Third, all classes of symptomatic medications, both migraine-specific (such

as ergots and triptans) and nonspecific analgesics (such as opiates and non-narcotic analgesics), are able to cause MOH if they are used excessively.[9] Clinical features of MOH caused by these abortive agents are quite similar, but not necessarily identical. Because BGB324 clinical trial these drugs have different pharmacological actions, it is unlikely that MOH is caused by the specific action of any single causative agent. The more likely, but as yet unproven, explanation is that all drugs share some common mechanism in generating this phenomenon. Finally, in addition to headache, patients with MOH also suffer from other clinical symptoms. These include depressed mood, sleep disturbance, and noncephalic body pain. MOH patients tend to have poor general health and poor quality of life.[10] These nonheadache

manifestations imply that chronic analgesic consumption not only affects nociceptive and pain perception processes, but also alters neural pathways that control vegetative functions. The clinical observations described above lead to the hypothesis that chronic medication may alter the central modulating system that controls nociception and other vegetative functions. This alteration may further affect the already vulnerable nervous systems of those with underlying primary headaches. Activation selleck screening library of the trigeminal system is an essential step in generating all forms of primary headaches. The primary afferents of trigeminal nociceptive fibers innervate pain-sensitive structures, including cranial vessels, meninges, and pericranial muscles and fascias. Activation of trigeminal nociceptive terminals stimulates the release of calcitonin gene-related peptide (CGRP). This

neuropeptide can increase the sensitivity PLEK2 of perivascular nociceptors and dilate cranial vessels. Central axons of the trigeminal ganglionic (TG) neurons terminate onto second-order neurons in the trigeminocervical complex (TCC), which includes the trigeminal nucleus caudalis (TNC), and CGRP release here can facilitate neurotransmission of nociceptive trigeminovascular input.[11] Both TG and TCC neurons are highly plastic, physiologically and anatomically. Their responses can change according to the patterns of their input. Chronic activation modulates the transcription of several proteins that are involved in nociceptive transduction. These modifications result in long-lasting changes in neuronal activity. The increases in response of TG neurons (known as peripheral sensitization) and TCC neurons (known as central sensitization) play major roles in the development of throbbing headache and cutaneous allodynia developed during the attacks of migraine.

14 Total cell RNAs from HCV-infected and mock-infected cells, 6 days postinfection, were hybridized to microchips affixed with the sequences of approximately 350 known human miRNAs. As shown in Fig. 1, the levels of miRNA expression in primary hepatocytes infected with the three major strains

of HCV were accentuated to various degrees. Consistently, cells infected with the HCV strains showed induced expression of miR-141, miR-200a, and Z-VAD-FMK nmr miR-200b and miR-200c to a lesser degree (Fig. 2; Supporting Information Table 1). miR-141 levels increased concomitantly with HCV infection. We chose miR-141 for further studies because it was consistently the most enriched miRNAs up-regulated in HCV-infected cells. The levels of miR-141 that are consistently accentuated in HCV infection is summarized in (Table 1). Previous studies have analyzed alterations in miRNA in liver cancer tissues compared with adjacent normal tissues. For the most part, miRNA expression appears to be accentuated in HCC, with down-regulated Neratinib miRNAs in HCC being rare.15, 16 Earlier studies of HCV-infected hepatocytes indicated that virus replication depends on host cell miR-12217–19

or the cellular RNA interference machinery in general.20 Because both miR-141 and miR-200a share a target sequence, we chose to study the biological effects of miR-141 up-regulated during HCV infection. We focused next on validating the target of miR-141 that is induced in HCV-infected cells. miRNAs act upon their mRNA targets by way of imperfect base pair complementarity, and subsequently modulate the translation of the mRNA. The most important determinant for targeting efficacy is the strength of the interaction at the 6- to 7-bp seed sequence

