Sodium butyrate alleviates deoxynivalenol-induced porcine intestinal barrier disruption by promoting mitochondrial homeostasis via PCK2 signaling.

Deoxynivalenol (DON) is one of the most plentiful trichothecenes occurring in food and feed, which brings severe health hazards to both animals and humans. This study aims to investigate whether sodium butyrate (NaB) can protect the porcine intestinal barrier from DON exposure through promoting mitochondrial homeostasis. In a 4-week feeding experiment, 28 male piglets were allocated according to a 2 by 2 factorial arrangement of treatments with the main factors including supplementation of DON (< 0.8 vs. 4.0 mg/kg) and NaB (0.0 vs. 2 g/kg) in a corn/soybean-based diet. Dietary NaB supplementation mitigated the damaged mitochondrial morphology within the jejunal mucosa and the disrupted gut epithelial tight junctions irritated by DON. In IPEC-J2 cells, we found efficient recovery of the intestinal epithelial barrier occurred following NaB administration. This intestinal barrier reparation was facilitated by NaB-induced PCK2-mediated glyceroneogenesis and restoration of mitochondrial structure and function. In conclusion, we elucidated a mechanism of PCK2-mediated improvement of mitochondrial function by NaB to repair porcine intestinal barrier disruption during chronic DON exposure. Our findings highlight the promise of NaB for use in protecting against DON-induced gut epithelial tight junction disruption in piglets.

Dual effects of zearalenone on aflatoxin B1-induced liver and mammary gland toxicity in pregnant and lactating rats.

Food and feed are frequently co-contaminated with aflatoxin B1 (AFB1) and zearalenone (ZEN). This study investigated the effects of ZEN on the AFB1-induced liver and mammary gland toxicity in pregnant and lactating rats. AFB1 and ZEN co-exposure inhibited the growth of rats and caused oxidative stress and inflammatory responses in the liver and mammary gland. Compared with the AFB1-only group, damage was aggravated in the AFB1 + 10 mg/kg ZEN group, and the AFB1 + 1 mg/kg ZEN group showed a reduction in some metrics. The metabolomic results of the mammary gland showed that metabolite changes were mainly in lipid, amino acid, and glucose metabolism. Compared with the AFB1 + 0 mg/kg ZEN group, the AFB1 + 1 mg/kg ZEN group had the most metabolite changes. Moreover, AFB1 and ZEN co-exposure reduced the levels of sex hormones and RNA m6A methylation in the mammary gland. We speculate that ZEN affects the toxicity of AFB1 to the liver and mammary gland by interfering with the function of sex hormones, regulating cell proliferation and metabolic processes.

Deoxynivalenol triggers porcine intestinal tight junction disorder through hijacking SLC5A1 and PGC1α-mediated mitochondrial function.

Deoxynivalenol (DON) is a mycotoxin frequently occurring in human and animal food worldwide, which raises increasing public health concerns. Growing evidence suggests that mitochondria is a pivotal molecular target for DON. However, the contribution of mitochondrial dysfunction to the pathogenesis of DON-induced gut epithelial barrier disruption remains poorly understood. In an animal experiment, piglets exposed to 2.89 mg DON/kg feed for 4 weeks showed altered metabolomic profiling in the serum and compromised transcriptome in the jejunum. DON exposure also impaired mitochondrial structure in the jejunal mucosa, corresponding with dysfunction of the tight junctions. In IPEC-J2 cells, metabolomic and transcriptomic analyses revealed that DON exposure perturbed biological processes occurring in the mitochondria and disordered the expression of genes involved in mitochondrial energy metabolism. Fuel utilization from glucose was affected by DON exposure, as were mitochondrial morphological dynamics leading to increased fragmentation. A marked loss of Na+/glucose cotransporter (SLC5A1) and peroxisome proliferator activated receptor-γ co-activator 1α (PGC1α) was observed in DON-treated cells. Taken together, our data highlight the critical role of impaired mitochondrial energy metabolism and mitochondrial biogenesis in abnormal intestinal tight junction upon DON exposure, and provide a potential mitochondrial target for intestinal mucosal restoration following DON exposure.

