Pharmacological and antibody treatment to either antagonize or pr

Pharmacological and antibody treatment to either antagonize or promote Hh signaling in liver cells at different points in the pathway had the same direct effects on HCV replication. Included in the current study was GDC-0449, an Hh pathway antagonist already in preclinical development for other indications, which we have shown can inhibit HCV replication. The observation that HCV replication is closely associated with Hh pathway activity has not been previously appreciated. Certainly it has never been explored as an explanation for why Huh7.5 cells are exceptionally permissive for HCV replication. Hh pathway components were

previously identified in a functional genomic primary screen, but were not identified in the secondary screen.31 This may be due to the broad changes in the intracellular environment induced by Hh pathway activation that may not be detected in single gene small interfering RNA (siRNA) knockdowns. Carfilzomib manufacturer It may be that the intracellular changes that occur upon AZD4547 in vivo Hh pathway activation and its possible association with EMT are part of the same continuum when considering an environment conducive to HCV infection. The concept of a continuum is supported by the mixed phenotype we detected in LH86 cells compared with Huh7.5 cells and how that correlates with the original observation that LH86 cells were less permissive than Huh7.5 cells.7 One of the key remaining questions is at what level

does Hh pathway activation exerts its effects on HCV replication. Although we used multiple agonists and antagonists, these agents all act close to the “top” of the pathway. We suspect the changes may occur further downstream and are likely to involve other pathways known to be associated with Hh in promoting an environment conducive for HCV replication. Our results may be further cause to reevaluate the model of HCV infection in the liver. Liang et al.3 demonstrated in their analysis of explanted livers from HCV patients with HCC that Core protein was detected in a minority of cells despite this advanced-stage

of disease. Perhaps Huh7.5 cells are representative of a minor population of liver cells that retain an MCE active Hh pathway.18 HCV may preferentially infect and replicate in this minority population of cells so hospitable to efficient replication. Infection of these cells combined with a possible contribution of the resulting interferon release may induce further Hh pathway activation, including increased Shh ligand production. Moreover, increased Shh ligand may serve as a paracrine factor that allows neighboring cells to become more easily infected by promoting a “transitional” phenotype, exposing the gap junction complexes to facilitate viral entry and/or altering the intracellular environment. The association between HCV and the Hh pathway will not alone settle the vigorous debate regarding the occurrence of EMT within the liver.

We found that TNFα induced early phosphorylation of JNK in the fi

We found that TNFα induced early phosphorylation of JNK in the first 30 minutes, although this was not as high as that with TNFα/ActD after 6 or 8 hours (Fig. 5A). To investigate the significance of this early JNK activation for apoptosis sensitization, we preincubated primary hepatocytes

with the JNK inhibitor anthra[1-9-cd]pyrazol-6(2H)-one (SP600125; 20μM), which was followed by FasL or a consecutive treatment with TNFα and FasL. Strikingly, JNK inhibition could effectively block the sensitizing effect of TNFα on caspase-3/caspase-7 activation selleck chemicals because DEVDase activity levels in the presence of SP600125, TNFα, and FasL were essentially the same as those with FasL alone (Fig. 5B). This decrease in caspase-3/caspase-7 activity resulted in a significant reduction in actual cell death and apoptosis (Supporting Fig. 8), and this supported the role of JNK in the sensitization. In contrast, the p38 mitogen-activated protein kinase inhibitor RN3503 (10 μM) had no effect (Supporting Fig. 9), and this indicated that JNK (but not p38 mitogen-activated protein kinase) was crucially involved in apoptosis sensitization by TNFα. It has recently been reported that Bid and Bim are both essential for TNFα-mediated hepatocyte apoptosis

in vivo.18 Furthermore, it is known that the proapoptotic activity of Bim can be regulated by JNK-mediated phosphorylation.17, 22 Consequently, we studied the role of Bim in the TNFα sensitization mechanism AZD6244 mw by down-regulating Bim expression by siRNA. The Bim mRNA and protein were effectively down-regulated by small interfering RNA targeting Bim (siBim); this was verified by qRT-PCR (Supporting Fig. 1A) and western blot analysis (Supporting Fig. 1B), respectively. Strikingly, although control siRNA did not affect caspase-3/caspase-7 activity levels in cells treated with TNFα and FasL, siBim significantly reduced them to the levels measured with FasL alone (Fig. 5C). In addition, the loss of Bim resulted

