Anti-inflammatory effect of polyherbal composition with hepatoprotective and choleretic properties on LPS-stimulated murine macrophages.

OBJECTIVES: A polyherbal formulation with hepatoprotective and choleretic properties combining pharmacological potential of eight medicinal plants was developed in Nargiz Medical center (Republic of Azerbaijan) for the use as herbal tea. To explore the effect of polyherbal composition on the metabolism of LPS-stimulated macrophages in vitro. METHODS: The qualitative and quantitative phytochemical analysis was conducted using specific color reactions and gas chromatography-mass spectrometry (GC-MS). Nitric oxide (NO) assay was determined using the Griess reaction. Reactive oxygen species (ROS) generation was measured using ROS-sensitive fluorescence indicator, H2DCFDA, by flow cytometry. Arginase activity was examined by colorimetric method. RESULTS: The studied polyherbal formulation exerted anti-inflammatory activity in LPS-stimulated macrophages which was evidenced by dose-dependent decrease of ROS generation and by shift of arginine metabolism to the increase of arginase activity and decrease of NO release. CONCLUSIONS: Our findings suggest that the herbal tea reduces macrophage inflammatory activity, that provide an important rationale to utilize it for the attenuation of chronic inflammation typical of hepatobiliary disorders.

Treatment of primary biliary cirrhosis with ursodeoxycholic acid combined with traditional Chinese medicine: A protocol for systematic review and meta analysis.

OBJECTIVE: Ursodeoxycholic acid is the priority drug of primary biliary cirrhosis (PBC) and is usually combined with traditional Chinese medicine. This study aimed to systematically evaluate the benefits of integrated Chinese and western interventions for PBC. METHODS: Searched the randomized controlled trials in PubMed, Web of Science, CNKI, CBM, Wanfang, VIP databases. The Cochrane risk of bias tool was used for methodological quality assessment and all data analysis was performed using Revman5.3 and Stata14.2 software. RESULT: 30 randomized controlled trials involving 10 interventions with a total of 1948 participants were included. Identified the direct and indirect evidence of trials, and used network meta analyses ranked the benefits of different interventions based on pairwise meta analysis. The primary outcom was clinical efficacy rate. Secondary outcome was liver function, including alkaline phosphataseand total bilirubin. CONCLUSION: The conclusion of this systematic review provide credible evidence - based for the relative advantages of integrated Chinese and western interventions for PBC.

Therapeutic potential of genipin in various acute liver injury, fulminant hepatitis, NAFLD and other non-cancer liver diseases: More friend than foe.

Genipin is an aglycone derived from the geniposide, the most abundant iridoid glucoside constituent of Gardenia jasminoides Ellis. For decades, genipin is the focus of studies as a versatile compound in the treatment of various pathogenic conditions. In particularly, Gardenia jasminoides Ellis has long been used in traditional Chinese medicine for the prevention and treatment of liver disease. Mounting experimental data has proved genipin possesses therapeutic potential for cholestatic, septic, ischemia/reperfusion-triggered acute liver injury, fulminant hepatitis and NAFLD. This critical review is a reflection on the valuable lessons from decades of research regarding pharmacological activities of genipin. Of note, genipin represents choleretic effect by potentiating bilirubin disposal and enhancement of genes in charge of the efflux of a number of organic anions. The anti-inflammatory capability of genipin is mediated by suppression of the production and function of pro-inflammatory cytokines and inflammasome. Moreover, genipin modulates various transcription factor and signal transduction pathway. Genipin appears to trigger the upregulation of several key genes encoding antioxidant and xenobiotic-metabolizing enzymes. Furthermore, the medicinal impact of genipin extends to modulation of regulated cell death, including autophagic cell death, apoptosis, necroptosis and pyroptosis, and modulation of quality of cellular organelle. Another crucial effect of genipin appears to be linked to dual role in targeting uncoupling protein 2 (UCP2). As a typical UCP2-inhibiting compound, genipin could inhibit AMP-activated protein kinase or NF-κB in circumstance. On the contrary, reactive oxygen species production and cellular lipid deposits mediated by genipin through the upregulation of UCP2 is observed in liver steatosis, suggesting the precise role of genipin is disease-specific. Collectively, we comprehensively summarize the mechanisms and pathways associated with the hepatoprotective activity of genipin and discuss potential toxic impact. Notably, our focus is the direct medicinal effect of genipin itself, whereas its utility as a crosslinking agent in tissue engineering is out of scope for the current review. Further studies are therefore required to disentangle these complicated pharmacological properties to confer this natural agent a far greater potency.

