Radish red attenuates chronic kidney disease in obese mice through repressing oxidative stress and ferroptosis via Nrf2 signaling improvement.

Chronic kidney disease (CKD) presents a significant public health concern, with obesity being a prominent contributing factor to kidney disorders by inducing oxidative stress, lipotoxicity, and tubular cell injury. Natural anthocyanins extracted from red radishes (Raphanus sativus L.) exert antioxidant and anti-apoptotic functions.

Targeting PYK2 with heterobifunctional T6BP helps mitigate MASLD and MASH-HCC progression.

Background & Aims: The mechanisms underlying the regulation of hepatocyte non-receptor tyrosine kinases in metabolic dysfunction-associated steatohepatitis (MASH) remain largely unclear.

Methods: Hepatocyte-specific overexpression or deletion and anti-protein tyrosine kinase 2 beta (PYK2) or anti-TRAF6-binding protein (T6BP) crosslinking were utilized to study fatty liver protection by T6BP. A P-PTC (peptide-proteolysis targeting chimera) degrades PYK2 to block MASH progression.

Exploring shared molecular signatures and regulatory mechanisms in nonalcoholic steatohepatitis and inflammatory bowel disease using integrative bioinformatics analysis.

The co-existence of inflammatory bowel disease (IBD) and non-alcoholic steatohepatitis (NASH) has raised interest in identifying shared molecular mechanisms and potential therapeutic targets. However, the relationship between these two diseases remains unclear and effective medical treatments are still lacking. Through the bioinformatics analysis in this study, 116 shared differentially expressed genes (SDEGs) were identified between IBD and NASH datasets.

Tripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation.

Currently potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-related pathopoiesis have failed to achieve expected therapeutic efficacy due to the complexity of the pathogenic mechanisms. Here we show Tripartite motif containing 26 (TRIM26) as a critical endogenous suppressor of CCAAT/enhancer binding protein delta (C/EBPδ), and we also confirm that TRIM26 is an C/EBPδ-interacting partner protein that catalyses the ubiquitination degradation of C/EBPδ in hepatocytes. Hepatocyte-specific loss of Trim26 disrupts liver metabolic homeostasis, followed by glucose metabolic disorder, lipid accumulation, increased hepatic inflammation, and fibrosis, and dramatically facilitates NASH-related phenotype progression.

Palmitoyltransferase ZDHHC3 Aggravates Nonalcoholic Steatohepatitis by Targeting S-Palmitoylated IRHOM2.

Underestimation of the complexity of pathogenesis in nonalcoholic steatohepatitis (NASH) significantly encumbers development of new drugs and targeted therapy strategies. Inactive rhomboid protein 2 (IRHOM2) has a multifunctional role in regulating inflammation, cell survival, and immunoreaction. Although cytokines and chemokines promote IRHOM2 trafficking or cooperate with partner factors by phosphorylation or ubiquitin ligases-mediated ubiquitination to perform physiological process, it remains unknown whether other regulators induce IRHOM2 activation via different mechanisms in NASH progression.

The deubiquitinating enzyme 13 retards non-alcoholic steatohepatitis blocking inactive rhomboid protein 2-dependent pathway.

Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are underestimated. Inactive rhomboid protein 2 (IRHOM2), a promising target for treatment of inflammation-related diseases, contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanism underlying Irhom2 regulation is still not completely understood.

Cynapanoside A exerts protective effects against obesity-induced diabetic nephropathy through ameliorating TRIM31-mediated inflammation, lipid synthesis and fibrosis.

Obesity is a major predictive factor for the diabetic nephropathy (DN). However, the precise mechanism and therapeutic approach still require to be investigated. Cynapanosides A (CPS-A) is a glycoside derived from the Chinese drug Cynanchum paniculatum that has numerous pharmacological activities, but its regulatory function on obesity-induced kidney disease is still obscure.

Hepatocyte phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK.

Nonalcoholic steatohepatitis (NASH), a common clinical disease, is becoming a leading cause of hepatocellular carcinoma (HCC). Dual specificity phosphatase 22 (DUSP22, also known as JKAP or JSP-1) expressed in numerous tissues plays essential biological functions in immune responses and tumor growth. However, the effects of DUSP22 on NASH still remain unknown.

Tripartite motif-containing protein 31 confers protection against nonalcoholic steatohepatitis by deactivating mitogen-activated protein kinase kinase kinase 7.

Background Aims: As a global health threat, NASH has been confirmed to be a chronic progressive liver disease that is strongly associated with obesity. However, no approved drugs or efficient therapeutic strategies are valid, mainly because its complicated pathological processes is underestimated.

Approach Results: We identified the RING-type E3 ubiquitin transferase-tripartite motif-containing protein 31 (TRIM31), a member of the E3 ubiquitin ligases family, as an efficient endogenous inhibitor of transforming growth factor-beta-activated kinase 1 (mitogen-activated protein kinase kinase kinase 7; MAP3K7), and we further confirmed that TRIM31 is an MAP3K7-interacting protein and promotes MAP3K7 degradation by enhancing ubiquitination of K48 linkage in hepatocytes.

Mulberrin confers protection against hepatic fibrosis by Trim31/Nrf2 signaling.

