Alpha-Melanocyte-Stimulating Hormone-Mediated Appetite Regulation in the Central Nervous System.

Understanding the complex action mechanism of appetite regulation peptides can significantly impact therapeutic options in the treatment of obesity and other metabolic diseases. Hypothalamic alpha-melanocyte-stimulating hormone (α-MSH) is an anorexigenic peptide, closely related to the occurrence of obesity, playing a central role in food intake and energy expenditure. In the central nervous system, α-MSH is cleaved from proopiomelanocortin and then released into different hypothalamic regions to act on melanocortin 3/4 receptor-expressing neurons, lowering food intake, and raising energy expenditure via appetite suppression and sympathetic nervous system. Furthermore, it can increase the transmission of some anorexigenic hormones (e.g., dopamine) and interact with other orexigenic factors (e.g., agouti-related protein, neuropeptide Y) to influence food reward rather than merely feeding behavior. Therefore, α-MSH is a critical node of the hypothalamus in transmitting appetite suppression signals and is a key component of the central appetite-regulating circuits. Herein, we describe the role of α-MSH in appetite suppression in terms of specific receptors, effector neurons, sites of action, and the interaction with other appetite-relative peptides, respectively. We focus on the role of α-MSH in obesity. The status of research on α-MSH-related drugs is also discussed. With the intention of illuminating a new approach for targeting α-MSH in the hypothalamus as a strategy to manage obesity, we hope to further understand the direct or indirect mechanisms by which α-MSH exerts its appetite-regulating effects.

Recent Research Progress on Natural Stilbenes in Dendrobium Species.

Dendrobium is the second biggest genus in the Orchidaceae family, and many of them have been utilized as a traditional Chinese medicine (TCM) for thousands of years in China. In the last few decades, constituents with great chemical diversity were isolated from Dendrobium, and a wide range of biological activities were detected, either for crude extracts or for pure compounds. Stilbene compound is one of the primary active constituents in the genus Dendrobium. At present, 267 stilbene compounds with clarified molecular structures have been extracted and isolated from 52 species of Dendrobium, including 124 phenanthrenes and 143 bibenzyls. At the same time, activity studies have indicated that 157 compounds have pharmaceutical activity. Among them, most of the compounds showed antitumor activity, followed by antioxidant, anti-inflammatory and anti-α-glucosidase inhibitory activities. Additionally, 54 compounds have multiple pharmacological activities, such as confusarin (14), 2,4,7-trihydroxy-9,10-dihydro-phenanthrene (43), moscatilin (148), gigantol (150) and batatasin III (151). This review summarizes current knowledge about the chemical composition of stilbene, bioactivities and pharmacologic effects in 52 species of Dendrobium. We also expect to provide a reference for further research, development and utilization of stilbene constituents in the Dendrobium genus.

Ameliorating effect on glycolipid metabolism and chemical profile of Millettia speciosa champ. extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Millettia speciosa Champ., also called Niu dali, is a fabaceous medicinal plant mainly distributed in southeast China, where it is a functional food for developing physical strength, and often used traditionally in medicinal treatment of numbness of the wrists, diabetes, hepatitis, and so on. AIM OF THE STUDY: To investigate the chemical profile, ameliorating effects of MSC on glycolipid metabolism in diabetic mice and to identify the possible mechanism of action. MATERIALS AND METHODS: High-performance liquid chromatography coupled with electrospray ionization quadrupole time of flight mass spectrometry (HPLC-ESI-QTOF-MS) was applied to analyze the chemical compositions from M. speciosa extract (MSC). MSC was orally administered to high-fat diet and STZ-induced diabetic mice at doses of 4.55, 9.10 and 13.65 mg/(kg·d) respectively for 10 weeks. Indices of glycolipid metabolism, including fasting blood glucose (FBG), fasting insulin, insulin resistance index (IRI), blood lipids, HPA-axis hormones, and related gene expressions were evaluated. RESULTS: 86 compounds were tentatively identified from MSC, counting for 91.97% of the total extract, mainly including 23 alkaloids (including 2 cyanogenetic glycosides firstly identified in this species, total content accounted to 39.71%), 23 flavonoids (11.91%), 17 acids (including 3 amino acids, 9 phenolic acids and 5 organic acids; 9.2%), 9 terpenoids and steroids (20.13%), 7 esters (3.33%), 3 lignans (3.73%), 3 saccharides (4.0%) and 1 anthraquinone (0.18%). MSC could ameliorate the glycolipid disorder in diabetic mice markedly, and significant regulations on CRH and ACTH hormones were observed. Moreover, the cellular morphology of liver and pancreas were significantly improved and the expressions of IRS2, PI3K, Akt and GLUT4 were significantly up-regulated by MSC treatment. CONCLUSION: This was the first time to study the chemical profile and ameliorating effect on glycolipid metabolism of M. speciosa. It was found to be rich in flavonoids and alkaloids, which might support the potential relation of material foundation and the activity in regulating glycolipid metabolism. The ameliorating effect on glycolipid disorder in diabetic mice might be associated to the regulation of related hormones of the HPA axis and the IRS2/PI3K/Akt/GLUT4 signalling pathway. It was of great significance for advanced directed separation and pharmacological activity research of MSC.

