Hyperbaric oxygen (HBO) has also been studied as a treatment for acute CH attacks.21,22 Weiss et al treated a CH patient with hyperbaric (2 atmospheres) 100% oxygen, after she had been refractory to conventional oxygen therapy.21 Two attacks were treated with HBO, with prompt and complete pain relief. Di Sabato et al treated 7 ECH patients with HBO in a placebo controlled study.22 Six patients responded well to treatment, with interruption of their attack. Moreover, in 3 of the responders the CH period ended after HBO treatment. Placebo treatment had no effect find more on pain. In summary, normobaric oxygen is an effective treatment of acute CH

attacks in the majority of patients. It is well tolerated and has virtually no AEs. selleck chemicals As opposed to triptans, there is no limitation to the number of times per

day it can be used. A proper technique of use is crucial for good results with oxygen therapy. The patient should be instructed to use the oxygen via a non-rebreathable mask, at a rate of 7-10 L/min, in a sitting position, for at least 15-20 minutes. Patients may increase the flow rate up to 15 L/min if needed. The optimal flow rate should be determined individually for each patient. The major disadvantage of oxygen therapy is its inconvenience of use, particularly when the patient is out of home. Portable oxygen tanks are available for patients who wish to use it in these circumstances. Oxygen therapy for CH should be used with caution, or even avoided, in patients with chronic obstructive pulmonary disease, because of the risk of respiratory depression. HBO may be considered for refractory CH patients. However, because this is not a readily available therapy, and there is no evidence for a sustained effect of it on CH,23 the majority of patients are not likely to benefit from it. Ergot derivatives were among the first agents to be used in CH treatment.

Reports on the efficacy of ergotamine for this indication date medchemexpress back to the 1940s and 1950s.1 These data, however, were based on small, open-label studies and on case reports. The drug has not been evaluated in controlled studies for this indication. Kudrow compared the efficacy of sublingual ergotamine with that of oxygen in 50 patients with CH.17 The response rate to ergotamine was 70%, as compared with 82% for oxygen (with no significant between-group difference). Oxygen was better tolerated than ergotamine; however, the latter was more convenient to use. Because of limited availability and potentially serious AEs, most notably those related to the drug’s vasoconstrictive effect, ergotamine is currently rarely used for acute CH. Dihydroergotamine (DHE) is available in injectable (intravenous, intramuscular, or subcutaneous) and intranasal formulations. Although no data from controlled trials are available, clinical experience suggests efficacy of intravenous DHE for acute CH.

Firefly luciferase activity was normalized to Renilla luciferase activity and total protein, determined using the bicinchoninic acid protein assay kit. For ease of comparison, values for cells with pGL3-Bach1 and pRL-TK transfection were Selleck Doxorubicin set equal to 1. The HCV infectious clone pJ6/JFH1, the full-length chimeric genome with the core-NS2 regions from the infectious J6 (genotype 2a) and NS3-NS5B regions from the infectious JFH1 (genotype 2a), was generously provided by C. M. Rice (the Rockefeller University, New York, NY). The production of J6/JFH1-based cell culture–generated

HCV has been reported.25 In brief, the pJ6/JFH1 plasmid was linearized with XbaI and purified by ethanol precipitation, digestion with proteinase K, and phenol-chloroform extraction. The linearized plasmid was used as a template for in vitro transcription using the MEGAscript T7 kit

(Ambion, Austin, TX). For HCV RNA transfection, Huh-7.5 cells were plated selleck inhibitor in 24-well plates 1 day prior to transfection and transfected at 70%–80% confluence. Cells were transfected at an RNA/Lipofectamine ratio of 1:2 by using 2 μg/well of HCV RNA and 4 μL/well Lipofectamine 2000 for 48 hours. To infect naïve Huh-7.5 cells, cell culture supernatants from the cells transfected with HCV RNA for 48 hours were collected and filtered through a 0.20 μm filter, and added to cultures of naïve Huh-7.5 cells. The pFK-Con1 construct (genotype 1b)21 was a kind gift of Dr. R. Bartenschlager (University of Heidelberg, Heidelberg, Germany). Mutant pFK-Con1 (pFK-Con1-Mut) with mutations in four nucleotides in the putative binding sites for miR-196 was generated by GENEWIZ, Inc. (South Plainfield, NJ) and confirmed by sequencing. pFK-Con1–wild-type (WT) and pFK-Con1-Mut were linearized with AseI and ScaI. In vitro transcription MCE and transfection were performed as described. Western blotting was performed using the standard

