Differential Modulators of NG2-Glia Differentiation into Neurons and Glia and Their Crosstalk.

As the fifth main cell population in the brain, NG2-glia are also known as oligodendrocyte precursor cells. NG2-glia express receptors and ion channels for fast modulation of neuronal activities and signaling with neuronal synapses, which are of functional significance in both physiological and pathological states. NG2-glia also participate in fast signaling with peripheral neurons via direct synaptic contacts in the brain. These distinctive glia have the unique capability of proliferating and differentiating into oligodendrocytes, which are critical for axonal myelination in the early developing brain. In neurodegenerative diseases, NG2-glia play an important role and undergo morphological modification, adapt the expression of their membrane receptors and ion channels, and display gene-modulated cell reprogramming and excitotoxicity-caused cell death. These modifications directly and indirectly influence populations of neurons and other glial cells. NG2-glia regulate their action and dynamics in response to neuronal behavior and disease, indicating a critical function to preserve and remodel myelin in physiological states and to repair it in pathological states. Here, we review in detail the differential modulators of NG2-glia into neurons and astrocytes, as well as interactions of NG2-glia with neurons, astrocytes, and microglia. We will also summarize a future potential exploitation of NG2-glia.

Trigonelline inhibits caspase 3 to protect ß cells apoptosis in streptozotocin-induced type 1 diabetic mice.

As a main active ingredient of Fenugreek, trigonelline has protective efficiency on type 2 diabetes and diabetic peripheral neuropathy in rats. This study investigates the protection of trigonelline on hyperglycemia, ß cell apoptosis, and inflammation in type 1 diabetic mice. Streptozotocin (160 mg/kg) was intraperitoneal injected to induce diabetic mice. There were 4 groups: normal control, diabetes, trigonelline-treated diabetes, and insulin-treated diabetes. After 4-week treatment, levels of blood glucose, serum insulin, and inflammatory factors, ß cell apoptosis, insulin content, and oxidative stress parameters in pancreas were calculated. Pancreas was examined by immunohistochemistry staining and hematoxylin/eosin. Trigonelline significantly declined the levels of blood glucose, serum tumor necrosis factor-α, interleukin-6, and interleukin-1ß, while increased the levels of serum insulin and adiponectin in diabetic mice. Insulin content, glutathione concentration, serum activities of superoxide dismutase and catalase in pancreas, and pancreas to body weight ratio were remarkably decreased, while serum malondialdehyde concentration was increased in diabetic mice. Trigonelline treatment restored the above mentioned parameters. Trigonelline even suppresses ß cell apoptosis via downregulating caspase 3 expression. These results imply that trigonelline protects diabetic mice mediated by decreasing blood glucose, increasing insulin expression in ß cells, regulating inflammatory response, suppressing ß cells apoptosis partly by downregulating caspase 3 expression, and raising antioxidant enzyme activity.

Trigonelline Inhibits Inflammation and Protects ß Cells to Prevent Fetal Growth Restriction during Pregnancy in a Mouse Model of Diabetes.

BACKGROUND: As an active component from traditional Chinese medicine, trigonelline has a protective effect on diabetes. This study evaluated the protective effects of trigonelline on diabetic mice during pregnancy. METHODS: Diabetes was induced in female mice by intraperitoneal injection for continuous 5-day of 40 mg/kg/day streptozotocin. Female mice were divided into 4 groups after they were allowed to mate with normal male mice: nondiabetic, nondiabetic treated with trigonelline (70 mg/kg) for 18 days, diabetic, and diabetic treated with trigonelline (70 mg/kg). RESULTS: Diabetic pregnant mice had significantly higher levels of blood glucose, serum total cholesterol, triglyceride, insulin, and leptin but lower serum omentin-1 level and insulin sensitivity index than the nondiabetic ones. Trigonelline improved the hyperglycemia, dyslipidemia, insulin resistance, and adipocytokine of diabetic pregnant mice. Diabetic pregnant mice had significantly reduced fetus numbers, fetal weight, and fetal/placental ratio, which were reversed by trigonelline. Trigonelline prevented the increase in proinflammatory cytokines and reduced interleukin-10 level in placenta of diabetic pregnant mice. Trigonelline increased ß-cell replication and the decreased ß-cell mass, and decreased the ß-cell apoptosis of diabetic pregnant mice. CONCLUSION: These findings suggest that trigonelline protects diabetic pregnancy partly by suppressing inflammation, regulating the secretion of adipocytokines, increasing ß-cell mass, replication, and decreasing ß-cell apoptosis.

