MicroRNA-124-3p alleviates cerebral ischaemia-induced neuroaxonal damage by enhancing Nrep expression.

OBJECTIVE: Ischaemic stroke has a high death rate and frequently results in long-term and severe brain damage in survivors. miRNA-124-3p (miR-124-3p) treatment has been suggested to reduce ischaemia and play a vital function in avoiding neuron death. An investigation of the role of miR-124-3p, in the ischaemia damage repair or protection in the middle cerebral artery occlusion (MCAO) model and oxygen-glucose deprivation/reperfusion (OGD/R) model, was the purpose of this research. METHODS: The expression of miRNA and mRNA in the MCAO model was predicted using bioinformatics analysis. The OGD/R neuronal model was developed. We examined the influence of a number of compounds on the OGD/R model in vitro using gain- and loss-of-function approaches. RESULTS: For starters, miR-124-3p and Nrep level in the MCAO model were found to be lower in the model predicted by bioinformatics than in the sham-operated group. And then in the OGD/R model, miR-124-3p treatment reduced OGD/R neuronal damage, increased neuronal survival, and reduced apoptosis in cell lines. Moreover, we further looked at the impact of miR-124-3p on downstream Rnf38 and Nrep using the OGD/R model. Western blot analysis and dual-luciferase reporter assays indicated that miR-124-3p binds and inhibits Rnf38. Finally, although Nrep expression was reduced in the OGD/R model neuronal model, it was shown that miR-124-3p administration reduced apoptosis and increased neuronal activity, particularly with regard to axon regeneration-related proteins. CONCLUSION: Our studies have shown that miR-124-3p may reduce neuronal injury by preventing Rnf38-mediated effects on the Nrep axis.

MiR-139-5p has an antidepressant-like effect by targeting phosphodiesterase 4D to activate the cAMP/PKA/CREB signaling pathway.

BACKGROUND: Phosphodiesterase 4D (PDE4D) inhibitor is commonly used to treat depression, but side effects seriously decrease its efficacy. PDE4D was a downstream target mRNA of miR-139-5p. Therefore, we examined the effects of hippocampal miR-139-5p gain- and loss-of-function on depression-like behaviors, the expression level of PDE4D, and hippocampus neurogenesis. METHODS: Bioinformatic analyses were carried out to to screen differential genes. Quantitative real-time polymerase chain reaction (qRT-PCR) and luciferase reporter assay were used to confirm the relationship between miR-139-5p and PDE4D. MiR-139-5p mimics, miR-139-5p inhibitor, or miR-NC were used to explore the function of miR-139-5p in HT-22 cells. We further explored the role of miR-139-5p in vivo using AAV-injection. Elisa, western blotting, and fluorescence in situ hybridization (FISH) were used to detect the expression of miR-139-5p and PDE4D in CRC tissues. RESULTS: Here, we showed that PDE4D messenger RNA (mRNA) was a direct target of microRNA (miR)-139-5p, which was downregulated in a chronic ultra-mild stress (CUMS)-induced depression mouse model. Moreover, in experiments in vitro, miR-139-5p mimic repressed PDE4D expression in HT-22 cells, but promoted phosphorylated cyclic-AMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) expression. Interestingly, adeno-associated virus (AAV)-miR-139-5p downregulated susceptibility to stress-induced depression-like behaviors in mice. AAV-miR-139-5p suppressed PDE4D in mouse hippocampal cells, increasing expression level of cyclic adenosine monophosphate (cAMP), p-CREB, and BDNF, and stimulating mouse hippocampal neurogenesis. CONCLUSIONS: Our findings suggested that miR-139-5p acted like an antidepressant by targeting PDE4D, thereby regulating the cAMP/protein kinase A (PKA)/CREB/BDNF pathway to improve depression.

Nuciferine administration in C57BL/6J mice with gestational diabetes mellitus induced by a high-fat diet: the improvement of glycolipid disorders and intestinal dysbacteriosis.

