Tetrahydrocurcumin Upregulates the Adiponectin-AdipoR Pathway and Improves Insulin Signaling and Pancreatic ß-Cell Function in High-Fat Diet/Streptozotocin-Induced Diabetic Obese Mice.

Impairment of adiponectin production and function is closely associated with insulin resistance and type 2 diabetes, which are linked to obesity. Studies in animal models have documented the anti-diabetic effects of tetrahydrocurcumin (THC). Although several possible mechanisms have been proposed, the contribution of adiponectin signaling on THC-mediated antihyperglycemic effects remains unknown. Here, we report that adiposity, steatosis, and hyperglycemia were potently attenuated in high-fat diet/streptozotocin-induced diabetic obese mice after they received 20 and 100 mg/kg THC for 14 weeks. THC upregulated UCP-1 in adipose tissue and elevated adiponectin levels in the circulation. THC upregulated the AdipoR1/R2-APPL1-mediated pathway in the liver and skeletal muscle, which contributes to improved insulin signaling, glucose utilization, and lipid metabolism. Furthermore, THC treatment significantly (p < 0.05) preserved islet mass, reduced apoptosis, and restored defective insulin expression in the pancreatic ß-cells of diabetic obese mice, which was accompanied by an elevation of AdipoR1 and APPL1. These results demonstrated a potential mechanism underlying the beneficial effects of THC against hyperglycemia via the adiponectin-AdipoR pathway, and thus, may lead to a novel therapeutic use for type 2 diabetes.

A mixture of citrus polymethoxyflavones, green tea polyphenols and lychee extracts attenuates adipogenesis in 3T3-L1 adipocytes and obesity-induced adipose inflammation in mice.

Adipocyte-macrophage interaction in obesity can cause adipose tissue inflammation and contribute to insulin resistance. Here, we investigated the effect of SlimTrym®-a formulated product containing citrus polymethoxyflavones (PMFs), green tea extract, and lychee polyphenols-on 3T3-L1 adipocyte differentiation and obesity-induced inflammation. SlimTrym® inhibited mitotic clonal expansion (MCE) of 3T3-L1 adipocytes by inducing G1 cell cycle arrest via upregulation of p21 and p53. SlimTrym® attenuated adipogenic differentiation by downregulating adipogenic factors, such as CCAAT-enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor γ (PPARγ), and upregulating AMP-activated protein kinase (AMPK). Pretreatment with compound C significantly reduced SlimTrym®-mediated suppression of lipid accumulation. SlimTrym® reduced the expression of pro-inflammatory cytokines, including monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-1ß and IL-6, in co-cultured 3T3-L1 adipocytes and RAW264.7 macrophages. C57BL/6 mice administered with SlimTrym® for 16 weeks showed markedly reduced high-fat diet (HFD)-induced infiltration of monocytes/macrophages in adipose tissue; however, the level of M2 macrophage markers (CD163 and IL-10) was increased. Taken together, these findings indicate that SlimTrym® exerts both anti-adipogenic and anti-inflammatory effects, and can potentially treat obesity and adipose tissue inflammation.

Combination of citrus polymethoxyflavones, green tea polyphenols, and Lychee extracts suppresses obesity and hepatic steatosis in high-fat diet induced obese mice.

SCOPE: SlimTrym® is a formulated product composed of citrus polymethoxyflavones (PMFs), green tea extract, and lychee extract. We investigated the effect of dietary SlimTrym® on diet-induced obesity and associated non-alcoholic fatty liver disease (NAFLD) in mice. METHODS AND RESULTS: Male C57BL/6 mice were fed a normal diet (ND), high fat diet (HFD) or HFD containing 0.1% or 0.5% SlimTrym® for 16 weeks. Dietary SlimTrym® significantly reduced weight gain and relative perigonadal, retroperitoneal, mesenteric fat weight as well as the size of adipocyte in HFD-fed mice. SlimTrym® supplementation also effectively diminished hepatic steatosis and the serum levels of glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), triacylglycerol (TG), and total cholesterol (TCHO). Down-regulation of peroxisome proliferator-activated receptor (PPAR)γ, sterol regulatory element-binding protein (SREBP)-1, and the activation of AMP-activated protein kinase (AMPK) signaling by SlimTrym® in both adipose tissue and liver may be responsible for the observed anti-obesity effects. CONCLUSION: SlimTrym® supplementation potentially diminished diet-induced obesity and hepatic steatosis via regulating AMPK signaling and molecules involved in lipid metabolism.

Chemoprevention of nonalcoholic fatty liver disease by dietary natural compounds.

Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver disease that is not from excess alcohol consumption, but is often associated with obesity, type 2 diabetes, and metabolic syndrome. NAFLD pathogenesis is complicated and involves oxidative stress, lipotoxicity, mitochondrial damage, insulin resistance, inflammation, and excessive dietary fat intake, which increase hepatic lipid influx and de novo lipogenesis and impair insulin signaling, thus promoting hepatic triglyceride accumulation and ultimately NAFLD. Overproduction of proinflammatory adipokines from adipose tissue also affects hepatic metabolic function. Current NAFLD therapies are limited; thus, much attention has been focused on identification of potential dietary substances from fruits, vegetables, and edible plants to provide a new strategy for NAFLD treatment. Dietary natural compounds, such as carotenoids, omega-3-PUFAs, flavonoids, isothiocyanates, terpenoids, curcumin, and resveratrol, act through a variety of mechanisms to prevent and improve NAFLD. Here, we summarize and briefly discuss the currently known targets and signaling pathways as well as the role of dietary natural compounds that interfere with NAFLD pathogenesis.

Chemopreventative effects of tetrahydrocurcumin on human diseases.

Chemoprevention is a relatively new and promising strategy to prevent human degenerative diseases, including cancer, and is defined as the use of natural dietary compounds and/or synthetic substances to block, inhibit, reverse, or retard the progress of human diseases. Tetrahydrocurcumin (THC) is a major metabolite of curcumin (extracted from the roots of the Curcuma longa Linn). THC has been demonstrated to prevent oxidative stress and inflammation, to act against neurodegeneration, and to possess anti-cancer activity. In this review, we summarize the current knowledge and underlying molecular mechanisms of the chemopreventative activities of THC and its potential effects on the development of various human diseases.

Inhibitory effects of Momordica grosvenori Swingle extracts on 12-O-tetradecanoylphorbol 13-acetate-induced skin inflammation and tumor promotion in mouse skin.

Our previous data showed that the Momordica grosvenori Swingle extract (MSE) exhibited the anti-inflammatory effect through markedly suppressed LPS-induced up-regulation of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) and ODC (ornithine decarboxylase) gene expression in RAW 264.7 cells. Regarding the link between inflammation and carcinogenesis, we further investigated the bio-molecular mechanisms of both anti-inflammatory and anti-tumor activities in vivo using a TPA (12-O-tetradecanoyl phorbol 13-acetate)-stimulated mouse skin model. Pretreatment with MSE in mouse skin has led to the reduction of TPA-induced nuclear translocation of the nuclear factor-κB (NFκB) subunits as well as phosphorylation of IκBα and p65 subsequent reduction of IκBα degradation. In addition, the MSE inhibitory effect on upstream of NFκB was found to involve the transcriptional effects of MAPK signaling as indicated by strong suppression on TPA-induced activation of extracellular signal regulate kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK)1/2, phosphatidylinositol 3-kinase (PI3K) and Akt. Moreover, MSE significantly inhibited 7,12-dimethylbenz[a]anthracene (DMBA)-TPA-induced skin tumor formation in mice measured by the tumor multiplicity of papillomas at 20 weeks. The results suggested that MSE contained promising functional ingredients capable of preventing inflammation-associated tumorigenesis.

Suppression of adipogenesis and obesity in high-fat induced mouse model by hydroxylated polymethoxyflavones.

This study demonstrated that hydroxylated polymethoxyflavones (HPMFs) effectively and dose-dependently suppressed accumulation of lipid droplets in adipocytes by approximately 51-55%. Western blot analysis revealed that HPMFs markedly down-regulated adipogenesis-related transcription factors peroxisome proliferator-activated receptor (PPAR) γ and sterol regulatory element-binding protein (SREBP)-1c as well as downstream target fatty acid binding protein 2 (aP2), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). In addition, HPMFs also activated adenosine monophosphate-activated protein kinase (AMPK) signaling in 3T3-L1 adipocytes. In the early phase of adipogenesis, HPMF-treated preadipocytes displayed a delayed cell cycle entry into G2/M phase at 24 h (35.5% for DMI group and 4.8% for 20 µg/mL HPMFs-treated group) after initiation of adipogenesis. Furthermore, administration of HPMFs (0.25 and 1%) decreased high-fat diet (HFD) induced weight gain (15.3 ± 3.9 g for HFD group, 10.3 ± 0.3 g and 7.9 ± 0.7 g for 0.25 and 1% HPMFs groups, respectively) and relative perigonadal, retroperitoneal, mesenteric fat weight in C57BL/6 mice. Administration of HPMFs reduced serum levels of aspartate aminotransferase (GOT), alanine aminotransferase (GPT), triglycerides (TG), and total cholesterol (T-cho). The results suggested that HPMFs may have a potential benefit in preventing obesity.

