPR plays a role in the malformations caused by some genetic and environmental factors. Exposure to flutamide during pregnancy will also cause abnormalities in some male offspring reproductive organs such as cryptorchidism. In this study, after administered the pregnant mouse orally at a dose of 300 mg/kg body weight every day during gestational day (GD)12 to GD18, flutamide can not only caused hypospadias in the male mouse offspring but also damaged the morphology and function of their testis. And the expression of UPR-related genes and proteins, autophagy, apoptosis, and angiogenesis-related genes of the damaged/teratogenic testis and penis in the mice were investigated to determine the role of UPR in this model. It was found that flutamide activated maybe the Atg7-Atg3-Lc3 pathway through the UPR pathway, caused cells excessive autophagy and apoptosis, and inhibited the formation of penile and testicular blood vessels by activating UPR and affecting the messenger RNA level of vascular endothelial growth factor and hypoxia-inducible factor 1.

Metformin attenuates the D‑galactose‑induced aging process via the UPR through the AMPK/ERK1/2 signaling pathways.

Age-related hearing loss, also termed central presbycusis, is a progressive neurodegenerative disease; it is a devastating disorder that severely affects the quality of life of elderly individuals. Substantial evidence has indicated that oxidative stress and associated protein folding dysfunction have a marked influence on neurodegenerative diseases. In this study, we aimed to cells to investigate whether metformin protects against age-related pathologies and to elucidate the underlying mechanisms; specifically, we focused on the role of unfolded protein response (UPR) via the AMPK/ERK1/2 signaling pathways. For this purpose, the biguanide compound, metformin, a medication widely used in the treatment of type 2 diabetes, was administered to rats in a model of mimetic aging. In addition, senescent PC12 were treated with metformin. Although it has been well established that UPR signaling is activated in response to cellular stress and is associated with the pathogenesis of neuronal deterioration, the detailed functions of the UPR in the auditory cortex remain unclear. We found that metformin treatment markedly affected the UPR and the AMPK/ERK1/2 signaling pathway, and maintained the auditory brainstem response (ABR) threshold during the aging process. The results indicated that the regulation of the UPR and AMPK/ERK1/2 signaling pathway by metformin significantly attenuated hearing loss, cell apoptosis and age-related neurodegeneration. Reversing these harmful effects through the use of metformin suggests its involvement in restoring the antioxidant status and protein homeostasis related to the underlying pathology of presbycusis. The findings of this study may provide a better approach for the treatment of age-related neurodegeneration diseases.