Comprehensive chemical analysis of Zhenshu Tiaozhi formula and its effect on ameliorating glucolipid metabolic disorders in diabetic rats.

The present study aims to reveal the compositions of Zhenshu TiaoZhi formula (FTZ) comprehensively, and investigate whether FTZ ameliorate glucolipid metabolism disorders in diabetic rats with the involvement of glucocorticoids in peripheral insulin-sensitive tissues. The fingerprint was established based on 11 batches of FTZ samples and chemical compostions of FTZ were identified by ultra performance liquid chromatography-time of flight/mass spectrometry (UPLC-TOF/MS). High-fat diet (HFD) and streptozotocin (STZ) induced diabetic rats were orally administrated with 3 and 6 g/kg body weight of FTZ for 8 weeks. Indices of glucolipid metabolism, including fasting blood glucose (FBG), fasting insulin, insulin resistance index (IRI) and blood lipids were evaluated after treatment of FTZ. The levels of HPA axis hormones were examined. Reverse transcription-polymerase chain reaction (RT-PCR) was adopted to investigate the relative mRNA expressions of 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) and glucolipid metabolic indicators. A reference fingerprint was established and 93 compounds of FTZ were tentatively identified. In vivo, FTZ treatment exerted antidiabetic and antidyslipidemic effects while decreased the level of corticotropin releasing hormone (CRH). 11ß-HSD1 mRNA showed similar trajectory in both liver, adipose and skeletal muscle tissues, which was up-regulated in diabetic group and ameliorated in FTZ groups. Furthermore, the expressions of glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK) and adipose triglyceride lipase (ATGL) were down-regulated in liver and skeletal muscle. These results elucidated the compositions of FTZ comprehensively and indicated its effect on ameliorating glucolipid metabolism of diabetic rats involved hypothalamus-pituitary-adrenal (HPA) axis homeostasis. Down-regulating 11ß-HSD1 in insulin-sensitive tissues might be a potential mechanism of FTZ in treating type 2 diabetes mellitus (T2DM).

Chinese Medicine FTZ Recipe Protects against High-Glucose-Induced Beta Cell Injury through Alleviating Oxidative Stress.

OBJECTIVE: To investigate the effect of FTZ on high-glucose-induced oxidative stress and underlying mechanisms. METHODS: We used a ß cell dysfunction and diabetes model that was induced in rats fed a high-fat high-sugar diet (HFHSD) for 6 weeks and injected once with 35 mg/kg streptozocin (STZ). Then, 3 and 6 g/kg of FTZ were administered by gavage for 8 weeks. In addition, an ex vivo model of oxidative stress was induced by stimulating INS-1 cells with 25 mmol/L glucose for 48 h. RESULT: The levels of fasting blood glucose (FBG) in diabetic model rats were obviously higher than those in the normal group; furthermore with reduced levels of ß cells, catalase (CAT), superoxide dismutase (SOD), and Bcl-2 increased lipid peroxide malondialdehyde (MDA) and caspase-3 in the pancreatic tissue of the diabetic model rats. Afterward, the cells were incubated with FTZ-containing serum and edaravone. The 25 mmol/L glucose-induced SOD reduction increased MDA and intracellular ROS. The protein expression level of Mn-SOD and CAT in the model group decreased significantly compared with that in the control group. CONCLUSION: FTZ treatment significantly improved the alteration in the level of SOD, CAT, Bcl-2, caspase-3, and MDA coupled with ß cell dysfunction in diabetic rats. Oxidative stress in INS-1 cells was closely associated with a higher rate of apoptosis, increased production of ROS and MDA, enhanced Bax expression, and caspase-3, -9 activities and markedly decreased protein expression of Mn-SOD and CAT. FTZ-containing serum incubation notably reversed the high-glucose-evoked increase in cell apoptosis, production of ROS and MDA, and Bax protein levels. Furthermore, FTZ stimulation upregulated the expression levels of several genes, including Mn-SOD, CAT, and Bcl-2/Bcl-xl. In addition, FTZ decreased the intracellular activity of caspase-3, -9 in INS-1 cells. FTZ protected ß-cells from oxidative stress induced by high glucose in vivo and in vitro. The beneficial effect of FTZ was closely associated with a decrease in the activity of caspase-3, -9 and intracellular production of ROS, MDA, and Bax coupled with an increase in the expression of Mn-SOD, CAT, and Bcl-2/Bcl-xl.

