Design and Synthesis of Novel Indole Ethylamine Derivatives as a Lipid Metabolism Regulator Targeting PPARα/CPT1 in AML12 Cells.

Peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) are important targets of lipid metabolism regulation for nonalcoholic fatty liver disease (NAFLD) therapy. In the present study, a set of novel indole ethylamine derivatives (4, 5, 8, 9) were designed and synthesized. The target product (compound 9) can effectively activate PPARα and CPT1a. Consistently, in vitro assays demonstrated its impact on the lipid accumulation of oleic acid (OA)-induced AML12 cells. Compared with AML12 cells treated only with OA, supplementation with 5, 10, and 20 µM of compound 9 reduced the levels of intracellular triglyceride (by 28.07%, 37.55%, and 51.33%) with greater inhibitory activity relative to the commercial PPARα agonist fenofibrate. Moreover, the compound 9 supplementations upregulated the expression of hormone-sensitive triglyceride lipase (HSL) and adipose triglyceride lipase (ATGL) and upregulated the phosphorylation of acetyl-CoA carboxylase (ACC) related to fatty acid oxidation and lipogenesis. This dual-target compound with lipid metabolism regulatory efficacy may represent a promising type of drug lead for NAFLD therapy.

Inhibition of Src/STAT3 signaling-mediated angiogenesis is involved in the anti-melanoma effects of dioscin.

Angiogenesis plays an important role in the growth and metastasis of solid tumors including melanoma. Inhibiting tumor-associated angiogenesis is a tactic in treating melanoma. Dioscin restrains angiogenesis in colon tumor and has anti-melanoma effects in cell and animal models. In a previous study, we found that dioscin inhibits Src/STAT3 signaling in melanoma cells. Activation of the Src/STAT3 pathway has been shown to promote tumor angiogenesis. This study aimed to determine whether dioscin's anti-melanoma effects is related to inhibiting Src/STAT3 signaling-mediated angiogenesis. In a B16F10 allograft mouse model, we found that dioscin inhibited melanoma growth and angiogenesis. To exclude the impact of tumor growth on angiogenesis, a chicken chorioallantoic membrane (CAM) model was used to verify the anti-angiogenic effect of dioscin. Results showed that dioscin suppressed vessel formation in CAM. To determine if tumor secreted pro-angiogenic cytokines are involved in the anti-angiogenic effect of dioscin, conditioned media from dioscin-treated A375 melanoma cells were used to culture human umbilical vein endothelial cells (HUVECs), and tube formation was monitored. It was observed that the tube formation of HUVECs was inhibited. Mechanistic studies revealed that dioscin inhibited the activation of Src and STAT3, and lowered mRNA and protein levels of STAT3 transcriptionally-regulated genes, in B16F10 melanomas. ELISA assays showed that dioscin decreased the secretion of MMP-2, MMP-9 and VEGF from A375 cells. Over-activation of STAT3 lessened the effects of dioscin in decreasing the secretion of pro-angiogenic cytokines from melanoma cells, and in inhibiting tube formation of HUVECs cultured with conditioned media from melanoma cell cultures. In summary, we for the first time demonstrated that inhibiting Src/STAT3 signaling-mediated angiogenesis is involved in the anti-melanoma effects of dioscin. This study provides further pharmacological groundwork for developing dioscin as an anti-melanoma agent.

Gomisin N Exerts Anti-liver Cancer Effects and Regulates PI3K-Akt and mTOR-ULK1 Pathways in Vitro.

