All TLR2−/− mice developed HCC at the end of the sixth month, but only 63% of WT mice developed such lesions at this time. However, 100% of WT or TLR2−/− mice developed liver tumors at the end of the eighth month after DEN injection (Fig. 1B). The number of HCC tumor nodules was also increased in the TLR2−/− mice Epigenetics inhibitor (Fig. 1C). Although the TLR2−/− mice displayed

no difference in a very early hepatic injury (Fig. S1E,F), they showed persistent elevated serum levels of ALT (Fig. 1E) as compared to WT mice after DEN injection. Thus, TLR2−/− mice with HCC had shorter mean survival times than WT mice (Fig. 1F). Collectively, the data indicate that knockout of TLR2 increases the susceptibility to the DEN-induced hepatocarcinogenesis

high throughput screening compounds and progression. DEN is a typical chemical carcinogen and forms adducts with DNA after liver metabolization by cytochrome P450 2E1. These adducts may cause liver injury, DNA mutation, and tumorigenesis.19 No significant difference in cytochrome P450 2E1 activity was detected between TLR2−/− and WT mice (data not shown), indicating that the elevated HCC development in TLR2−/− livers did not simply result from changes in DEN metabolites. Further, the TLR2−/− mice exhibited enhanced accumulation of ROS in their liver tissues (Fig. 2A), which was sustained from the early to the late phase of HCC progression (Fig. 2B). Additionally, we found that TLR2−/− livers showed an accumulation of oxidative stress-associated products, including protein carbonyl and 8-OHdG-linked proteins (Fig. S2A) and

the activation of lipid peroxides (LPO) (Fig. S2B). Generally, cellular stress and oxidative damage should induce programmed cell death in the liver through apoptosis and autophagy. However, TLR2−/− mice displayed a persistent decrease in cell death (Fig. 2C,D) compared to WT mice. Indeed, TLR2−/− mice exhibited a decrease in autophagy-associated cell death as marked by Lamp1 and TUNEL double staining (6.0 ± 1.7 versus 1.5 ± 0.3, P < 0.05) (Fig. 3A,B) as well as a decrease in apoptotic cell death as evidenced by suppressed cleavage of caspase-3 (Fig. 3C,D). These results indicate that TLR2 deficiency protects liver cells from oxidative stress-induced death. Cellular senescence is regarded ADP ribosylation factor as a physiological barrier against carcinogenesis and tumor progression.20-22 Senescence can be induced by many stimuli, such as dysfunctional telomeres and other sources of DNA damage.21 As a typical biomarker of senescence, SA β-galactosidase (β-gal) staining was increased in WT livers but not in TLR2−/− livers after DEN treatment (Fig. 4A,B). Despite ROS accumulation (Fig. 2A) and DNA damage (Fig. S2A) in the liver tissue, γ-H2A.X (phosphorylated histone H2A.X), a typical biomarker of DNA damage repair, was suppressed in TLR2−/− livers (Fig.

Bile acids were significantly higher in patients with pruritus (p<0.001), particularly in those with resistant pruritus. Cortisol (p=0.02) and androsterone selleck screening library sulfate were in lower levels, while pregnenolone sulfate and an isomer of dehydroe-piandrosterone sulfate (DHEAS) were higher in patients with pruritus. Most metabolites decreased in sera after MARS and the differences were particularly significant for sterols, N-acyl ethanolamines, 1-ether,2–acylglycero-phosphoetanolamine and free sphingoid bases. MARS treatment

resulted in a significant reduction of primary bile acids (p = 0.03) and secondary bile acids, pregnenolone sulfate (p=0.007), DHEAS (p=0.02), an androsterone sulfate isomer (p=0.003), some glycero-phospholipids and kynurenine (p=0.02). Four of these serum metabolites, including bile acids were identified in the albumin dialysate. Conclusion: Cholestatic pruritus DMXAA mw is associated with increased bile acids and changes in the lipid profile. MARS therapy for pruritus results in a decrease of circulating metabolites especially phospholipids, primary bile acids and