Neuroprotective effect of berberine is mediated by MAPK signaling pathway in experimental diabetic neuropathy in rats.

The mechanisms leading to diabetic neuropathy are complex. As an active component in several traditional Chinese medicines, berberine has a beneficial effect in the treatment of diabetes with hyperlipidemia. This study evaluated the protective effects of berberine on diabetic neuropathy induced by streptozotocin and a high-carbohydrate/high-fat diet in rats. Diabetic neuropathy was induced in rats by intraperitoneal injection of 35 mg/kg streptozotocin and a high-carbohydrate/high-fat diet. Two weeks after diabetes induction, rats were treated with berberine (100 mg/kg) and rosiglitazone (4 mg/kg) for 24 weeks. Rats were studied using evoked potentials, the Morris water maze, transmission electron microscopy, real-time PCR, and Western blotting. Blood glucose, glycated hemoglobin, lipid profile, body weight, evoked potentials, and memory were altered in diabetic rats, as was the hippocampal expression of neuritin mRNA, p38 mitogen-activated protein kinase mRNA, c-Jun N-terminal kinase (JNK) mRNA, extracellular signal-regulated kinase mRNA and the phospho-proteins of p38, JNK, and extracellular signal-regulated kinase. In diabetic rats, berberine decreased body weight and the blood levels of glucose, glycated hemoglobin, triglyceride, and total cholesterol, improved memory and affected evoked potential by decreasing latency. Berberine decreased the mRNA expression of neuritin, p38, and JNK and the protein expression of neuritin, p-p38, and p-JNK. Slight micropathological changes were observed in the hippocampus of berberine-treated diabetic rats. These findings suggest that berberine has a beneficial effect against diabetic neuropathy by improving micropathology and increasing neuritin expression via the mitogen-activated protein kinase signaling pathway.

Swertianlarin, an Herbal Agent Derived from Swertia mussotii Franch, Attenuates Liver Injury, Inflammation, and Cholestasis in Common Bile Duct-Ligated Rats.

Swertianlarin is an herbal agent abundantly distributed in Swertia mussotii Franch, a Chinese traditional herb used for treatment of jaundice. To study the therapeutic effect of swertianlarin on cholestasis, liver injury, serum proinflammatory cytokines, and bile salt concentrations were measured by comparing rats treated with swertianlarin 100 mg/kg/d or saline for 3, 7, or 14 days after bile duct ligation (BDL). Serum alanine aminotransferase (ATL) and aspartate aminotransferase (AST) levels were significantly decreased in BDL rats treated with swertianlarin for 14 days (P < 0.05). The reduced liver injury in BDL rats by swertianlarin treatment for 14 days was further confirmed by liver histopathology. Levels of serum tumor necrosis factor alpha (TNFα) were decreased by swertianlarin in BDL rats for 3 and 7 days (P < 0.05). Moreover, reductions in serum interleukins IL-1ß and IL-6 levels were also observed in BDL rats treated with swertianlarin (P < 0.05). In addition, most of serum toxic bile salt concentrations (e.g., chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA)) in cholestatic rats were decreased by swertianlarin (P < 0.05). In conclusion, the data suggest that swertianlarin derived from Swertia mussotii Franch attenuates liver injury, inflammation, and cholestasis in bile duct-ligated rats.

Oral administration of oleanolic acid, isolated from Swertia mussotii Franch, attenuates liver injury, inflammation, and cholestasis in bile duct-ligated rats.