protocols of our laboratory as reported.10 The method is described in detail in the Supporting Materials and Methods. Total RNA from tested cells was extracted, and complementary DNA was synthesized.10 qRT-PCR was performed using primers as reported19, 26 and as described in detail in the Supporting Material and Methods. Initial analysis showed that results were normally distributed. Therefore, parametric statistical procedures were used. The Student t test (for comparison of two conditions) or analysis of variance (for comparisons among more than two) was used to analyze the differences among means. Values of P < 0.05 were considered statistically significant. Experiments were repeated at least three times with similar results. All experiments included at least triplicate samples for each treatment group. Representative results from single experiments are presented. Statistical analyses were performed with JMP 4.0.4 software from SAS Institute (Cary, NC). An online search of the TargetScan 4.2 database (http://www.targetscan.

This case-control study aimed to evaluate the associations with the development of hepatocellular carcinoma (HCC) for these two candidate SNPs and other SNPs near IL28A and IL28B genes among patients

infected with HCV genotype 1 or non-1. Methods: There were 1295 study participants Pritelivir seropositive for antibodies against HCV recruited from R.E.V.E.A.L-HCV cohort and Taiwan Liver Cancer Network. In total, there were 853 non-HCC cases and 442 HCC cases. The demographic characteristics and habits of cigarette smoking and alcohol drinking were collected through personal interview using structured questionnaires. A total of 72 SNPs near IL28A and IL28B genes were genotyped using Illumina VeraCode GoldenGate genotyping assay. Olaparib price The deviation from Hardy-Weinberg equilibrium for each marker was examined by Chi-squared tests. The adjusted odds ratios (ORadj) and 95% confidence interval (CI) were estimated by logistic regression models after adjustment for age, sex, habits of cigarette smoking and alcohol drinking, and serum levels of alanine aminotransferase. Results: The HCC cases had a higher proportion to carry the genotype unfavorable for antiviral treatment on rs12979860 and rs8099917. There were 12.7% HCC cases and 8.6% controls carried TG/GG on rs8099917

(p = 0.02); 14.5% HCC cases and 10.0% controls carried TT or TC on rs12979860 (p = 0.02). An increased HCC risk was observed for participants who carried the TG or GG genotype on rs8099917 (ORadj, 1.66; 95% CI, 0.92–2.86) or the TT or TC genotype on rs12979860 (ORadj,

1.63; 95% CI, 1.00–2.70). Among other SNPs genotyped, rs35790907 was associated with an increased HCC risk (ORadj, 1.93; 95% CI, 1.18–3.16). In addition, the significant association between rs35790907 genotype and HCC risk was found only in participants with HCV genotype 1 infection (ORadj, 2.19; 95% CI, 1.02–4.71), but not in those infected with HCV genotype non-1 (ORadj, 0.80; 95% CI, 0.28–2.24). Conclusion: This large case-control study showed the SNPs 上海皓元医药股份有限公司 near IL28A and IL28B were associated with HCC risk among patients with HCV genotype 1 infection. However, the findings need further validation in an external population. Key Word(s): 1. HCC; 2. IL28B gene; 3. IL28A gene; 4. HCV; Presenting Author: RONGHUA WANG Additional Authors: JING LUO, PENG WANG, QIAN SUN, BIN CHENG Corresponding Author: BIN CHENG Affiliations: Dept. of Gastroenterology and Hepatology, Tongji Hospital, Huazhong University of Science and Technology Objective: Hepatocellular carcinoma (HCC), the fifth most common and third most deadly malignancy with observable heterogeneity, are thought to contain liver cancer stem cells (LCSCs) which have been identified as a distinct population responsible for tumor relapse and metastasis. CD90 and CD44 have been used as specific cell surface markers to enrich CSCs in HCC.