at the 5′ end of the miRNA.21–24 We used bioinformatics methods to determine a small number of candidate mRNA targets for the four miRNAs (miR-141, miR-200a, miR-200b, miR-200c) based on the following criteria: (1) strength of the miRNA-target duplex, particularly at the seed position; (2) combinatorial effects Cobimetinib in vitro of multiple binding sites of the same miRNA or of multiple miRNAs targeting the same gene; and (3) conservation of miRNA target sites in multiple related species, which increases their likelihood to be functional.21, 25 Using Pictar software,26 we searched for genes containing multiple miR-141, miR-200a, miR-200b, and miR-200c target sites that are conserved in humans, chimpanzees, mice, rats, and dogs. Whereas Pictar reported 100-200 target genes for each of the miRNAs individually, the combinatorial search revealed a more specific set of 65 potential genes (Supporting Information Table 2). We narrowed down the set of targets further based on the functional characterization of genes, prioritizing those likely associated with HCV infection and liver disease. DLC-1 (GenBank accession no.

PGE2 carried by IDENs has at least two unique characteristics in comparison with the free form of PGE2. First, the stability of PGE2 carried by IDENs is increased significantly, as shown by the fact that the half-life of PGE2 is approximately 30 seconds in mTOR inhibitor the circulator system,36,37 and intravenous injection of chemically synthesized PGE2 did not have any effect on the induction

of IFN-γ and IL-4 of mice treated with α-GalCer (data not shown) and therefore could have no effect on the activation of Wnt signaling in NKT cells. Besides the stability of PGE2 regulated by the local balance between the COX2-driven synthesis and 15-hydroxyprostaglandin dehydrogenase–mediated degradation of PGE2,38,39 in this study, we demonstrated that the amount of PGE2 carried by IDENs is also associated with the potency of induction of liver NKT AZD8055 purchase cell anergy (Supporting Figs. 5 and 6). It is conceivable that the factors regulating the amount available and the affinity of IDEN binding to PGE2 may

also contribute to PGE2-mediated Wnt signaling. The role of ceramide40 and others factors that affect COX2/15-hydroxyprostaglandin dehydrogenase–mediated PGE2 synthesis and degradation warrants further study. In addition, factors regulating gut permeability which are critical factors in regulating the amount of nanoparticle trafficking from the gut to the liver41–43 needs further study to. Caution should be exercised when drawing conclusions regarding Ureohydrolase the biological effect of PGE2 on IDENs. Effects on the Wnt signaling pathway may be different when comparing PGE2 on IDENs to that of free form of PGE2, since microRNAs and other lipids are packed in the IDENs

and may also contribute to the PGE2-mediated Wnt signaling pathway. Identifying whether IDEN microRNAs and/or lipids have a role in PGE2-mediated Wnt signaling pathway needs further study. Second, PGE2 carried by IDENs induces anergy of NKT cells not only through direct targeting of NKT cells but also through DC activation via a TLR-mediated pathway. The finding that IDENs can carry a number of therapeutic agents44 and target APCs may provide an avenue to pursue IDEN modulation of APC function and their role in gut immune tolerance. These findings also open up a new avenue for investigating further the possible role of IDENs carrying other molecules released in gut that could induce both gut and liver immune tolerance. Furthermore, from therapeutic standard point, IDENs from intestines of other species may also be a useful vehicle for delivering therapeutic reagents44,45 to treat gastrointestinal diseases as well as diseases such as liver diseases treated by oral administration. In this study, the finding that IDEN-PGE2 activated the Wnt pathway and suppressed cytokine expression via inactivation of the GSK3/β-catenin pathway raises a number of important questions that need to be addressed in future studies.

1 We thank Prof. P. Georgel, Ph.D. (University of Strasbourg) for critical reading of the manuscript and helpful discussions. “
“CT, computed tomography; FLHCC, fibrolamellar hepatocellular carcinoma; HCC, hepatocellular carcinoma; IVC, inferior vena cava. A 24-year-old man was evaluated for 3 months of abdominal pain and new selleck products onset of shortness of breath, increased abdominal girth, and leg swelling. On physical examination, he was tachypneic, had dullness in flanks, and

bilateral lower extremity edema. Liver biochemical tests were notable for marginal derangement and a normal alpha-fetoprotein. An abdominal computed tomography (CT) scan showed an 11.5-cm hepatic mass with satellite lesions, ascites, tumor extension into the inferior vena cava (IVC) causing obstruction, and bland thrombus extending from the lower IVC to