sterols. This metabolomic analysis identifies a panel of biomarkers that could participate into the pathogenesis of cholestatic pruritus. Disclosures: Albert Pares – Consulting: Lumena Pharmaceuticals The following people have nothing to disclose: Miriam Perez-Cormenzana, Alvaro Diaz-Gonzalez, Rebeca Mayo, Azucena Castro, Antoni Mas Purose: Recently, it has been reported that the migration of inflammatory cells via high endothelial venules (HEVs) is related to the pathogenesis in various chronic inflammatory diseases. Moreover, it is known that inflammatory areas with HEVs sometimes show the characteristics of secondary lym-phoid tissue, and these Urease structures are called “tertiary lymphoid organs (TLOs)”. In the present study, to examine whether the neogenesis of HEVs and the formation of TLOs are occurred in primary biliary cirrhosis (PBC), we performed the histopathological study. Methods: We examined the liver

specimens of 21 PBC cases, 13 chronic viral hepatitis-C (CVH) cases, and 5 normal cases. We performed immunohistochemistry for MECA-79, which is well-established marker of HEVs, CD3, CD20, CD21, CD83, and CCR-7. Results: In PBC livers, HEVs labeled by MECA-79 were observed more frequently in portal areas with lymphoid aggregation in PBC than in CVH (78% versus 27%; p < 0.01 Fisher’s exact test). On the other hand, HEVs were never observed in normal livers. In addition, CCR-7+ lymphocytes, which migrate to peripheral tissues via HEVs, were observed more frequently in inflammatory cites in PBC livers compared to CVH livers. Moreover, in PBC livers, HEVs were observed in 77% of portal areas with bile duct obstruction, whereas they were observed in 28% of portal areas without bile duct obstruction (p < 0.01 Fisher’s exact test). Next, we examined whether TLO’s features are recognized in 13 PBC cases, in which HEVs were remarkably observed.

Transcatheter arterial chemoembolization (TACE) was important treatment method, and stereotactic conformal radiotherapy (SCRT) was also used in unresectable HCC. In this study, the clinical application and therapeutic effects of TACE combined with and SCRT were evaluated on patients with advanced unresectable HCC. Methods: Forty-five patients with advanced unresectable HCC hospitalized from

February 2009 to February 2011 received the treatment of TACE combined with SCRT. Firstly, these patients were treated by two or three time procedure TACE. For TACE, 5-fluorouracil (1000–1500 mg) and cisplatin (60–80 mg) were perfused into the hepatic arteries, then mitomycin C (20 mg) and iodized oil (10–20 ml) were mixed and were given to emobolized compound screening assay the hepatic arteries. Secondly, SCRT were applied

on these cases. For SCRT, gamma knife stereotaxis radiation therapy was carried out. There were planning of treatment from 3 to 10 dots, 3–6 Gy per-fraction, 5 times per week, and the total treatment dose was 30–50 Gy. ≥50% isodose include PTV. The tumor size and serum AFP level were observed at per-3 months after combination treatment. The 1-, 2-year survival rates of the patients were analyzed. Results: Mean serum AFP level was significant decreased from 1824.0 ng/L to 212.6 ng/L. The average diameter of tumor before and after combination treatment were (7.21 ± 2.12)cm and (4.12 ± 1.53)cm. The survival rate of 1 and 2-year were 75.6% and 51.1% respectively. Conclusion: TACE AG-14699 combined with SCRT is effective for advanced unresectable HCC. Further clinical study on the

combination application of TACE with SCRT is needed. Niclosamide Key Word(s): 1. HCC; 2. TACE; 3. radiotherapy; Presenting Author: RAMIN ATAEE Additional Authors: ATEFEH ASEMI, MOHAMMAD SHOKRZADE, AMIN ATAEE Corresponding Author: RAMIN ATAEE Affiliations: Pharmaceutical Sciences Research center; Department of Pharmacology Objective: Melatonin is an important hormone which has important role in in circadian rhythm of human body, recently it has been cleared that it can have important role in regulating of some physiologic and pathological conditions especially cancer prevention though its’ role in inhibiting of breast and colon cancer has been confirmed but its’ role in gastric cancer is poor understood and this study aimed to show this role in gastric cancer Methods: For in vitro study we have used AGS adenocarcinoma cell line cultured in 96 wells (10000 cells in each well in 96 cultureplate) and also for proliferation assay we used MTT Elisa Method and for apoptosis we used TUNEL in-situ fluorescent microscopic assay. Also for each MTT and TUNEL assay, 5 concentrations of melatonin (200,100,50,25,12.5,6.