Primary liver cancer is a lethal cancer. The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway has been implicated in the pathogenesis of liver cancer. Gomisin N (GN), a lignan isolated from the dried fruits of Schisandra chinensis (Turca.) Baill., has been reported to reduce viability of, and induce apoptosis in, HepG2 liver cancer cells. In preadipocytes, GN was found to inhibit Akt activity. In the present study, Akt signaling-related anti-liver cancer mechanisms of GN were investigated. We confirmed that GN reduces cell viability of, and triggers apoptosis in, more liver cancer cell lines. Mechanistic studies revealed that GN lowers protein levels of phospho-PI3K (p85 tyrosine (Tyr)458), phospho-Akt (serine (Ser)473), and Akt downstream molecules Mcl-1 in HepG2 and HCCLM3 cells. Meanwhile, GN activates mTOR and inhibits ULK1 (a negative downstream effector of mTOR) activities. Activation of mTOR has been reported to suppress ULK1 activity and repress autophagy. Indeed, we observed that GN inhibits autophagy in liver cancer cells. In summary, we for the first time demonstrated that GN inhibits the PI3K-Akt pathway and regulates the mTOR-ULK1 pathway in liver cancer cells.

A TCM formula comprising Sophorae Flos and Lonicerae Japonicae Flos alters compositions of immune cells and molecules of the STAT3 pathway in melanoma microenvironment.

A traditional Chinese medicine (TCM) formula (SL) comprising Sophorae Flos and Lonicerae Japonicae Flos was used for treating melanoma in ancient China. We have previously shown that an ethanolic extract of SL (SLE) possesses anti-melanoma effects and suppresses STAT3 signaling in vitro and in vivo. STAT3 has been linked to the development of melanoma immunosuppressive microenvironment. In this work, we investigated whether SLE inhibits melanoma growth by reprogramming the tumor microenvironment in mouse and co-culture cell models. In B16F10 melanoma-bearing mice, we found that intragastric administration of SLE (1.2 g/kg) dramatically inhibited tumor growth. This observation was associated with the downregulation of protein levels of phospho-STAT3 (Tyr 705) and STAT3-regulated immunosuppressive cytokines, and mRNA levels of STAT3-targeted genes involved in tumor growth and immune evasion. We also observed increased Th, Tc and dendritic cells in the melanomas and spleens in SLE-treated mice compared to that in control mice. In a co-culture system composed of B16F10 cells and mouse primary splenic lymphocytes, it was found that SLE not only inhibited STAT3 activation in B16F10 cells, but also downregulated mRNA levels of STAT3-targeted genes in the splenic lymphocytes. In this co-culture setting, SLE decreased the levels of STAT3-regulated immunosuppressive cytokines, increased the percentages of Th, Tc and dendritic cells as well. Furthermore, effects of SLE on STAT3 phosphorylation, cytokine levels and immune cell subtype percentages were significantly weaker in the B16STAT3C cells (stable cells harboring a constitutively active STAT3 variant STAT3C)/splenic lymphocytes co-culture system than in the B16V cells (cells stably transfected with the empty vector)/splenic lymphocytes co-culture system, indicating that STAT3 over-activation diminishes SLE's effects. In summary, our findings indicate that reprograming the immune microenvironment, partially mediated by inhibiting STAT3 signaling, contributes to the anti-melanoma mechanisms of SLE. This study provides further pharmacological groundwork for developing SLE as a modern agent for melanoma prevention/treatment, and supports the notion that reprograming immunosuppressive microenvironment is a viable anti-melanoma strategy.

The JAK2/STAT3 pathway is involved in the anti-melanoma effects of atractylenolide I.

In this study, we aimed to investigate the anti-melanoma effects and the JAK2/STAT3 pathway-related mechanism of action of atractylenolide I in human melanoma cells. Our results showed that atractylenolide I effectively reduced viability, induced apoptosis and inhibited migration of melanoma cells. Meanwhile, atractylenolide I decreased the protein expression levels of phospho-JAK2 and phospho-STAT3, and in turn downregulated the mRNA levels of STAT3-targeted genes, including Bcl-xL, MMP-2 and MMP-9. Furthermore, the cytotoxic effect of atractylenolide I was attenuated in STAT3-overactivated A375 cells. These findings indicate that inhibition of JAK2/STAT3 signalling contributes to the anti-melanoma effects of atractylenolide I.

Comparison of the chemical profiles and inflammatory mediator-inhibitory effects of three Siegesbeckia herbs used as Herba Siegesbeckiae (Xixiancao).