Methods:  Serum levels of CypB in gastric cancer patients and healthy volunteers were measured by ELISA. The expression patterns of CypB were observed in gastric cancer and adjacent non-tumor tissue using immunohistochemistry. MTT, colony formation and cell cycle assays were used to examine the effects of knock-down CypB on the cell growth, proliferation. DNA aptamers specific to CypB were islolated

by SELEX. Binding affinity (Kd) was determined in direct binding assay by flow cytometry analysis. Results:  CypB is over-expressed in both serum and tissues of gastric cancer patients. Knock-down of CypB can inhibit gastric cancer cell NVP-BKM120 molecular weight growth, proliferation, cell cycle progress and tumorigenesis. Two aptmers which can bind to CypB protein with high affinity and specificity were isolated through SELEX. Conclusion: These findings indiccate CypB could be a potential biomarker and therapeutic target for MLN8237 chemical structure gastric cancer. CypB-specific aptamers were succusfully isolated, which may be used in further study and future application of CypB. Key Word(s): 1. CypB; 2. gastric cancer; 3. aptamer; 4. SELEX; Presenting

Author: WANG AIYING Additional Authors: ZHU DAN Corresponding Author: WANG AIYING Affiliations: Peking University Third Hospital Objective: This study was to evaluate expression of Bax, Cyt- C and Ki – 67 in DMH induced rat small intestinal and colorectal tumor. Methods: 7 small tumors and 28 colon tumors specimens from 25 male Wistar rats induced by DMH, 9 control only rats, were detected by 上海皓元医药股份有限公司 Pathology and immunohistochemistry detection. The immunohistochemical detection expression of Bax, Cyt −C and Ki – 67 in the tumor and normal tissue, the statistical processing using chi-square test. Results: (1) the positive expression of Bax in the normal tissue and tumor of small intestine were 88.89% and 14.29% respectively; (2) positive expression of Bax in normal tissue and tumor of colon were 44.44% and 89.29% respectively; (3) Cyt – C positive expression

were 100% and 42.86% in normal small intestine and tumors; (4) Cyt C positive expression were 88.89% and 32.14% respectively in normal colon and tumor; (5) normal intestine without positive expression of Ki – 67, small intestine tumor 71.43% positive expression; (6) positive expression of Ki – 67 was 22.22% in normal colon, and 67.86% in colon cancer. Above all have significant difference between groups (P < 0.05). Conclusion: Cyt-C down regulation and Ki- 67 up regulation may promote the occurrence of small and large intestinan tumor. In the normal small intestinal tissue, the expression of Bax was higher than normal colon tissues, Cyt – C high expression and no expression of Ki – 67, may explains the significant difference in tumor incurrence between small intestine and colon. Key Word(s): 1. intestinal tumor; 2. Bax; 3. Cyt-C; 4.

Methods:  Serum levels of CypB in gastric cancer patients and healthy volunteers were measured by ELISA. The expression patterns of CypB were observed in gastric cancer and adjacent non-tumor tissue using immunohistochemistry. MTT, colony formation and cell cycle assays were used to examine the effects of knock-down CypB on the cell growth, proliferation. DNA aptamers specific to CypB were islolated

by SELEX. Binding affinity (Kd) was determined in direct binding assay by flow cytometry analysis. Results:  CypB is over-expressed in both serum and tissues of gastric cancer patients. Knock-down of CypB can inhibit gastric cancer cell Daporinad in vivo growth, proliferation, cell cycle progress and tumorigenesis. Two aptmers which can bind to CypB protein with high affinity and specificity were isolated through SELEX. Conclusion: These findings indiccate CypB could be a potential biomarker and therapeutic target for Ensartinib concentration gastric cancer. CypB-specific aptamers were succusfully isolated, which may be used in further study and future application of CypB. Key Word(s): 1. CypB; 2. gastric cancer; 3. aptamer; 4. SELEX; Presenting

Author: WANG AIYING Additional Authors: ZHU DAN Corresponding Author: WANG AIYING Affiliations: Peking University Third Hospital Objective: This study was to evaluate expression of Bax, Cyt- C and Ki – 67 in DMH induced rat small intestinal and colorectal tumor. Methods: 7 small tumors and 28 colon tumors specimens from 25 male Wistar rats induced by DMH, 9 control only rats, were detected by 上海皓元 Pathology and immunohistochemistry detection. The immunohistochemical detection expression of Bax, Cyt −C and Ki – 67 in the tumor and normal tissue, the statistical processing using chi-square test. Results: (1) the positive expression of Bax in the normal tissue and tumor of small intestine were 88.89% and 14.29% respectively; (2) positive expression of Bax in normal tissue and tumor of colon were 44.44% and 89.29% respectively; (3) Cyt – C positive expression

were 100% and 42.86% in normal small intestine and tumors; (4) Cyt C positive expression were 88.89% and 32.14% respectively in normal colon and tumor; (5) normal intestine without positive expression of Ki – 67, small intestine tumor 71.43% positive expression; (6) positive expression of Ki – 67 was 22.22% in normal colon, and 67.86% in colon cancer. Above all have significant difference between groups (P < 0.05). Conclusion: Cyt-C down regulation and Ki- 67 up regulation may promote the occurrence of small and large intestinan tumor. In the normal small intestinal tissue, the expression of Bax was higher than normal colon tissues, Cyt – C high expression and no expression of Ki – 67, may explains the significant difference in tumor incurrence between small intestine and colon. Key Word(s): 1. intestinal tumor; 2. Bax; 3. Cyt-C; 4.