The letter also provided information about HCV transmission, effect on the liver, and effect on general health. In addition, beginning in 2005-2006, serum samples from participants with a positive or indeterminate result for anti-HCV were tested for hepatitis C RNA (HCV-RNA);

starting in 2007, participants with an indeterminate test result for anti-HCV and a positive HCV-RNA also were sent an ROF letter. Because a primary aim of the follow-up survey was to assess what actions participants selleckchem took after becoming aware of their first positive test result, attempts to administer a follow-up telephone questionnaire to all those who were sent an ROF letter began 6 months after examination (approximately 4-5 months after the ROF letter was mailed) to allow participants time to have initiated or implemented actions after notification. Persons ≥18 years of age were interviewed directly; an adult proxy provided information

for participants who were <18 years of age and for individuals unable to answer the questions themselves. The HCV Follow-up Questionnaire (available at: www.cdc.gov/nchs/nhanes/nhanes2003-2004/questexam03_04.htm) was mentioned in the informed consent and also in the ROF letter. Bilingual Wnt antagonist (i.e., English and Spanish) trained interviewers contacted eligible participants by telephone for the interview. Participants who lived in households with no telephones were sent a letter asking them to call a toll-free number to answer a few questions about their hepatitis C results. Participants with communication

or cognitive difficulties that made it impossible to respond to the questionnaire, and for whom a parent or guardian was not available to complete the interview, were excluded. For the main NHANES survey, participants were interviewed in their homes to ascertain demographic characteristics, access to care, and health insurance coverage, using the Computer-Assisted Personal Interviewing (i.e., interviewer-administered) system. Having a usual source of medical care was determined by responses to the question: “Is there a place that Rho you/sampled person usually go/goes when you are/he/she is sick or you/s/he needs advice about your/his/her health? Qualitative determination of anti-HCV in blood serum or plasma was measured using direct solid-phase enzyme immunoassay with an anti-HCV screening enzyme-linked immunosorbent assay (ELISA) (Ortho CD VITROS Anti-HCV Immunodiagnostic System; Ortho Clinical Diagnostics, Raritan, NJ). Positive specimens were repeated in duplicate according to the same procedure. Repeatedly positive specimens were then tested using a confirmatory recombinant immunoblotting assay (RIBA) (Chiron RIBA Processor System, Chiron RIBA HCV 3.0 Strip SIA; Chiron Corporation, Inc., Emeryville, CA), an in vitro qualitative enzyme immunoassay for the detection of anti-HCV in human serum or plasma.

The letter also provided information about HCV transmission, effect on the liver, and effect on general health. In addition, beginning in 2005-2006, serum samples from participants with a positive or indeterminate result for anti-HCV were tested for hepatitis C RNA (HCV-RNA);

starting in 2007, participants with an indeterminate test result for anti-HCV and a positive HCV-RNA also were sent an ROF letter. Because a primary aim of the follow-up survey was to assess what actions participants selleck screening library took after becoming aware of their first positive test result, attempts to administer a follow-up telephone questionnaire to all those who were sent an ROF letter began 6 months after examination (approximately 4-5 months after the ROF letter was mailed) to allow participants time to have initiated or implemented actions after notification. Persons ≥18 years of age were interviewed directly; an adult proxy provided information

for participants who were <18 years of age and for individuals unable to answer the questions themselves. The HCV Follow-up Questionnaire (available at: www.cdc.gov/nchs/nhanes/nhanes2003-2004/questexam03_04.htm) was mentioned in the informed consent and also in the ROF letter. Bilingual Epigenetics inhibitor (i.e., English and Spanish) trained interviewers contacted eligible participants by telephone for the interview. Participants who lived in households with no telephones were sent a letter asking them to call a toll-free number to answer a few questions about their hepatitis C results. Participants with communication

or cognitive difficulties that made it impossible to respond to the questionnaire, and for whom a parent or guardian was not available to complete the interview, were excluded. For the main NHANES survey, participants were interviewed in their homes to ascertain demographic characteristics, access to care, and health insurance coverage, using the Computer-Assisted Personal Interviewing (i.e., interviewer-administered) system. Having a usual source of medical care was determined by responses to the question: “Is there a place that Rebamipide you/sampled person usually go/goes when you are/he/she is sick or you/s/he needs advice about your/his/her health? Qualitative determination of anti-HCV in blood serum or plasma was measured using direct solid-phase enzyme immunoassay with an anti-HCV screening enzyme-linked immunosorbent assay (ELISA) (Ortho CD VITROS Anti-HCV Immunodiagnostic System; Ortho Clinical Diagnostics, Raritan, NJ). Positive specimens were repeated in duplicate according to the same procedure. Repeatedly positive specimens were then tested using a confirmatory recombinant immunoblotting assay (RIBA) (Chiron RIBA Processor System, Chiron RIBA HCV 3.0 Strip SIA; Chiron Corporation, Inc., Emeryville, CA), an in vitro qualitative enzyme immunoassay for the detection of anti-HCV in human serum or plasma.