A new furostanol saponin from Dendrobium chrysanthum Lindl. with cytotoxic activity.

A new furostanol saponin, (25R)-26-O-(α-d-glucopyranosyl)-(1→2)-α-l-rhamnopyranosyl-furost-5-ene-3ß, 22α, 26-triol-3-O-α-d-glucopyranoside (1), together with four known compounds 2-5 were isolated from the ethanolic extract of the stems of Dendrobium chrysanthum Lindl. The structures of these new compounds were identified by extensive spectroscopic analysis including 1D and 2D NMR and HR-ESI-MS, as well as chemical methods. Compounds 1-3 were isolated from D. chrysanthum for the first time. Furthermore, the inhibitory effects of the compounds on tumor cells were evaluated, and compounds 1-2 exhibited significant cytotoxic activities potentially against SPC-A1, MCF-7 and HeLa human cancer cell lines. Compounds 3-5 showed inhibitory activity against the SPC-A1 and MCF-7.

Detection of new phenylpropanoids from Dendrobium chrysanthum.

Herba Dendrobii has been documented in the Compendium of Materia Medica, with special efficacy in nourishing Yin and treating diabetes. However, the chemical profile of Dendrobium chrysanthum Lindl. has not been reported yet. The compositions were analysed with UPLC/Q-TOF-MS/MS. 53 compounds were tentatively characterised, and 14 compounds might be new compounds. Some novel lactones of poly-phenylpropanoids were firstly detected, and di-p-hydroxyphenylpropionic acidic p-coumaric acid lactone, a new compound of the first example, was obtained and identified. UPLC/Q-TOF-MS/MS was a feasible and efficient method to discover the unique compounds in complex matrices of D. chrysanthum.

Activity of Isoliensinine in Improving the Symptoms of Type 2 Diabetic Mice via Activation of AMP-Activated Kinase and Regulation of PPARγ.

This study was designed to explore the effects and mechanism of isoliensinine (isolie) from embryos of Nelumbo nucifera on type 2 diabetes and dyslipidemia in vivo and in vitro. The in vitro study showed that isolie increased the GLUT4 translocation by 2.5-fold in L6 cells. Furthermore, after 4 weeks of treatment, the in vivo biochemical study indexes revealed that isolie had a positive effect on decreasing serum insulin level (42.2 ± 5.10 vs 55.7 ± 6.33 mU/L, P < 0.05) and reducing fast blood glucose (9.4 ± 1.5 vs 18.7 ± 2.3 mmol/L, P < 0.001) and body weight (37.8 ± 2.9 vs 46.9 ± 5.4 g, P < 0.05) compared with the KK-Ay model mice. Isolie treatment led to significant increases in GLUT4 proteins (∼2.7-fold in skeletal muscle and ∼2.4-fold in WAT) and phosphorylated AMP-activated protein kinase (∼1.4-fold in skeletal muscle, ∼3.1-fold in WAT, and ∼2.3-fold in liver). However, isolie caused a significant decrease in lipogenesis protein expressions of PPARγ and SREBP-1c, and decreased the activity of ACC by increasing the phospho-ACC level. Our findings showed that isolie has the potential to alleviate type 2 diabetes associated with hyperlipidemia in KK-Ay mice. Regulation of GLUT4, SREBP-1c, PPARγ, AMPK phosphorylation, and ACC phosphorylation is implicated in the antidiabetic effects of isolie.

Two new megastigmanes from Chinese traditional medicinal plant Sedum sarmentosum.

