Oxidative phosphorylation regulates interleukin-10 production in regulatory B cells via the extracellular signal-related kinase pathway.

Regulatory B cells (Bregs) are immune cells that constrain autoimmune response and restrict inflammation via their expression of interleukin (IL)-10. However, the molecular mechanisms underlying Breg differentiation and IL-10 secretion remain unclear. Previous data suggest that cellular metabolism determines both the fate and function of these cells. Here, we suggest an essential role for mitochondrial oxidative phosphorylation (OXPHOS) in the regulation of IL-10 in these Bregs. We found that IL-10+ B cells from IL-10-green fluorescent protein-expressing mice had higher oxygen consumption rate than IL-10- B cells. In addition, inhibition of OXPHOS decreased the expression of IL-10 in B cells. Furthermore, suppression of OXPHOS diminished the expression of surface markers for Bregs and impaired their therapeutic effects in dextran sulphate sodium (DSS)-induced colitis. Mechanistically, mitochondrial OXPHOS was found to regulate the transcription factor HIF-1α through the extracellular signal-related kinase pathway. Taken together, this study reveals a strong correlation between mitochondrial OXPHOS and Breg phenotype/function, indicating OXPHOS as a therapeutic target in autoimmune diseases driven by Breg dysfunction.

Amphiregulin alleviated concanavalin A-induced acute liver injury via IL-22.

OBJECTIVES: Amphiregulin (Areg), a glycoprotein from the epidermal growth factor receptor (EGFR) ligand family, has a well-documented protective role against tissue injury; however, its effects on immune-mediated liver injury are still unclear. Here, we used a concanavalin A (ConA)-induced acute liver hepatitis model to explore the effects of Areg on immune-mediated acute liver injury. MATERIALS AND METHODS: Some C57BL/6 mice were administered ConA at a dose of 20 mg/kg (model mice), and some received 5 µg of Areg (treated mice). Then, their survival rates over 36 h were analyzed. After 5 h of treatment, liver function, hepatic histology, and apoptosis in liver tissue were investigated, and cytokine expression and neutrophil infiltration and activity in the liver were detected. Moreover, the protective effects of Areg were also evaluated without IL-22 in vivo. RESULTS: Our results showed that Areg administration increased acute liver failure (ALF) mouse survival, restored liver function, and alleviated liver damage. Interestingly, Areg administration increased IL-22 production in hepatic T cells and upregulated IL-22 concentrations in the serum and liver, whereas IL-22 neutralization completely abolished the therapeutic effect of Areg. Meanwhile, Areg administration was concomitant with increased expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL, which are important in the hepatoprotective mechanism of IL-22. CONCLUSIONS: Areg showed direct protective effects against ConA-induced acute liver injury, which suggests the potential therapeutic application of Areg in immune-mediated ALF.

Wogonin Strengthens the Therapeutic Effects of Mesenchymal Stem Cells in DSS-Induced Colitis via Promoting IL-10 Production.

Inflammatory bowel diseases (IBD) are prevalent and debilitating diseases; their clinical remedy is desperately unmet. Mesenchymal stem cells (MSCs) are pluripotent stem cells with multiple immunomodulatory effects, which are attributed to their efficacy in the IBD rodent model. Optimization of MSC regimes in IBD is a crucial step for their further clinical application. Wogonin is a flavonoid-like compound, which showed extensive immunomodulatory and adjuvant effects. This research is aimed at investigating whether and how Wogonin boosted the therapeutic efficiency of MSCs on DSS-induced colitis. Our results showed that the MSC treatment with Wogonin significantly alleviated the intestinal inflammation in IBD mice by increased IL-10 expression. In vitro experiments, Wogonin obviously raised the IL-10 production and ROS levels of MSCs in a dose-dependent manner. Meanwhile, western blot data suggested Wogonin improves the IL-10 production by inducing transcript factor HIF-1α expression via AKT/GSK3ß signal pathway. Finally, the favorable effects of Wogonin on MSCs were confirmed by IL-10 blockade experiment in vivo. Together, our results suggested that Wogonin significantly increased the IL-10 production and enhanced the therapeutic effects of MSCs in DSS-induced colitis. This work suggested Wogonin as a novel optimal strategy for MSC clinical application.

Hepatoprotective effects and mechanisms of Ixeris denticulate water extract on liver cirrhosis in experimental rat.