the femoral veins bilaterally (Fig. 1A). A chest CT showed selleckchem bilateral pulmonary emboli and bilateral pleural effusions. A 2D echocardiogram showed a presumed right atrial tumor thrombus (Fig. 1B). A liver biopsy showed large polygonal tumor cells with eosinophilic granular cytoplasm (positive stain for Heppar-1) surrounded by abundant fibrous stroma in parallel lamellae, consistent with a well-differentiated fibrolamellar variant of hepatocellular carcinoma (Fig. 1C,D). Given his advanced disease, he was not a candidate for hepatectomy, systemic chemotherapy, vascular intervention, or liver transplantation and was discharged to hospice care with symptomatic palliation. Fibrolamellar hepatocellular carcinoma (FLHCC) differs from traditional hepatocellular very carcinoma (HCC) in patient demographics (mean age 25 years, equal sex distribution), and absence

of underlying cirrhosis or usual risk factors. 1 Our patient presented with rare manifestations that included secondary Budd-Chiari syndrome and significant clot burden causing lower extremity edema and ascites, bilateral pulmonary emboli causing shortness of breath, and a right atrial thrombus. 2 He had both tumor thrombus and bland thrombus, with the latter likely related to a hypercoagulable state. Alpha-fetoprotein levels are usually normal. On imaging a heterogeneous mass characterized by hypervascularity and a central scar in the background of normal liver parenchyma is appreciated. Metastatic tumor burden, hepatic adenoma, focal nodular hyperplasia, traditional HCC, and hemangioma are in the differential diagnosis. In contrast to the central scar of focal nodular hyperplasia (FNH), the central scar has low attenuation on T2 images. 3 On biopsy, the presence of large polygonal tumor cells with vesicular nuclei and large nucleoli, eosinophilic granular cytoplasm, and abundant fibrous stroma in thin parallel lamellae around tumor cells support the diagnosis.

1 We thank Prof. P. Georgel, Ph.D. (University of Strasbourg) for critical reading of the manuscript and helpful discussions. “
“CT, computed tomography; FLHCC, fibrolamellar hepatocellular carcinoma; HCC, hepatocellular carcinoma; IVC, inferior vena cava. A 24-year-old man was evaluated for 3 months of abdominal pain and new Y-27632 in vivo onset of shortness of breath, increased abdominal girth, and leg swelling. On physical examination, he was tachypneic, had dullness in flanks, and

bilateral lower extremity edema. Liver biochemical tests were notable for marginal derangement and a normal alpha-fetoprotein. An abdominal computed tomography (CT) scan showed an 11.5-cm hepatic mass with satellite lesions, ascites, tumor extension into the inferior vena cava (IVC) causing obstruction, and bland thrombus extending from the lower IVC to

the femoral veins bilaterally (Fig. 1A). A chest CT showed selleck inhibitor bilateral pulmonary emboli and bilateral pleural effusions. A 2D echocardiogram showed a presumed right atrial tumor thrombus (Fig. 1B). A liver biopsy showed large polygonal tumor cells with eosinophilic granular cytoplasm (positive stain for Heppar-1) surrounded by abundant fibrous stroma in parallel lamellae, consistent with a well-differentiated fibrolamellar variant of hepatocellular carcinoma (Fig. 1C,D). Given his advanced disease, he was not a candidate for hepatectomy, systemic chemotherapy, vascular intervention, or liver transplantation and was discharged to hospice care with symptomatic palliation. Fibrolamellar hepatocellular carcinoma (FLHCC) differs from traditional hepatocellular Rebamipide carcinoma (HCC) in patient demographics (mean age 25 years, equal sex distribution), and absence

of underlying cirrhosis or usual risk factors. 1 Our patient presented with rare manifestations that included secondary Budd-Chiari syndrome and significant clot burden causing lower extremity edema and ascites, bilateral pulmonary emboli causing shortness of breath, and a right atrial thrombus. 2 He had both tumor thrombus and bland thrombus, with the latter likely related to a hypercoagulable state. Alpha-fetoprotein levels are usually normal. On imaging a heterogeneous mass characterized by hypervascularity and a central scar in the background of normal liver parenchyma is appreciated. Metastatic tumor burden, hepatic adenoma, focal nodular hyperplasia, traditional HCC, and hemangioma are in the differential diagnosis. In contrast to the central scar of focal nodular hyperplasia (FNH), the central scar has low attenuation on T2 images. 3 On biopsy, the presence of large polygonal tumor cells with vesicular nuclei and large nucleoli, eosinophilic granular cytoplasm, and abundant fibrous stroma in thin parallel lamellae around tumor cells support the diagnosis.