BACKGROUND: Herba Siegesbeckiae (HS, Xixiancao in Chinese) is a commonly used traditional Chinese medicinal herb for soothing joints. In ancient materia medica books, HS is recorded to be the aerial part of Siegesbeckia pubescens Makino (SP) which is also the only origin of HS in the 1963 edition of the Chinese Pharmacopeia (ChP). The aerial parts of Siegesbeckia orientalis L. (SO) and Siegesbeckia glabrescens Makino (SG) have been included as two additional origins for HS in each edition of ChP since 1977. However, chemical and pharmacological comparisons among these three species have not been conducted. METHODS: An HPLC with diode array detector (HPLC-DAD) method combined with similarity analysis, hierarchical cluster analysis (HCA) and principal component analysis (PCA) was developed for comparing the fingerprint chromatograms of the three species. The inhibitory effects of the three species on NO production and IL-6 secretion in LPS-stimulated RAW264.7 macrophages were compared. RESULTS: Fingerprint chromatograms of the three species showed different profiles, but had 13 common peaks. Results from HCA and PCA of the common peaks demonstrated that all 14 herbal samples of the three species tended to be grouped and separated species dependently. The extents of inhibition on NO production and IL-6 secretion of the three species were different, with SG being the most and SP the least potent. CONCLUSIONS: Both chemical profiles and inflammatory mediator-inhibitory effects of the three species were different. These findings provide a chemical and pharmacological basis for determining whether the three species can all serve as the origins of HS.

The anticancer and antiobesity effects of Mediterranean diet.

Cancers have been the leading cause of death worldwide and the prevalence of obesity is also increasing in these few decades. Interestingly, there is a direct association between cancer and obesity. Each year, more than 90,000 cancer deaths are caused by obesity or overweight. The dietary pattern in Crete, referred as the traditional Mediterranean diet, is believed to confer Crete people the low mortality rates from cancers. Nevertheless, the antiobesity effect of the Mediterranean diet is less studied. Given the causal relationship between obesity and cancer, the antiobesity effect of traditional Mediterranean diet might contribute to its anticancer effects. In this regard, we will critically review the anticancer and antiobesity effects of this diet and its dietary factors. The possible mechanisms underlying these effects will also be discussed.

Biochemical mechanism underlying hypertriglyceridemia and hepatic steatosis/hepatomegaly induced by acute schisandrin B treatment in mice.

BACKGROUND: It has been demonstrated that acute oral administration of schisandrin B (Sch B), an active dibenzocyclooctadiene isolated from Schisandrae Fructus (a commonly used traditional Chinese herb), increased serum and hepatic triglyceride (TG) levels and hepatic mass in mice. The present study aimed to investigate the biochemical mechanism underlying the Sch B-induced hypertriglyceridemia, hepatic steatosis and hepatomegaly. METHODS: Male ICR mice were given a single oral dose of Sch B (0.25-2 g/kg). Sch B-induced changes in serum levels of biomarkers, such as TG, total cholesterol (TC), apolipoprotein B48 (ApoB 48), very-low-density lipoprotein (VLDL), non-esterified fatty acid (NEFA) and hepatic growth factor (HGF), as well as hepatic lipids and mass, epididymal adipose tissue (EAT) and adipocyte size, and histological changes of the liver and EAT were examined over a period of 12-120 h after Sch B treatment. RESULTS: Serum and hepatic TG levels were increased by 1.0-4.3 fold and 40-158% at 12-72 h and 12-96 h, respectively, after Sch B administration. Sch B treatment elevated serum ApoB 48 level (up to 12%), a marker of exogenous TG, but not VLDL, as compared with the vehicle treatment. Treatment with Sch B caused a time-/dose-dependent reduction in EAT index (up to 39%) and adipocyte size (up to 67%) and elevation in serum NEFA level (up to 55%). Sch B treatment induced hepatic steatosis in a time-/dose-dependent manner, as indicated by increases in total vacuole area (up to 3.2 fold vs. the vehicle control) and lipid positive staining area (up to 17.5 × 103 µm2) in liver tissue. Hepatic index and serum HGF levels were increased by 18-60% and 42-71% at 12-120 h and 24-72 h post-Sch B dosing, respectively. In addition, ultrastructural changes, such as increase in size and disruption of cristae, in hepatic mitochondria were observed in Sch B-treated mice. CONCLUSION: Our findings suggest that exogenous sources of TG and the breakdown of fat storage in the body contribute to Sch B-induced hypertriglyceridemia and hepatic steatosis in mice. Hepatomegaly (a probable hepatotoxic action) caused by Sch B may result from the fat accumulation and mitochondrial damage in liver tissue.