It has, therefore, become the screening tool of choice. However, it should be noted that a proportion of cirrhotic patients have intrapulmonary vasodilation detected at echocardiography without gas exchange abnormalities, and in general these patients do not appear to develop hypoxemia

over time.[15, 56] In bubble contrast echocardiography, a sample of liquid (normally saline) is vigorously shaken to produce microbubbles, and then injected into an arm vein while the cardiac chambers are visualized via a transthoracic approach. Normally, BGB324 cell line these bubbles, which are > 25 μm in diameter, are trapped in the alveolar capillary bed, where the vessels have a diameter of 5–8 μm. Therefore, their appearance in the left atrium after intravenous injection suggests that pulmonary BVD-523 vasodilation has allowed them to traverse the capillary bed, reaching the left side of the heart. A positive study can of course also occur due to the passage of bubbles through a cardiac defect, but in this case the bubbles appear in the left atrium much sooner (within three cycles) after their first appearance in the right atrium. In practice, an intracardiac shunt cannot be definitively excluded in a small proportion of patients with positive studies, and this may require further cardiac investigations. MAA perfusion lung scan is performed by peripheral venous injection of MAA particles that

have been radio-labeled with technetium-99 m, followed MCE by whole body scanning to estimate the extrapulmonary shunt fraction. These radio-labeled particles have a diameter

of 10–90 μm and are removed in the normal pulmonary circulation. Thus, the detection of a significant amount of radiation in the brain or kidneys suggests intrapulmonary vasodilation or intracardiac shunting. MAA scanning appears to be highly specific but less sensitive than bubble contrast echo for detecting intrapulmonary dilatation consistent with HPS, and may fail to detect the presence of intrapulmonary vasodilation in the absence of hypoxia.[15] However, its high specificity makes it useful in diagnosing HPS in patients with coexisting lung disease,[15] and it has the advantage of being quantitative. Chest X-ray may be normal or may show increased vascular markings in the lower zones. High resolution computerized tomography can be helpful in selected patients to exclude intrinsic lung disease, but the absence of vascular abnormalities does not preclude the diagnosis of HPS. A reduced carbon monoxide diffusing capacity is frequently seen in cirrhotic patients and is almost universal in HPS,[10, 12] possibly reflecting diffusion limitation at the alveolus. In the absence of intrinsic lung disease, other pulmonary function tests are normal. Pulmonary angiography can be normal in HPS and is rarely required.

2B). These results indicate

that infectious HCV particles and lipoproteins are internalized with different kinetics, suggesting distinct uptake pathways. Hence, this suggests that the lipoproteins associated with HCVcc virions do not affect the rate of infectious virus entry. We analyzed the effect of blocking LDLR with a specific mAb C7. This mAb is well characterized and binds the first repeat of the LDLR ligand-binding domain and partially blocks lipoprotein binding27 (Fig. 3A). When mAb C7 was present during the 2 hours of virus infection, no decrease in HCVcc infectivity was observed (Fig. 3B). However, HCVcc infectivity was reduced to approximately 40% when mAb C7 was present in the cell-culture supernatant for approximately 24 hours (Fig.

3B). Furthermore, when the mAb was added overnight at 8 hours postinfection, R788 we also observed a drop in HCVcc infectivity to 56%. These observations suggest that instead of playing Selleckchem Vorinostat an active role in HCV entry, the LDLR might rather be involved in a postentry step. To further investigate this hypothesis, Huh-7 cells were electroporated with HCV RNA and incubated in the presence or absence of mAb C7. This induced a decrease in HCV replication (Fig. 3C). Indeed, the luciferase activity was reduced by 1 log10 at 24 hours postelectroporation, but no further decrease was observed over time. However, we cannot exclude that, at later time points, replication in the presence of mAb C7 was less affected as a result of constant antibody internalization, leading to a decrease in their concentration. Furthermore, upon HCV infection, intracellular lipid biosynthesis pathways can be up-regulated, potentially decreasing the role of lipids taken up by the LDLR. Finally, it is possible that lipids are more important early during HCV replication. The effect exerted by C7 was specific for HCV, because only a slight decrease in SINV replication was MCE公司 observed at 24 hours postelectroporation (Fig. 3C). The level of SINV replication was the same as for the controls at 48 hours, whereas at 72 hours, a slight increase in replication was observed. The differences in the shapes of the curves

