- [Show abstract] [Hide abstract] ABSTRACT: Obesity and its major co-morbidity, type 2 diabetes, have reached an alarming epidemic prevalence without an effective treatment available. It has been demonstrated that inhibition of SREBP pathway may be a useful strategy to treat obesity with type 2 diabetes. Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the expression of genes involved in biosynthesis of cholesterol, fatty acid and triglyceride. In current study, we identified a small molecule, curcumin, inhibited the SREBP expression in vitro. The inhibition of SREBP by curcumin decreased the biosynthesis of cholesterol and fatty acid. In vivo, curcumin ameliorated HFD-induced body weight gain and fat accumulation in liver or adipose tissues, and improved serum lipid levels and insulin sensitivity in HFD-induced obese mice. Consistently, curcumin regulates SREBPs target genes and metabolism associated genes in liver or adipose tissues, which may directly contribute to the lower lipid level and improvement of insulin resistance. Take together, curcumin, a major active component of Curcuma longa could be a potential leading compound for development of drugs for the prevention of obesity and insulin resistance.
- [Show abstract] [Hide abstract] ABSTRACT: Plantaginis Semen is commonly used in traditional medicine to treat edema, hypertension, and diabetes. The commercially available Plantaginis Semen in China mainly come from three species. In order to clarify the chemical composition and distinct different species of Plantaginis Semen, we established a metabolite profiling method based on ultra high performance liquid chromatography with electrospray ionization quadrupole time-of-flight tandem mass spectrometry coupled with elevated energy technique. A total of 108 compounds, including phenylethanoid glycosides, flavonoids, guanidine derivatives, terpenoids, organic acids, and fatty acids, were identified from Plantago asiatica L., P. depressa Willd., and P. major L. Results showed significant differences in chemical components among the three species, particularly flavonoids. This study is the first to provide a comprehensive chemical profile of Plantaginis Semen, which could be involved into the quality control, medication guide, and developing new drug of Plantago seeds. This article is protected by copyright. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Two new alkaloids, plantadeprate A (1) and 1'-(4″-hydroxybutyl)plantagoguanidinic acid (2), along with three known compounds, were isolated from the seeds of Plantago depressa. Their structures were elucidated by physical data analyses including NMR, MS, and electronic circular dichroism (ECD) methods. Plantadeprate A (1), a monoterpene zwitterionic guanidium, possesses a unique 5/5/6-tricyclic ring system. Its absolute configuration was determined by X-ray crystallography and computational methods. Compound 1, plumbagine D (3), and plantagoguanidinic acid (4) exhibited potential antihyperglycemic properties attributed to suppression of hepatic gluconeogenesis with inhibitory rates of 8.2%, 18.5%, and 12.5% at 40 μM, respectively.
- [Show abstract] [Hide abstract] ABSTRACT: Currently, obesity has become a worldwide epidemic associated with Type 2 diabetes, dyslipidemia, cardiovascular disease and chronic metabolic diseases. Emodin is one of the active anthraquinone derivatives from Rheum palmatum and some other Chinese herbs with anti-inflammatory, anticancer and hepatoprotective properties. In the present study, we investigated the anti-obesity effects of emodin in obese mice and explore its potential pharmacological mechanisms. Male C57BL/6 mice were fed with high-fat diet for 12 weeks to induce obesity. Then the obese mice were divided into four groups randomly, HFD or emodin (40mg/kg/day and 80mg/kg/day) or lovastatin (30mg/kg/ day) for another 6 weeks. Body weight and food intake were recorded every week. At the end of the treatment, the fasting blood glucose, glucose and insulin tolerance test, serum and hepatic lipid levels were assayed. The gene expressions of liver and adipose tissues were analyzed with a quantitative PCR assay. Here, we found that emodin inhibited sterol regulatory element-binding proteins (SREBPs) transactivity in huh7 cell line. Furthermore, emodin (80mg/kg/day) treatment blocked body weight gain, decreased blood lipids, hepatic cholesterol and triglyceride content, ameliorated insulin sensitivity, and reduced the size of white and brown adipocytes. Consistently, SREBP-1 and SREBP-2 mRNA levels were significantly reduced in the liver and adipose tissue after emodin treatment. These data demonstrated that emodin could improve high-fat diet-induced obesity and associated metabolic disturbances. The underlying mechanism is probably associated with regulating SREBP pathway.
