Zongyao Zou

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 Hypoglycemic and Synergistic Effect of Loganin, Morroniside, and Ursolic Acid Isolated from the Fruits of Cornus officinalis

Hypoglycemic activity‐guided separation of ethanol extracts from the fruits of Cornus officinalis Sieb. et Zucc (CO) led to the isolation of loganin, morroniside, and ursolic acid. The antidiabetic capacity of CO extracts and related compounds was further investigated in diabetes mellitus mice. The results suggested that both CO extracts and pure compounds could ameliorate diabetes‐associated damages and complications. Oral administration of loganin and morroniside decreased fasting blood glucose levels in diabetes mellitus mice. Ursolic acid exhibited the highest reactive oxygen species scavenging activity and α‐glucosidase inhibitory activity. Notably, we noticed an interesting synergistic effect between loganin and ursolic acid. Given these favorable hypoglycemic properties, C. officinalis, a food and medicinal plant in China, may be used as a valuable food supplement for the treatment of diabetes mellitus. Copyright

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.

Hypolipidemic Effects of Alkaloids from Rhizoma Coptidis in Diet-Induced Hyperlipidemic Hamsters

This study was conducted to evaluate the antihyperlipidemic activity of five major alkaloids in Rhizoma Coptidis using high-fat- and high-cholesterol-induced hyperlipidemic hamsters. Hyperlipidemic hamsters were treated with coptisine, berberine, jatrorrhizine, palmatine, epiberberine, and total Rhizoma Coptidis alkaloids with a dose of 46.7 mg/kg × day for 140 days. Serum total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total bile acids were examined after alkaloid treatment. The results showed that all therapy agents prevented body weight gain, reduced the serum total cholesterol, and increased the high-density lipoprotein cholesterol of hamsters. Berberine, jatrorrhizine, and total Rhizoma Coptidis alkaloids decreased the triglyceride level in hyperlipidemic hamsters, while coptisine, jatrorrhizine, palmatine, and total Rhizoma Coptidis alkaloids significantly suppressed the elevation of the low-density lipoprotein cholesterol level. The fecal excretion of bile acids was significantly elevated by berberine, coptisine, jatrorrhizine, palmatine, total Rhizoma Coptidis alkaloids, and orlistat. Notably, total Rhizoma Coptidis alkaloids possess a much stronger lipid-lowering effect than the pure Rhizoma Coptidis alkaloids. Quantitative reverse transcription-polymerase chain reaction analyses revealed that Rhizoma Coptidis alkaloids could retard the synthesis of cholesterol by downregulating the mRNA expression of 3-hydroxy-3-methyl glutaryl coenzyme A reductase and accelerate the clearance of lipids by upregulating the low-density lipoprotein receptor, cholesterol 7α-hydroxylase, and uncoupling protein-2 expression. These findings highlight the critical role of Rhizoma Coptidis alkaloids in hyperlipidemia treatment. Thus, they need to be considered in future therapeutic approaches.

Antihyperglycemia and Antihyperlipidemia Effect of Protoberberine Alkaloids From Rhizoma Coptidis in HepG2 Cell and Diabetic KK-Ay Mice.

Preclinical Research

Rhizoma Coptidis alkaloids alleviate hyperlipidemia in B6 mice by modulating gut microbiota and bile acid pathways.