between HCV and SINV are the result of differences in the kinetics of replication between these two viruses. The effect of mAb C7 on HCV replication is potentially the result of a decrease in lipoprotein uptake, which might result in an intracellular decrease of some lipids essential for HCV replication. Therefore, we analyzed the lipid content of Huh-7 cells after treatment with mAb C7 and found that both neutral lipid and phospholipid contents were modified. In cells treated with mAb C7, the ratio between free cholesterol and cholesterol esters (CEs) shifted in favor of CEs (Fig. 3D). Moreover, changes were also observed in phospholipid content. Phosphatidylethanolamine (PE) and phosphatidylcholine (PC) are the major phospholipids in cell membranes.

2B). These results indicate

that infectious HCV particles and lipoproteins are internalized with different kinetics, suggesting distinct uptake pathways. Hence, this suggests that the lipoproteins associated with HCVcc virions do not affect the rate of infectious virus entry. We analyzed the effect of blocking LDLR with a specific mAb C7. This mAb is well characterized and binds the first repeat of the LDLR ligand-binding domain and partially blocks lipoprotein binding27 (Fig. 3A). When mAb C7 was present during the 2 hours of virus infection, no decrease in HCVcc infectivity was observed (Fig. 3B). However, HCVcc infectivity was reduced to approximately 40% when mAb C7 was present in the cell-culture supernatant for approximately 24 hours (Fig.

3B). Furthermore, when the mAb was added overnight at 8 hours postinfection, buy Carfilzomib we also observed a drop in HCVcc infectivity to 56%. These observations suggest that instead of playing RXDX-106 nmr an active role in HCV entry, the LDLR might rather be involved in a postentry step. To further investigate this hypothesis, Huh-7 cells were electroporated with HCV RNA and incubated in the presence or absence of mAb C7. This induced a decrease in HCV replication (Fig. 3C). Indeed, the luciferase activity was reduced by 1 log10 at 24 hours postelectroporation, but no further decrease was observed over time. However, we cannot exclude that, at later time points, replication in the presence of mAb C7 was less affected as a result of constant antibody internalization, leading to a decrease in their concentration. Furthermore, upon HCV infection, intracellular lipid biosynthesis pathways can be up-regulated, potentially decreasing the role of lipids taken up by the LDLR. Finally, it is possible that lipids are more important early during HCV replication. The effect exerted by C7 was specific for HCV, because only a slight decrease in SINV replication was 上海皓元 observed at 24 hours postelectroporation (Fig. 3C). The level of SINV replication was the same as for the controls at 48 hours, whereas at 72 hours, a slight increase in replication was observed. The differences in the shapes of the curves

between HCV and SINV are the result of differences in the kinetics of replication between these two viruses. The effect of mAb C7 on HCV replication is potentially the result of a decrease in lipoprotein uptake, which might result in an intracellular decrease of some lipids essential for HCV replication. Therefore, we analyzed the lipid content of Huh-7 cells after treatment with mAb C7 and found that both neutral lipid and phospholipid contents were modified. In cells treated with mAb C7, the ratio between free cholesterol and cholesterol esters (CEs) shifted in favor of CEs (Fig. 3D). Moreover, changes were also observed in phospholipid content. Phosphatidylethanolamine (PE) and phosphatidylcholine (PC) are the major phospholipids in cell membranes.

We assessed functional status of PZ system

in 158 patients with liver cirrhosis and 59 healthy controls. Plasma PZ and ZPI levels were measured by enzyme immunoassay. Thrombin generation assays (TGA) were performed with and without thrombomodulin (TM) or PZ, and the ratios were calculated by dividing TGA values with TM or PZ by Romidepsin chemical structure values without TM or PZ. PZ and ZPI levels were reduced and elevated in advanced cirrhosis, respectively. The lag time ratio–PZ was significantly higher in cirrhosis patients than controls and correlated with the model for end-stage liver disease (MELD) score. The peak thrombin ratio–PZ and endogenous thrombin potential (ETP) ratio–PZ were significantly lower in cirrhosis patients than controls and correlated with the severity of liver cirrhosis. The peak thrombin ratio–PZ was dramatically reduced in advanced cirrhosis. Cirrhosis patients had a significantly higher ETP ratio–TM than the controls, although the ratio was not correlated