- [Show abstract] [Hide abstract] ABSTRACT: Angiotensin-converting enzyme (ACE) plays a critical role in rennin-angiotensin system. Recently, natural products isolated from herbal medicines revealed inhibitory effects against ACE which suggested their potential activities in regulating blood pressure. In this study, ACE inhibition (ACEI) of 21 phenylethanoid glycosides and related phenolic compounds were investigated by measuring the production of HA a rapid, sensitive, accurate and specific ultra-performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-MS/MS) method. The test compounds showed different inhibitory potencies on ACE ranging from 5.29 to 95.01% at 50 mM, and the compounds with ACEI higher than 50% were selected for further IC50 determination. The IC50 values were from 0.53 ± 0.04 to 15.035 ± 0.036 mM. The structure-inhibition relationship were then explored and the result showed that cinnamoyl groups played an essential role in ACEI of phenylethanoid glycosides. Furthermore, the sub-structures of increasing ACEI for phenylethanoid glycosides is more hydroxyls and less steric hindrance to chelate the active site Zn2+ of ACE. In summary, our results suggested that phenylethanoid glycosides are a widely available source of anti-hypertensive natural products and the information provided from structure-inhibition relationship study could aid the design of structurally modified phenylethanoid glycosides as anti-hypertensive drugs.
- [Show abstract] [Hide abstract] ABSTRACT: The toxicity assessment of herbal medicines is important for human health and appropriate utilization of these medicines. However, challenges have to be overcome because of the complexity of coexisting multiple components in herbal medicines and the highly interconnected organismal system. In this study, a target profiling approach was established by combining the characteristic fingerprint analysis of herbal chemicals with potential toxicity through a precursor ion scan-based mass spectroscopy and the target profiling analysis of biomarkers responsible for the toxicity. Through this newly developed approach, the comparative hepatotoxicity assessment of two herbal medicines from the same genus, Senecio vulgaris L. and Senecio scandens Buch.-Ham, was performed. Significant differences were found between the two species in their chemical markers (i.e., pyrrolizidine alkaloids) and biomarkers (i.e., bile acids) responsible for their toxicities. This result was consistent with the conventional toxicity assessment conducted by histopathological examination and clinical serum index assay on experimental animal models. In conclusion, this study provided a new approach for the hepatotoxicity assessment of herbal medicines containing pyrrolizidine alkaloids, which are widely distributed in various herbal medicines. The target profiling approach may shed light on the toxicity assessment of other herbal medicines with potential toxicity.
- [Show abstract] [Hide abstract] ABSTRACT: Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the expression of genes involved in biosynthesis of cholesterol, fatty acid and triglyceride. We investigated the effect of the specific SREBP suppressor andrographolide, a natural compound isolated from Andrographis paniculata, on the regulation of SREBP signaling by western blot, reporter gene assay and Q-PCR analysis. In addition, the anti-obesity effects of andrographolide were evaluated in C57BL/6 mice with high-fat diet (HFD)-induced obesity. Our results showed that andrographolide downregulated the expressions of SREBPs target genes and decreases cellular lipid accumulation in vitro. Further, andrographolide (100 mg/kg/day) attenuated HFD-induced body weight gain and fat accumulation in liver or adipose tissues, and improved serum lipid levels and insulin or glucose sensitivity in HFD-induced obese mice. Meanwhile, andrographolide effectively suppressed the respiratory quotient (RQ), energy expenditure (EE) and their oxygen consumption, which might contribute to the decreased body-weight gain of the obese mice fed with a HFD. Consistently, andrographolide regulates SREBPs target genes and metabolism associated genes in liver or brown adipose tissue (BAT), which may directly contribute to the lower lipid level and enhanced insulin sensitivity. Take together, andrographolide ameliorates lipid metabolism and improved glucose utilization in the HFD-induced obesity mice. Therefore, andrographolide could be a potential leading compound used for the prevention or treatment of obesity and insulin resistance.