BACKGROUND & AIMS: Oleanolic acid is abundantly distributed in Swertia mussotii Franch, a Chinese traditional herb for the treatment of jaundice. However, the hepatoprotective role of oleanolic acid in obstructive cholestasis and its underlying molecular mechanism are unclear. METHODS: Normal rats and bile duct-ligated (BDL) rats were given oleanolic acid and serum biochemistry, bile salts, and pro-inflammatory factors were measured, as well as the expression levels of liver bile acid synthesis and detoxification enzymes, membrane transporters, nuclear receptors, and transcriptional factors. RESULTS: Oral administration of oleanolic acid at 100 mg/kg did not cause rat liver injury. However, it significantly reduced the serum levels of alanine aminotransferase (ALT) on days 7 and 14, aspartate aminotransferase (AST) and TNF-α on day 14, and alkaline phosphatase (ALP) and IL-1ß on days 3, 7, and 14 in the BDL rats. Furthermore, the serum levels of total bile acid (TBA) and bile acids, including CDCA, CA, DCA, and Tα/ßMCA were significantly reduced by oleanolic acid on day 3 in the BDL rats. In addition, the expression levels of detoxification enzymes Cyp3a, Ugt2b, Sult2a1, Gsta1-2, and Gstm1-3, membrane transporters Mrp3, Mrp4, Ostß, Mdr1, Mdr2, and Bsep, nuclear receptors Pxr, Vdr, Hnf4α, Rxrα, Rarα, Lxr, and Lrh-1, and transcriptional factors Nrf2, Hnf3ß, and Ahr were significantly increased in oleanolic acid-treated rats. CONCLUSION: We demonstrated that the oral administration of oleanolic acid attenuates liver injury, inflammation, and cholestasis in BDL rats. The anti-cholestatic effect may be associated with the induction of hepatic detoxification enzymes and efflux transporters mediated by nuclear receptors and transcriptional factors.

Swertianlarin, isolated from Swertia mussotii Franch, increases detoxification enzymes and efflux transporters expression in rats.

Swertianlarin, isolated from Swertia mussotii Franch and Enicostemma axillare, has hepatoprotective effects against cholestasis in rat models of hepatotoxicity. However, the underlying molecular mechanism is not clear. We then treated rats with swertianlarin for 7 d and then measured serum liver injury markers, lipids, and bile salts, as well as the expression of bile acid synthesis and detoxification enzymes (e.g. Cyp7a1 and Cyp3a), membrane influx and efflux transporters (e.g. Ntcp and Mrp3), nuclear receptors (e.g. Pxr and Fxr/Shp) and transcriptional factors (e.g. Nrf2 and Hnf3ß) in the liver. We found a significant induction of the expression of the basolateral efflux transporters Mrp3 and Mrp4 and canalicular transporter Mdr1 in rats treated with swertianlarin, compared with the controls (1.9-fold and 2.2-fold, P < 0.005, and 3.4-fold, P < 0.05, respectively). The expression of detoxification enzymes Cyp3a, Ugt2b, Sult2a1 and Gsta1 in rats treated with swertianlarin was significantly higher than that in controls (3.7-fold, 2.8-fold, 2.1-fold, and 1.7-fold, respectively, all P < 0.05). Expression of the synthetic enzyme, Cyp8b1, was higher in rats treated with swertianlarin than that in controls (1.8-fold at mRNA level and 3.4-flod at protein level, P < 0.05). Elevated serum levels of the conjugated bile acids, taurocholic acid and taurodeoxycholic acid, and a reduction in levels of serum ALP, unconjugated bile acid αMCA, and TG were observed (all P < 0.05). In conclusion, swertianlarin significantly up-regulates hepatic bile acid detoxification enzymes and efflux transporters in rats, which can increase the water solubility of hydrophobic bile acids and elimination of conjugated bile acids.

Protective effect of total flavonoids of seabuckthorn (Hippophae rhamnoides) in simulated high-altitude polycythemia in rats.

Seabuckthorn (Hippophae rhamnoides L.) has been used to treat high altitude diseases. The effects of five-week treatment with total flavonoids of seabuckthorn (35, 70, 140 mg/kg, ig) on cobalt chloride (5.5 mg/kg, ip)- and hypobaric chamber (simulating 5,000 m)-induced high-altitude polycythemia in rats were measured. Total flavonoids decreased red blood cell number, hemoglobin, hematocrit, mean corpuscular hemoglobin levels, span of red blood cell electrophoretic mobility, aggregation index of red blood cell, plasma viscosity, whole blood viscosity, and increased deformation index of red blood cell, erythropoietin level in serum. Total flavonoids increased pH, pO2, Sp(O2), pCO2 levels in arterial blood, and increased Na⁺, HCO3⁻, Cl⁻, but decreased K⁺ concentrations. Total flavonoids increased mean arterial pressure, left ventricular systolic pressure, end-diastolic pressure, maximal rate of rise and decrease, decreased heart rate and protected right ventricle morphology. Changes in hemodynamic, hematologic parameters, and erythropoietin content suggest that administration of total flavonoids from seabuckthorn may be useful in the prevention of high altitude polycythaemia in rats.