with cirrhosis severity. The lag time ratio–PZ and peak time ratio–PZ were significantly correlated with the levels of all coagulation and anticoagulation factors. Interestingly, the lag time ratio–PZ and peak thrombin ratio–PZ were significantly associated with thrombotic events. The anticoagulant role of PZ is insufficient in advanced stages of cirrhosis. Our newly developed functional assay for measuring the PZ system is expected to reflect the ongoing hypercoagulability of cirrhosis. “
“Background and Aim:  The development of endoscopic treatment, such as endoscopic click here submucosal dissection, extends the indications for endoscopic resection in patients with early gastric cancer (EGC). Endoscopic ultrasonography (EUS) is the first-choice imaging modality for determining the depth of invasion of gastric cancer. The aim of the present study was to prospectively assess the accuracy of EUS for determining the depth of EGC, according to the accepted/extended indications. Methods:  We prospectively included

a total of 181 lesions in 178 MCE patients, with an endoscopic diagnosis of EGC, who underwent EUS for staging the depth of tumor invasion using a 20-MHz catheter probe. We investigated the accuracy of EUS for determining the depth of endoscopically-suspected EGC and then analyzed the difference in the accuracy of EUS according to the accepted/extended indications. Results:  Of the 178 patients, five patients were dropped because of the absence of final histological results. For the 176 lesions in 173 patients, the accuracy of EUS assessment for the depth of tumor invasion was 80.7% (142 of 176 lesions). The accuracy of EUS for the lesions with accepted indications and with extended indications was 97.6% (40 of 41 lesions) and 83.6% (46 of 57 lesions), respectively (P = 0.040). Of the lesions with extended indications, the accuracy of EUS decreased especially for the lesions with ulceration and those with minute submucosal invasion (79.

Here we show that an unusual phosphatidyl-choline species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine

(DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose Selleck DMXAA homeostasis. The orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) is regarded as a central regulator of bile salt biosynthesis and bile salts are increasingly recognized as modulators

of glucose and lipid metabolism in mice and men. In their remarkable study, Lee et al.1 identified a ligand for LRH-1, dilauroyl phosphatidylcholine (DLPC), a C12:0/C12:0 phospholipid, which had potent effects on glucose, BIBW2992 lipid, and bile salt homeostasis in vivo. In a cell-free system, Lee et al. demonstrated by mass spectrometry that DLPC specifically binds to a recombinant LRH-1 ligand-binding domain. Agonism for LRH-1 could be confirmed in an elegant mammalian two-hybrid assay for DLPC and its sister-molecule diundecanoyl phosphatidylcholine (DUPC; C11:0/C11:0). On functional level, DLPC and even more DUPC were strong activators of both human and mouse LRH-1, whereas other nuclear receptors including FXR, CAR, PXR, PPARα and PPARγ were all unaffected in cell culture. DLPC and

DUPC induced transactivation of the native mouse Shp and Oct4 promoters, in line with previous studies on Lrh-1.2, 3 In the human hepatoma cell line HepG2, DLPC induced the expression of CYP8B1. When orally applied to wildtype mice, DLPC and DUPC induced the expression of hepatic Cyp7a1, Cyp8b1, and Sr-b1 but repressed Shp, leading to a modest increase in serum bile salts and total bile salt pool. These findings were consistent with previous observations in 上海皓元医药股份有限公司 liver-specific Lrh-1 knockouts.4 More strikingly, DUPC- and DLPC-treated mice showed significantly decreased serum glucose, serum nonesterified fatty acids (NEFAs), and hepatic triglycerides. The effects of DLPC were lost in LRH-1 floxed (Lrh-1f/f) mice after administration of adenoviral Cre (Ad-Cre) vector, deleting LRH-1. Comparative oral administration of cholate (100 mg/kg body weight twice daily) improved serum NEFAs and hepatic triglycerides to a similar degree, but did not affect serum glucose. The surprising effects of DLPC on glucose metabolism were further investigated in a diabetic model, utilizing insulin-resistant leptin receptor deficient db/db mice. DLPC improved glucose homeostasis, as assessed by serum insulin, glucose tolerance test (GTT), and insulin tolerance test (ITT).