[Advances in research of traditional Chinese medicine for promoting bile secretion and excretion].

Cholagogic traditional Chinese medicines refer to those that can promote bile secretion and excretion, strengthen gallbladder contraction and promote gallbladder emptying. They are mainly used to treat cholecystitis, gallstones, cholestasis, biliary tract infection, jaundice hepatitis and other diseases in clinical application. As a traditional medicine in our country, Chinese herbal medicines have many advantages, such as extensive resources, low cost, little or no toxic and side effects, and in addition, it is not easy for animals to produce drug resistance. With the progress of science and technology and the rapid development of traditional Chinese medicine, many achievements have been made in the research of cholagogic traditional Chinese medicines. Traditional Chinese medicine plays a cholagogic role mainly by promoting bile secretion, regulating SCP2 mRNA, FXR, BSEP and efflux transporter protein, dissolving cholesterol, promoting the relaxation of Oddi's sphincter and changing the composition of bile, etc. Traditional Chinese medicine decoction, traditional Chinese medicine preparation, Chinese medicine combined with acupuncture, ear acupoint pressing, soaking bath, western medicine and alike are often used to treat biliary system diseases in clinical practice. The effective rate of combination of traditional Chinese medicine and other methods was significantly higher than that of compound prescription, western medicine, acupuncture and soaking bath alone. General attack therapy and new therapies are also used in clinical treatment. The clinical effect of traditional Chinese medicine is remarkable. By means of literature review, the pharmacological effects, mechanism and clinical application of Chinese herbal medicines and compound prescriptions with gallbladder-promoting effect in the past 15 years were summarized in this paper. At the same time, some existing problems were found and prospects were expected.

The endoplasmic reticulum stress-autophagy pathway controls hypothalamic development and energy balance regulation in leptin-deficient neonates.

Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Here, we show that leptin-deficient ob/ob mice display elevated hypothalamic ER stress as early as postnatal day 10, i.e., prior to the development of obesity in this mouse model. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Cells exposed to ER stress often activate autophagy. Accordingly, we report that in vitro induction of ER stress and neonatal leptin deficiency in vivo activate hypothalamic autophagy-related genes. Furthermore, genetic deletion of autophagy in pro-opiomelanocortin neurons of ob/ob mice worsens their glucose homeostasis, adiposity, hyperphagia, and POMC neuronal projections, all of which are ameliorated with neonatal TUDCA treatment. Together, our data highlight the importance of early life ER stress-autophagy pathway in influencing hypothalamic circuits and metabolic regulation.

Treatment with milk thistle extract (Silybum marianum), ursodeoxycholic acid, or their combination attenuates cholestatic liver injury in rats: Role of the hepatic stem cells.

BACKGROUND/AIMS: Cholestasis, which results in hepatic cell death, fibrosis, cirrhosis, and eventually liver failure, is associated with oxidative stress. The aim of this study was to evaluate the effects of milk thistle (MT, Silybum marianum) and ursodeoxycholic acid (UDCA) or their combination on the activation of hepatic stem cells and on the severity of cholestasis liver injury in rats. MATERIALS AND METHODS: Under anesthesia, bile ducts of female Sprague Dawley rats were ligated (BDL) or had sham operation. BDL rats were administered saline, UDCA (15 mg/kg/d), MT (600 mg/kg/d), or UDCA+MT by gavage for 10 days. On the 11th day, rats were sacrificed and blood and liver samples were obtained. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic malondialdehyde (MDA) levels, and myeloperoxidase (MPO) activity were measured. Hepatic injury, a-smooth muscle actin expression, and stem cell markers c-kit, c-Myc, Oct3/4, and SSEA-1 were histologically determined. RESULTS: Histological scores, serum ALT, and hepatic MDA levels were higher in BDL group than in the sham rats, while all treatments significantly reduced these levels. The reduction in ALT was significantly greater in UCDA+MT-treated group than in other treatment groups. c-Kit, c-Myc, Oct3/4, and SSEA-1 were increased in saline-treated BDL group with respect to sham-operated control group, and these markers were significantly reduced in all treatment groups. CONCLUSION: In addition to a modulatory effect on the stem cell-induced regenerative response of the liver, UDCA, MT, and their combination demonstrated similar anti-inflammatory and antiproliferative effects on cholestasis-induced hepatic injury.

