Hunan insect tea polyphenols provide protection against gastric injury induced by HCl/ethanol through an antioxidant mechanism in mice.

The purposes of this study were to explore the preventive and treatment effects of Hunan insect tea polyphenols (HITPs) on gastric injury in mice induced by HCl/ethanol and to investigate their molecular mechanisms of action. Both HITPs and ranitidine inhibited the formation and further deterioration of gastric mucosal lesions, reduced the secretion of gastric juice, and raised gastric juice pH compared to the control. The HITPs-H treated group had lower serum levels of motilin, substance P, and endothelin than the control group, but they had higher serum levels of vasoactive intestinal peptide and somatostatin. Mice treated with HITPs had lower serum levels of cytokines interleukin (IL)-6, IL-12, tumor necrosis factor-α (TNF-α), and interferon-γ than the control group. The activities of superoxide dismutase (SOD), nitric oxide, and glutathione peroxidase (GSH-Px) were higher in the gastric tissues of HITP-treated mice, but the malondialdehyde content was lower. Quantitative PCR analysis indicated that the mRNA expression of occludin, epidermal growth factor (EGF), EGF receptor (EGFR), vascular EGF (VEGF), inhibitor kappaB-α, cuprozinc-superoxide dismutase, manganese-superoxide dismutase, GSH-Px, neuronal nitric oxide synthase, and endothelial NOS increased significantly in the gastric tissues of HITP-treated mice. However, the activated B cell, inducible NOS, cyclooxygenase-2, TNF-α, IL-1 beta, and IL-6 mRNA expression levels in the HITPs group were lower than those in the control group. The protective effect of a high concentration (200 mg per kg bw) of HITPs on gastric injury induced by HCl/ethanol was stronger than that of a low concentration (100 mg per kg bw) of HITPs. High-performance liquid chromatography (HPLC) revealed that the HITPs contained cryptochlorogenic acid, (-)-epicatechin gallate, and isochlorogenic acid C. Taken together, our findings indicate that the HITPs played a role in the prevention of gastric damage. The antioxidant effect of the HITPs contributed to their potential value in the prevention and treatment of gastric injury. HITPs have broad prospects as biologically active substances for food development.

Pretreatment with Lactobacillus fermentum XY18 Relieves Gastric Injury Induced by HCl/Ethanol in Mice via Antioxidant and Anti-Inflammatory Mechanisms.

AIM: Lactobacillus fermentum XY18 (LF-XY18) is a bacterial strain with satisfactory antioxidant properties in vitro that we previously isolated from Xinjiang yogurt. This article will explore the preventive effect of LF-XY18 on acute gastric injury and provide the basis for the innovative development and application of lactic acid bacteria (LAB). METHODS: Kunming mice underwent gastric injury induced by hydrochloric acid and ethanol. LF-XY18 isolated from yogurt in Xinyuan County in the Yili region of Xinjiang was subsequently administered intragastrically to mice for 2 weeks to explore the mechanism of LF-XY18 in preventing gastric injury via its antioxidant effects. RESULTS: There was decreased gastric juice volume, gastric injury area, and formation of gastric mucosal lesions in the LF-XY18 mice as compared to those in the control mice, while LF-XY18 prevented the decrease in the gastric juice pH value in mice. Compared with the gastric injury model group mice, LF-XY18 reduced the serum levels of motilin, substance P, interleukin-6, interleukin-12, tumor necrosis factor-α, and interferon-γ but increased the serum levels of somatostatin and vasoactive intestinal peptide. The activities of superoxide dismutase, glutathione peroxidase, glutathione, and nitric oxide were increased in the gastric tissue of the LF-XY18 mice compared with the control mice, but malondialdehyde activity was decreased in the LF-XY18 mice. Quantitative polymerase chain reaction analysis illustrated that in the gastric tissue of LF-XY18 mice, the messenger RNA (mRNA) expression of occludin, epidermal growth factor (EGF), EGF receptor, vascular EGF, inhibitor kappa-B-α, neuronal nitric oxide synthase, endothelial nitric oxide synthase, cuprozinc superoxide dismutase, manganese superoxide dismutase, and catalase was stronger than that in the control mice, but the mRNA expression of activated B cells (NF-κB), inducible nitric oxide synthase, and cyclooxygenase-2 was weaker than in the control mice. CONCLUSION: These results indicate that LF-XY18 has a potential role in the prevention of gastric injury through antioxidant effects, and a high concentration (1.0 × 109 CFU/kg b.w.) of LF-XY18 has a stronger anti-gastric injury effect than a low concentration (1.0 × 108 CFU/kg b.w.).

