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. However, the precise mechanisms by which iRhom2-regulated inflammation promotes NAFLD progression remain to be elucidated. APPROACH AND RESULTS: Here, we report that insulin resistance, hepatic steatosis, and specific macrophage inflammatory activation are significantly alleviated in iRhom2-deficient (knockout [KO]) mice, but aggravated in iRhom2 overexpressing mice. We further show that, mechanistically, in response to a high-fat diet (HFD), iRhom2 KO mice and mice with iRhom2 deficiency in myeloid cells only showed less severe hepatic steatosis and insulin resistance than controls. Inversely, transplantation of bone marrow cells from healthy mice to iRhom2 KO mice expedited the severity of insulin resistance and hepatic dyslipidemia. Of note, in response to HFD, hepatic iRhom2 binds to mitogen-activated protein kinase kinase kinase 7 (MAP3K7) to facilitate MAP3K7 phosphorylation and nuclear factor kappa B cascade activation, thereby promoting the activation of c-Jun N-terminal kinase/insulin receptor substrate 1 signaling, but disturbing AKT/glycogen synthase kinase 3ß-associated insulin signaling. The iRhom2/MAP3K7 axis is essential for iRhom2-regulated liver steatosis. CONCLUSIONS: iRhom2 may represent a therapeutic target for the treatment of HFD-induced hepatic steatosis and insulin resistance.

The differences of gonadal hormones and uterine transcriptome during shell calcification of hens laying hard or weak-shelled eggs.

BACKGROUND: Eggshell breaking strength is critical to reduce egg breaking rate and avoid economic loss. The process of eggshell calcification initiates with the egg entering the uterus and lasts about 18 h. It follows a temporal sequence corresponding to the initiation, growth and termination periods of shell calcification. During each period of shell calcification, our study investigated the differences of gonadal hormones and uterine transcriptome in laying hens producing a high or low breaking strength shell. RESULTS: 60 Hy-line Brown laying hens were selected and divided into two groups according to eggshell breaking strength. Eggshell breaking strength of 44.57 ± 0.91 N and 26.68 ± 0.38 N were considered to be the high strength group (HS) and low strength group (LS), respectively. The results showed that mammillary thickness and mammillary knob width of eggshells were significantly lower in the HS. Serum progesterone (P4) and 1,25-dihydroxy vitamin D3 [1,25-(OH)2D3] were significantly higher in the HS compared to the LS during the initiation period of calcification. Serum estradiol (E2) and calcium did not change significantly. All factors mentioned above had no significant differences in the growth and termination periods of calcification. The relative expression of CaBP-D28k and PMCA 1b were not significantly different between HS and LS. The relative expression of NCX1 was significantly higher in HS compared to LS. Moreover, 1777 differentially expressed genes (DEGs) were obtained in the initiation period of calcification. However, few DEGs were identified in the growth or termination periods of calcification. 30 DEGs were selected as candidate genes involved in eggshell calcification during the initiation period of calcification by the analysis of GO terms and KEGG pathways. CONCLUSIONS: Our study concluded that mammillary thickness and mammillary knob width of the HS were significantly lower than LS. P4 and 1,25-(OH)2D3 were significantly higher in the initiation period of HS. They may impact initial calcification when the mammillary layer is formed. The initiation period of calcification determined eggshell strength rather than the growth or termination periods. We inferred P4 or 1,25-(OH)2D3 may effect the ultrastructure of the mammillary layer by regulating the expression of uterine genes.

Multifunctional pH-responsive hydrogel dressings based on carboxymethyl chitosan: Synthesis, characterization fostering the wound healing.

Antibiotic abuse is increasing the present rate of drug-resistant bacterial wound infections, producing a significant healthcare burden globally. Herein, we prepared a pH-responsive CMCS/PVP/TA (CPT) multifunctional hydrogel dressing by embedding the natural plant extract TA as a nonantibiotic and cross-linking agent in carboxymethyl chitosan (CMCS) and polyvinylpyrrolidone (PVP) to prompt wound healing. The CPT hydrogel demonstrated excellent self-healing, self-adaptive, and adhesion properties to match different wound requirements. Importantly, this hydrogel showed pH sensitivity and exhibited good activity against resistant bacteria and antioxidant activity by releasing TA in case of bacterial infection (alkaline). Furthermore, the CPT hydrogel exhibited coagulant ability and could rapidly stop bleeding within 30 s. The biocompatible hydrogel effectively accelerated wound healing in a full-thickness skin defect model by thickening granulation tissue, increasing collagen deposition, vascular proliferation, and M2-type macrophage polarization. In conclusion, this study demonstrates that multifunctional CPT hydrogel offers a candidate material with potential applications for infected skin wound healing.

Arabinose confers protection against intestinal injury by improving integrity of intestinal mucosal barrier.