Up-regulation of BSEP and MRP2 by Calculus Bovis administration in 17α-ethynylestradiol-induced cholestasis: Involvement of PI3K/Akt signaling pathway.

ETHNOPHARMACOLOGY RELEVANCE: Calculus Bovis, also known as Niuhuang, is a rare traditional Chinese medicine that has been widely used in China for 2000 years in pharmacology for sedation, anti-spasm, relieving fever, diminishing inflammation and recovering gallbladder functions. AIM OF THE STUDY: This study aimed to investigate the choleretic potential and molecular responses in rats to Calculus Bovis (CB) administration after 17α-ethynylestradiol (EE)-induced cholestasis. MATERIAL AND METHODS: CB (50 and 100mg/kg per day) was intragastrically (i. g.) given to experimental rats for five consecutive days in coadministration with EE (5mg/kg daily for five days, s.c.). The levels of serum biomarkers were determined biochemically. The histopathology of the liver tissue was evaluated. Expression of bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2) were studied by western blot and immunohistochemical assay. The expression of Akt and phospho-Akt (pAkt) were also measured by western blot. RESULTS: In response to EE, CB treatment significantly prevented an increase in serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyltransferase (GGT) and total bilirubin (TBIL). CB treatment also repaired tissue lesions caused by EE. Western blots showed that EE significantly decreased the protein expression of BSEP and MRP2. EE also dramatically increased levels of pAkt and decreased levels of Akt. Compared to the EE group, CB treatment increased levels of hepatic BSEP and MRP2 while pAkt levels decreased and Akt levels increased. Immunohistochemistry also indicated that EE decreased the expression of BSEP and MRP2. LY294002 is a selective PI3K inhibitor and showed similar beneficial effects as CB. Decreased expression of BSEP and MRP2 caused by EE were also prevented by LY294002 treatment. CONCLUSION: Calculus Bovis administration can alleviate liver injury and up-regulate the expression of BSEP and MRP2 in 17α-ethynylestradiol-induced cholestasis by a mechanism that may involve inhibiting the activated PI3K/Akt signaling pathway.

Choleretic Activity of Turmeric and its Active Ingredients.

Turmeric, a rhizome of Curcumin longa L. is widely used as both a spice and an herbal medicine. The traditional use of turmeric in gastroenterology is mainly based on its choleretic activity. The aim of this study is to determine the effects of turmeric on bile flow (BF) and total bile acids (TBAs) excretion in a bile fistula rat model after acute duodenal administration. A significant dose-dependent enhancement in both BF and TBAs was detected after treatment with the turmeric decoctions which suggested the choleretic activity was bile acid-dependent secretion. In order to direct the active group of compounds, aqueous (AE), ethyl acetate (EtOAc), and petroleum ether (PE) extracts were investigated. The EtOAc and PE extracts showing high effects were purified to locate the active ingredients. Three curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) and 2 sesquiterpenes (bisacurone B and ar-turmerone) were isolated. It was found Bisacurone B was the most potent choleretic ingredient followed by ar-turmerone, bisdemethoxycurcumin demethoxycurcumin, and then curcumin. The amounts of the active ingredients were quantitatively analyzed by high-performance liquid chromatography. The EtOAc and PE extracts had high sesquiterpenes and curcuminoids content, while the AE extract had poor content of sesquiterpenes and curcuminoids which affected neither BF nor TBAs. Based on the results of multiple linear regression analysis, the content of BIS and TUR were dominant factors (P < 0.01) of controlling BL and TBAs in EtOAC and PE extracts.