Pancreatic fibroblast growth factor 21 protects against type 2 diabetes in mice by promoting insulin expression and secretion in a PI3K/Akt signaling-dependent manner.

Fibroblast growth factor 21 (FGF21) is important in glucose, lipid homeostasis and insulin sensitivity. However, it remains unknown whether FGF21 is involved in insulin expression and secretion that are dysregulated in type 2 diabetes mellitus (T2DM). In this study, we found that FGF21 was down-regulated in pancreatic islets of db/db mice, a mouse model of T2DM, along with decreased insulin expression, suggesting the possible involvement of FGF21 in maintaining insulin homeostasis and islet ß-cell function. Importantly, FGF21 knockout exacerbated palmitate-induced islet ß-cell failure and suppression of glucose-stimulated insulin secretion (GSIS). Pancreatic FGF21 overexpression significantly increased insulin expression, enhanced GSIS, improved islet morphology and reduced ß-cell apoptosis in db/db mice. Mechanistically, FGF21 promoted expression of insulin gene transcription factors and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, the major regulators of insulin secretion, as well as activating phosphatidylinositol 3-kinase (PI3K)/Akt signaling in islets of db/db mice. In addition, pharmaceutical inhibition of PI3K/Akt signaling effectively suppressed FGF21-induced expression of insulin gene transcription factors and SNARE proteins, suggesting an essential role of PI3K/Akt signaling in FGF21-induced insulin expression and secretion. Taken together, our results demonstrate a protective role of pancreatic FGF21 in T2DM mice through inducing PI3K/Akt signaling-dependent insulin expression and secretion.

FGF21 Prevents Angiotensin II-Induced Hypertension and Vascular Dysfunction by Activation of ACE2/Angiotensin-(1-7) Axis in Mice.

Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. However, the role of FGF21 in hypertension remains elusive. Here we show that FGF21 deficiency significantly exacerbates angiotensin II-induced hypertension and vascular dysfunction, whereas such negative effects are reversed by replenishment of FGF21. Mechanistically, FGF21 acts on adipocytes and renal cells to promote induction of angiotensin-converting enzyme 2 (ACE2), which in turn converts angiotensin II to angiotensin-(1-7), then inhibits hypertension and reverses vascular damage. In addition, ACE2 deficiency strikingly abrogates these beneficial effects of FGF21 in mice, including alleviation of angiotensin II-associated hypertension and vascular damage. Otherwise, pharmaceutical inhibition of angiotensin-(1-7) attenuates the protective effect of FGF21 on angiotensin II-induced vascular dysfunction, but not on hypertension. Thus, FGF21 protects against angiotensin II-induced hypertension and vascular impairment by activation of the ACE2/angiotensin-(1-7) axis via fine-tuning the multi-organ crosstalk between liver, adipose tissue, kidney, and blood vessels.

FGF21 mediates the protective effect of fenofibrate against acetaminophen -induced hepatotoxicity via activating autophagy in mice.

