Hongxiang Hui

Hypoglycemic herbs and their action mechanisms

Conventional drugs treat diabetes by improving insulin sensitivity, increasing insulin production and/or decreasing the amount of glucose in blood. Several herbal preparations are used to treat diabetes, but their reported hypoglycemic effects are complex or even paradoxical in some cases. This article reviews recent findings about some of the most popular hypoglycemic herbs, such as ginseng, bitter melon and Coptis chinensis. Several popular commercially available herbal preparations are also discussed, including ADHF (anti-diabetes herbal formulation), Jiangtangkeli, YGD (Yerbe Mate-Guarana-Damiana) and BN (Byakko-ka-ninjin-to). The efficacy of hypoglycemic herbs is achieved by increasing insulin secretion, enhancing glucose uptake by adipose and muscle tissues, inhibiting glucose absorption from intestine and inhibiting glucose production from heptocytes.

Ellagic Acid and Embelin Affect Key Cellular Components of Pancreatic Adenocarcinoma, Cancer, and Stellate Cells

Ellagic acid is a polyphenolic phytochemical present in many fruits and nuts with anticancer properties demonstrated in experimental tumor studies. Embelin is a benzoquinone phytochemical isolated from the Japanese herb Ardisiae Japonicae and has been shown to induce apoptosis in cancer cells. We found that ellagic acid and embelin each dose-dependently increased apoptosis and inhibited proliferation in human pancreatic cancer cells, MIA PaCa-2 and HPAF-II cells, and in pancreatic stellate cells, which are progenitors of pancreatic cancer desmoplasia. In each of these cell types, combinations of ellagic acid and embelin at low micromolar concentrations (0.5–3 μM) induced synergistic increases in apoptosis and decreases in proliferation. Ellagic acid decreased NF-κB transcriptional activity, whereas embelin decreased STAT-3 phosphorylation and protein expression of its downstream target survivin in cancer cells. In vivo dietary ellagic acid alone or in combination with embelin decreased tumor size and tumor cellularity in a subcutaneous xenograft mouse model of pancreatic cancer. These results show that ellagic acid and embelin interact with divergent intracellular signaling pathways resulting in augmentation of apoptosis and inhibition of proliferation at low micromolar concentrations for the key cellular components of pancreatic adenocarcinoma.

Alterations in fecal Lactobacillus and Bifidobacterium species in type 2 diabetic patients in Southern China population

Background: The connection between gut microbiota and metabolism and its role in the pathogenesis of diabetes are increasingly recognized. The objective of this study was to quantitatively measure Bifidobacterium and Lactobacillus species, members of commensal bacteria found in human gut, in type 2 diabetic patients (T2D) patients from Southern China. Methods: Fifty patients with T2D and thirty control individuals of similar body mass index (BMI) were recruited from Southern China. T2D and control subjects were confirmed with both oral glucose tolerance test (OGTT) and HbA1c measurements. Bifidobacterium and Lactobacillus species in feces were measured by real-time quantitative PCR. Data were analyzed with STATA 11.0 statistical software. Results: In comparison to control subjects T2D patients had significantly more total Lactobacillus (+18%), L. bugaricus (+13%), L. rhamnosum (+37%) and L. acidophilus (+48%) (P < 0.05). In contrast, T2D patients had less amounts of total Bifidobacteria (−7%) and B. adolescentis (−12%) (P < 0.05). Cluster analysis showed that gut microbiota pattern of T2D patients is characterized by greater numbers of L. rhamnosus and L. acidophillus, together with lesser numbers of B. adolescentis (P < 0.05). Conclusion: The gut microflora in T2D patients is characterized by greater numbers of Lactobacillus and lesser numbers of Bifidobacterium species.

Glucagon like peptide-1-directed human embryonic stem cells differentiation into insulin-producing cells via hedgehog, cAMP, and PI3K pathways.

Objectives: That glucagonlike peptide-1 (GLP-1) induces differentiation of primate embryonic stem (ES) cells into insulin-producing cells has been reported by several groups and also confirmed with our observations. Methods: To further elucidate the process in detail and the signaling pathways involved in this differentiation, we induced human ES cells HUES1 differentiated into insulin secretion cells by GLP-1 treatment. Results: A time-dependent pattern of down expression of the stem cell markers (human telomerase reverse transcriptase and octamer-4), and the appearance of multiple &bgr;-cell-specific proteins (insulin, glucokinase, glucose transporter, type 2, and islet duodenal homeobox 1) and hedgehog signal molecules (Indian hedgehog, sonic hedgehog, and hedgehog receptor, patched) have been identified. Cotreatment with hedgehog signal inhibitor cytopamine was able to block this differentiation, providing evidence of the involvement of the hedgehog signaling pathway in GLP-1-induced differentiation. We also observed increased transcripts of the transcription factors of activator protein 1, serum response element-1, DNA-binding transcription factors, and cAMP response element in GLP-1-induced ES cell differentiation. Inhibition profile by its specific inhibitors indicated that the cyclic adenosine monophosphate and phosphatidylinositol-3-kinase pathways, but not the mitogen-activated protein kinase pathway, were required for the induced differentiation of ES cells. Conclusions: These data support that GLP-1 directs human ES cell differentiation into insulin-producing cells via hedgehog, cyclic adenosine monophosphate, and phosphatidylinositol-3-kinase pathways.Abbreviations: AP-1 - the activator protein 1, cAMP - cyclic adenosine monophosphate, CRE - cAMP response element, DHH - desert hedgehog, E2F - DNA-binding transcription factors, EB - embryoid body, EG - embryonic germ, ERK - extracellular receptor kinases, ES - embryonic stem (cells), HTERT - human telomerase reverse transcriptase, IDX-1 - islet duodenal homeobox 1, IHH - Indian hedgehog, GK - glucokinase, GLP-1 - glucagonlike peptide-1, Glut2 - glucose transporter, type 2, MAPK - mitogen-activated protein kinase, PDX-1 - pancreatic and duodenal homeobox 1, Oct-4 - octamer-4, PTC - hedgehog receptor, patched, PI3K - phosphatidylinositol-3-kinase, SHH - sonic hedgehog, SRE - serum response element-1