Testicular immunohistochemical and Ultrastructural changes associated with chronic cholestasis in rats: Effect of ursodeoxycholic acid.

AIMS: Testicular atrophy has been commonly reported in patients with chronic liver diseases. Ursodeoxycholic acid is the most widely used drug for the treatment of many liver diseases. However, its effect on testicular ultrastructure associated with chronic cholestasis has never been studied. Thus, this study aimed to assess how chronic obstructive jaundice affects the testicular ultrastructure and whether it affects the androgen receptor or the proliferating cell nuclear antigen. The role of ursodeoxycholic acid was also investigated. MAIN METHODS: Cholestasis was induced by bile duct ligation. Samples were collected 4weeks postoperative. Testicular changes were assessed using immunohistochemistry and transmission electron microscopy. KEY FINDINGS: Chronic cholestasis resulted in testicular atrophy evidenced by shrinkage and deformation of seminiferous tubules, thickening of peritubular boundaries, vacuolation, disorganization of germ cells, and maturation arrest. This was accompanied by decreased immunoreactivity of androgen receptors and proliferating cell nuclear antigen. Administration of ursodeoxycholic acid improved the testicular morphology and reversed cholestasis-induced immunohistochemical and ultrastructural changes. SIGNIFICANCE: Ursodeoxycholic acid can improve the testicular ultrastructure and restore the spermatogenic process in rats with chronic cholestasis. These findings support the clinical application of ursodeoxycholic acid in cholestatic patients especially those with hypogonadism.

Boldine enhances bile production in rats via osmotic and farnesoid X receptor dependent mechanisms.

Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 µM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine.

Omega-3 polyunsaturated fatty acid and ursodeoxycholic acid have an additive effect in attenuating diet-induced nonalcoholic steatohepatitis in mice.

Nonalcoholic steatohepatitis (NASH) can progress into liver cirrhosis; however, no definite treatment is available. Omega-3 polyunsaturated fatty acid (omega-3) has been reported to alleviate experimental NASH, although its beneficial effect was not evident when tested clinically. Thus, this study aimed to investigate the additive effect of omega-3 and ursodeoxycholic acid (UDCA) on diet-induced NASH in mice. C57BL/6 mice were given a high-fat diet (HFD) for 24 weeks, at which point the mice were divided into three groups and fed HFD alone, HFD with omega-3 or HFD with omega-3 in combination with UDCA for another 24 weeks. Feeding mice an HFD and administering omega-3 improved histologically assessed liver fibrosis, and UDCA in combination with omega-3 further attenuated this disease. The assessment of collagen α1(I) expression agreed with the histological evaluation. Omega-3 in combination with UDCA resulted in a significant attenuation of inflammation whereas administering omega-3 alone failed to improve histologically assessed liver inflammation. Quantitative analysis of tumor necrosis factor α showed an additive effect of omega-3 and UDCA on liver inflammation. HFD-induced hepatic triglyceride accumulation was attenuated by omega-3 and adding UDCA accentuated this effect. In accordance with this result, the expression of sterol regulatory binding protein-1c decreased after omega-3 administration and adding UDCA further diminished SREBP-1c expression. The expression of inducible nitric oxide synthase (iNOS), which may reflect oxidative stress-induced tissue damage, was suppressed by omega-3 administration and adding UDCA further attenuated iNOS expression. These results demonstrated an additive effect of omega-3 and UDCA for alleviating fibrosis, inflammation and steatosis in diet-induced NASH.

Genipin inhibits IL-1ß-induced CCL20 and IL-6 production from human periodontal ligament cells.