Phyto-power dietary supplement potently inhibits dimethylnitrosamine-induced liver fibrosis in rats.

Curcumin has been extensively studied for its therapeutic effects in a variety of disorders. Fermented soy consumption is associated with a low incidence rate of chronic diseases in many Asian countries. The aim of this study was to investigate the potential underlying mechanisms of the effect of a phyto-power dietary supplement on liver fibrosis. Sprague-Dawley rats were intraperitoneally injected with dimethylnitrosamine (DMN; 10 mg kg(-1)) three times a week for four consecutive weeks. A phyto-power dietary supplement (50 or 100 mg kg(-1)) was administered by oral gavage daily for four weeks. Liver morphology, function, and fibrotic status were examined in DMN induced hepatic fibrogenesis. However, a phyto-power dietary supplement alleviated liver damage as indicated by histopathological examination of the α-smooth muscle actin (α-SMA) and collagen I, accompanied by the concomitant reduction of transforming growth factor-ß1 (TGF-ß1) and matrix metalloproteinase 2 (MMP2). These data indicate that the phyto-power dietary supplement may inhibit the TGF-ß1/Smad signaling and relieve liver damage in experimental fibrosis.

Xanthigen suppresses preadipocyte differentiation and adipogenesis through down-regulation of PPARγ and C/EBPs and modulation of SIRT-1, AMPK, and FoxO pathways.

Xanthigen is a source of punicic acid and fucoxanthin derived from pomegranate seed and brown seaweed, respectively with recognized triacylglycerol-lowering effects in humans, yet the mechanism remains to be fully elucidated. The present study investigated the inhibitory effects of Xanthigen, fucoxanthin, and punicic acid (70% in pomegranate seed oil) on the differentiation of 3T3-L1 preadipocytes. Xanthigen potently and dose-dependently suppressed accumulation of lipid droplets in adipocytes compared to its individual components, fucoxanthin and pomegranate seed oil. Western blot analysis revealed that Xanthigen markedly down-regulated the protein levels of key adipogenesis transcription factors peroxisome proliferator-activated receptor (PPAR)γ, CCAAT/enhancer binding protein (C/EBP) ß, and C/EBPδ as well as a key enzyme involved in adipogenesis, fatty acid synthase (FAS). Xanthigen up-regulated the NAD(+)-dependent histone deacetylases (SIRT1) and activated AMP-activated protein kinase (AMPK) signaling in differentiated 3T3-L1 adipocytes. In addition, Xanthigen may also stimulate insulin trigger signaling and result in Akt-dependent phosphorylation of forkhead/winged helix O (FoxO)1 and FoxO3a. These results indicate that Xanthigen suppresses adipocyte differentiation and lipid accumulation through multiple mechanisms and may have applications for the treatment of obesity.

Does conductance catheter measurement system give consistent and reliable pressure-volume relations in rats?

The conductance catheter technique was developed in the 1980s to measure instantaneous ventricular conductance. After converting measured conductance to volume signals by use of the classic Baan conductance-to-volume equation, real-time pressure-volume (PV) relations can be obtained. A nonlinear conductance-to-volume conversion equation was proposed by Wei in 2005 to improve the accuracy of the conductance catheter system. This study tested the in vivo applicability of the nonlinear conversion equation, particularly focusing on the effect of deviation in catheter position. By altering catheter position, PV loops obtained by using the classic Baan's equation and the nonlinear equation were compared. The comparison results show that the nonlinear equation indeed compensates for the errors introduced by catheter position deviation, and gives more consistent and reliable PV relations. Moreover, the effect of variations in blood resistivity was analyzed. To obtain consistent and reliable PV relations, the nonlinear equation is suggested for use, and changes in blood resistivity should be carefully monitored.

Rosmanol potently induces apoptosis through both the mitochondrial apoptotic pathway and death receptor pathway in human colon adenocarcinoma COLO 205 cells.