Treating obstructive sleep apnea with continuous positive airway pressure benefits type 2 diabetes management.

Type 2 diabetes mellitus (T2DM) and obstructive sleep apnea (OSA) are both common major public health concerns. Epidemiological and clinical evidence postulates that OSA may be a causal factor in the pathogenesis of T2DM. This review examines recent empirical developments in theory, research, and practice regarding T2DM and OSA. We first examined the data from 10 studies that covered 281 patients with T2DM who used continuous positive airway pressure therapy, followed by research that describes how hypoxia/reoxygenation in OSA may be key triggers that initiate or contribute to the status of insulin resistance and inflammation. We then propose mechanisms that may relate diabetes with OSA. The issues that should be addressed in the future are outlined. We suggest that intervention with continuous positive airway pressure may improve diabetic symptoms and should be encouraged for patients with diabetes.

Stem Cells: General Features and Characteristics

Hongxiang Hui1,2,5,6, Yongming Tang2,4, Min Hu2,3 and Xiaoning Zhao2,4 1Center for Metabolic Diseases, Southern Medical University (SMU), Guangzhou, 2Institute of Dongguan SMU Metabolic Science, Dongguan 3Regen Biotech Company, Beijing 4Cedars-Sinai Medical Center, Los Angeles, CA 5UCLA Center for Excellence in Pancreatic Diseases, Los Angeles, CA 6Department of Medicine, VA Greater Los Angeles Health Care System, Los Angeles, CA 1,2,3PR. China 4,5,6USA

Abstract 1895: Phytochemicals inhibit proliferation and promote death through NADPH oxidase and G6PD

Background & Aims: Pancreatic cancer is a very aggressive disease that is resistant to therapy. Evidence from population studies indicates a protective effect of fruits and vegetables in the diet on cancer including pancreatic cancer. In vitro and in vivo studies, including our own, suggest that several phytochemicals, such as ellagic acid and lycopene may be involved in this beneficial effect. In this study we investigated the effect of these phytochemicals, alone and in combination, on apoptosis and proliferation of pancreatic cancer cells in vitro, and we analyzed their mechanism of action. Methods: We measured the effect of ellagic acid and lycopene on DNA fragmentation using Cell Death Detection ELISA and on proliferation using 3H-thymidine incorporation into DNA in pancreatic cancer cell line MIA PaCa-2. Molecular signaling mechanisms were evaluated with Western. NF-kB activity was measured using electromobility shift assay. Metabolic phenotype of the cells was analyzed using mass spectrometry and the glucose molecule labeled with stable isotope D-glucose (1,2-13C2). Results: Both lycopene and ellagic acid at doses from 0.1 to 30 μM induced increases in DNA fragmentation and inhibited proliferation in pancreatic cancer cells. Combinations of ellagic acid with lycopene at low doses (1 µM) induced a synergistic effect on DNA fragmentation and proliferation. Ellagic acid induced apoptosis by decreasing NF-kB activity in pancreatic cancer cells. Lycopene decreased NADPH oxidase activity. Combined compounds had a synergistic effect on the inhibition of glucose-6-phosphate dehydrogenase (G6PD) activity as measured by mass spectrometry leading to a synergistic inhibition of DNA synthesis. Conclusions: Combination of ellagic acid and lycopene induced a synergistic effect on apoptosis and proliferation in pancreatic cancer cells. The synergistic effect is due to different mechanisms of action of these phytochemicals leading to the inhibition of G6PD activity, a key step in DNA synthesis. Our study suggests a potentially beneficial role for combinations of ellagic acid and lycopene in prevention and treatment strategies of pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1895.

