Pyroptosis in diabetes and diabetic nephropathy

Abstract Background Hepatic inflammation is a common initiator of liver diseases and considered as the primary driver of hepatocellular carcinoma (HCC). However, the precise mechanism of inflammation-induced HCC development and immune evasion remains elusive and requires extensive investigation. This study sought to identify the new target that is involved in inflammation-related liver tumorigenesis. Methods RNA-sequencing (RNA-seq) analysis was performed to identify the differential gene expression signature in primary human hepatocytes treated with or without inflammatory stimulus. A giant E3 ubiquitin protein ligase, HECT domain and RCC1-like domain 2 (HERC2), was identified in the analysis. Prognostic performance in the TCGA validation dataset was illustrated by Kaplan–Meier plot. The functional role of HERC2 in HCC progression was determined by knocking out and over-expressing HERC2 in various HCC cells. The precise molecular mechanism and signaling pathway networks associated with HERC2 in HCC stemness and immune evasion were determined by quantitative real-time PCR, immunofluorescence, western blot, and transcriptomic profiling analyses. To investigate the role of HERC2 in the etiology of HCC in vivo, we applied the chemical carcinogen diethylnitrosamine (DEN) to hepatocyte-specific HERC2-knockout mice. Additionally, the orthotopic transplantation mouse model of HCC was established to determine the effect of HERC2 during HCC development. Results We found that increased HERC2 expression was correlated with poor prognosis in HCC patients. HERC2 enhanced the stemness and PD-L1-mediated immune evasion of HCC cells, which is associated with the activation of signal transducer and activator of transcription 3 (STAT3) pathway during the inflammation-cancer transition. Mechanically, HERC2 coupled with the endoplasmic reticulum (ER)-resident protein tyrosine phosphatase 1B (PTP1B) and limited PTP1B translocation from ER to ER-plasma membrane junction, which ameliorated the inhibitory role of PTP1B in Janus kinase 2 (JAK2) phosphorylation. Furthermore, HERC2 knockout in hepatocytes limited hepatic PD-L1 expression and ameliorated HCC progression in DEN-induced mouse liver carcinogenesis. In contrast, HERC2 overexpression promoted tumor development and progression in the orthotopic transplantation HCC model. Conclusion Our data identified HERC2 functions as a previously unknown modulator of the JAK2/STAT3 pathway, thereby promoting inflammation-induced stemness and immune evasion in HCC. 

/pdf/herc2-promotes-inflammation-driven-cancer-stemness-and-1y7pny4n.pdf

HERC2 promotes inflammation-driven cancer stemness and immune evasion in hepatocellular carcinoma by activating STAT3 pathway

Inflammation plays a pivotal in the occurrence and development of coronary heart disease (CHD). We aim to investigate the association between the Dietary Inflammatory Index (DII) and CHD in the present study. In this cross-sectional study, adult participants from the National Health and Nutrition Examination Survey (NHANES) (1999–2018) were enrolled. The social demographic information, lifestyle factors, blood biochemical measurements, dietary information, and CHD status of all the participants were systematically collected. Multivariable logistic regression was adopted to investigate the association between the risk of CHD and the DII. Besides, restricted cubic spline (RCS) analysis was used to explore whether there was a nonlinear association of the DII and CHD. Subgroup analysis stratified by sex, age, race/ethnicity, and BMI was conducted to evaluate the association of the DII and CHD among different populations. A total of 45,306 adults from NHANES (1999–2018) were included. Compared with individuals without CHD, the DIIs of the participants with CHD were significantly elevated. A positive association was observed between the DII and CHD in multivariable logistic analysis after adjusting for age, sex, race/ethnicity, education levels, smoking, drinking, diabetes, hypertension, and body mass index (BMI). Results of RCS analysis suggested a nonlinear relationship between the DII and CHD. In addition, the increment of the DII had a greater impact on female individuals compared with male individuals. The DII is closely associated with the risk of CHD. For better prevention and treatment of CHD, more attention should be paid to controlling dietary inflammation.