To discover new bioactive compounds from nature plants, a primary screening of traditional Chinese medicines had been taken. The screening results showed that a EtOAc extract of Sedum sarmentosum displayed a certain degree of cytotoxic activity and bioassay-directed isolation of EtOAc extract gave two new megastigmanes, (6S,9R)-2-hydroxy-4-(2,6,6-trimethyl-4-oxo-cyclohex-2-enyl)-butyric acid (1) and (6S,9R)-2-hydroxy-4-(2,6,6-trimethyl-4-oxo-cyclohex-2-enyl)-butyric acid methyl ester (2) together with seven known flavonoids. The chemical structures of 1 and 2 were elucidated on the basis of detailed 1D, 2D NMR and MS data. When tested against HepG2 and Hep3B hepatocellular carcinoma cell lines, compounds 1-9 showed weak anti-HCC activity. In addition, in vitro antioxidant activities of 1-9 were evaluated by ABTS radical cation-scavenging assay. 1 and 2 exhibited weak activity with per micromoles equivalent to 0.039 and 0.042 µM of Trolox, respectively. The flavonoid component, quercetin (9) showed the highest antioxidant activities with per micromoles equivalent 0.67 µM of Trolox.

Chemical profiling of anti-hepatocellular carcinoma constituents from Caragana tangutica Maxim. by off-line semi-preparative HPLC-NMR.

An EtOAc fraction from the roots of Caragana tangutica Maxim. (CTEA) displayed promising anti-hepatocellular carcinoma (HCC) activity during screening of a traditional Chinese ethnic herb library against HepG2 and Hep3B cell lines. HPLC-based activity profiling of CTEA by combination of MS-guided large-scale semi-preparative HPLC and NMR methods led to the identification of a new pterocarpan glycoside, (-)-maackiain 3-O-6'-O-methyl malonyl-ß-d-glucopyranoside (1), together with three known pterocarpan glycosides, (-)-maackiain 3-O-ß-d-glucopyranoside (2), 3-O-6'-O-acrylyl-ß-d-galactopyranoside (3), and (-)-maackiain 3-O-6'-O-acetyl-ß-d-glucopyranoside (4). Compound 1 was isolated during a drug discovery programme aimed at identifying new anti-HCC leads from a natural product library. Anti-HCC study showed that all four compounds exhibited cytotoxic activity with IC50 values range of 29.1-53.5 µg/mL against HepG2 and Hep3B cell lines.

Potent protein tyrosine phosphatase 1B (PTP1B) inhibiting constituents from Anoectochilus chapaensis and molecular docking studies.

CONTEXT: Anoectochilus chapaensis Gagnep. (Orchidaceae), an indigenous and valuable Chinese folk medicine, has been used as an antidiabetic remedy. However, the bioactive constituents have not been reported. OBJECTIVE: To explore potent protein tyrosine phosphatase 1B (PTP1B) inhibitors from the whole herbs of A. chapaensis for the treatment of diabetes. MATERIALS AND METHODS: The compounds were obtained by PTP1B bioactivity-guided isolation from the active fraction of ethonal extract of A. chapaensis, and elucidated by extensive spectroscopic methods and evaluated for their potential to inhibit PTP1B with a series of doses in dimethyl sulphoxide by a colorimetric assay in vitro. The Autodock program was used to dock the active compounds into the binding sites. RESULTS: Fifteen compounds were identified; epifriedelanol, friedelane, 2α, 3ß-dihydroxyolean-12-en-23, 28, 30-trioic acid, dibutyl-phthalate, and 7-hydroxy-2-methoxy-9,10-dihydrophenanthrene-1,4-dione were isolated from the genera Anoectochilus for the first time. All 15 compounds were tested for their inhibitory activity against PTP1B in vitro. Nine active compounds exhibited potent inhibitory effect with IC50 values of 1.16-6.21 µM, which were comparable with the positive control suramin. The 3D-docking simulations showed negative binding energies of -7.4 to -8.5 kcal/mol and supported a high affinity to PTP1B residues in the pocket site, indicating that they may stabilize the open form and generate tighter binding to the catalytic sites of PTP1B. DISCUSSION AND CONCLUSION: The results clearly demonstrated that the potential active constituents from A. chapaensis could inhibit PTP1B, which may be mainly attributed to a combination of triterpenoids and flavonoids.

Effects of the novel pyrimidynyloxybenzoic herbicide ZJ0273 on enzyme activities, microorganisms and its degradation in Chinese soils.