The Global Transcriptional Response of Isolated Human Islets of Langerhans to Glucagon-Like Peptide-1 Receptor Agonist Liraglutide

GLP-1 and its analog have been used in diabetes treatment; however, the direct alteration of gene expression profile in human islets induced by GLP-1 has not been reported. In present study, transcriptional gene expression in the liraglutide-treated human islets was analyzed with 12 human U133A chips including 23000 probe sets. The data compared between liraglutide and control groups showed a significant difference on glucose-induced insulin secretion, rather than viability. Microarray analysis identified 7000 genes expressed in human islets. Eighty genes were found to be modulated by liraglutide treatment. Furthermore, the products of these genes are proteins involved in binding capability, enzyme activity, transporter function, signal transduction, cell proliferation, apoptosis, and cell differentiation. Our data provides a set of information in the complex events, following the activation of the GLP-1 receptor in the islets of Langerhans.

Mo1954 Rottlerin Promotes Apoptosis and Autophagy in Pancreatic Stellate Cells via AMPK Activation

Background and Significance: Phytochemicals may play roles to reduce carcinogenesis by modulating central metabolic pathways in cancer and tumor stromal cells. AMP-activated kinases (AMPK) are key regulators of cellular metabolism, cell growth and proliferation. Activation of AMPK kinases by low energy status inhibits anabolic processes such as protein and fatty acid synthesis, activates autophagy and can lead to apoptosis. AMPK actions are mediated at least in part by inhibition of mTOR complex-1 (TORC1). Previous studies from our group showed that rottlerin, a phytochemical from the kamala tree, reduced pancreatic tumor volume in an orthotopic model of pancreatic cancer. Here we investigated the effects of rottlerin on AMPK/mTORC1 pathways in the pancreatic stellate cell (PaSC), a key cell type in the tumor microenvironment that promotes pancreatic carcinogenesis. Methods: Culture-activated primary mouse PaSC were incubated for up to 72 h in 10% FBS in the absence (control) or presence of rottlerin (0.5-10 μM). We then measured 1) activation of AMPK and Akt/mTORC1 pathways by Western blot analysis to assess phosphorylated states of intermediate proteins, 2) autophagy by Western blot and immunofluorescence to detect levels of and localize autophagic markers, 3) apoptosis by caspase-3 activity and ELISA to detect internucleosomal DNA fragmentation, and 4) cell viability/proliferation by MTT assay/ cell counting. Results: Rottlerin at concentrations as low as 0.5 μM induced rapid, sustained activation of AMPK, as determined by a significant increase in PaSC levels of phosphoAMPKα (Thr172). A marked inhibition of the Akt/mTOR pathway was indicated by reduced phosphorylation of Akt (Ser473) and the mTORC1 substrates p70 S6 kinase and 4EBP1. Further, mTORC1 inhibition blocked protein translation, and induced endoplasmic reticulum (ER) stress as indicated by phosphorylation of the translation initiator protein eiF2α (Ser51) and upregulation of the proapoptotic transcription factor CHOP. In addition, rottlerin treatment rapidly (within 15 min) induced LC3I-LC3II conversion that was sustained at least 48 h, and significantly increased p62/SQSTM1 protein expression. Together, these data suggest accumulation of autophagosomes as well as reduced autophagic flux in rottlerintreated PaSC. Interestingly, preincubation with the AMPK inhibitor compound C (20 μM) greatly reduced rottlerin-induced ER stress and autophagy. Furthermore, rottlerin dosedependently induced PaSC apoptosis, to a 6-fold increase over control at 1 μM and 36-fold at 10 μM after 72 h, and reduced cell viability by 35% at 0.5 μM, and by 70% at 10 μM. Conclusion: Our data elucidate the AMPK/mTOR pathways as a key target of rottlerin in PaSC and reinforce the notion that phytochemicals are therapeutically useful to reduce pancreatic cancer progression by eliminating pancreatic stellate cells.

Glucagon like peptide-1 increases gemcitabine cytotoxicity in human pancreatic cancer stem cells (PCSC)

biologically active peptides. These peptides are produced by a variety of gastrointestinal cancers and may accelerate cancer development because of their effects on cell growth, migration and apoptosis. However it is not clear which of the various post-translationally processed PG molecules are biologically relevant. Our group has previously shown that the C-terminal flanking peptide (CTFP) is a major stored and circulating gastrin form in sheep and humans and is biologically active. Here we further explore the biological profile of CTFP and compare it to another non-amidated form of gastrin, glycine-extended gastrin (Ggly). Aims: To compare the biological activities of two non-amidated products of PG: CTFP and Ggly. Methods: Ggly and CTFP were compared using gastric (AGS) and colonic (DLD-1) cell lines in a series of in vitro assays including cell survival (MTT), proliferation (cell division), migration (transwell) and induction of signal transduction pathways. We also studied the effects of Ggly and CTFP on colonic proliferation (immunohistochemistry) in gastrin-deficient mice. Results: CTFP and Ggly stimulated significant increases in cell survival, proliferation and migration in vitro. CTFP and Ggly activated procarcinogenic pathways by stimulating phosphorylation of Akt and beta-catenin/Tcf-4 transcription. Ggly and CTFP also significantly increased colonic proliferation in vivo. Discussion: CTFP shares many biological activities with Ggly but is expressed at higher levels. Thus CTFP should be considered as a relevant form of PG in terms of its procarcinogenic potential.