[9] Especially, the latter has been attributed to the deficits in motion processing, such as motion aftereffect prolongation,[10] and a decreased ability to detect coherent motion.[11, 12] fMRI relies on the measurement of altered metabolic requirements

that are influenced by neuronal activity. The highly complex mechanism underlying this process of neurovascular coupling is not completely understood, find more but is believed to be based on local changes in cerebral blood flow, arterial and venous cerebral blood volume, and cerebral metabolic rate of oxygen utilization, among others. Thereby, fMRI detects neuronal activity indirectly through the blood oxygenation level dependent (BOLD) effect,[13] and offers a detection of brain activation patterns with high spatial Adriamycin in vivo resolution. While fMRI has been used to characterize the visual system in healthy humans,[14] similar studies in migraine patients are rare and the results are conflictive. To date, only one previous study has performed MRI with emphasis on interictal motion processing and found that compared with healthy controls, migraine patients showed significantly stronger activation

in the left middle-temporal complex.[15] fTCD assesses vasomotor reactivity within the arterial territory of supply: a task-specific neuronal activation causes an increase in local cerebral blood flow. This method has been applied in migraine patients during visual stimulation showing – among other findings – a greater cerebrovascular response in the middle and posterior cerebral arteries in migraineurs with lesser habituation.[3, 16] Even though Suplatast tosilate lateralization

is a typical clinical feature of migraine, this aspect has been analyzed less frequently in electrophysiological visual processing and cerebral blood flow studies, and the few published studies yielded inconclusive results. While several reports with different techniques did report an interattack asymmetry of findings, a consistent relationship between the side of headache or aura and interictal distribution of functional findings has not been demonstrated.3,17-19 One obvious methodological difference between studies of the visual areas involved in motion perception in migraine patients is the use of a variety of visual stimuli, such as moving dots, rings, gratings, or a black/white checkerboard. As in previous studies,[3, 20] we chose to use a complex, moving, colored visual stimulus resulting in maximum activation of the primary and secondary visual cortices and leading to vertical optokinetic stimulation. Optokinetic stimulation can cause motion sickness due to the mismatch of visual and vestibular perception in otherwise healthy individuals.[21] Migraine sufferers, in turn, have a heightened vulnerability to motion sickness even following milder vestibular stimulation.

We thank P.J. McKenzie, J. Zackeru, and L. MacTurk for assistance in isolating and characterizing new Esoptrodinium isolates, and Dr. C. F. Delwiche and Dr. D. Wayne Coats for thoughtful advice and comments on this work. Supported in part by NSF grant 0629624. “
“In the NE Pacific, Ulvaria obscura is a common component of “green tide” blooms. It is also the only alga known to

produce dopamine, which is released into seawater on sunny days when Ulvaria is emersed and then rehydrated. To better understand the mechanisms associated with dopamine release, we experimentally determined whether light quantity and quality, desiccation, temperature, exudates from conspecifics, and dissolved dopamine caused dopamine release. Pictilisib mouse We also examined the effects of desiccation on Ulvaria’s ability to photosynthesize, grow, and survive. Desiccation learn more was the only factor that caused significant amounts of dopamine to be lost from U. obscura tissues. The loss of water from Ulvaria tissues was strongly and positively correlated with the loss of dopamine after rehydration. Only 56% of desiccated algae survived for 1 week, compared to 100% of undesiccated control algae. Desiccated algae lost 77% of their pigmented surface area and grew only 15% as much as undesiccated algae, which remained fully pigmented. The oxygen saturation of water containing Ulvaria that was desiccated and then rehydrated was significantly lower than that of seawater containing undesiccated

algae. Thus, desiccation, which is coupled with dopamine release, is associated with the deterioration and death of some, but not all, tissues in Ulvaria. Although dopamine released into seawater can reduce the survival or growth of potential competitors, its release is associated with significant physiological stress and tissue mortality. However, the survival and continued growth of some Ulvaria tissues indicates that a net fitness benefit to release dopamine following desiccation cannot be ruled out. “
“Some abiotic conditions are well EGFR antibody known to play disproportionately large roles in shaping contemporary assemblages, yet their roles may not continue to have similar magnitudes of effect into the future. We tested

whether forecasted levels of CO2 could alter the strength of influence of an abiotic factor (i.e., light intensity) well known for its strength of influence on the subtidal ecology of photosynthetic organisms. We investigated these dynamics in two subtidal algal species that form contrasting associations with kelp forests, one negatively associated with kelp canopies (turf-forming brown algae, Feldmannia spp.) and the other positively associated with kelp as understory (calcifying red crustose algae, Lithophyllum sp.). Using an experimental approach, we assessed the independent and combined effects of [CO2] (control and elevated) and light (shade, low ultraviolet B [UVB], full light) on growth, recruitment, and relative electron transport rate (rETR).