Gestational diabetes mellitus (GDM) has become a global health concern as the main result of its contribution to the high risk of adverse pregnancy outcomes for both the mother and fetus. However, there is absence of an ideal and widely acceptable therapy. Nuciferine has previously been shown to exert beneficial effects in various metabolic diseases. This study aimed to investigate the potential therapeutic efficacy of nuciferine on GDM in C57BL/6J mice induced by a high-fat diet (HFD), which has not been reported before. The results showed that nuciferine improved glucose intolerance, reduced lipid accumulation and increased the glycogen content within hepatocytes, and decreased placental lipid and glycogen deposition, thus ameliorating glycolipid disorders in GDM mice. Additionally, nuciferine protected against histological degeneration of metabolism-associated critical organs including the liver, pancreas, and abdominal adipose tissue. Most interestingly, nuciferine could correct intestinal dysbacteriosis in GDM mice, as evidenced by the elevation of probiotic abundances consisting of Akkermansia, Lactobacillus, and Bifidobacterium, which were all negatively correlated with serum and liver triglyceride (TG) and positively associated with hepatic glycogen, and the reduction of conditional pathogen abundances including Escherichia-Shigella and Staphylococcus, and the latter was positively related to serum and liver TG and negatively linked with liver glycogen. Collectively, these findings suggest that nuciferine as a food-borne strategy played important roles in the management of GDM.

Characterization of four major degradation products in metformin by 2D LC-QTOF/MS/MS.

A two-dimensional liquid chromatography coupled with quadrupole time-of-flight mass spectrometry(2D LC-QTOF/MS/MS) method was developed for the characterization of four major degradation products in metformin under acidic, basic, oxidative and 6 months accelerated conditions. A CAPCELL PAK SCX TYPE UG80 column(5 µm, 4.6 × 150 mm) was applied using 17 g/L ammonium dihydrogen phosphate adjusted to pH 3.0 by phosphoric acid as the mobile phase at a flow rate of 1.0 mL/min in the first dimension (D1), and the collected fractions further flowed to a Waters Xbridge C18 column(5 µm, 4.6 mm × 250 mm) with a mobile phase consisting of 0.1 % formic acid and acetonitrile (95:5 v/v) at the same flow rate as the second dimension(D2). Two of the impurities were never reported as the degradation of metformin, and all the four structures, as well as the proposed fragmentation patterns were inferred in this research.

RETRACTED: Polysaccharide from Angelica sinensis ameliorates high-fat diet and STZ-induced hepatic oxidative stress and inflammation in diabetic mice by activating the Sirt1-AMPK pathway.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief because of duplication of data already published in the following paper in Food & Function: "Protective effects of Angelica sinensis polysaccharide against hyperglycemia and liver injury in multiple low-dose streptozotocin-induced type 2 diabetic BALB/c mice" by Wang K et al. in Food Funct 2016; 7; 4889-4897. The following data are the same in both papers: 1 The results of liver slices of oil red O staining in JNB Figure 1 are the same as Figure 6 in Food & Function. 2 JNB Figures 1 A and B are the same as Figure 7 B in the paper in Food & Function. 3 JNB Table 1 is the same as data presented in Figures 6 A-D and parts of Figure 3 A in the paper in Food & Function.

Protective effects of Angelica sinensis polysaccharide against hyperglycemia and liver injury in multiple low-dose streptozotocin-induced type 2 diabetic BALB/c mice.