in decreased apoptosis-associated DNA fragmentation and cytotoxicity upon treatment with MCE公司 TNFα and FasL (Supporting Fig. 10). Thus, both Bid and Bim seem to be required for the sensitization effect of TNFα on the FasL-induced apoptosis of primary mouse hepatocytes. Because JNK is also crucial for this effect and the inhibition of JNK could not abrogate tBid formation (Fig. 4B), we suggest that the implication of Bim involves its JNK-mediated phosphorylation, as previously shown.17, 22, 23 Both Bid and Bim relay apoptotic signals to the activation of Bax/Bak, which in turn triggers MOMP and the release of cytochrome c and other apoptogenic factors (type II signaling). We therefore tested whether TNFα-mediated sensitization to FasL-induced apoptosis involved cytochrome c release. For that purpose, we prepared cytosolic and mitochondrial fractions from TNFα-treated, FasL-treated, or TNFα/FasL-treated hepatocytes, verified their purity by western blot analysis (Supporting Fig.

The invasion of Rnd3-silenced cells was strongly inhibited by Rac

The invasion of Rnd3-silenced cells was strongly inhibited by Rac1 or Cdc42, but not by RhoA knockdown (Fig. 6C). Rac1 requirement

was also demonstrated using the pharmacological Rac1 inhibitor, EHT186428 (Fig. 6D; Supporting Fig. 6D). Collectively, our data show that Rnd3 knockdown induces HCC cell invasion through a Rac1-dependent and MMP-independent mechanism, thus suggesting an amoeboid pseudopodal-like mechanism.29 We report that RND3 is down-regulated in a majority of HCC cell lines and tissues. Previously, Rnd3 expression was also reported as low in biopsies from prostate and gastric cancers15, 30 and was suggested to act as a tumor suppressor in these cancers. However, RND3 expression was not systematically decreased in tumors because it was found high in non-small-cell lung31, 32 and pancreatic cancers.33 Ulixertinib mouse Thus, despite its ubiquitous expression in healthy tissues,34 Rnd3 regulation and

biological effect may be significantly different in various tumors. Rnd3 belongs to the Rnd subfamily of the Rho GTPase family. Because Rnd proteins are not regulated by the typical GTP/GDP cycle, they are thought to be regulated primarily at their transcriptional level. Here, using qRT-PCR, immunoblotting analysis, and IHC, DAPT mw we showed a down-regulation of RND3 mRNA and protein in HCC. The mechanism for Rnd3 down-regulation is still unclear. Although RND3 was reported to be a direct transcriptional target of p53,35 no correlation with p53 mutations could be established in our HCC samples (data not shown). Recently, it was reported that the miRNA miR-200b, directly reduced the expression of RND3 in HeLa cells.36 However, the relevance of this regulation in HCC remains to be evaluated.37 In addition, it was described that Rnd3 is regulated by histone deacetylation in gastric cancer cells,30 raising the hypothesis that it may also be regulated at the epigenetic level in hepatic tumors. Rnd3 has been involved in diverse

cellular functions, including actin cytoskeleton MCE公司 remodeling and cell-cycle progression.8 Because of the striking down-regulation of RND3 in HCC and of its biological functions, we hypothesized that the low expression of RND3 would give an advantage to liver tumor cells and contribute to the development of HCC. Surprisingly, we found that Rnd3 knockdown inhibited HCC cell growth. However, cells with reduced Rnd3 expression also acquired invasive capacity. This suggests that Rnd3 regulates a switch to attenuate cell growth and favor cell invasion. This is consistent with the concept that profound morphological changes are incompatible with high proliferation, and that attenuation of cell proliferation favors invasion versus tumor growth.2 In this respect, the EMT-promoting factor, Snail, was described to induce partial G1/S cell-cycle arrest that is, at least in part, a result of the repression of CCND2-encoding cyclin D2.

Laboratory test manifested leukocytosis (714%) The mucosal chan

Laboratory test manifested leukocytosis (71.4%). The mucosal changes which included diffuse mucosal hemorrhage and erosion were mainly located at the ascending colons under colonoscopy. Histopathologic examination showed chronic inflammatory of colonic mucosa and red blood cell infiltration into the interstitial. Cessation of oral antibiotics, supporting treatment and glucocorticoids were administrated.

