X‐box binding protein 1 (XBP1) function in diseases

Recent progress has been made in understanding the roles and mechanisms of endoplasmic reticulum (ER) stress in the development and pathogenesis of diabetic nephropathy (DN). Hyperglycemia induces ER stress and apoptosis in renal cells. The induction of ER stress can be cytoprotective or cytotoxic. Experimental treatment of animals with ER stress inhibitors alleviated renal damage. Considering these findings, the normalization of ER stress by pharmacological agents is a promising approach to prevent or arrest DN progression. The current article reviews the mechanisms, roles, and therapeutic aspects of these findings.

Section: Mechanism Of Er Stress In Dnmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Diabetic Nephrology: Regulation, Pathological Role, and Therapeutic Potential

Yuan

2021

“…In this study, we first identified the endoplasmic reticulum (ER) stress effector Xbp1 as a common TF for HO bulk-RNA-seq, HO scRNA-seq, and the integrated scRNA data (including GSE168153, GSE138515, and GSE102929 datasets under simulated HO pathological conditions) using a comprehensive network analysis combined with a modified SCENIC approach. XBP1 was found to be an important regulatory pathway for the unfolding protein response that occurred in response to ER stress and played an important role in both physiological and pathological conditions, and its activity had a significant effect on the progression and prognosis of numerous diseases [ 104 ]. In this study, 160 genes were identified as core downstream regulatory targets of XBP1, with significant interactions among them, and they mainly played important roles in the Golgi vesicle transport, ER protein processing, cellular communication, and translocation.…”

Section: Discussionmentioning

confidence: 99%

Single‐Cell Integration Analysis of Heterotopic Ossification and Fibrocartilage Developmental Lineage: Endoplasmic Reticulum Stress Effector Xbp1 Transcriptionally Regulates the Notch Signaling Pathway to Mediate Fibrocartilage Differentiation

Chen

Sun

et al. 2021

Introduction. Regeneration of fibrochondrocytes is essential for the healing of the tendon-bone interface (TBI), which is similar to the formation of neurogenic heterotopic ossification (HO). Through single-cell integrative analysis, this study explored the homogeneity of HO cells and fibrochondrocytes. Methods. This study integrated six datasets, namely, GSE94683, GSE144306, GSE168153, GSE138515, GSE102929, and GSE110993. The differentiation trajectory and key transcription factors (TFs) for HO occurrence were systematically analyzed by integrating single-cell RNA (scRNA) sequencing, bulk RNA sequencing, and assay of transposase accessible chromatin seq. The differential expression and enrichment pathways of TFs in heterotopically ossified tissues were identified. Results. HO that mimicked pathological cells was classified into HO1 and HO2 cell subsets. Results of the pseudo-temporal sequence analysis suggested that HO2 is a differentiated precursor cell of HO1. The analysis of integrated scRNA data revealed that ectopically ossified cells have similar transcriptional characteristics to cells in the fibrocartilaginous zone of tendons. The modified SCENIC method was used to identify specific transcriptional regulators associated with ectopic ossification. Xbp1 was defined as a common key transcriptional regulator of ectopically ossified tissues and the fibrocartilaginous zone of tendons. Subsequently, the CellPhoneDB database was completed for the cellular ligand-receptor analysis. With further pathway screening, this study is the first to propose that Xbp1 may upregulate the Notch signaling pathway through Jag1 transcription. Twenty-four microRNAs were screened and were found to be potentially associated with upregulation of XBP1 expression after acute ischemic stroke. Conclusion. A systematic analysis of the differentiation landscape and cellular homogeneity facilitated a molecular understanding of the phenotypic similarities between cells in the fibrocartilaginous region of tendon and HO cells. Furthermore, by identifying Xbp1 as a hub regulator and by conducting a ligand–receptor analysis, we propose a potential Xbp1/Jag1/Notch signaling pathway.

“…The luminal domain of IRE1 dissociates from GRP78 under ER stress conditions, which causes the phosphorylation and dimerization of IRE1, which activates endoribonuclease and forms mature XBP1. Mature XBP1 regulates ERAD, ER chaperones, and the protein transport and lipid synthesis processes to maintain homeostasis in the ER environment [ 160 , 161 ]. PERK is the main protein that is responsible for the attenuation of mRNA translation under ER stress conditions and prevents newly synthesized proteins from entering the ER lumen.…”

Section: Mechanisms In Anticancer Actions Of Bioactive Compoundsmentioning

confidence: 99%

The Role of Bioactive Compounds in Natural Products Extracted from Plants in Cancer Treatment and Their Mechanisms Related to Anticancer Effects

Yuan

Zhang

Bai

et al. 2022

Cancer is one of the greatest causes of death worldwide. With the development of surgery, radiotherapy, and medical agents, the outcomes of cancer patients have greatly improved. However, the underlying mechanisms of cancer are not yet fully understood. Recently, natural products have been proven to be beneficial for various conditions and have played important roles in the development of novel therapies. A substantial amount of evidence indicates that bioactive compounds could improve the outcomes of cancer patients via various pathways, such as endoplasmic reticulum stress, epigenetic modification, and modulation of oxidative stress. Here, we review the current evidence of bioactive compounds in natural products for the treatment of cancer and summarize the underlying mechanisms in this pathological process.