- [Show abstract] [Hide abstract] ABSTRACT: Pyrrolizidine alkaloids (PAs) are among the most hepatotoxic natural products that produce irreversible injury to humans via consumption of herbal medicine, tea preparation, and honey. Toxicity and death caused by PA exposure have been reported worldwide. Metabolomics and genomics provide scientific and systematic views of living organism, and have become powerful techniques for toxicology research. In this study, senecionine hepatotoxicity on rats was determined via a combination of metabolomic and genomic analyses. From the global analysis generated from two omics data, the compromised bile acid homeostasis in vivo was innovatively demonstrated and confirmed. Serum profiling of bile acids was altered with significantly elevated conjugated bile acids after senecionine exposure, which was in accordance with toxicity. Similarly, the hepatic mRNA levels of several key genes associated with bile acid metabolism were significantly changed. This process included cholesterol 7- hydroxylase, bile acid CoA-amino acid N-acetyltransferase, sodium taurocholate co-transporting polypeptide, organic anion-transporting polypeptides, and multi-drug-resistance-associated protein 3. In conclusion, cross-omics study provides a comprehensive analysis method for studying the toxicity caused by senecionine, which is a hepatotoxic PA. Moreover, the change in bile acid metabolism and the respective transporters may provide a new PA toxicity mechanism.
- [Show abstract] [Hide abstract] ABSTRACT: In this study, metabolites in the urine samples of rats orally administered with acteoside, a phenylethanoid glycoside compound, were detected and identified using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC/ESI-QTOF-MS) combined with an automated MS(E) technique. Up to 35 metabolites (19 metabolites of the parent drug and 16 metabolites of the degradation products) were observed, including processes of oxidization, glucuronidation, sulfation, and methyl conjugation. According to the metabolic pathways, acteoside mainly functioned as a prodrug and underwent hydrolysis before being absorbed into the blood. The degradation products, especially caffeic acid and hydroxytyrosol, were involved in further metabolism which was responsible for the low oral bioavailability but obvious pharmacological activities of acteoside. In summary, this work provided valuable information on acteoside metabolism through the rapid and reliable UPLC/ESI-QTOF-MS technique, which could be widely used for the investigation of natural product metabolites.
- [Show abstract] [Hide abstract] ABSTRACT: Phenylethanoid glycosides are a group of phenolic compounds with diverse biological activities such as hypotensive, diuretic, and hypoglycemic effects. In this study, a target profiling analysis approach using ultra-performance liquid chromatography coupled with tandem quadrupole mass spectrometry (MS) was established on the basis of parent ion scanning for m/z 161, the characteristic product ion for phenylethanoid glycosides. It was successfully employed to discriminate the chemical composition of phenylethanoid glycosides between Plantaginis Herba and Plantaginis Semen, two medicinal parts of Plantago plants, which are widely used as herbal medicine in China. Totally, 34 phenylethanoid glycosides were characterized and tentatively identified by their retention times, MS, and tandem quadrupole MS (MS/MS) data. Combined with chemometrics analysis of principal component analysis and orthogonal projection to latent structural discriminate analysis, eight of them, especially acteoside and plantamajoside, were picked out and contributed to the chemical distinction between Plantaginis Herba and Plantaginis Semen, which might be responsible for the differences in diuretic and hypotensive effects between the two medicinal parts. This new approach for target profiling provides not only a novel idea for specific analysis of active chemical constituents in the same type, but also a promising and reference method for quality evaluation of traditional Chinese medicines.
- [Show abstract] [Hide abstract] ABSTRACT: To establish a method for quick investigating the absorption ingredients of Plantaginis semen and guiding the index selection for its quality control. The absorption of three concentrations of Plantaginis semem was investigated with the in vitro everted intestinal sac (VEIS) model The intestinal sac contents of jejunum and ileum were collected at different time and geniposidic acid was detected by HPLC and LC-MS(n) as the representative marker. Six ingredients could be detected. At different concentrations of Plantaginis semen, geniposidic acid tested by VEIS showed that there was a good linear correlation between the drug absorption from the medium across the intestinal epithelium into the sac contents in various intestines section. The absorption of the gut sacs from 0 to 90 min manifested a significant time-dependent manner. The Ka of geniposidic acid in the jejunum and ileum increased along with the raised dosage of the Plantaginis Semen (P < 0.05), which indicated a passive absorption manner. This method can be used as a tool to investigate the absorption ingredients of Plantaginis Semen. Comparing with the jejunum, the ileum can provide more absorption information faster. The optimal incubation time in intestinal sac was 90 min.
Shanghai University of Traditional Chinese MedicineShanghai, Shanghai Shi, China