Enzyme activity and microbial population in soils have important roles in keeping soil fertility. ZJ0273 is a novel pyrimidynyloxybenzoic-based herbicide, which was recently developed in China. The effect of ZJ0273 on soil enzyme activity and microbial population in two different soils was investigated in this study for the first time. The protease activity was significantly inhibited by ZJ0273 and this inhibiting effect gradually weakened after 60-day incubation. The results also showed that ZJ0273 had different stimulating effects on the activities of dehydrogenase, urease, and catalase. Dehydrogenase was consistently stimulated by all the applied concentrations of ZJ0273. The stimulating effect on urease weakened after 60-day incubation. Catalase activity was subject to variations during the period of the experiments. The results of microbial population showed that the number of bacteria and actinomycetes increased in ZJ0273-treated soil compared with the control after 20 days of incubation, while fungal number decreased after only 10 days of incubation in soils. DT50 (half-life value) and k (degradation rate constant) of ZJ0273 in S1 (marine-fluvigenic yellow loamy soil) and S2 (Huangshi soil) were found 69.31 and 49.50 days and 0.010 and 0.014 day(-1), respectively.

Stimulating effect of a new triterpene derived from Anoectochilus elwesii on glucose uptake in insulin-resistant human HepG2 cells.

A new triterpene (1), 3-ß-O-olean-11,13 (18)-diene-23,28-dioic acid, together with five known compounds (2-6), was isolated from Anoectochilus elwesii and their structures were elucidated by extensive spectroscopic methods and comparison with the literature data. Compound 1 was the first example of highly oxygenated triterpene obtained from Anoectochilus genus. The isolated compounds were evaluated on insulin-resistant human HepG2 cells for stimulating glucose uptake activity and the new compound displayed highly potent effect on the stimulation of glucose uptake in human HepG2 cells.

[Study on chemical constituents from Anoectochilus chapaensis].

OBJECTIVE: To investigate the chemical constituents from the whole herbs of Anoectochilus chapaensis. METHODS: The chemical constituents were isolated and purified by repeated column chromatographies with silica gel, Sephadex LH-20 and preparative TLC. Their structures were identified by their physiochemical property and spectral data. RESULTS: 6 compounds were isolated and elucidated as follows: (1) Friedelin, (2) Sorghumol, (3) 5alpha, 8alpha-epidioxyergost-22-en-3beta-ol, (4) Stearic acid, (5) Octadecane and (6) Epifriedelanol. CONCLUSION: Compound (1), (2) and (4) are isolated from this plant for the first time, and compound (3), (5) and (6) are isolated from genera Anoectochilus for the first time.

[Studies on chemical constituents from Anoectochilus roxburghii].

OBJECTIVE: To investigate the chemical constituents from Anoectochilus roxburghii. METHODS: The compounds were isolated and purified by repeated column chromatographies with silica gel, Macroporous resin and Sephadex LH-20, and their structures were identified by their physical and spectral datas. RESULTS: Ten compounds were isolated and elucidated as: beta-D-glucopyranosyl-(3R)-hydroxybutanolide (I), stearic acid (II), palmitic acid (III), beta-sitosterol (IV) and succinic acid (V), p-hydroxy benzaldehyde (VI), daucosterol (VII), and methyl 4-beta-D-glucopyranosyl-hutanoate (VIII); as well as p-hydroxy cinnamic acid (IX) and o-hydroxy phenol (X) were identified. CONCLUSION: Compound I ,VIII, X are firstly isolated from this species.

Antihyperglycemic activity of kinsenoside, a high yielding constituent from Anoectochilus roxburghii in streptozotocin diabetic rats.

Different doses of kinsenoside, a high yielding constituent from Anoectochilus roxburghii, was orally administered to further investigate its biological activity and pharmacological mechanisms that involve in the hypoglycemic effect on streptozotocin (STZ) diabetic rats. Our study showed that this compound exhibited significantly antihyperglycemic activity at the dose of 15mg/kg body weight, which is speculated to be partially attributed to modulating the activity of enzymatic antioxidants, scavenging free radicals, and reducing the content of factor NO. Much more intact beta cells in the islets of Langerhans with denser insulin in kinsenoside-treated groups than the negative control were observed, which greatly supported the morphological and functional elucidation. These results displayed that kinsenoside could be useful for repairing beta cells in pancreatic islet injury as well as improving its function. The OGTT evidenced that this compound could promote the glucose tolerance of acute glucose increase in both diabetic and normal healthy rats.