Mulberrin (Mul) is a key component of the traditional Chinese medicine Romulus Mori with various biological functions. However, the effects of Mul on liver fibrosis have not been addressed, and thus were investigated in our present study, as well as the underlying mechanisms. Here, we found that Mul administration significantly ameliorated carbon tetrachloride (CCl)-induced liver injury and dysfunction in mice.

The E3 ubiquitin-protein ligase Trim31 alleviates non-alcoholic fatty liver disease by targeting Rhbdf2 in mouse hepatocytes.

Systemic metabolic syndrome significantly increases the risk of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). However, no effective therapeutic strategies are available, practically because our understanding of its complicated pathogenesis is poor. Here we identify the tripartite motif-containing protein 31 (Trim31) as an endogenous inhibitor of rhomboid 5 homolog 2 (Rhbdf2), and we further determine that Trim31 directly binds to Rhbdf2 and facilitates its proteasomal degradation.

Carminic acid mitigates fructose-triggered hepatic steatosis by inhibition of oxidative stress and inflammatory reaction.

Excessive fructose (Fru) consumption has been reported to favor nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanism is still elusive, lacking effective therapeutic strategies. Carminic acid (CA), a glucosylated anthraquinone found in scale insects like Dactylopius coccus, exerts anti-tumor and anti-oxidant activities.

Carminic acid supplementation protects against fructose-induced kidney injury mainly through suppressing inflammation and oxidative stress via improving Nrf-2 signaling.

Excessive fructose (Fru) intake has become an increased risk for chronic kidney disease progression. Despite extensive researches that have been performed to develop effective treatments against Fru-induced renal injury, the outcome has achieved limited success. In this study, we attempted to explore whether carminic acid (CA) could influence the progression of Fru-induced kidney injury, and the underlying molecular mechanism.

Juglanin protects against high fat diet-induced renal injury by suppressing inflammation and dyslipidemia via regulating NF-κB/HDAC3 signaling.

Obesity is an important factor implicated in chronic kidney disease (CKD). Juglanin (Jug) is a natural compound extracted from the crude Polygonumaviculare, showing anti-inflammatory and anti-diabetic effects. However, whether Jug has protective effects against obesity-induced renal injury, little has been investigated.

Fisetin protects against high fat diet-induced nephropathy by inhibiting inflammation and oxidative stress via the blockage of iRhom2/NF-κB signaling.

Promoted inflammation enhances the development of nephropathy in obesity. Fisetin (3,3',4',7-tetrahydroxyflavone, FIS) is a naturally occurring dietary flavonoid, and exhibits anti-inflammatory and anti-oxidative properties. Inactive rhomboid protein 2 (iRhom2), an inactive member of the rhomboid intramembrane proteinase family, is an essential inflammation-associated regulator.

Nrf2 mitigates prolonged PM2.5 exposure-triggered liver inflammation by positively regulating SIKE activity: Protection by Juglanin.

Air pollution containing particulate matter (PM) less than 2.5 μm (PM) plays an essential role in regulating hepatic disease. However, its molecular mechanism is not yet clear, lacking effective therapeutic strategies.

Deacetylation of HSD17B10 by SIRT3 regulates cell growth and cell resistance under oxidative and starvation stresses.

17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) plays an important role in mitochondrial fatty acid metabolism and is also involved in mitochondrial tRNA maturation. HSD17B10 missense mutations cause HSD10 mitochondrial disease (HSD10MD). HSD17B10 with mutations identified from cases of HSD10MD show loss of function in dehydrogenase activity and mitochondrial tRNA maturation, resulting in mitochondrial dysfunction.

iRhom2 Promotes Hepatic Steatosis by Activating MAP3K7-Dependent Pathway.

Background And Aims: Nonalcoholic fatty liver disease (NAFLD) has been widely recognized as a precursor to metabolic complications. Elevated inflammation levels are predictive of NAFLD-associated metabolic disorder. Inactive rhomboid-like protein 2 (iRhom2) is regarded as a key regulator in inflammation.

Nrf2 deficiency aggravates PM-induced cardiomyopathy by enhancing oxidative stress, fibrosis and inflammation via RIPK3-regulated mitochondrial disorder.

PM is a well-known air pollutant threatening public health, and long-term exposure to PM increases the risk of cardiovascular diseases. Nrf2 plays a pivotal role in the amelioration of PM-induced lung injury. However, if Nrf2 is involved in PM-induced heart injury, and the underlying molecular mechanisms have not been explored.

Functional loss of inactive rhomboid-like protein 2 mitigates obesity by suppressing pro-inflammatory macrophage activation-triggered adipose inflammation.

Objective: Chronic inflammation of adipose tissues contributes to obesity-triggered insulin resistance. Unfortunately, the potential molecular mechanisms regarding obesity-associated systemic inflammation and metabolic disorder remain complicated. Here, we report that inactive rhomboid-like protein 2 (iRhom2) was increased in overweight mice with adipose inflammation.

Effects of XIAP on high fat diet-induced hepatic steatosis: a mechanism involving NLRP3 inflammasome and oxidative stress.

Increasing evidence indicates that prolonged fat-rich diet (HFD) ingestion is a predisposing factor for metabolic disorder-associated system inflammation and oxidative stress injury, which contributes to the occurrence of non-alcoholic fatty liver disease (NAFLD). NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-mediated inflammatory infiltration was determined to participate in NAFLD. X-linked inhibitor of apoptosis protein (XIAP) was recently confirmed as an essential regulator for apoptosis in cells.