Rosemary (Rosmarinus officinalis), a culinary spice and medicinal herb, has been widely used in European folk medicine to treat numerous ailments. Many studies have shown that rosemary extracts play important roles in anti-inflammation, anti-tumor, and anti-proliferation in various in vitro and in vivo settings. The roles of tumor suppression of rosemary have been attributed to the major components, including carnosic acid, carnosol, and rosmarinic acid, rosmanol, and ursolic acid. This study was to explore the effect of rosmanol on the growth of COLO 205 human colorectal adenocarcinoma cells and to delineate the underlying mechanisms. When treated with 50 µM of rosmanol for 24h, COLO 205 cells displayed a strong apoptosis-inducing response with a 51% apoptotic ratio (IC(50) ∼42 µM). Rosmanol increased the expression of Fas and FasL, led to the cleavage and activation of pro-caspase-8 and Bid, and mobilized Bax from cytosol into mitochondria. The mutual activation between tBid and Bad decreased the mitochondrial membrane potential and released cytochrome c and apoptosis-inducing factor (AIF) to cytosol. In turn, cytochrome c induced the processing of pro-caspase-9 and pro-caspase-3, followed by the cleavage of poly-(ADP-ribose) polymerase (PARP) and DNA fragmentation factor (DFF-45). These results demonstrate that the rosmanol-induced apoptosis in COLO 205 cells is involvement of caspase activation and involving complicated regulation of both the mitochondrial apoptotic pathway and death receptor pathway.

Anti-inflammatory activity of traditional Chinese medicinal herbs.

Accumulating epidemiological and clinical evidence shows that inflammation is an important risk factor for various human diseases. Thus, suppressing chronic inflammation has the potential to delay, prevent, and control various chronic diseases, including cerebrovascular, cardiovascular, joint, skin, pulmonary, blood, lymph, liver, pancreatic, and intestinal diseases. Various natural products from traditional Chinese medicine (TCM) have been shown to safely suppress proinflammatory pathways and control inflammation-associated disease. In vivo and/or in vitro studies have demonstrated that anti-inflammatory effects of TCM occur by inhibition of the expression of master transcription factors (for example, nuclear factor-κB (NF-κB)), pro-inflammatory cytokines (for example, tumor necrosis factor-α (TNF-α), chemokines (for example, chemokine (C-C motif) ligand (CCL)-24), intercellular adhesion molecule expression and pro-inflammatory mediators (for example, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2)). However, a handful of review articles have focused on the anti-inflammatory activities of TCM and explore their possible mechanisms of action. In this review, we summarize recent research attempting to identify the anti-inflammatory constituents of TCM and their molecular targets that may create new opportunities for innovation in modern pharmacology.

Induction of apoptosis by [8]-shogaol via reactive oxygen species generation, glutathione depletion, and caspase activation in human leukemia cells.

Ginger, the rhizome of Zingiber officinale , is a traditional medicine with a carminative effect and antinausea, anti-inflammatory, and anticarcinogenic properties. This study examined the growth inhibitory effects of [8]-shogaol, one of the pungent phenolic compounds in ginger, on human leukemia HL-60 cells. It demonstrated that [8]-shogaol was able to induce apoptosis in a time- and concentration-dependent manner. Treatment with [8]-shogaol caused a rapid loss of mitochondrial transmembrane potential, stimulation of reactive oxygen species (ROS) production, release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 and procaspase-3 processing. Taken together, these results suggest for the first time that ROS production and depletion of glutathione that contributed to [8]-shogaol-induced apoptosis in HL-60 cells.

Garcinol inhibits cell growth in hepatocellular carcinoma Hep3B cells through induction of ROS-dependent apoptosis.

Garcinol, derived from Garcinia indica and other related species, has been found to modulate several cell signalling pathways involved in apoptosis and cancer development. Growth arrest and DNA damage-inducible gene 153 (GADD153) is a member of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors; it is expressed at low levels under normal conditions but strongly induced upon growth arrest, DNA damage, and endoplasmic reticulum (ER) stress. This study investigated the effect of garcinol on Hep3B cells, a human hepatocellular cancer cell line lacking functional p53, with the goal of elucidating the molecular mechanisms of p53-independent apoptosis in hepatocellular cancer. Overall, garcinol activated not only the death receptor and the mitochondrial apoptosis pathways but also the ER stress modulator GADD153. Garcinol treatment led to the accumulation of reactive oxygen species (ROS), increased GADD153 expression, and reduced mitochondrial membrane potential. An increase in the Bax/Bcl-2 ratio resulted in enhanced apoptosis. Caspase-8 and tBid (truncated Bid) expression also increased in a time-dependent manner. The enzymatic activities of caspase-3 and caspase-9 increased approximately 13-fold and 7.8-fold, respectively. In addition, the proteolytic cleavage of poly-(ADP-ribose)-polymerase (PARP) and DNA fragmentation factor-45 (DFF-45) increased in dose- and time-dependent manners. Our data suggest a promising therapeutic application of garcinol in p53-independent apoptosis in cancers.