[Status and suggestions for adjuvant standard for Chinese materia medica processing in China].

In this paper, the status of adjuvant standard for Chinese materia medica processing in the Chinese Pharmacopoeia 2015 edition, the National Specification of Chinese Materia Medica Processing, and the 29 provincial specification of Chinese materia medica was summarized, and the the status including general requirements, specific requirements, and quality standard in the three grade official specifications was collected and analyzed according to the "medicine-adjuvant homology" and "food-adjuvant homology" features of adjuvants. This paper also introduced the research situation of adjuvant standard for Chinese materia medica processing in China; In addition, analyzed and discussed the problems existing in the standard system of adjuvant for Chinese materia medica processing, such as lack of general requirements, low level of standard, inconsistent standard references, and lack of research on the standard, and provided suggestions for the further establishment of the national standards system of adjuvant for Chinese materia medica processing.

The genus Rosa and arthritis: Overview on pharmacological perspectives.

The genus Rosa (roses) has long been used in traditional or folk medicine worldwide for the treatment of various types of arthritis including rheumatoid arthritis and osteoarthritis. The active constituents of Rosa spp., such as flavonoids, triterpenoids, and phytosterols, could act on different targets in the NF-κB signalling pathway, inhibit pro-inflammatory enzymes (e.g. MMPs and COX-2), lower the production of inflammatory cytokines and chemokines (e.g. TNF-α, IL-1ß, IL-6, CCL5), and reduce oxidative stress, which in turn suppress inflammatory processes. Preclinical and clinical studies have demonstrated that these species possess analgesic, anti-arthritic, anti-inflammatory, anti-oxidative and bone-preserving activities. This review presents comprehensive overview of the mode and mechanism of action of various extracts, preparations, and active constituents from this genus. The dynamic beneficial effects of the products prepared from this genus in arthritis management are summarized. The Rosa genus is a treasure waiting for further exploration by researchers interested in the development of safe and effective anti-arthritic agents.

Ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry analysis of the impact of processing on toxic components of Kansui Radix.

BACKGROUND: Kansui Radix (Gansui in Chinese), the dried tuber of Euphorbia kansui, is a Chinese medicinal herb commonly used for the treatment of oedema and ascites with dyspnea. Because of its toxic nature, the herb is usually processed with vinegar to reduce the toxicity. A report has shown that the contents of toxic terpenoids in Gansui decreased after processing with vinegar. However, comprehensive comparison of the chemical profiles between vinegar-processed and raw Gansui has not yet been conducted. METHODS: An ultra-high-performance liquid chromatography in conjunction with ultra-high resolution quadrupole time-of-flight mass spectrometry (UHPLC UHD Q-TOF MS/MS) method was developed for the analysis of chemical profiles of vinegar-processed and raw Gansui in this study. RESULTS: Results showed that processing with vinegar caused conspicuous chemical changes. Among the altered components, 11 toxic terpenoids, 3-O-benzoyl-13-O- dodecanoylingenol/20-O-benzoyl-13-O-dodecanoylingenol, kansuinine D, kansuinine A, 3-O-benzoyl-13-O-dodecanoylingenol/20-O-benzoyl-13-O-dodecanoylingenol, 3-O- benzoylingenol/20-O-benzoylingenol, 20-O-(2'E,4'Z-decadienoyl)ingenol/20-O-(2'E,4'E- decadienoyl)ingenol/3-O-(2'E,4'Z-decadienoyl)ingenol/3-O-(2'E,4'E-decadienoyl)ingenol, 3-O-(2'E,4'Z-decadienoyl)-20-deoxyingenol,3-O-(2'E,4'Z-,ecadienoyl)-5-O-acetylingenol,3-O-(2'E,4'Z-decadienoyl)-20-O-acetylingenol,3-O-(2,3-dimethylbutanoyl)-13-O-dodecanoylingenol, were tentatively identified. The contents of most of these terpenoids were obviously decreased after processing with reductions of 6.66-95.25%. CONCLUSION: Our findings could help us understand the chemical basis for the toxicity reduction of Gansui afforded by processing with vinegar. Further investigations are warranted to establish the relationship between processing-induced chemical changes and the reduction of toxicity of Gansui.