BACKGROUND: To explore the protective effect and mechanisms of Ixeris denticulate water extract (IDWE) in the development of liver cirrhosis in experimental rat. METHODS: Sixty rats were randomly divided into five groups: control group, model group and IDWE (2, 4 and 8 g/kg) treatment groups. Alanine transferase (ALT), aspartate transaminase (AST), albumin (ALB), tumor necrosis factor-alpha (TNF-α), Interleukin (IL)-6 and IL-8 in serum and superoxide dismutase (SOD), malondialdehyde (MDA) in liver tissue were evaluated, respectively. The liver index, liver morphology and liver histopathological analysis were detected as a supportive data. The liver protein expression of Bcl-2 and Bax were assessed by western blot, and NF-κB p65 protein expression was determined by immunohistochemistry analysis. RESULTS: The result showed that a significantly decrease in the levels of serum AST, ALT and serum inflammatory factors TNF-α, IL-6 and IL-8 in IDWE-treated rats. The levels of serum ALB and SOD in liver tissue were markedly increased after IDWE treated, compared with model rats. Furthermore, IDWE-treated group also exhibited a down-regulated protein expression of NF-κB p65 and Bax, up-regulated Bcl-2 protein expression. CONCLUSIONS: IDWE could effectively alleviate the course of liver cirrhosis in rat model, which may be a potent hepatoprotective agent in clinical therapy in the future.

Saikosaponin a ameliorates lipopolysaccharide and d­galactosamine-induced liver injury via activating LXRα.

Saikosaponin a (SSa), one of the major active components of Bupleurum falcatum, has antioxidant and anti-inflammatory pharmacological properties. However, the effects of SSa on liver injury have not been reported. In the present study, we evaluated the protective effects and mechanisms of SSa on lipopolysaccharide (LPS)/d­galactosamine (D-GalN)-induced liver injury. The mice were pretreated with SSa 1 h before LPS/D-GalN treatment. The liver MPO, MDA, and the serum AST and ALT levels were tested by specific determination kits. The pro-inflammatory cytokines TNF-α and IL-1ß were tested by ELISA kits. The expression of NF-κB signaling pathway and LXRα were tested by western blot analysis. The results showed that SSa significantly reduced the levels of liver MPO, MDA, and serum AST, ALT levels induced by LPS/D-GalN. SSa also dose-dependently inhibited LPS/D-GalN-induced pro-inflammatory cytokines TNF-α and IL-1ß production. Furthermore, we found that SSa inhibited NF-κB signaling pathway activation induced by LPS/D-GalN. In addition, SSa dose-dependently increased the expression of LXRα. In conclusion, the results demonstrated that SSa had protective effect on liver injury and the anti-inflammatory mechanisms of SSa on LPS/D-GalN-induced liver injury may be due to its ability to increase LXRα expression. SSa might be a potential treatment for liver injury.

Down-regulation of LncRNA UCA1 alleviates liver injury in rats with liver cirrhosis.

OBJECTIVE: The purpose of this study is to explore the role of long non-coding RNA HULC (lncRNA HULC) in liver injury of rats with cirrhosis. METHODS: The rat model of liver cirrhosis was induced by dimethylnitrosamine (DMN), which was intraperitoneally injected with siRNA-negative control (NC) or HULC siRNA. HULC expression in rat liver tissues was detected by qRT-PCR. The amounts of alanine transaminase (ALT) and aspartate aminotransferase (AST) in serum and levels of malonyldialdehyde (MDA) and superoxide dismutase (SOD) in liver tissues were measured. TUNEL staining was used to determine hepatocyte apoptosis. Western blot analysis was used to detect the expression of Caspase-3, Bax, and Bcl-2 in liver tissues. qRT-PCR and ELISA were used to detect the mRNA levels and contents of IL-1ß and TNF-α in liver tissues and serum of rats, respectively. RESULTS: High expression of HULC was found in liver tissues of rats with liver cirrhosis. Downregulation of HULC reduced the contents of ALT and AST in serum of rats, inhibited liver tissue lesions and liver fibrosis in rats, suppressed apoptosis (lower expression of caspase-3 and Bax as well as higher BCL-2 expression) of hepatocytes in rats, and inhibited oxidative stress (decreased MDA and increased SOD) and inflammatory injury (decreased IL-1ß and TNF-α) in rats with cirrhosis. CONCLUSION: The findings in this study highlight that the expression of HULC is up-regulated in liver tissues of rats with cirrhosis, and down-regulation of UCA1 could inhibit liver injury in rats with cirrhosis.

Zinc-Enriched Yeast Improves Learning and Memory Impairments in Zinc-Deficient Rats.

Zinc (Zn) highly concentrates in the brain and plays a key role in memory formation and learning processes. Zn deficiency results in cognitive impairments, memory deficits, alterations of neuropsychological behavior, and motor development. Although Zn-enriched yeast (ZnY) is widely used for dietary fortification and supplementation of Zn, the effect of ZnY on cognition still remains unclear. The purpose of the study was to investigate the effect of ZnY on behavior in Zn-deficient and Zn-sufficient rats. Three-week-old rats were fed low Zn diets for 145 days to establish Zn-deficient rats. ZnY was orally administered to Zn-deficient rats at three dose levels of 1, 2, and 4 mg Zn/kg/day for 55 days. Rat appearance, body weight, plasma and brain Zn, Morris water maze test, and step-through passive avoidance test were observed. Compared to Zn-sufficient rats, body weight gain, plasma zinc level, resident time, and step-through time in Zn-deficient rats were significantly lower. Zn deficiency impaired functions of learning and memory, while ZnY as a plausible therapeutic intervention alleviated the cognitive impairments caused by Zn deficiency.