BACKGROUND/AIMS: Genipin, the aglycon of geniposide found in gardenia fruit has long been considered for treatment of various diseases in traditional oriental medicine. Genipin has been used as a blue colorant in food industry. Genipin has recently been reported to have some pharmacological functions, such as antimicrobial, antitumor, and anti-inflammatory effects. The aim of this study was to examine whether genipin could modify CCL20 and IL-6, which are related to bone resorption in periodontal disease, expression in human periodontal ligament cells (HPDLCs). METHODS: CCL20 and IL-6 productions from HPDLCs were determined by ELISA. Western blot analysis was used for the detection of signal transduction molecules expressions in HPDLCs. RESULTS: Genipin prevented IL-1ß-mediated CCL20 and IL-6 production in HPDLCs. Moreover, genipin could suppress nuclear factor kappa B (NF-κB) p65, extracellular signalregulated kinase (ERK) and MAPK/ERK kinase (MEK) phosphorylations in IL-1ß-stimulated HPDLCs. NF-κB inhibitor and ERK inhibitor significantly inhibited IL-6 and CCL20 productions from IL-1ß-stimulated HPDLCs. CONCLUSIONS: These data provide a novel mechanism through which genipin could be used to provide direct benefits in periodontal disease to inhibit IL-6 and CCL20 productions in periodontal lesions.

Omega-3 polyunsaturated fatty acid and ursodeoxycholic acid have an additive effect in attenuating diet-induced nonalcoholic steatohepatitis in mice

Nonalcoholic steatohepatitis (NASH) can progress into liver cirrhosis; however, no definite treatment is available. Omega-3 polyunsaturated fatty acid (omega-3) has been reported to alleviate experimental NASH, although its beneficial effect was not evident when tested clinically. Thus, this study aimed to investigate the additive effect of omega-3 and ursodeoxycholic acid (UDCA) on diet-induced NASH in mice. C57BL/6 mice were given a high-fat diet (HFD) for 24 weeks, at which point the mice were divided into three groups and fed HFD alone, HFD with omega-3 or HFD with omega-3 in combination with UDCA for another 24 weeks. Feeding mice an HFD and administering omega-3 improved histologically assessed liver fibrosis, and UDCA in combination with omega-3 further attenuated this disease. The assessment of collagen alpha1(I) expression agreed with the histological evaluation. Omega-3 in combination with UDCA resulted in a significant attenuation of inflammation whereas administering omega-3 alone failed to improve histologically assessed liver inflammation. Quantitative analysis of tumor necrosis factor alpha showed an additive effect of omega-3 and UDCA on liver inflammation. HFD-induced hepatic triglyceride accumulation was attenuated by omega-3 and adding UDCA accentuated this effect. In accordance with this result, the expression of sterol regulatory binding protein-1c decreased after omega-3 administration and adding UDCA further diminished SREBP-1c expression. The expression of inducible nitric oxide synthase (iNOS), which may reflect oxidative stress-induced tissue damage, was suppressed by omega-3 administration and adding UDCA further attenuated iNOS expression. These results demonstrated an additive effect of omega-3 and UDCA for alleviating fibrosis, inflammation and steatosis in diet-induced NASH.

Ursodeoxycholic acid pretreatment reduces oral bioavailability of the multiple drug resistance-associated protein 2 substrate baicalin in rats.

Baicalin is a major bioactive component of Scutellaria baicalensis and a substrate of multiple drug resistance-associated protein 2. Expression of multiple drug resistance-associated protein 2 is regulated by NF-E2-related factor 2. The aim of this study was to explore whether ursodeoxycholic acid, an NF-E2-related factor 2 activator, could influence the oral bioavailability of baicalin. A single dose of baicalin (200 mg/kg) was given orally to rats pretreated with ursodeoxycholic acid (75 mg/kg and 150 mg/kg, per day, intragastrically) or normal saline (per day, intragastrically) for six consecutive days. The plasma concentration of baicalin was measured with the HPLC method. The result indicated that the oral bioavailability of baicalin was significantly and dose-dependently reduced in rats pretreated with ursodeoxycholic acid. Compared with control rats, the mean area under concentration-time curve of baicalin was reduced from 13.25 ± 0.24 mg/L h to 7.62 ± 0.15 mg/L h and 4.97 ± 0.21 mg/L h, and the C(max) value was decreased from 1.31 ± 0.03 mg/L to 0.62 ± 0.05 mg/L and 0.36 ± 0.04 mg/L in rats pretreated with ursodeoxycholic acid at doses of 75 mg/kg and 150 mg/kg, respectively, for six consecutive days. Hence, ursodeoxycholic acid treatment reduced the oral bioavailability of baicalin in rats, probably due to the enhanced efflux of baicalin from the intestine and liver by multiple drug resistance-associated protein 2.