Comparison of the toxicities, activities and chemical profiles of raw and processed Xanthii Fructus.

BACKGROUND: Although toxic, the Chinese medicinal herb Xanthii Fructus (XF) is commonly used to treat traditional Chinese medicine (TCM) symptoms that resemble cold, sinusitis and arthritis. According to TCM theory, stir-baking (a processing method) can reduce the toxicity and enhance the efficacy of XF. METHODS: Cytotoxicities of raw XF and processed XF (stir-baked XF, SBXF) were determined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay in normal liver derived MIHA cells. Nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) mRNA expression were measured by the Griess reagent and quantitative real-time PCR, respectively. The chemical profiles of XF and SBXF were compared using an established ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS) method. RESULTS: SBXF was less toxic than XF in MIHA cells. Both XF and SBXF had anti-inflammatory effects as demonstrated by their abilities to reduce nitric oxide production as well as inducible nitric oxide synthase mRNA expression in lipopolysaccharide-stimulated RAW 264.7 macrophages. Interestingly, the anti-inflammatory effects of SBXF were more potent than that of XF. By comparing the chemical profiles, we found that seven peaks were lower, while nine other peaks were higher in SBXF than in XF. Eleven compounds including carboxyatractyloside, atractyloside and chlorogenic acid corresponding to eleven individual changed peaks were tentatively identified by matching with empirical molecular formulae and mass fragments, as well as literature data. CONCLUSION: Our study showed that stir-baking significantly reduced the cytotoxicity and enhanced the anti-inflammatory effects of XF; moreover, with a developed ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry method we differentiated XF and SBXF by their chemical profiles. Further studies are warranted to establish the relationship between the alteration of chemical profiles and the changes of medicinal properties caused by stir-baking.

Subcutaneous adipocytes promote melanoma cell growth by activating the Akt signaling pathway: role of palmitic acid.

Tumorigenesis involves constant communication between tumor cells and neighboring normal cells such as adipocytes. The canonical function of adipocytes is to store triglyceride and release fatty acids for other tissues. This study was aimed to find out if adipocytes promoted melanoma cell growth and to investigate the underlying mechanism. Here we isolated adipocytes from inguinal adipose tissue in mice and co-cultured with melanoma cells. We found that the co-cultured melanoma had higher lipid accumulation compared with mono-cultured melanoma. In addition, fluorescently labeled fatty acid BODIPY® FLC16 signal was detected in melanoma co-cultured with the adipocytes that had been loaded with the fluorescent dye, suggesting that the adipocytes provide fatty acids to melanoma cells. Compared with mono-cultured melanoma, co-cultured melanoma cells had a higher proliferation and phospho-Akt (Ser-473 and Thr-450) expression. Overexpression of Akt mutants in melanoma cells reduced the co-culture-enhanced proliferation. A lipidomic study showed that the co-cultured melanoma had an elevated palmitic acid level. Interestingly, we found that palmitic acid stimulated melanoma cell proliferation, changed the cell cycle distribution, and increased phospho-Akt (Ser-473 and Thr-450) and PI3K but not phospho-PTEN (phosphophosphatase and tensin homolog) expressions. More importantly, the palmitic acid-stimulated proliferation was further enhanced in the Akt-overexpressed melanoma cells and was reduced by LY294002 or knockdown of endogenous Akt or overexpression of Akt mutants. We also found that palmitic acid-pretreated B16F10 cells were grown to a significantly larger tumor in mice compared with control cells. Taken together, we suggest that adipocytes may serve as an exogenous source of palmitic acid that promotes melanoma cell growth by activating Akt.