It is hypothesized that Rhizoma Coptidis (RC) alkaloids exert their hypolipidemic effects primarily by targeting the gastrointestinal tract and liver. Thus, this study was conducted to evaluate the antihyperlipidemic mechanisms of RC alkaloids (at a daily dose of 140mg/kg for 35days) in high-fat and high-cholesterol induced hyperlipidemic B6 mice. After treatment, serum lipid parameters were determined, the expression of lipid metabolism related genes and pathways such as the sterol regulatory element binding proteins (SREBPs) and bile acid signaling in mice were also investigated. Meanwhile, Illumina sequencing was used to investigate the differences in gut microbiota of B6 mice. The results indicated that RC alkaloids reduced the body weight gain and serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), total bile acids (TBA) and lipopolysaccharide of B6 mice. Liver fat deposition and epididymal adipose cell size were also deceased in therapy group. RC alkaloids feeding significantly promoted the abundance of Sporobacter termitidis, Alcaligenes faecalis, Akkermansia muciniphila in the gut of mice, whereas, the abundance of Escherichia coli, Desulfovibrio C21_c20, Parabacteroides distasonis was suppressed. The observed antihyperlipidemic effects of RC alkaloids can also be attributed to their action as agonists of FXR and TGR5, activators for SREBP2, LDLR, UCP2 and CYP7A1, inhibitors of HMGCR, TXNIP, TLR4 and JNK. Therefore, this study expands current knowledge on hypolipidemic mechanisms of RC alkaloids and presents new evidence supporting a key role for RC alkaloids as regulators of lipid homeostasis by modulation gut microbiota and hepatic lipid metabolism.

Hypolipidemic Effect and Mechanism of Palmatine from Coptis chinensis in Hamsters Fed High‐Fat diet

Palmatine (PAL) is one of the main alkaloids in Coptis chinensis. The present aim was to investigate the hypolipidemic effect and mechanism of palmatine in hamsters fed with high‐fat diet (HFD). PAL treatment decreased serum total cholesterol (TC), triglyceride (TG), and low‐density lipoprotein cholesterol (LDL‐C) levels, as well as increased fecal excretion of TC and total bile acids (TBA) in hyperlipidemic hamsters. Furthermore, PAL treatment up‐regulated low‐density lipoprotein receptor (LDLR) and cholesterol 7α‐hydroxylase (CYP7A1) mRNA and protein expression and down‐regulated apical sodium‐dependent bile salt transporter (ASBT) mRNA and protein expression. These results demonstrated that PAL as a potential natural cholesterol lowering agent works by up‐regulating LDLR and CYP7A1 mRNA and protein expression, down‐regulating ASBT mRNA and protein expression, as well as enhancing fecal excretion of TC and TBA. The findings in our study suggest that palmatine could be a potential natural agent for treating hyperlipidemia. Copyright

Activation of Akt and JNK/Nrf2/NQO1 pathway contributes to the protective effect of coptisine against AAPH-induced oxidative stress

Coptisine (COP) is one of the main active constituents of Coptidis Rhizoma. Previous studies have clarified that COP possesses antioxidant activity, but its defensive effects against pathological characteristics accompanied by oxidative damage in animal models and antioxidant mechanism are still unclear. Therefore, our purpose was to confirm the antioxidant activity of COP and explore its mechanism of action. We first detected the effects of COP on intracellular reactive oxygen species (ROS), heart beating rate, lipid peroxidation and cell death in zebrafish model with AAPH-induced oxidative stress. The results showed that COP of 10μg/mL significantly reduced ROS production, the increase of heart beating rate, lipid peroxidation and cell death by 41.3%, 24.5%, 26.5% and 30.0%, respectively. In addition, COP of 0.8μg/mL also decreased ROS, increased glutathione (GSH) content and elevated activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) by 40.1%, 19.8%, 18.3% and 49.3%, respectively in HepG2 cells. Further assays were carried out to explore the mRNA expression in zebrafish and protein expression of key factors in HepG2 cells. We demonstrated that COP up-regulated phase II antioxidant enzymes NAD(P)H/quinone oxidoreductase 1 (NQO1) through activating the nuclear factor erythroid-2 related factor 2 (Nrf2). Moreover, as the upstream signalings of Nrf2, the protein kinase B (Akt) and c-Jun NH2-terminal kinase (JNK) signalings were also induced by COP. And up-regulating Nrf2-mediated NQO1 expression of COP was in Akt and JNK-dependent manner. Taken together, COP exerted its antioxidant activity against AAPH-induced toxicity involving in activating Akt and JNK/Nrf2/NQO1 pathway.