Overdose of acetaminophen (APAP) induces acute liver injury due in part to destruction of mitochondria and resulted oxidative stress. Recently, FGF21 has been demonstrated to be an endocrine factor to protect liver from oxidative stress. The aim of present study is to explore the role of fibroblast growth factor 21 (FGF21) in the protective effect of fenofibrate, an agonist of peroxisome proliferator-activated receptor alpha (PPARα), against acetaminophen (APAP)-induced liver injury. Mice and primary cultured hepatocytes were used to test the potential hepatoprotective effect of fenofibrate against APAP-induced hepatotoxicity. FGF21 deficient mice were used to evaluate the role of FGF21 in fenofibrate against APAP-induced acute liver injury. Post-treatment with fenofibrate significantly inhibits APAP-induced hepatotoxicity, as evidenced by decreased serum ALT and AST levels and hepatic necrosis in liver tissue as well as increased the surviving rate in response to APAP overdose, whereas this protective effect of fenofibrate is largely attenuated in FGF21 KO mice. Interestingly, administration of fenofibrate efficiently increases autophagy, which was companied with alleviating hepatotoxicity in APAP-treated WT mice. However, such effect is significantly attenuated in APAP-treated FGF21 KO mice. In conclusion, our findings suggest that fenofibrate against APAP-induced hepatotoxicity is at least in part mediated by up-regulating the expression of FGF21, which in turn promotes autophagy-mediated hepatoprotective effects.

Cerebrospinal fluid FGF23 levels correlate with a measure of impulsivity.

Fibroblast growth factor 23 (FGF23) is a bone-derived protein produced mainly by osteocytes and osteoblasts and at low levels in specific parts of the brain. It has been shown to associate with mood regulation. Lithium treatment gives rise to significant elevations of serum FGF23 levels in depressive patients. High peripheral blood FGF23 levels correlated with poor cognitive performance in hemodialysis patients. However, no direct evidence demonstrates a relationship between FGF23 and mood regulation. In this study, we aimed to measure the concentration of cerebrospinal fluid (CSF) FGF23 and to explore its relationship with a cluster of emotional characteristics. We measured CSF FGF23 levels in 96 male Chinese subjects. All subjects completed the Chinese version of the Barratt Impulsiveness Scale (BIS 11), the Beck Depression Inventory (BDI) and the Self-Rating Anxiety Scale (SAS). CSF FGF23 levels ranged from 12.8 to 99.3 pg/mL. Negative correlations were found between CSF FGF23 concentrations and BIS non-planning, BIS cognition and BIS total score (all p < 0.05). Nevertheless, except for the BIS cognition scores, these correlations became insignificant after Bonferroni correction. No correlations were found between CSF FGF23 concentrations and BDI or SAS scores. These findings suggest that CSF FGF23 levels correlate with a measure of impulsivity.

FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice.

The aim of the present study is to explore the molecular mechanism of fibroblast growth factor 21 (FGF21) in protecting against diabetic cardiomyopathy (DCM). Streptozotocin/high-fat diet (STZ/HFD) was used to induced diabetes in FGF21-deficient mice and their wild-type littermates, followed by evaluation of the difference in DCM between the two genotypes. Primary cultured cardiomyocytes were also used to explore the potential molecular mechanism of FGF21 in the protection of high glucose (HG)-induced cardiomyocyte injury. STZ/HFD-induced cardiomyopathy was exacerbated in FGF21 knockout mice, which was accompanied by a significant reduction in cardiac AMP-activated protein kinase (AMPK) activity and paraoxonase 1 (PON1) expression. By contrast, adeno-associated virus (AAV)-mediated overexpression of FGF21 in STZ/HFD-induced diabetic mice significantly enhanced cardiac AMPK activity, PON1 expression and its biological activity, resulting in alleviated DCM. In cultured cardiomyocytes, treatment with recombinant mouse FGF21 (rmFGF21) counteracted HG-induced oxidative stress, mitochondrial dysfunction, and inflammatory responses, leading to increased AMPK activity and PON1 expression. However, these beneficial effects of FGF21 were markedly weakened by genetic blockage of AMPK or PON1. Furthermore, inactivation of AMPK also markedly blunted FGF21-induced PON1 expression but significantly increased HG-induced cytotoxicity in cardiomyocytes, the latter of which was largely reversed by adenovirus-mediated PON1 overexpression. These findings suggest that FGF21 ameliorates DCM in part by activation of the AMPK-PON1 axis.