Ent-kaurane diterpenoids from Rabdosia rubescens and their cytotoxic effects on human cancer cell lines.

Two new ent-kaurane diterpenoids, 16,17-exo-epoxide-oridonin ( 1) and 11,15- O,O-diacetyl-rabdoternins D ( 2), together with thirteen known ones, were isolated from the aerial parts of Rabdosia rubescens. Their structures were established on the basis of high-field 1D and 2D NMR methods supported by HRMS. All diterpenoids were tested for cytotoxicity against human Hep G2, COLO 205, MCF-7, and HL-60 cancer cells. The compounds oridonin ( 3), 14- O-acetyl-oridonin ( 4), 1,14- O,O-diacetyl-oridonin ( 5), rosthorin ( 6), effusanin E ( 7), and ponicidin ( 8), as well as six alpha-methylene gamma-ketone bearing diterpenoids, were modestly active in these assays.

Enhancement of vascular formation but not improvement of ventricular function of infarcted rat hearts by a high dose of adenovirus-carried VEGF transgene.

The purpose of this study was to examine the influence of adenovirus-carried VEGF165 transgene at 5 x 10(10) pfu (Ad-VEGF) on vascular formation, cardiac geometry and ventricular function in infarcted hearts of the rat and to explore the mechanism of Ad-VEGF-mediated actions on ventricular function by quantitative proteomic analysis. Seven days after coronary occlusion, intramyocardial injection with normal saline (vehicle control), adenovirus-carried beta-galactosidase gene (Ad-LacZ, vector control) or Ad-VEGF to infarcted hearts was conducted. Seven days after intramyocardial injection, ventricular function, cardiac morphology and vascular density were assessed after echocardiographic analysis and immunohistological staining. One dimensional gel electrophoresis coupled with stable isotope dimethyl labeling and LC/MS/MS was used to quantify the abundance ratio of each protein pair in Ad-VEGF- and Ad-LacZ-treated hearts. Our data indicated that both Ad-VEGF and Ad-LacZ increased arteriolar densities. However, the former increased arterial densities but the latter did not. Compared with the vehicle control, Ad-LacZ reversed occlusion-induced wall thinning and functional impairment but Ad-VEGF did not. Quantitative proteomic analysis showed increased ratios of plasma proteins (such as albumin) and oxygen carriers (such as myoglobin) by Ad-VEGF and decreased ratios of proteins involved in glycolysis, calcium homeostasis and lipolysis by Ad-VEGF. Taken together, our functional, morphological and proteomic data suggest that intramuscular delivery of Ad-LacZ at higher doses may improve ventricular function and wall thinning with arteriolar formation. Excessive amounts of VEGF by Ad-VEGF may offset Ad-LacZ-induced improvement in ventricular functions by interfering with calcium homeostasis and lipolysis in infarcted hearts.

Lipoxygenase from banana leaf: purification and characterization of an enzyme that catalyzes linoleic acid oxygenation at the 9-position.

The objective of the present study was to purify and characterize the lipoxygenase (LOX) from banana leaf (Giant Cavendishii, AAA), an unutilized bioresource. LOX was extracted, isolated, and purified 327-fold using 25-50% saturation of ammonium sulfate fractionation, hydroxyapatite column separation, and gel filtration on Superdex 200. The molecular mass of the purified LOX was 85 kDa, K(m) was 0.15 mM, and V(max) was 2.4 microM/min.mg using linoleic acid as substrate. Triton X-100 was required in the extraction medium; otherwise, no LOX activity was detected. LOX activity increased with the concentration of Triton X-100 with an optimum at 0.1%. The optimal pH of the purified LOX from banana leaf was 6.2, and optimal temperature was 40 degrees C. The LOX showed the highest reactivity toward 18:2 followed by 18:3 and 20:4. A very low reaction rate was observed toward 20:5 and 22:6. On the basis of retention time in normal phase HPLC, the products of 18:2 or 18:3 catalyzed by purified LOX were hydroperoxyoctadecadienoic acid or hydroperoxyoctadecatrienoic acid. It seems that 9-LOX is the predominant enzyme in banana leaf. Banada leaf dried at 110 degrees C for 2 h developed algal aroma. Banana leaf extract stored at 10 degrees C for 12 h formed an oolong tea-like flavor. Banana leaf extract reacted with 18:2 or soybean oil pretreated with bacterial lipase produced green and melon-like aroma, whereas the same reaction with 18:3 produced a sweet, fruity, cucumber-like flavor note.