Comparative effect of berberine and its derivative 8-cetylberberine on attenuating atherosclerosis in ApoE−/− mice

&NA; Berberine (BBR), one of the main bioactive compounds in Rhizoma coptidis, has multiple pharmacological activities. It has been reported that 8‐cetylberberine (8‐BBR‐C16) has increased anti‐microbial property in vivo and a higher bioavailability in hamsters. Therefore, in the present study, we used apolipoprotein E‐deficient mice (ApoE−/−) as an atherosclerosis model to investigate the anti‐atherosclerosis effects of 8‐BBR‐C16. After 12 weeks of treatment, the atherosclerotic plaque area of the aorta, serum lipid profile, the plasma redox state and the expression of inflammatory cytokines in ApoE−/− mice were determined. Both BBR and 8‐BBR‐C16 significantly decreased the atherosclerotic plaque area by suppressing inflammatory and oxidative markers in ApoE−/− mice. Treatment with BBR or 8‐BBR‐C16, decreased serum levels of IL‐1&bgr; and TNF‐&agr; as well as mRNA levels of NF‐&kgr;Bp65, i‐NOS, ICAM‐1, IL‐6 in the aorta. In addition, the expression of NF‐&kgr;B p65 protein decreased in the nucleus, whereas I&kgr;B&agr; levels increased in the cytosol. The anti‐inflammatory and anti‐oxidative effect of BBR and 8‐BBR‐C16 attributed to inhibition of the translocation of NF‐&kgr;B to the nucleus. Since the dosage of BBR used was 10 fold higher than that of 8‐cetylberberine, we conclude that 8‐BBR‐C16 is more efficient in treating atherosclerosis in ApoE−/− mice. HighlightsBoth BBR and 8‐BBR‐C16 have potential anti‐atherosclerosis effects in WT diet induced ApoE−/− mice.Both BBR and 8‐BBR‐C16 inhibit oxidation and inflammation cytokine expressions.BBR and 8‐BBR‐C16 inhibit the translocation of NF‐&kgr;B to the nucleus.8‐BBR‐C16 is more efficient in treating atherosclerosis in ApoE−/− mice than BBR.

The protective effect of coptisine on experimental atherosclerosis ApoE−/− mice is mediated by MAPK/NF-κB-dependent pathway

Coptisine is one of main bioactive compounds extracted from the traditional Chinese herbal medicine Rhizoma Coptidis. It is reported that coptisine can attenuate obesity-related inflammation and oxidant damage in Syrian golden hamsters. Therefore，coptisine may exhibit beneficial effects for the treatment of atherosclerosis (AS) due to its hypolipidemic and anti-inflammation activities. The present study investigated the anti-atherosclerotic and anti-inflammatory properties of coptisine using apoE-/- mice as AS model. The atherosclerotic plaque area of aorta, serum lipid profile and the expression of inflammatory cytokines were determined. After coptisine treatment, the serum level of TC, TG and LDL-C decreased; the serum level of IL-6, IL-1β and TNF-α were decreased; the mRNA levels of NF-κBp65, VCAM-1, ICAM-1, IL-6 and IL-1β in both aorta and liver were down-regulated; the p-p38 and p-JNK1/2 protein expression level were decreased. Coptisine decreased atherosclerotic plaque area significantly through both anti-inflammation and lipid lowering effect. The anti-inflammatory effect of coptisine is achieved through inhibiting activation of MAPK signaling pathways and NF-κB nuclear translocation. Therefore，the combined anti-inflammation and lipid lowering effect of coptisine attributed the decreased atherosclerotic plaque area in coptisine treated apoE-/- mice. The results of this study will afford a novel application for coptisine in the treatment of atherosclerosis and other chronic inflammatory disease.