Infants in the group of treated mothers had a lower HBsAg seropositivity (10/56 vs 23/59 or 18% vs 39%, P = 0.014).34 Unfortunately, Protease Inhibitor Library chemical structure the high rate of lost to follow up or consent withdrawal weakened the conclusions of this important study. Hence, whether giving antivirals to near-term HBV carrier mothers will decrease the perinatal mother-to-infant HBV infection needs to be addressed further with randomized control trials. In dealing with this issue, the cost and safety in both the mothers

and newborns should also be considered. Pregnancy category of the currently available drugs for the treatment of chronic hepatitis B is shown in Table 2. In most instances, the reservation is because of insufficient data in humans to guarantee absence of embryonal adverse effects including teratogenicity. In this regard, the experience in HIV infection is extremely helpful.35 Because humans are the only reservoir of HBV, if HBV can be eradicated, or strongly and

effectively suppressed in the human HBsAg carriers, it will prevent spreading HBV to others, and thus will be an important step toward the elimination and eradication of hepatitis B. The transmission routes of HBV can be classified into horizontal and perinatal (“vertical”) modes (Fig. 2). HBV is highly infectious, because a very tiny amount of body fluids from an HBV carrier can contain a large number of viruses, and infect a susceptible person through mucocutaneous disruptions. Intimate contacts with a virus carrier AZD1208 solubility dmso such as household activities and sharing toys among children can cause the infection. Sexual transmissions are also well-documented. Use of condoms may help to prevent such transmissions. Ear or other body piercings, acupuncture, tattoo or any procedures that disrupt mucocutaneous barriers are

all potentially dangerous. All the instruments that are used in these procedures should be adequately sterilized. Unsafe injections by using unsterilized or inadequately sterilized needles and syringes also result in the spread of HBV.36 This is most serious in illicit injection drug users. Galeterone Whether a needle/syringe exchange program will reduce the risk of HBV infection among the injection drug users remains to be seen.37,38 Insect bites have also been suspected to spread HBV, but the evidence does not seem strong. On the other hand, transfusion of blood or blood products is also an important route of transmission. Despite screening by sensitive serological assays, HBV transmission still occurs in a substantial proportion of susceptible recipients.39 Based on the results of a prospective study in Taiwan from 1987–1994, it was projected that approximately 200 cases of post-transfusion HBV infection could occur for every 1 million units of transfused blood in Taiwan where HBV infection is hyperendemic.

10 Therefore, we undertook a comprehensive approach to determine potential roles of eNOS

in hepatocyte proliferation by conducting a systematic analysis of hepatocyte proliferative response, based on the sequential induction of key cyclins that drive cell-cycle Y-27632 cell line progression at the G1, G1/S, and G2/M phases, as well as BrdU-incorporation kinetics over 24-96 hours. Corresponding to early events, hepatocyte cell-cycle progression and proliferation in response to PH were significantly attenuated in eNOS−/− livers. Most notably, cyclin E and cyclin A protein induction in response to PH were dependent on eNOS expression. Peak BrdU incorporation, reflecting active DNA synthesis, was observed at 45 hours post-PH, which was significantly attenuated in eNOS−/− mice. It should be noted that analysis of BrdU incorporation over extended post-PH periods confirms the lack of compensatory or delayed DNA synthetic responses in eNOS−/− livers and highlights the functional significance of eNOS in hepatocyte proliferation in response to PH. We did not

observe any compensatory increase in iNOS protein or mRNA expression in eNOS−/− livers subjected to PH. Our studies confirm C646 chemical structure previous observations that the iNOS isoform does not compensate for eNOS deficiency in regenerating livers.25 Despite distinct impairments in hepatocyte proliferation, liver growth at 8 days post-PH was comparable between WT and eNOS−/−