It was agreed to test whether other haemophilia nurses perceived such a need by means

of a short five-item questionnaire devised by the group and made available to all members of the UK’s Haemophilia Nurse’s Association via Survey-Monkey. Final responses from 59 haemophilia nurses across the UK have selleck chemical been analysed. Most nurses agreed that there was value in the development of a haemophilia link nurse role within UK hospitals and thought their trusts would support it. While barriers and potential downsides were acknowledged, this was seen as a useful way of sharing information and knowledge with colleagues from different specialties and of raising awareness of bleeding disorders among the general nursing community. Haemophilia nurses should coordinate the development of a Haemophilia Link Nurse training and education click here pack. “
“Summary.  Bleeding disorders secondary to acquired non-inhibitory antibodies directed against vitamin K-dependent coagulation proteins are rare. In this report, the authors describe a patient with a low grade lymphoma who presented with a fatal acquired bleeding manifestation and abnormal

hemostatic studies resulting from deficiencies in both prothrombin and factor X. Patient plasma samples were collected and studied for the presence of an acquired inhibitor. Levels of plasma coagulation proteins were measured using immunoassay. Patient anti-prothrombin immunoglobulin G was isolated and binding to prothrombin, prothrombin F1.2, factors IX and X was evaluated using immunoblots and competition immunoassay.

Prolongation in the prothrombin time and activated partial thromboplastin time suggested a factor deficiency in the common pathway of coagulation. Functional and antigenic levels of both prothrombin and factor X were decreased. An IgG subtype-4 antibody was isolated from patient plasma using affinity chromatography on prothrombin-sepharose. This antibody was found to bind to a common metal-ion-dependent conformational epitope found on the γ-carboxyglutamic acid (Gla) domain of prothrombin, factor X and factor IX. This report represents the first description of an acquired bleeding disorder resulting Arachidonate 15-lipoxygenase from a unique cross-reactive auto-antibody against a common metal-ion-dependent antigenic structure on the Gla-domain of the vitamin K-dependent proteins. “
“Summary.  Cranial haemorrhage (CH) is a potentially serious complication in patients with severe congenital haemophilia with inhibitors (CHwI). Treatment includes bypassing agents, such as recombinant activated factor VII (rFVIIa). To examine the US experience in treating CH with rFVIIa, a retrospective review of the Hemophilia and Thrombosis Research Society 2004–2008 database was conducted.

3A and

Supporting Fig. 4E). Third, we found that TGR5 KO mice were significantly more sensitive to extrahepatic cholestasis induced by BDL, because they exhibited larger and more numerous necrotic areas on H&E-stained liver sections, higher ALT, bilirubin, and ALP elevations in plasma, and increased BA overload, as compared to WT mice (Fig. 3B,C and Supporting Fig. 4F). Finally, we found that TGR5 KO mice fed with a 1% cholic acid (CA)-enriched diet exhibited an increase in plasma ALT, ALP, and bilirubin (Supporting Fig. 4G), hepatic BA overload, parenchymal neutrophil infiltration, hepatic necrosis, and elevated tumor necrosis factor alpha (TNF-α) mRNA, whereas WT mice did not[21] (Fig. 3D,E). In agreement with

the inhibitory effect of TGR5 on cytokine gene induction and production in macrophages and KCs,[10, 12, 14] we found that plasma rise in interleukin (IL)−6, TNF-α www.selleckchem.com/products/Y-27632.html and IL-1β concentrations 4 hours after PH was significantly higher in TGR5 KO than in WT mice (Fig. 4A). Hepatic infiltration by neutrophils was also strikingly more intense in TGR5 KO than WT mice after PH or BDL (Fig. 4B). Interestingly, KC depletion with clodronate liposomes, significantly reducing the post-PH induction of cytokine gene, also reduced the occurrence of hepatic necrosis Talazoparib 72 hours after PH (Fig. 4C). Altogether, these data suggest that TGR5 is mandatory for liver protection against BA toxicity and excessive cytokine production, as revealed in different experimental settings of BA overload (PH, BDL, and 1% CA-enriched diet) and BA sequestration (CT diet). Based on these