There is a growing amount of research that highlights the significant involvement of metabolic imbalance and the inflammatory response in the advancement of colitis. Arabinose is a naturally occurring bioactive monosaccharide that plays a crucial role in the metabolic processes and synthesis of many compounds in living organisms. However, the more detailed molecular mechanism by which the administration of arabinose alleviates the progression of colitis and its associated carcinogenesis is still not fully understood. In the present study, arabinose is recognized as a significant and inherent protector of the intestinal mucosal barrier through its role in preserving the integrity of tight junctions within the intestines. Also, it is important to note that there is a positive correlation between the severity of inflammatory bowel disease (IBD) and colorectal cancer (CRC), as well as chemically-induced colitis in mice, and lower levels of arabinose in the bloodstream. In two mouse models of colitis, caused by dextran sodium sulfate (DSS) or by spontaneous colitis in IL-10-/- mice, damage to the intestinal mucosa was reduced by giving the mice arabinose. When arabinose is administrated to model with colitis, it sets off a chain of events that help keep the lysosomes together and stop cathepsin B from being released. During the progression of intestinal epithelial injury, this process blocks myosin light chain kinase (MLCK) from damaging tight junctions and causing mitochondrial dysfunction. In summary, the results of the study have provided evidence supporting the beneficial effects of arabinose in mitigating the progression of colitis. This is achieved through its ability to avoid dysregulation of the intestinal barrier. Consequently, arabinose may hold promise as a therapeutic supplementation for the management of colitis.

A dsRNA delivery system based on the rosin-modified polyethylene glycol and chitosan induces gene silencing and mortality in Nilaparvata lugens.

BACKGROUND: RNA interference (RNAi) technology has been considered as a promising pest control strategy due to its species selectivity. One of the popular RNAs is exogenous double strand RNA (dsRNA). However, dsRNA is easily degraded by nucleases and is difficult to pass through the insect body walls, and these factors restrict the application of RNAi technology in pest management. Here, the brown planthopper (BPH, Nilaparvata lugens), a major hemipteran pest of rice in Asia countries was used as a model insect, and a dsRNA topical delivery system was constructed. RESULTS: The carrier part of the delivery system was composed of rosin-modified polyethylene glycol and chitosan, termed ROPE@C. When the N/P ratio was greater than 1:1.25, the dsRNA/ROPE@C complex encouraged full binding of the dsRNA. The gel electrophoresis results showed that ROPE@C improved the stability of dsRNA in the presence of nucleases in gut and lumen contents for at least 6 h and in the temperature range from 4 °C to 37 °C. The dsNlCHSA/ROPE@C/alkyl polyglycoside (APG) nano-formulation directly penetrated the body walls reaching hemocoel within 6 h, and consequently, the relative expression of chitin synthetase A (CHSA) in BPH was reduced by 54.3% and the mortality rate was 65.8%. CONCLUSION: We developed an appropriate delivery method for dsRNA application in BPH, which is helpful for a large-scale application of RNAi pesticides. © 2022 Society of Chemical Industry.

Cannabidiol-loaded injectable chitosan-based hydrogels promote spinal cord injury repair by enhancing mitochondrial biogenesis.

The treatment of traumatic spinal cord injury (SCI) remains challenging as the neuron regeneration is impaired by irregular cavity and apoptosis. An injectable in situ gelling hydrogel is therefore developed for the local delivery of cannabidiol (CBD) through a novel method based on polyelectrolyte (PEC) interaction of sodium carboxymethylcellulose (CMC) and chitosan (CS). It can be injected into the spinal cord cavity with a 26-gauge syringe before gelation, and gelled after 110 ± 10 s. Of note, the in-situ forming hydrogel has mechanical properties similar to spinal cord. Moreover, the CBD-loaded hydrogels sustain delivery of CBD for up to 72 h, resulting in reducing apoptosis in SCI by enhancing mitochondrial biogenesis. Importantly, the CBD-loaded hydrogels raise neurogenesis more than pure hydrogels both in vivo and in vitro, further achieving significant recovery of motor and urinary function in SCI rats. Thus, it suggested that CMC/CS/CBD hydrogels could be used as promising biomaterials for tissue engineering and SCI.

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. Hepatocyte-specific Trim31 ablation facilitates NAFLD-associated phenotypes in mice. Inversely, transgenic or ex vivo gene therapy-mediated Trim31 gain-of-function in mice with NAFLD phenotypes virtually alleviates severe deterioration and progression of steatohepatitis. The current findings suggest that Trim31 is an endogenous inhibitor of Rhbdf2 and downstream cascades in the pathogenic process of steatohepatitis and that it may serve as a feasible therapeutical target for the treatment of NAFLD/NASH and associated metabolic disorders.

Oral flavonoid fisetin treatment protects against prolonged high-fat-diet-induced cardiac dysfunction by regulation of multicombined signaling.

Excess high-fat diet (HFD) intake predisposes the occurrence of obesity-associated heart injury, but the mechanism is elusive. Fisetin (FIS), as a natural flavonoid, has potential activities to alleviate obesity-induced metabolic syndrome. However, the underlying molecular mechanisms of FIS against HFD-induced cardiac injury remain unclear. The present study was to explore the protective effects of FIS on cardiac dysfunction in HFD-fed mice. We found that FIS alleviated HFD-triggered metabolic disorder by reducing body weight, fasting blood glucose and insulin levels, and insulin resistance. Moreover, FIS supplements significantly alleviated dyslipidemia in both mouse hearts and cardiomyocytes stimulated by metabolic stress. FIS treatment abolished HFD-induced inflammatory response in heart tissues through suppressing TNF receptor-1/TNF receptor-associated factor-2 (Tnfr-1/Traf-2) signaling. Furthermore, FIS induced a strong reduction in the expression of fibrosis-related genes, contributing to the inhibition of fibrosis by inactivating transforming growth factor (Tgf)-ß1/Smads/Erk1/2 signaling. Collectively, these results demonstrated that FIS could be a promising therapeutic strategy for the treatment of obesity-associated cardiac injury.