The patients recovered quickly without any complications. Conclusion: It is important to inquire the history of medication when patients suffered bloody diarrhea, especially amoxicillin and penicillin derivatives. The history of antibiotic medication and colonoscopy play an important role in the diagnosis of AAHC. Key Word(s): 1. hemorrhagic colitis; 2. amoxicillin; 3. hematochezia; Presenting Author: FERNANDO MAN Additional Authors: LUIS BUSTOS FERNANDEZ, CAROLINA BOLINO Corresponding Author: FERNANDO MAN Affiliations: none Objective: Introduction: Belinostat Irritable bowel syndrome (IBS) is a highly prevalent functional disease accounting for huge expenses in medical resources and loss of working days. The possibility that the enteric flora could play a role in the pathogenesis of IBS has recently gained interest. Evidence to support this concept has been extant for some time (post-infectious IBS, low grade inflammation). The occurrence of

small intestinal bacterial overgrowth (SIBO) has PF-01367338 in vivo been associated with IBS, and its eradication with symptomatic relief. Aim: 1. To study the prevalence of abnormal H2 excretion with lactulose breath test in non constipated IBS (non C-IBS). Methods: Adults with non C-IBS according to Rome III criteria were consecutively included at 2 private GI centers in Buenos Aires, Argentina, between Jan 2009 and Sept 2012. Use of antibiotics, prokinetics, proton pump inhibitors and bowel cleansing procedures 4 weeks before the procedure; diabetes, celiac disease and GI surgery were exclusion criteria. Study design: prospective, descriptive and cross sectional. SIBO was assessed with lactulose breath test (LBT). After 上海皓元医药股份有限公司 an overnight fast and, having

excluded fermentable food for 24 hrs, patients were given 20 g of lactulose. Breath samples were collected at baseline and every 15 min up to 180 min using a breath H2 monitor (Gastrolyzer Bedfont Inc.) SIBO was diagnosed when there was an increase in H2 ≥ 20 ppm above baseline values within 90 minutes after lactulose ingestion. Additionally, we evaluated the area under de curve in a subgroup of patients. Values of area >3000 within the study period were considered positive. Statistical analysis: VCCstat 1.0; CI 95% were estimated; Fischer test. Results: 379 patients were included. 67% (253/379) were female; average age was 45,8 years (range 16–89). Predominant symptoms were registered as follows: diarrhea 63% (239/379), bloating 37% (139/379). The overall prevalence of SIBO was 163/379 (43%; 95% CI 38–48).

pylori strains are described as mostly “innocuous or only mildly

pylori strains are described as mostly “innocuous or only mildly pathogenic”. It is certain that these genomes representing Indian patients would rekindle our understanding of the genetic makeup and evolutionary relationships of this pathogen in India. Furthermore, the genome sequence data would allow newer insights into the enigmatic situation, wherein high infection burden predicts the lowest rates of gastric or duodenal ulcers and gastric carcinoma. Draft genome sequences from nine functional dyspeptic patients and one gastric cancer patient from Kuala Lumpur, Malaysia were also

published [9]. In contrast to the situations in China and India, Malaysia presents an interesting canvas to study host–pathogen coevolution in multiple ways. Being an immigrant society located along major shipping routes between China and India, Malaysia has three major ethnic populations, Selleck BAY 73-4506 Malay, Chinese, and Indian. Besides its ethnic diversity, the country also presents a coexisting array of H. pylori that Wnt inhibitor can be identified to various ancestral populations:

hpEastAsia, hpAsia2, and hpEurope [10]. Availability of genomic sequences from this region of South-East Asia will serve as a linking piece on the human migration puzzle, as well as aiding in the study of the role of the transmission and coevolution of H. pylori with its host. The H. pylori genome is well known to be “highly sexual” given high frequency of horizontal gene transfers. For the first time, a global survey of the genome-wide distribution of outcrossing homologous recombination in H. pylori has been shown and this illustrated how mutual recombination can shape a bacterial species [11]. Mosaic genes, possibly formed following frequent recombination episodes and discordant phylogenies, medchemexpress were distributed throughout H. pylori genomes with most genes exhibiting at least one unique recombination event. Genes with high recombination rates comprised those

entailing DNA transformation, core cellular functions (biosynthesis and metabolism), and host-pathogen interactions (outer membrane proteins and lipopolysaccharide synthesis). Helicobacter pylori is highly diverse on a global scale but geographic separation reduces the recombination frequency between strains from a local area relative to those from outside. This leads to the establishment of a clonal population structure for H. pylori in a given geographic area. For each population, H. pylori has undergone relatively independent evolution processes, resulting in locale specific genomic diversity and differential potential for virulence. Further study to characterize these differences within a local population may help elucidate mechanisms involved in the development of gastroduodenal diseases triggered by H. pylori [12].