livers. During liver regeneration, numerous cytokines, growth factors, and transcription factors are activated and function synergistically, which, in turn, initiate and promote hepatocyte proliferation, angiogenesis, and organ growth.1, 2, 26 Our findings validate the current consensus that multiple redundant mechanisms are in place to ensure liver regeneration in response to hepatic insufficiency, and that no single factor is independently sufficient to induce and complete liver regeneration. Several factors may account for attenuated hepatocyte proliferation in eNOS−/− livers. First, efficient transcriptional activation of cyclins, such as cyclins D1, E, and A, are dependent on c-Jun/AP-1 activity. Second, the ERK-signaling Astemizole cascade is involved in the regulation of G1 phase progression in liver regeneration.27 The present study reveals a novel role of eNOS-mediated signaling on ERK activation in regenerating livers, as evidenced by impaired MEK/ERK signaling in eNOS−/− mice early (5 minutes) after liver resection. Third, early activation of MMPs, such as MMP-9, is essential for the dissolution of ECM and proteolytic activation latent growth factors, such as HGF.28-30 Interestingly, our findings suggest that eNOS signaling influences the early induction of MMP-9 in regenerating livers, as evidenced by the delay and dysregulation of MMP-9 protein expression in the remnant livers of eNOS−/−.

10 Therefore, we undertook a comprehensive approach to determine potential roles of eNOS

in hepatocyte proliferation by conducting a systematic analysis of hepatocyte proliferative response, based on the sequential induction of key cyclins that drive cell-cycle Lorlatinib progression at the G1, G1/S, and G2/M phases, as well as BrdU-incorporation kinetics over 24-96 hours. Corresponding to early events, hepatocyte cell-cycle progression and proliferation in response to PH were significantly attenuated in eNOS−/− livers. Most notably, cyclin E and cyclin A protein induction in response to PH were dependent on eNOS expression. Peak BrdU incorporation, reflecting active DNA synthesis, was observed at 45 hours post-PH, which was significantly attenuated in eNOS−/− mice. It should be noted that analysis of BrdU incorporation over extended post-PH periods confirms the lack of compensatory or delayed DNA synthetic responses in eNOS−/− livers and highlights the functional significance of eNOS in hepatocyte proliferation in response to PH. We did not

observe any compensatory increase in iNOS protein or mRNA expression in eNOS−/− livers subjected to PH. Our studies confirm selleck compound previous observations that the iNOS isoform does not compensate for eNOS deficiency in regenerating livers.25 Despite distinct impairments in hepatocyte proliferation, liver growth at 8 days post-PH was comparable between WT and eNOS−/−

livers. During liver regeneration, numerous cytokines, growth factors, and transcription factors are activated and function synergistically, which, in turn, initiate and promote hepatocyte proliferation, angiogenesis, and organ growth.1, 2, 26 Our findings validate the current consensus that multiple redundant mechanisms are in place to ensure liver regeneration in response to hepatic insufficiency, and that no single factor is independently sufficient to induce and complete liver regeneration. Several factors may account for attenuated hepatocyte proliferation in eNOS−/− livers. First, efficient transcriptional activation of cyclins, such as cyclins D1, E, and A, are dependent on c-Jun/AP-1 activity. Second, the ERK-signaling during cascade is involved in the regulation of G1 phase progression in liver regeneration.27 The present study reveals a novel role of eNOS-mediated signaling on ERK activation in regenerating livers, as evidenced by impaired MEK/ERK signaling in eNOS−/− mice early (5 minutes) after liver resection. Third, early activation of MMPs, such as MMP-9, is essential for the dissolution of ECM and proteolytic activation latent growth factors, such as HGF.28-30 Interestingly, our findings suggest that eNOS signaling influences the early induction of MMP-9 in regenerating livers, as evidenced by the delay and dysregulation of MMP-9 protein expression in the remnant livers of eNOS−/−.

