Curcumin ameliorates HO-induced injury through SIRT1-PERK-CHOP pathway in pancreatic beta cells.

Oxidative stress and endoplasmic reticulum (ER) stress play crucial roles in pancreatic ß cell destruction, leading to the development and progression of type 1 diabetes mellitus (T1DM). Curcumin, extracted from plant turmeric, possesses multiple bioactivities such as antioxidant, anti-inflammatory and anti-apoptosis properties and . However, it remains unknown whether curcumin improves ER stress to prevent ß cells from apoptosis. In this study, we aim to investigate the role and mechanism of curcumin in ameliorating HO-induced injury in MIN6 (a mouse insulinoma cell line) cells. Cell viability is examined by CCK8 assay. Hoechst 33258 staining, TUNEL and flow cytometric assay are performed to detect cell apoptosis. The relative amounts of reactive oxygen species (ROS) are measured by DCFH-DA. WST-8 is used to determine the total superoxide dismutase (SOD) activity. Protein expressions are determined by western blot analysis and immunofluorescence staining. Pretreatment with curcumin prevents MIN6 cells from HO-induced cell apoptosis. Curcumin decreases ROS generation and inhibits protein kinase like ER kinase (PERK)-C/EBP homologous protein (CHOP) signaling axis, one of the critical branches of ER stress pathway. Moreover, incubation with curcumin activates silent information regulator 1 (SIRT1) expression and subsequently decreases the expression of CHOP. Additionally, EX527, a specific inhibitor of SIRT1, blocks the protective effect of curcumin on MIN6 cells exposed to HO. In sum, curcumin inhibits the PERK-CHOP pathway of ER stress mediated by SIRT1 and thus ameliorates HO-induced MIN6 cell apoptosis, suggesting that curcumin and SIRT1 may provide a potential therapeutic approach for T1DM.

PFKL, a novel regulatory node for NOX2-dependent oxidative burst and NETosis.

Neutrophils are predominant leukocytes in the circulation, which are essential for killing invading pathogens via the activation of effector responses and the production of reactive oxygen species (ROS), also named as "oxidative burst." When infected, activated neutrophils fight bacteria, fungi, and viruses through oxidative burst, phagocytosis, degranulation, and the production of neutrophil extracellular traps (NETs) in a neutrophil death process named as "NETosis" (Mutua and Gershwin, 2021). NETs, consisting of DNA fibers decorated with modified histones and numerous antimicrobial proteins from cytoplasmic granules and the nucleus, can either be beneficial or detrimental (Mutua and Gershwin, 2021). Several pathways can lead to this death process. In response to various stimuli, NETosis traps and clears pathogens, facilitating phagocytosis by other neutrophils and phagocytes. However, excessive NETosis often results in disease due to increasing the pro-inflammatory response and perpetuating the inflammatory condition (Hellebrekers et al., 2018; Hidalgo et al., 2019; Klopf et al., 2021). Accordingly, inhibiting aberrant NETosis may alleviate the severity of various autoimmune and inflammatory diseases.

Pyroptosis in diabetes and diabetic nephropathy.

Pyroptosis is identified as a pro-inflammatory programmed cell death, mediated by gasdermins (GSDMs) family of proteins accompanied by pro-inflammatory signals release. As essential players in innate immunity, inflammasomes are intracellular protein complexes which cleave gasdermin D (GSDMD), forming structurally stable pores in the cell membrane, subsequently inducing pyroptosis. Extensive evidence indicates that inflammasomes and pyroptosis contributes to tumors, nerve injury, inflammatory diseases and metabolic disorders. As a metabolic disorder, diabetes is characterized with hyperglycemia, insulin resistance and chronic inflammation. Meanwhile, aberrant pyroptosis exerts a key role in the occurrence and progression of diabetes and its common complication, diabetic nephropathy (DN). Furthermore, evidence has shown that DN patients and animal models exhibit increased circulating IL-1ß and inflammasome, while decreasing the expression of key components of the inflammasome mitigates kidney damage and delays progression. Current research has reported that non-coding RNAs (ncRNAs) are involved in activation of inflammasomes and play a crucial role in the control of pyroptosis in DN pathogenesis. In addition, studies have indicated that some natural plant compounds have therapeutic potential via regulation of inflammasomes and pyroptosis to prevent and potentially treat DN. This mini-review examines the molecular mechanism of inflammasome activation and pyroptosis, highlights the critical roles of ncRNA and explores potential therapeutics to regulate pyroptosis in DN.

Puerarin Inhibits the PERK-eIF2[Formula: see text]-ATF4-CHOP Pathway through Inactivating JAK2/STAT3 Signal in Pancreatic beta-Cells.

Type 1 diabetes (T1D) is an autoimmune and inflammatory disease with excessive loss of pancreatic islet [Formula: see text]-cells. Accumulating evidence indicated that endoplasmic reticulum (ER) stress played a critical role in [Formula: see text]-cells loss, leading to T1D. Therefore, promoting the survival of pancreatic [Formula: see text]cells would be beneficial for patients with T1D. Puerarin is a natural isoflavone that has been demonstrated to be able to decrease blood glucose in patients with T1D. However, it remains unknown whether puerarin improves ER stress to prevent [Formula: see text]-cells from apoptosis. Here, we sought to investigate the role of puerarin in ER stress-associated apoptosis and explore its underlying mechanism in the mouse insulinoma cell line (MIN6). Flow cytometry and cell counting kit-8 (CCK8) experiments showed that puerarin caused a significant increase in the viability of MIN6 cells injured by H2O2. Furthermore, the protein kinase R-like ER kinase (PERK) signal pathway, a critical branch of ER stress response, was found to be involved in this process. Puerarin inhibited the phosphorylation of PERK, subsequently suppressed the phosphorylation of eukaryotic initiation factor 2[Formula: see text] (eIF2[Formula: see text], then decreased the activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression, ultimately attenuating ER stress to prevent MIN6 cells from apoptosis. In addition, puerarin inhibited the activation of Janus kinase 2 (JAK2)/signal transducer and activators of transcription 3 (STAT3), which suppressed the PERK signal cascade with decreased ATF4 and CHOP levels. Taken together, our results firstly demonstrated that puerarin could prevent MIN6 cells from apoptosis at least in part by inhibiting the PERK-eIF2[Formula: see text]-ATF4-CHOP axis under ER stress conditions, which might be mediated by inactivation of the JAK2/STAT3 signal pathway. Therefore, investigating the mechanism underlying the effects of puerarin might highlight the potential roles of puerarin developing into an antidiabetic drug.