If bile-duct stones are strongly suspected,

endoscopic re

If bile-duct stones are strongly suspected,

endoscopic retrograde cholangiopancreatography (ERCP) with transpapillary stone extraction is the method of choice. Endoscopic ultrasound and magnetic resonance cholangiopancreatography (MRCP) are less invasive diagnostic tools in patients with KU-60019 intermediate probability of intraductal stones. Treatment comprises medical therapy for acute pain and/or bacterial infection and endoscopic interventions for common bile-duct stones, cholangitis, or biliary pancreatitis in selected patients. Laparoscopic cholecystectomy is the treatment of choice for symptomatic gallbladder stones and cholecystitis. It should also be performed after other complications of cholelithiasis (e.g., biliary pancreatitis, cholangitis) to prevent recurrence. “
“This chapter contains sections titled: Introduction Background The role of the gastrointestinal tract in ingestive behavior Gastrointestinal symptoms and disease in the obese patient Bariatric surgery – a primer for the gastroenterologist Considerations in

endoscopy Endoscopic treatments for obesity References “
“Hepatitis B virus (HBV) causes important human health problems. It has infected one-third of the world’s population and approximately 360 million people are chronic carriers. Worldwide, 0.5–1.2 million deaths are attributed to HBV infection annually. Therefore, see more global control of HBV infection is important. HBV infection can be intervened by interrupting routes of transmission, treating the chronically infected, and preventing the susceptibles with immunoprophylaxis. All these measures are effective. Nevertheless, although pegylated interferons or nucleos(t)ide analogs are effective for the treatment of chronic hepatitis B, chronic carriage of HBV is not easy to eliminate, as revealed by the frequent persistence of hepatitis B surface antigen, despite satisfactory responses to these treatments. On the other hand, hepatitis B vaccination 上海皓元医药股份有限公司 has been shown to preclude HBV infection effectively.

This is particularly true for pre-exposure prophylaxis. Worthy of note is the universal vaccination of newborn infants. This is the most effective means of preventing HBV infection, especially for those born to HBV carrier mothers. To eliminate and eradicate hepatitis B, first, HBV in the chronically infected should be eradicated or strongly and efficiently suppressed, so that the infection does not spread rampantly. Second, all the transmission routes should be interrupted. Lastly, but most effectively, is to immunize all susceptibles. The difficulties and possible solutions of each approach are discussed. In conclusion, the existing means to prevent and treat HBV infection render our goal toward eliminating and eradicating hepatitis B possible, although it will take much time and effort to achieve this objective. Hepatitis B virus (HBV) is one of the most important human pathogens. It causes significant diseases spanning from fulminant hepatitis to end-stage liver disease.

pylori gastritis were dependent on the extent, topography and sev

pylori gastritis were dependent on the extent, topography and severity of the infection; e.g. the gastric cancer risk increased exponentially with the progression of gastritis towards an achlorhydric or hypochlorhydric stomach with PI3K inhibitor severe mucosal atrophy and intestinal metaplasia. The earlier studies of Strickland and McKay proposed the topographic classification of atrophic gastritis into types A and B which constituted the core issue of the System. The A type indicating a corpus limited atrophic gastritis of autoimmune origin in patients with achlorhydria and with serological signs of the autoimmunity.8

Type B indicated atrophic gastritis without an autoimmune background and with atrophy limited to the antrum. This B subtype was considered “idiopathic” but was, after the discovery of H. pylori, realized to be typically related to H. pylori infection. It corresponds with the type of atrophic gastritis considered multifocal (MAG; multifocal atrophic gastritis) by Pelayo Correa in his reports from the 80s,14 or atrophic gastritis of the AB type by Glass and Pitchumoni from the 70s.15 In 1988, gastritis of “C type” was proposed by Wyatt and Dixon indicating reactive gastric lesions that were neither H. pylori associated nor autoimmune, and believed to be “chemical”