[Beneficial effects of preoperative administration of Inchinkoto in patients undergoing major hepatectomy].

Inchinkoto (ICKT) is one of the most commonly used herbal medicines and is a hepatoprotective agent. Among the numerous chemical compounds included in ICKT, geniposide is the most abundant component. After oral intake, geniposide is converted into the active metabolite genipin by intestinal bacteria and absorbed in the portal circulation. The biological properties of ICKT and its major active ingredient genipin have been studied in numerous experiments using cells and animals. ICKT or genipin administration exerts a choleretic effect through upregulation of multidrug resistance-associated protein 2 in hepatocytes. ICKT also exerts antiapoptoic activity by inhibiting the transforming growth factor beta 1- or tumor necrosis factor alpha-dependent signaling pathway. The excessive inflammatory response induced by various forms of hepatic stress is also attenuated by ICKT preadministration. Proinflammatory cytokine-induced upregulation of inducible nitric oxide synthase is strongly attenuated by ICKT in both in vivo and in vitro experiments. Moreover, ICKT enhances antioxidant enzymes in the liver under oxidative stress. These experimental results clearly indicate the effects of ICKT on hepatic stress. To date, however, clinical data on the benefits of ICKT for liver disease are very rare. To extend the clinical applications of ICKT in humans, it is crucial to design and perform a rigorous clinical trial. In this review article, recent evidence relating to the hepatoprotective effects of ICKT in the field of basic and clinical science is summarized and discussed.

Minireview on Achillea millefolium Linn.

Yarrow (Achillea millefolium L.) is an important medicinal plant with different pharmaceutical uses. A. millefolium has been used for centuries to treat various diseases including malaria, hepatitis and jaundice. A. millefolium is commonly prescribed to treat liver disorders. It is also used as an anti-inflammatory agent and is a hepatoprotective herb. A. millefolium is considered safe for supplemental use. It has antihepatotoxic effects also. It is prescribed as an astringent agent. It is prescribed in hemorrhoids, headache, bleeding disorders, bruises, cough, influenza, pneumonia, kidney stones, high blood pressure, menstrual disorders, fever, rheumatoid arthritis, gout, osteoarthritis, hemorrhagic disorders, chicken pox, cystitis, diabetes mellitus, indigestion, dyspepsia, eczema, psoriasis and boils.

Tauroursodeoxycholic acid (TUDCA) supplementation prevents cognitive impairment and amyloid deposition in APP/PS1 mice.

Alzheimer's disease (AD) is a neurodegenerative disease hallmarked by extracellular Aß(1-42) containing plaques, and intracellular neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein. Progressively, memory deficits and cognitive disabilities start to occur as these hallmarks affect hippocampus and frontal cortex, regions highly involved in memory. Connective tissue growth factor (CTGF) expression, which is high in the vicinity of Aß plaques and NFTs, was found to influence γ-secretase activity, the molecular crux in Aß(1-42) production. Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that downregulates CTGF expression in hepatocytes and has been shown to possess therapeutic efficacy in neurodegenerative models. To investigate the possible in vivo therapeutic effects of TUDCA, we provided 0.4% TUDCA-supplemented food to APP/PS1 mice, a well-established AD mouse model. Six months of TUDCA supplementation prevented the spatial, recognition and contextual memory defects observed in APP/PS1 mice at 8 months of age. Furthermore, TUDCA-supplemented APP/PS1 mice displayed reduced hippocampal and prefrontal amyloid deposition. These effects of TUDCA supplementation suggest a novel mechanistic route for Alzheimer therapeutics.

Effects of rectal administration of taurocholic acid on glucagon-like peptide-1 and peptide YY secretion in healthy humans.

Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), secreted by enteroendocrine L-cells located most densely in the colon and rectum, are of fundamental importance in blood glucose and appetite regulation. In animal models, colonic administration of bile acids can stimulate GLP-1 and PYY by TGR5 receptor activation. We evaluated the effects of taurocholic acid (TCA), administered as an enema, on plasma GLP-1 and PYY, as well as gastrointestinal sensations in 10 healthy male subjects, and observed that rectal administration of TCA promptly stimulated secretion of both GLP-1 and PYY, and increased fullness, in a dose-dependent manner. These observations confirm that topical application of bile acids to the distal gut may have potential for the management of type 2 diabetes and obesity.