data, we investigated whether TGR5 may contribute to adapt bile flow in circumstances of BA overload after PH or BDL. Interestingly, ever biliary BA composition was more hydrophobic in TGR5 KO than in WT mice, as calculated on the basis of mass spectrometry analysis,[22] both before and after PH (Fig. 5A). This more hydrophobic BA composition in TGR5 KO mice was also found in plasma and liver before and after PH (Fig. 5B,C) as well as in feces (Supporting Fig. 5A). Namely, muricholic acid (MCA), a hydrophilic primary BA in mice, whose relative concentration is maintained or increased during cholestasis,[21] as well as the MCA/CA ratio taken as a marker of hydrophobicity, were strongly reduced in TGR5 KO mice before and after PH, as compared to WT mice (Fig. 5B,C and Supporting Fig. 5A). Of note, cytochrome P450 (7a1, 8b1, 27a1, 3A11, and 2b10) and sulfotransferase 2a mRNA expressions were similar in WT and TGR5 KO mice (Supporting Fig. 5B). Basal bile flow was slightly smaller in TGR5 KO than in WT mice, as previously reported[17]; however, 48 hours after PH, bile flow increased significantly in WT, as previously described,[5] but not in TGR5 KO mice (Fig. 6A).

3A and

Supporting Fig. 4E). Third, we found that TGR5 KO mice were significantly more sensitive to extrahepatic cholestasis induced by BDL, because they exhibited larger and more numerous necrotic areas on H&E-stained liver sections, higher ALT, bilirubin, and ALP elevations in plasma, and increased BA overload, as compared to WT mice (Fig. 3B,C and Supporting Fig. 4F). Finally, we found that TGR5 KO mice fed with a 1% cholic acid (CA)-enriched diet exhibited an increase in plasma ALT, ALP, and bilirubin (Supporting Fig. 4G), hepatic BA overload, parenchymal neutrophil infiltration, hepatic necrosis, and elevated tumor necrosis factor alpha (TNF-α) mRNA, whereas WT mice did not[21] (Fig. 3D,E). In agreement with

the inhibitory effect of TGR5 on cytokine gene induction and production in macrophages and KCs,[10, 12, 14] we found that plasma rise in interleukin (IL)−6, TNF-α INCB018424 purchase and IL-1β concentrations 4 hours after PH was significantly higher in TGR5 KO than in WT mice (Fig. 4A). Hepatic infiltration by neutrophils was also strikingly more intense in TGR5 KO than WT mice after PH or BDL (Fig. 4B). Interestingly, KC depletion with clodronate liposomes, significantly reducing the post-PH induction of cytokine gene, also reduced the occurrence of hepatic necrosis this website 72 hours after PH (Fig. 4C). Altogether, these data suggest that TGR5 is mandatory for liver protection against BA toxicity and excessive cytokine production, as revealed in different experimental settings of BA overload (PH, BDL, and 1% CA-enriched diet) and BA sequestration (CT diet). Based on these

data, we investigated whether TGR5 may contribute to adapt bile flow in circumstances of BA overload after PH or BDL. Interestingly, BCKDHA biliary BA composition was more hydrophobic in TGR5 KO than in WT mice, as calculated on the basis of mass spectrometry analysis,[22] both before and after PH (Fig. 5A). This more hydrophobic BA composition in TGR5 KO mice was also found in plasma and liver before and after PH (Fig. 5B,C) as well as in feces (Supporting Fig. 5A). Namely, muricholic acid (MCA), a hydrophilic primary BA in mice, whose relative concentration is maintained or increased during cholestasis,[21] as well as the MCA/CA ratio taken as a marker of hydrophobicity, were strongly reduced in TGR5 KO mice before and after PH, as compared to WT mice (Fig. 5B,C and Supporting Fig. 5A). Of note, cytochrome P450 (7a1, 8b1, 27a1, 3A11, and 2b10) and sulfotransferase 2a mRNA expressions were similar in WT and TGR5 KO mice (Supporting Fig. 5B). Basal bile flow was slightly smaller in TGR5 KO than in WT mice, as previously reported[17]; however, 48 hours after PH, bile flow increased significantly in WT, as previously described,[5] but not in TGR5 KO mice (Fig. 6A).