(reactive) or drug induced in nature.16 Atezolizumab ic50 An important morphological parameter incorporated into the Sydney System from the literature was the “activity” of the gastritis. The activity of gastritis was first proposed and emphasized by Whitehead, Truelove and Gear in 1972.17 In their classification medchemexpress of gastritis, the Schindler—Glass-Pitchumoni—type topographical pattern of chronic gastritis was accepted but was complemented with the

concept of the “activity”. The “activity” indicated the co-existence of polymorphonuclear inflammation alongside the mononuclear one. This phenomenon we now consider to reflect the reaction of the host against the infection and to be strongly associated with the risk of the progression of gastritis to an atrophic pattern which is also related to the acquisitions of cytotoxic H. pylori strains. It is noteworthy that the guidelines presented in the Sydney System are still valid and applicable some 20 years later. In our view this is because the Sydney System was an appropriate synthesis at the time of the old knowledge on chronic gastritis mentioned above with the new data and knowledges about H. pylori acquisition and its consequences. It must be said the Sydney System was not a classification in strict terms but more a practical guideline that provided what we hoped might become a flexible universal gastritis reporting grid. It allowed for a standard rapid documentation of the extent and severity of the gastritis at the time of examination of the patient. H.

1, 2 Viruses

1, 2 Viruses CP-673451 purchase have evolved different mechanisms to inhibit type I IFN response and block various aspects of the signaling

pathway, thus escaping the host immune response and causing infection. Hepatitis E, caused by hepatitis E virus (HEV), is an emerging public health problem in both developing and developed countries. Hepatitis E mostly manifests as a self-limiting, icteric hepatitis in most individuals. However, substantially high mortality rates of as much as 20% are observed in pregnant women.3 Furthermore, organ transplant recipients, as well as human immunodeficiency virus (HIV)-infected and other immunocompromised individuals, run the risk of developing chronic liver disease when infected with HEV.4 Treatment of chronically infected patients with pegylated interferon-α2a/α2b or ribavirin for 3-12 months has been shown to achieve

a sustained virological response for 3-6 months after completion of the therapy.5, 6 HEV is a nonenveloped virus with a single positive-sense RNA genome of approximately 7.2 kb and is classified in the Hepevirus genus within the family Hepeviridae.3 The viral RNA consists of a short 5′ noncoding region (NCR), three open reading frames (ORFs), FGFR inhibitor and a 3′ NCR. A cap structure has been identified at the 5′ end of the viral genome, which may play a role in the initiation of HEV replication.7 ORF1, located at the 5′ end of the genome, encodes nonstructural polyproteins that are involved in viral

replication.8, 9 ORF2, located at 上海皓元医药股份有限公司 the 3′ end of the genome, encodes the viral capsid protein, which plays an important role in viral immune response.10 ORF3 encodes a cytoskeleton-associated phosphoprotein11 that is responsible for virion egress from infected cells and is essential for virus infectivity in vivo, although it is not required for virus infection in vitro.12 Viruses have been reported to influence the IFN regulatory pathway,13, 14 but effects of HEV on IFN signaling have not been studied so far because of the lack of an efficient HEV cell culture system or a small animal model of infection. Propagation and production of HEV in vitro have been attempted in many cell lines, but culturing HEV has proven to be difficult.15 Recently, successful propagation of HEV in A549 cells, a human lung adenocarcinoma epithelial cell line, was reported.15, 16 In this study, we describe the generation of an A549 cell line (HEV-A549) persistently infected with the genotype 3 HEV strain. Using this cell line, we investigated whether HEV inhibits IFN-α signaling.

Many novel IFN-free antiviral regimens for HCV are now under clin

Many novel IFN-free antiviral regimens for HCV are now under clinical investigation.[23, 24] Some of these include RBV in combination with one or two direct-acting antiviral agents.[25, 26] RBV will remain a key drug for the treatment of chronic HCV infection in the forthcoming era of oral combination therapy. Therefore, it is critical to

establish effective strategies for managing RBV-induced anemia, including the use of erythropoietin, Erlotinib clinical trial and determine its optimal dose for Japanese patients. The mechanism of RBV-induced hemolytic anemia is not completely understood. In erythrocytes, RBV is converted into mono-, bi- and finally triphosphate forms. The active forms of RBV accumulate in red blood cells because of a lack of phosphatases required to hydrolyze them, probably leading to hemolysis. Fellay et al.[27] show that genetic variants near the inosine triphosphatase (ITPA) gene protect

against hemolytic anemia in HCV-infected patients receiving RBV. One possible Adriamycin explanation for this finding is that ITPA deficiency caused by the ITPA gene variation leads to an accumulation of inosine triphosphate, which can compete with the triphosphate form of RBV in red blood cells, thereby protecting cells from the lytic effects of the active form. Ochi et al.[28] report that 75.1% of Japanese patients with chronic hepatitis C are homozygous for the major allele CC at rs1127354. All three patients in the present report had the ITPA major type associated with treatment-induced anemia (Table 1). Erythrocyte-stimulating agents epoetin-α and