Inhibition of P-glycoprotein-mediated transport by S-adenosylmethionine and cynarin in multidrug-resistant human uterine sarcoma MES-SA/Dx5 cells.

Multidrug resistance (MDR) to anticancer chemotherapy is often mediated by the overexpression of the plasma membrane drug transporter P-glycoprotein (Pgp) encoded by multidrug resistance gene (MDR1). Various chemosensitizing agents are able to inhibit Pgp activity but their clinical application is limited by their toxicity. Furthermore, hepatotoxicity related to chemotherapy causes delays of treatment in cancer patients and often requires supplementation of anti-tumour therapy with hepatoprotective agents. In this in vitro study, we investigated the effectiveness of an endogenous hepatoprotective agent, S-adenosylmethionine (SAMe), and a natural hepatoprotective compound, Cynarin (Cyn), to inhibit Pgp activity in order to evaluate their potential use as chemosensitizing agents. Human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) expressing high levels of Pgp were treated with two hepatoprotectors at various concentrations (1, 5 and 10 microM) that are clinically achievable, in the presence or absence of three different concentrations of doxo (2, 4 and 8 microM). In order to evaluate the effects of both hepatoprotectors, we measured the intracellular accumulation and cytotoxicity of doxo, the cellular GSH level, ROS production and catalase (CAT) activity. We found that treatment with 2, 4 and 8 microM doxo in the presence of SAMe or Cyn significantly increased the doxo accumulation and cytotoxicity on MES-SA/Dx5 cells, when compared to control cells receiving doxo alone. Moreover, treatment with SAMe or Cyn significantly increased GSH content, greater than 80 percent and 60 percent, respectively) and CAT activity greater than 60 and 150 percent, respectively) in resistant cancer cells, while ROS production was below the values of corresponding untreated control cells. Our in vitro findings provide a rationale for the potential clinical use of these hepatoprotectors both as chemosensitizing agents, to reverse Pgp-mediated MDR, and as antioxidants to protect normal cells from chemotherapy-induced cytotoxixity.

N-3 polyunsaturated fatty acid attenuates cholesterol gallstones by suppressing mucin production with a high cholesterol diet in mice.

BACKGROUND AND AIM: The increasing prevalence of cholesterol gallstone (CG) disease has become an economic burden to the healthcare system. Ursodeoxycholic acid (UDCA) is the only established medical agent used to dissolve gallstones. In investigating novel therapeutics for CG, we assessed the preventive effects of n-3 polyunsaturated fatty acids (n-3PUFA) on the formation of CG induced by feeding a lithogenic diet (LD) containing high cholesterol levels to mice. METHODS: Mice were divided into the following six groups: (A) regular diet (RD); (B) RD+n-3PUFA; (C) LD; (D) LD+n-3PUFA; (E) LD+UDCA; (F) LD+n-3PUFA+UDCA. After RD/LD feeding for 2 weeks, n-3PUFA or UDCA was administered orally and the diet maintained for 8 weeks. The levels of phospholipids and cholesterol in bile, CG formation, gallbladder wall thickness, MUC gene expression in gallbladder were analyzed. RESULTS: No stone or sludge was evident in the RD groups (Groups A, B). Mice in the n-3PUFA treatment (Groups D, F) showed significantly lower stone formation than the other LD groups (Groups C, E). The combination treatment of n-3PUFA and UDCA suppressed stone formation more than mono-therapy with n-3PUFA or UDCA. Bile phospholipid levels were significantly elevated in the Group F. Hypertrophy of the gallbladder wall was evident in mice fed LD. MUC 2, 5AC, 5B and 6 mRNA expression levels were significantly elevated in the LD-fed group, and this was suppressed by n-3PUFA with or without UDCA. CONCLUSIONS: N-3PUFA attenuated gallstone formation in mouse, through increasing the levels of bile phospholipids and suppressing bile mucin formation.