Mechanism of deoxynivalenol mediated gastrointestinal toxicity: Insights from mitochondrial dysfunction.

Deoxynivalenol (DON) is a mycotoxin predominantly produced by Fusarium genus, and widely contaminates cereals and associated products all over the world. The intestinal toxicity of DON is well established. However, intestinal homeostasis involves mitochondria, which has rarely been considered in the context of DON exposure. We summarize the recent knowledge on mitochondria as a key player in maintaining intestinal homeostasis based on their functions in cellular energy metabolism, redox homeostasis, apoptosis, intestinal immune responses, and orchestrated bidirectional cross-talk with gut microbe. In addition, we discuss the pivotal roles of mitochondrial dysfunction in the intestinal toxicity of DON and highlight promising mitochondrial-targeted therapeutics for DON-induced intestinal injury. Recent studies support that the intestinal toxicity of DON is attributed to mitochondrial dysfunction as a critical factor. Mitochondrial dysfunction characterized by failure in respiratory capacities and ROS overproduction has been demonstrated in intestinal cells exposed to DON. Perturbation of mitochondrial respiration leading to ROS accumulation is implicated in the early initiation of apoptosis. DON-induced intestinal inflammatory response is tightly linked to the mitochondrial ROS, whereas immunosuppression is intimately associated with mitophagy inhibition. DON perturbs the orchestrated bidirectional cross-talk between gut microbe and host mitochondria, which may be involved in DON-induced intestinal toxicity.

MiR-101 relates to chronic peripheral neuropathic pain through targeting KPNB1 and regulating NF-κB signaling.

Accumulating evidences indicates that chronic neuropathic pain is a kind of neuro-immune disorder with enhanced activation of the immune system. Although the prevalence is very high, neuropathic pain remains extremely difficult to cure. miRNAs are a group of short nonprotein coding RNAs, regulating target genes expression via targeting 3'-untranslated region. More and more research indicates that altered miRNAs expression profile relates to the pathogenesis of neuropathic pain. In this study, we firstly detected the expression of six candidate miRNAs in the plasma samples from 23 patients with neuropathic pain and 10 healthy controls. Subsequently, the level of miR-132 and miR-101 was detected in the sural nerve biopsies. We found miR-101 level was significantly repressed in both the plasma samples and sural nerve biopsies from neuropathic pain patients. Predicted by bioinformatics tools and confirmed by dual luciferase assay and immunoblotting, we identified that KPNB1 is a direct target of miR-101. The negative correlation between miR-101 and KPNB1 was also confirmed in the sural nerve biopsies, and miR-101 reduction relates to the activation of NF-κB signaling in vivo and in vitro which contributes to the pathogenesis of neuropathic pain.

[Study on membrane injury mechanism of total alkaloids and berberine from Coptidis Rhizoma on Aeromonas hydrophila].

To explore the antibacterial activity and mechanism of total alkaloids and berberine from Coptidis Rhizoma on Aeromonas hydrophila, and determine the effect of total alkaloids and berberine from Coptidis Rhizoma on minimum inhibitory concentrations, permeability and fluidity of cell membrane, conformation of membrane proteins and virulence factors of A. hydrophila. The results showed that both total alkaloids and berberine from Coptidis Rhizoma had antibacterial activities on A. hydrophila, with minimum inhibitory concentrations of 62.5 and 125 mg · L(-1), respectively. Total alkaloids and berberine from Coptidis Rhizoma could increase the fluidity of membrane, change the conformation of membrane porteins and increase the permeability of bacteria membrane by 24.52% and 19.66%, respectively. Besides, total alkaloids and berberine from Coptidis Rhizoma significantly decreased the hemolysis of exotoxin and the mRNA expressions of aerA and hlyA (P < 0.05, P < 0.01), the secretion of endotoxin and the mRNA expression of LpxC (P < 0.05, P < 0.01). The results suggested that the antibacterial activity of total alkaloids and berberine from Coptidis Rhizoma on A. hydrophila may be related to the bacteria membrane injury. They inhibited the bacterial growth by increasing membrane lipid fluidity and changing conformation of membrane proteins, and reduced the secretion of virulence factors of A. hydrophila to weaken the pathogenicity.