Angelica sinensis polysaccharide (ASP), one of the major active ingredients isolated from the roots of Angelica sinensis (Oliv.) Diels, possesses numerous bioactivities. The aim of the present study was to explore the mechanisms of ASP-mediated hypoglycemic effects in type 2 diabetic BALB/c mice induced by multiple low-dose streptozotocin (STZ) injections plus a long-term high-fat diet (HFD) feeding. The potential mechanism explicating the hepatoprotective effect was also considered. Specifically, serum and hepatic biochemical parameters were determined, as well as the key proteins involved in glucose metabolism and apoptosis. The multiple low-dose STZ injection plus HFD treatment induced significant hyperglycemia, hyperlipidemia and marked liver injury. Our results showed that ASP had beneficial effects in preventing hyperglycemia, stimulating insulin secretion, promoting hepatic glycogen synthesis, regulating adipokine release, reducing liver fat accumulation, and attenuating liver injury. Moreover, mechanistic studies illustrated that ASP could upregulate the expression of PPARγ and liver insulin signaling proteins, including IRS-2, PI3K, Akt, p-Akt and GLUT2, increase anti-apoptotic protein Bcl-2, decrease pro-apoptotic protein Bax expressions, and protect the mice against hepatic damage. These findings revealed the potential mechanisms of ASP-mediated therapeutic effects in diabetic mice. It suggested that ASP might be used in prescriptions or functional foods for the prevention or treatment of diabetes and liver diseases.

Chronic administration of Angelica sinensis polysaccharide effectively improves fatty liver and glucose homeostasis in high-fat diet-fed mice.

This study aimed to investigate the therapeutic effects of Angelica sinensis polysaccharide (ASP), an active component derived from a water extract of Angelica sinensis, in high-fat diet (HFD)-fed BALB/c mice. The potential mechanisms underlying the activity of this compound were also considered. Specifically, serum and hepatic biochemical parameters were evaluated, and key proteins involved in the lipid/glucose metabolism were analyzed. Long-term feeding with a HFD induced severe fatty liver and hyperglycemia. Histological examination clearly showed that ASP reduced lipid accumulation in the liver and attenuated hepatic steatosis in HFD-fed mice. In addition, ASP markedly alleviated serum and liver lipid disorders and fatty liver via the upregulation of PPARγ expression and the activation of adiponectin-SIRT1-AMPK signaling. Furthermore, ASP also significantly relieved severe oxidative stress, demonstrating that ASP might attenuate nonalcoholic fatty liver disease via a "two-hit" mechanism. In addition, ASP reduced blood glucose levels and ameliorated insulin resistance via the regulation of related metabolic enzymes and by activating the PI3K/Akt pathway in HFD-fed mice. Our findings revealed that ASP might be used as an alternative dietary supplement or health care product to ameliorate metabolic syndrome in populations that consistently consume HFDs.

Angelica sinensis polysaccharide regulates glucose and lipid metabolism disorder in prediabetic and streptozotocin-induced diabetic mice through the elevation of glycogen levels and reduction of inflammatory factors.

The present study was designed to evaluate the potential hypoglycemic and hypolipidemic effects of Angelica sinensis polysaccharide (ASP), purified from the fresh roots of Angelica sinensis (AS), in prediabetic and streptozotocin (STZ)-induced diabetic BALB/c mice. It was observed that fasting blood glucose (FBG) levels in both models were reduced after a 4-week oral administration of ASP or metformin, and abnormal fasting serum insulin (FINS) concentrations were ameliorated as well. Moreover, the homeostasis model assessment-insulin resistance (HOMA-IR) index was decreased strikingly and body weight (BW) was reduced significantly in prediabetic mice after treatment with ASP. In addition, ASP also contributed to improving the dyslipidemia conditions. Elevated serum total cholesterol (TC) or triglyceride (TG) concentrations were reduced after treatment with ASP in prediabetic mice or STZ-induced diabetic mice. Meanwhile, hepatic glycogen (HG) and muscle glycogen (MG) concentrations were increased while insulin resistance (IR)-related inflammatory factors IL-6 and TNF-α in serum were reduced in STZ-induced diabetic mice. Histopathological examination indicated that the impaired pancreatic/hepatic tissues or adipose tissues were effectively restored in STZ-induced diabetic mice or prediabetic mice after the ASP treatment. Taken together, these results revealed that ASP efficiently exerted hypoglycemic and hypolipidemic benefits, and its potential effect was associated with the amelioration of IR. ASP can be applied in the prevention and treatment of diabetes.