/pdf/dietary-inflammatory-index-and-its-association-with-the-3ukkg4ba.pdf

Dietary Inflammatory Index and Its Association with the Prevalence of Coronary Heart Disease among 45,306 US Adults

Diabetic kidney disease (DKD) is the principal culprit behind chronic kidney disease (CKD), ultimately developing end-stage renal disease (ESRD) and necessitating costly dialysis or kidney transplantation. The limited therapeutic efficiency among individuals with DKD is a result of our finite understanding of its pathogenesis. DKD is the result of complex interactions between various factors. Oxidative stress is a fundamental factor that can establish a link between hyperglycemia and the vascular complications frequently encountered in diabetes, particularly DKD. It is crucial to recognize the essential and integral role of oxidative stress in the development of diabetic vascular complications, particularly DKD. Hyperglycemia is the primary culprit that can trigger an upsurge in the production of reactive oxygen species (ROS), ultimately sparking oxidative stress. The main endogenous sources of ROS include mitochondrial ROS production, NADPH oxidases (Nox), uncoupled endothelial nitric oxide synthase (eNOS), xanthine oxidase (XO), cytochrome P450 (CYP450), and lipoxygenase. Under persistent high glucose levels, immune cells, the complement system, advanced glycation end products (AGEs), protein kinase C (PKC), polyol pathway, and the hexosamine pathway are activated. Consequently, the oxidant–antioxidant balance within the body is disrupted, which triggers a series of reactions in various downstream pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), transforming growth factor beta/p38-mitogen-activated protein kinase (TGF-β/p38-MAPK), nuclear factor kappa B (NF-κB), adenosine monophosphate-activated protein kinase (AMPK), and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. The disease might persist even if strict glucose control is achieved, which can be attributed to epigenetic modifications. The treatment of DKD remains an unresolved issue. Therefore, reducing ROS is an intriguing therapeutic target. The clinical trials have shown that bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, blood glucose-lowering drugs, such as sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can effectively slow down the progression of DKD by reducing oxidative stress. Other antioxidants, including vitamins, lipoic acid, Nox inhibitors, epigenetic regulators, and complement inhibitors, present a promising therapeutic option for the treatment of DKD. In this review, we conduct a thorough assessment of both preclinical studies and current findings from clinical studies that focus on targeted interventions aimed at manipulating these pathways. We aim to provide a comprehensive overview of the current state of research in this area and identify key areas for future exploration. 

Oxidative Stress: A Culprit in the Progression of Diabetic Kidney Disease

Diabetic nephropathy (DN) is a renal complication of diabetic hyperglycemia. The Signal transducer and activator of transcription 3 (Stat3) is a center molecule of the chronic inflammation causing DN progression. Therefore, the study investigated the possible inhibitory effects of Rutin (Ru) and Selenium (Se), formulated as nanoparticles (SeNPs), on Stat3 pathway in streptozotocin (STZ)-induced DN in Sprague-Dawley rats. Ru (100 mg/kg/orally) and SeNPs (equivalent to 5 mg of Se/kg/orally) were given as treatment for eight weeks. An assessment of fasting blood glucose, renal function biomarkers, GSH, and MDA was carried out spectrophotometrically. ELISA assessment of renal IL-6, NF-κB, TNF-α, Jak-2, and p-Stat3 was performed. Sirt-1, Nrf-2, and HO-1 were assessed immunohistochemically. DN group receiving Ru + SeNPs showed a decrease in fasting blood glucose, serum creatinine, and urea (163.8 ± 22.8, 0.54 ± 0.1, and 53.6 ± 25.7 mg/dl, respectively), compared to the DN group (443.8 ± 42.72, 1.58 ± 0.4, and 281.8 ± 47.35 mg/dl, respectively). In addition, it exhibited elevation in the levels of Sirt-1, Nrf-2 and HO-1 compared to the DN group. Finally, Ru + SeNPs exhibited a significant reduction in IL-6, NF-κB, TNF-α, Jak-2, and p-Stat3 (42.8 ± 10.3, 1.2 ± 0.1, 53.4 ± 3.87, 0.8 ± 0.06 and 1.1 ± 0.2 U/g tissue, respectively) when compared to the DN group (155.3 ± 13.97, 2.8 ± 0.3, 105.5 ± 32.84, 2.03 ± 0.2 and 2.56 ± 0.15 U/g tissue, respectively). Therefore, combining Ru with SeNPs has a potential renoprotective effect against DN by upregulating Nrf-2/HO-1 and downregulating Jak-2/Stat3 Pathways. 

Rutin and selenium nanoparticles protected against STZ-induced diabetic nephropathy in rats through downregulating Jak-2/Stat3 pathway and upregulating Nrf-2/HO-1 pathway.

Diabetic kidney disease (DKD) is a major contributor to end-stage renal disease. Several microRNAs (miRNAs) have been found to be enriched in exosomes of DKD patients, but it remains unclear if any of these miRNAs play an important role in the pathogenesis of DKD. Exosomes from diabetic kidney disease (DKD) patients were isolated, and the expression of miR-4449 was measured by qRT-PCR. Reactive oxygen species (ROS) was determined by DCDFA assay kit, and pyroptosis was measured by quantifying the level of activated caspase 1. mRNA and protein levels were quantified by qRT-PCR and WB. In this study, we demonstrated that miR-4449 is enriched in the serum exosomes of DKD patients, and these exosomes regulate the expression of pro-inflammatory cytokines, ROS levels, and pyroptosis through miR-4449. Our study uncovered a novel mechanism for the progression of DKD that is mediated through miR-4449 in serum exosomes, which highlights an important role for exosomes in the pathogenesis of DKD.