Quercetin inhibits HGF/c-Met signaling and HGF-stimulated melanoma cell migration and invasion.

BACKGROUND: Melanoma is notorious for its propensity to metastasize, which makes treatment extremely difficult. Receptor tyrosine kinase c-Met is activated in human melanoma and is involved in melanoma progression and metastasis. Hepatocyte growth factor (HGF)-mediated activation of c-Met signaling has been suggested as a therapeutic target for melanoma metastasis. Quercetin is a dietary flavonoid that exerts anti-metastatic effect in various types of cancer including melanoma. In a previous report, we demonstrated that quercetin inhibited melanoma cell migration and invasion in vitro, and prevented melanoma cell lung metastasis in vivo. In this study, we sought to determine the involvement of HGF/c-Met signaling in the anti-metastatic action of quercetin in melanoma. METHODS: Transwell chamber assay was conducted to determine the cell migratory and invasive abilities. Western blotting was performed to determine the expression levels and activities of c-Met and its downstream molecules. And immunoblotting was performed in BS(3) cross-linked cells to examine the homo-dimerization of c-Met. Quantitative real-time PCR analysis was carried out to evaluate the mRNA expression level of HGF. Transient transfection was used to overexpress PAK or FAK in cell models. Student's t-test was used in analyzing differences between two groups. RESULTS: Quercetin dose-dependently suppressed HGF-stimulated melanoma cell migration and invasion. Further study indicated that quercetin inhibited c-Met phosphorylation, reduced c-Met homo-dimerization and decreased c-Met protein expression. The effect of quercetin on c-Met expression was associated with a reduced expression of fatty acid synthase. In addition, quercetin suppressed the phosphorylation of c-Met downstream molecules including Gab1 (GRB2-associated-binding protein 1), FAK (Focal Adhesion Kinase) and PAK (p21-activated kinases). More importantly, overexpression of FAK or PAK significantly reduced the inhibitory effect of quercetin on the migration of the melanoma cells. CONCLUSIONS: Our findings suggest that suppression of the HGF/c-Met signaling pathway contributes to the anti-metastatic action of quercetin in melanoma.

New perspectives on dietary-derived treatments and food safety-antinomy in a new era.

Despite the advances in science and technology and wide use of chemical drugs, dietary intervention (or food therapy) remains useful in preventing or treating many human diseases. A huge body of evidence shows that the dietary pattern or habit is also an important contributing factor to the development of chronic diseases such as hypertension, type 2 diabetes, hyperlipidemia, and cancers. In recent years, over-the-counter health foods, nutraceuticals, and plant-derived medicinal products have been gaining popularity all over the world, particularly in developed countries. Unfortunately, owing to the contamination with various harmful substances in foods and the presence of toxic food components, food-borne diseases have also become increasingly problematic. Incidents of food poisonings or tainted food have been increasing worldwide, particularly in China and other developing countries. Therefore, the government should put in a greater effort in enforcing food safety by improving the surveillance mechanism and exerting highest standards of quality control for foods.

A comparative study between Wuweizi seed and its post-ethanol extraction residue in normal and hypercholesterolemic mice.