[Regulatory effect of coptisine on key genes involved in cholesterol metabolism].

To study the effect of cholesterol and 25-OH-cholesterol on cholesterol metabolism in HepG2 cells and the effect of coptisine (Cop) extracted from Coptidis Rhizoma (CR) in reducing and regulating cholesterol. In this study, TC, TG, LDL-c and HDL-c were measured by biochemical analysis; mRNA and protein expressions of LDLR, HMGCR and CYP7A1 were detected by qRT-PCR and Western blot. According to the results, cholesterol and 25-OH-cholesterol inducing could decrease in mRNA and protein expressions of LDLR and CYP7A1, so as to increase TC and LDL-c contents. However, Cop could up-regulate mRNA and protein expressions of LDLR and CYP7A1 and down-regulate that of HMGCR, so as to reduce TC and LDL-c levels. These findings suggested that Cop has potential pharmacological activity for reducing cholesterol, and may reduce cholesterol by regulating mRNA and protein expressions of key genes involved in cholesterol metabolism, such as LDLR, CYP7A1 and HMGCR. This study laid a firm theoretical foundation for developing new natural drugs with the cholesterol-lowering activity.

Coptisine attenuates obesity-related inflammation through LPS/TLR-4-mediated signaling pathway in Syrian golden hamsters.

It is known that obesity resulted from consumption of diets high in fat and calories and associated with a chronic low-grade inflammation. Because the fat, sterol and bile acid metabolism of male Syrian golden hamster are more similar to that of human, in the present study, high fat and high cholesterol (HFHC) induced obese hamsters were used to evaluate the anti-inflammation and hypolipidemic role of coptisine. The results showed that body weight, plasma lipid levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein-cholesterol (LDL-c), very low density lipoprotein-cholesterol (VLDL-c), ApoB and pro-inflammatory cytokines including TNF-α, IL-6 and lipopolysaccharide (LPS) were significantly altered in hamsters fed with HFHC diet. A strong correlation was observed between the LPS level in serum and the level of LBP and pro-inflammatory cytokines. Coptisine from the concentrations of 60 to 700 mg/L dose-dependently inhibited Enterobacter cloacae growth, which can easily induce obesity and insulin resistance. The results of endotoxin neutralization assay suggest that coptisine is capable of reducing the LPS content under inflammation status. Real time RT-PCR analyses revealed that coptisine suppressed TLR-4 in visceral fat of hamsters and decreased CD14 expression in livers of hamsters. These encouraging findings make the development of coptisine a good candidate for preventing obesity-related diseases through the LPS/TLR-4-mediated signaling pathway.

The antihypercholesterolemic effect of jatrorrhizine isolated from Rhizoma Coptidis.

Current work was conducted to evaluate the safety and antihypercholesterolemic activity of jatrorrhizine extracted from Rhizoma Coptidis (RC) and its potential mechanism on regulating cholesterol metabolism. It was found that the LD50 of jatrorrhizine in mice was more than 5,500 mg/kg and there were no influences on clinical signs, organ weight changes, urinalysis and hematological parameters, gross necropsy and histological alterations in jatrorrhizine-treated rats during the 3-month period, compared to the control group. Jatrorrhizine showed a strong lipid-lowering effect in a dose-dependent manner. Oral administration of 70.05 mg/kg of jatrorrhizine on Mesocricetus auratus (Syrian golden hamsters) exhibited significant decrease in TC, TG, and LDL-c levels by 20%, 43%, and 19%, respectively, and increase in HDL-c and total bile acids (TBA) content in feces (p<0.01), compared to high-fat and high-cholesterol (HFHC) group. Besides, jatrorrhizine dose-dependently slowed the rate of weight gain. The results of qRT-PCR, western blotting and ELISA revealed that jatrorrhizine significantly up-regulated the mRNA and protein expression of LDLR and CYP7A1, but exhibited no significant effect on mRNA and protein expression of HMGR and ASBT in hamsters. In conclusion, jatrorrhizine was a safe and potential antihypercholesterolemic agent from RC which could improve the utilization and excretion of cholesterol by up-regulating the mRNA and protein expression of LDLR and CYP7A1.