Serum exosomes from diabetic kidney disease patients promote pyroptosis and oxidative stress through the miR-4449/HIC1 pathway

Cardamomin protects from diabetes-induced kidney damage through modulating PI3K/AKT and JAK/STAT signaling pathways in rats.

Diabetic kidney disease (DKD) has become a key cause of end-stage renal disease worldwide. Inflammation and fibrosis have been shown to play important roles in the pathogenesis of DKD. MID1, also known as TRIM18, is an E3 ubiquitin ligase of the tripartite motif (TRIM) subfamily of RING-containing proteins and increased in renal tubule in patients with DKD. However, the function and molecular mechanism of TRIM18 in DKD remain unexplored. Herein we report that TRIM18 expression levels were increased in patients with DKD. An animal study confirms that TRIM18 is involved in kidney injury and fibrosis in diabetic mice. TRIM18 knockdown inhibits high glucose (HG)-induced epithelial-mesenchymal transition (EMT), inflammation, and fibrosis of HK-2 cells. This is accompanied by decreased levels of tumor necrosis factor alpha, interleukin-6, hydroxyproline (Hyp), connective tissue growth factor, and α-smooth muscle actin. Additionally, TRIM18 knockdown inhibits HG-induced increase in the phosphorylated-/total signal transducer and activator of transcription (STAT3). Treatment with niclosamide (STAT3 inhibitor) or protein tyrosine phosphatase-1B (PTP1B) overexpression blocked the TRIM18 induced EMT, inflammation and fibrosis. Co-immunoprecipitation and Western blot assays showed that TRIM18 promoted the ubiquitination of PTP1B. These findings highlight the importance of the TRIM18/PTP1B/STAT3 signaling pathway in DKD and can help in the development of new therapeutics for DKD treatment.

/pdf/trim18-regulated-stat3-signaling-pathway-via-ptp1b-promotes-2cxyzt3v9i.pdf

TRIM18-Regulated STAT3 Signaling Pathway via PTP1B Promotes Renal Epithelial-Mesenchymal Transition, Inflammation, and Fibrosis in Diabetic Kidney Disease.

Background To detect the serum procalcitonin (PCT) levels of peritoneal dialysis (PD) patients. Methods We analyzed the relationship between the PCT Level and dialysis adequacy. We studied 120 peritoneal dialysis patients without signs of infection in Affiliated Hangzhou First People's Hospital and 120 controls from Jan 2014 to Apr 2016. PCT and high sensitivity C-reactive protein (hs-CRP) were detected. 120 PD patients were divided into two groups according to the dialysis adequacy. A correlation analysis was processed between the PCT level and the total solute clearance (Kt/V). The value of PCT for identifying the dialysis adequacy in PD patients was assessed by ROC curve analysis. Results PCT level in serum of PD group (0.29±0.24 ng/ml) was higher than that of the control group (0.02±0.01 ng/ml) (P<0.01). Compared with the inadequate dialysis group (0.5±0.37 ng/ml), the PCT Level of the adequate dialysis group (0.23±0.15 ng/ml) was lower (P<0.01). There were negative correlations between PCT and Kt/v(r=-0.451), Prealbumin (PA) (r=-0.258), Glomerular Filtration Rate (eGFR; r=-0.280), while there was positive correlation between PCT and Hypersensitive c-reactive protein (r=0.458) (P<0.01). At a serum PCT cut-off value of 0.283 ng/ml, the sensitivity and specificity for identifying the dialysis adequacy in PD patients were 0.913 and 0.805 respectively. The serum levels of PCT in peritoneal dialysis patients were significantly higher than the levels in healthy controls. Conclusion The serum level of PCT can be used as an indirect maker to evaluate the adequacy of dialysis.

The Relationship between Serum Procalcitonin and Dialysis Adequacy in Peritoneal Dialysis Patients.

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Serum exosomes from diabetic kidney disease patients promote pyroptosis and oxidative stress through the miR-4449/HIC1 pathway

Cardamomin protects from diabetes-induced kidney damage through modulating PI3K/AKT and JAK/STAT signaling pathways in rats.

TRIM18-Regulated STAT3 Signaling Pathway via PTP1B Promotes Renal Epithelial-Mesenchymal Transition, Inflammation, and Fibrosis in Diabetic Kidney Disease.

The Relationship between Serum Procalcitonin and Dialysis Adequacy in Peritoneal Dialysis Patients.