BACKGROUND: At the present, a shift from drug therapy, especially herbal therapy, to dietary supplementation is a trend in the management of dyslipidemia and related diseases. Therefore, the optimal utilization of herbal resource is important for a sustainable development of herbal medicine. Here, we compared the effects of dietary supplementation with Chinese medicine Schisandrae Chinensis Fructus seed (FSC-S) and the post-ethanol extraction residue of FSC-S (FSC-SpEt) on normal diet-fed (normal) and experimental hypercholesterolemic (HCL) mice. METHODS: Male ICR mice (n = 10 in each group), weighing 17-21 g, were fed with normal diet (ND) or high cholesterol/bile salt (1/0.3 %, w/w) diet (HCBD) with or without supplemented with FSC-S, FSC-SpEt), or lipid-lowering agent fenofibrate (FF). Ten days later, serum/hepatic lipid and glucose (GLU) levels, body weight, organ/epididymal fat masses, and food/water intake were measured. Lipid level measurements included those of total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), HDL/LDL ratio, LDL/HDL ratio, and non-HDL (N-HDL). RESULTS: Supplementation with FSC-S and FSC-SpEt increased serum TC (by 64 and 25 %, respectively) and LDL (by 60 and 27 %, respectively) in normal mice. FSC-S supplementation elevated serum TC, TG, HDL, LDL, and LDL/HDL ratio (up to 64, 118, 77, 197, and 51 %, respectively) in HCL mice. FSC-SpEt supplementation reduced serum TG (by 15 %) and LDL/HDL ratio (by 18 %), as well as increased serum HDL (by 22 %) and HDL/LDL ratio (by 21 %) in HCBD-fed mice. FSC-S decreased hepatic TC (by 19 %) contents and increased hepatic TG contents by 14 % in normal mice. FSC-S reduced hepatic GLU level in both normal and HCL mice by 24 and 22 %, respectively. Hepatic TC and TG contents were lowered in FSC-SpEt-supplemented normal mice by 16 and 20 %, respectively. The body/fatty masse and food intake were lowered, but the feed efficiency index (FEI), weight gain per unit of food ingested, was increased in FSC-S-supplemented normal and HCL mice. FF supplements reduced serum/hepatic lipids, hepatic GLU contents, and epididymal fat mass, but it induced hepatomegaly and high serum alanine aminotransferase (ALT) activity in normal and/or HCL mice. CONCLUSION: The ensemble of results indicated that while FSC-SpEt supplementation is beneficial for the treatment of hyperlipidemia/fatty liver, FSC-S is potentially useful for the management of overweight/obesity.

The herbal compound cryptotanshinone restores sensitivity in cancer cells that are resistant to the tumor necrosis factor-related apoptosis-inducing ligand.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis and kills cancer cells but not normal cells. However, TRAIL resistance due to low level of TRAIL receptor expression is widely found in cancer cells and hampers its development for cancer treatment. Thus, the agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are urgently needed. We investigated whether tanshinones, the major bioactive compounds of Salvia miltiorrhiza (danshen), can up-regulate TRAIL receptor expression. Among the major tanshinones being tested, cryptotanshinone (CT) showed the best ability to induce TRAIL receptor 2 (DR5) expression. We further showed that CT was capable of promoting TRAIL-induced cell death and apoptosis in A375 melanoma cells. CT-induced DR5 induction was not cell type-specific, as DR5 induction was observed in other cancer cell types. DR5 knockdown abolished the enhancing effect of CT on TRAIL responses. Mechanistically, induction of the DR5 by CT was found to be p53-independent but dependent on the induction of CCAAT/enhancer-binding protein-homologous protein (CHOP). Knockdown of CHOP abolished CT-induced DR5 expression and the associated potentiation of TRAIL-mediated cell death. In addition, CT-induced ROS production preceded up-regulation of CHOP and DR5 and consequent sensitization of cells to TRAIL. Interestingly, CT also converted TRAIL-resistant lung A549 cancer cells into TRAIL-sensitive cells. Taken together, our results indicate that CT can potentiate TRAIL-induced apoptosis through up-regulation of DR5.

Inhibition of STAT3 signalling contributes to the antimelanoma action of atractylenolide II.

Our previous studies showed that atractylenolide II (AT-II) has antimelanoma effects in B16 melanoma cells. In this study, we investigated the involvement of STAT3 signalling in the antimelanoma action of AT-II. Daily administration of AT-II (12.5, 25 mg/kg, i.g.) for 14 days significantly inhibited tumor growth in a B16 xenograft mouse model and inhibited the activation/phosphorylation of STAT3 and Src in the xenografts. In B16 and A375 cells, AT-II (20, 40 µm) treatment for 48 h dose-dependently reduced protein expression levels of phospho-STAT3, phospho-Src, as well as STAT3-regulated Mcl-1 and Bcl-xL. Overexpression of a constitutively active variant of STAT3, STAT3C in A375 cells diminished the antiproliferative and apoptotic effects of AT-II. These data suggest that inhibition of STAT3 signalling contributes to the antimelanoma action of AT-II. Our findings shed new light on the mechanism of action underlying the antimelanoma effects of AT-II and provide further pharmacological basis for developing AT-II as a novel melanoma chemopreventive/chemotherapeutic agent.