epoetin-β are the two forms of human recombinant erythropoietin; both are synthesized in Chinese hamster ovary cells, which are commonly used to treat anemia in chronic kidney disease.[29] Although there are some differences in the glycosylation of the polypeptide in post-translational processing, epoetin-α and epoetin-β essentially have the same clinical efficacy. A higher dose of erythropoietin is required 上海皓元 to maintain hemoglobin levels in chronic hepatitis C patients with preserved production of endogenous erythropoietin than in patients with chronic kidney disease. Most clinical studies conducted in the USA used epoetin-α at a dose of 40 000–60 000 IU once weekly. In their preliminary dose-finding study, Kanai et al.[30] report that 24 000–36 000 IU epoetin-β appears to be the optimal dose for Japanese patients with chronic HCV infection. Accordingly, we adopted 24 000 IU epoetin-β. Biweekly dosing of erythropoietin is commonly used in clinical practice to treat anemia in chronic kidney disease as a maintenance therapy if hemoglobin level is elevated by weekly dosing. Therefore, we administrated epoetin-β weekly six times followed by biweekly three times. No significant reductions in the dose of RBV were required after initiation or discontinuation of the biweekly epoetin-β dosing (Fig. 3).

13 Although NOX plays an important role in HSC activation and hep

13 Although NOX plays an important role in HSC activation and hepatic fibrosis, how various NOX homologues expressed in different hepatic cell types contribute to hepatic fibrogenesis MI-503 chemical structure is unknown. The purpose of the present study was to investigate the contributory role of NOX1 and NOX2 in hepatic fibrosis. We evaluated the effect of genetic NOX1 and NOX2 inactivation on hepatic fibrosis in two different models of experimental fibrogenesis. We also identified NOX1- and NOX2-expressing cell types in the liver. The functional contribution of NOX1 and NOX2 in endogenous liver cells, including HSCs, and in bone marrow (BM)-derived

cells, including Kupffer cells (KCs), to hepatic fibrosis was assessed using either NOX1 or NOX2 BM chimeric mice. Our data indicate that both NOX1 and NOX2 have an important role in hepatic fibrosis in endogenous liver cells, whereas NOX2 has a lesser role in BM-derived cells. These findings may provide new insight into the development of antifibrotic therapy this website targeting nonphagocytic NOX signaling

in the liver without suppression of NOX2-mediated host defense mechanism. α-SMA, α-smooth muscle actin; ALT, alanine aminotransferase; Ang II, angiotensin II; BDL, bile duct ligation; BM, bone marrow; BMT, bone marrow transplantation; CCl4, carbon tetrachloride; CM-H2DCFDA, 2′7′-dichlorofluorescein diacetate; DMEM, Dulbecco’s modified Eagle’s medium; HSC, hepatic stellate cell; KC, Kupffer cell; KO, knockout; mRNA, messenger RNA; NOX, nicotinamide adenine

dinucleotide phosphate oxidase; PCR, polymerase chain reaction; ROS, reactive oxygen species; SEC, sinusoid endothelial cell; TGF-β, transforming growth factor β; WT, wild-type. NOX2 knockout (NOX2KO) mice15 with a C57BL/6 background, which lack a catalytic subunit of phagocytic NOX complex, and WT C57BL/6 control mice were purchased from The Jackson Laboratory (Bar Harbor, MA). NOX1 knockout (NOX1KO) mice16 with a C57BL/6 background were a kind gift from John Engelhardt of the University of Iowa. Eight- to 10-week-old male mice were used. Liver fibrosis was induced either by way of intraperitoneal injection of hepatotoxin carbon tetrachloride (CCl4) or by way of BDL. CCl4 (Sigma Aldrich, St. Louis, MO; diluted 上海皓元医药股份有限公司 1:3 in corn oil) or a vehicle (corn oil) was injected on every third day at a concentration of 2 μL/g body weight 12 times per day. BDL was performed as described, and a sham operation group was used as a control.17 Animals were sacrificed 72 hours after the last CCl4 injection or 3 weeks after BDL and blood and liver samples were collected. All animal studies were approved by The University of California, San Diego Institutional Animal Care and Use Committee (protocol number: S-07088). We performed BM transplantation (BMT) experiments as described with slight modifications.18-21 We flushed the tibias and femurs of donor mice to obtain BM.