UHPLC UHD Q-TOF MS/MS analysis of the impact of sulfur fumigation on the chemical profile of Codonopsis Radix (Dangshen).

Over recent decades sulfur fumigation has been becoming abused in processing some freshly harvested Chinese medicinal herbs, although it is questioned whether sulfur fumigation can result in changes in efficacy and safety of the herbs. One of the herbs commonly processed by sulfur fumigation is Codonopsis Radix (Dangshen). A report showed that lobetyolin content in sulfur-fumigated Dangshen was lower than in air-dried Dangshen. Whereas there is no investigation designed to compare the chemical profiles of the sulfur-fumigated Dangshen and the air-dried Dangshen. In the present study, a rapid and versatile ultra-high-performance liquid chromatography coupled with ultra-high resolution quadrupole time-of-flight mass spectrometry (UHPLC UHD Q-TOF MS/MS) method was developed for comprehensive analysis of the chemical profiles of sulfur-fumigated and air-dried Dangshen samples. Principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) demonstrated that there were significant chemical differences between sulfur-fumigated and air-dried Dangshen samples. Among the changed components, 57 compounds were identified, in which 15 sulfur-containing compounds were detected only in sulfur-fumigated samples. The established methods were successfully applied to discriminate sulfur-fumigated Dangshen among commercial samples. Whether the chemical changes caused by sulfur fumigation affect the clinical efficacy and safety of Dangshen needs to be further investigated.

Dietary pulp from Fructus Schisandra Chinensis supplementation reduces serum/hepatic lipid and hepatic glucose levels in mice fed a normal or high cholesterol/bile salt diet.

BACKGROUND: Recently, it has been found that Fructus Schisandra Chinensis (FSC), a Chinese herbal medicine, and its related compounds have a profound impact on lipid metabolism process. FSC can be divided into two parts, i.e., seed and pulp. The current study aimed to examine the effect of aqueous extracts of FSC pulp (AqFSC-P) on serum/hepatic lipid and glucose levels in mice fed with a normal diet (ND) or a high cholesterol/bile salt diet (HCBD). METHODS: The AqFSC-P used in the present study was fractionated into supernatant (SAqFSC-P) and precipitate (PAqFSC-P) separated by centrifugation. Male ICR mice were fed with ND or HCBD, without or with supplementation of 1%, 3%, or 9% (w/w) SAqFSC-P or PAqFSC-P for 10 days. Biomarkers were determined according to the manufacturer's instruction. RESULTS: Supplementation with SAqFSC-P or PAqFSC-P significantly reduced serum and hepatic triglyceride levels (approximately 40%) in ND- and/or HCBD-fed mice. The supplementation with SAqFSC-P or PAqFSC-P reduced hepatic total cholesterol levels (by 27-46%) in HCBD-fed mice. Supplementation with SAqFSC-P or PAqFSC-P markedly lowered hepatic glucose levels (by 13-30%) in ND- and HCBD-fed mice. SAqFSC-P decreased serum alanine aminotransferase (ALT) activity, but PAqFSC-P increased hepatic protein contents in ND-fed mice. Bicylol, as a positive control, reduced ALT activity. In addition, mice supplemented with FSC-P or bicylol showed a smaller body weight gain and adipose tissue mass as compared to the respective un-supplemented ND- or HCBD-fed mice. CONCLUSION: The results indicate that SAqFSC-P and PAqFSC-P produce hepatic lipid- and glucose-lowering as well as serum TG-lowering effects in hypercholesterolemic mice. FSC pulp may provide a safe alternative for the management of fatty liver and/or lipid disorders in humans.