Discrimination and calibration of this new model were compared against existing models including Barcelona Clinic Liver

Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), and Japan Integrated Staging (JIS) scores. The majority of the patients had viral hepatitis as the underlying liver disease (100% in the derivation cohort and 85% in the validation cohort). The survival model incorporated MELD, age, number of tumor nodules, size of the largest nodule, vascular invasion, metastasis, serum albumin, and alpha-fetoprotein. In cross-validation, the coefficients remained Adriamycin largely unchanged between iterations. Observed survival in the validation cohort matched closely with what was predicted by the model. The concordance (c)-statistic for this model (0.77) was superior to that for BCLC (0.71), CLIP (0.70), or JIS (0.70). The score was able to further classify patient survival within each stage of the BCLC classification. Conclusion: A new model to predict survival of HCC patients based on objective parameters PD332991 provides refined prognostication and supplements the BCLC classification. (HEPATOLOGY 2012) Liver cancer is a common yet lethal malignancy globally, claiming nearly

700,000 lives as of 2008. It is the third leading cause of cancer deaths in the world.1 In the U.S., the incidence of hepatocellular carcinoma (HCC) has been reported to have tripled over the past 3 decades2 and, because of the poor survival of these patients, mortality associated with HCC also rose in parallel with Cytidine deaminase the incidence.3 HCC is unique in that survival of patients is determined

not only by the extent of the tumor, but also by the severity of underlying liver dysfunction. In addressing the interrelationship of prognostic factors in HCC, there have been at least seven staging systems developed for HCC. These include the Barcelona Clinic Liver Cancer system (BCLC),4 Cancer of the Liver Italian Program score (CLIP),5, 6 Japan Integrated Staging score (JIS),7 the American Joint Committee on Cancer, Tumor, Node, Metastasis (AJCC TNM),8 Okuda,9 Chinese University Prognostic Index (CUPI),10 and Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire Prognostic classification (GETCH).11 Most of these systems include some measures of the tumor extent and abnormal physiology associated with liver disease. The BCLC staging system has been endorsed by the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL) as a standard staging system in HCC. However, drawbacks of the BCLC system include the use of subjective components, particularly performance status and the Child-Turcott-Pugh score and a wide range of patients’ prognosis within a given category. The overall aim of this study was to develop and validate a multivariate survival model for patients with HCC so as to produce prognostic information that may be standardized.

1C,F, 2C-F, 4C). However, CB2 receptor expression was similar between the HF/MCD-Zucker rats and normal-Zucker rats (data not shown). Besides the progressive increase in IHR, acute intraportal infusion of leptin ICG-001 significantly increased endocannabinoid levels in the liver samples collected at the end of perfusion study (Fig. 5A,B). In fact, the number of sticky leukocytes was positively correlated with hepatic endocannabinoid levels in the HF/MCD-Zucker and HF/MCD+leptin-lean rat livers (Fig. 4F). Furthermore, inactivation of Kupffer cells by GdCl3 reduced IHR and endocannabinoid production in the HF/MCD-Zucker and HF/MCD+leptin-lean

rat livers (Fig. 5A,B). Compared with normal-lean rats, increased CYP2E1 activity and protein were found in the HF/MCD-Zucker

rats with hyperleptinemia (Fig. 5C,D). In contrast to the attenuation in leptin-induced increase in IHR and endocannabinoids production, CYP2E1 activity and protein expression were not modified by pretreatment with GdCl3 when Zucker rat livers were examined (Fig. 5C,D). These results indicated that the leptin-induced increase in IHR and endocannabinoids production were independent of hepatic microsomal Romidepsin datasheet CYP2E1 in our NASH rat livers. Paralleling the elevated plasma leptin, an increase in hepatic endothelin-1, ETAR, and activator protein-1 expression were observed in HF/MCD-Zucker rats (Table 1, Figs. 1E, 2E, 3E). In contrast to the other lean rat livers (normal-lean, HF/MCD-lean, and normal+leptin lean rats), an increase in hepatic endothelin-1 levels, activator protein-1, and ETAR mRNAs levels were observed only in HF/MCD+leptin-lean rat livers (Table 1, Figs. 1E, 3E,F). Parvulin However, hepatic ETBR

expression did not differ between the above groups (data not shown). Using the liver perfusion system, it was found that incubation with endothelin-1 significantly increased IHR in all livers (Fig. 5E). Notably, the magnitude of endothelin-1-induced elevation of IHR in the HF/MCD-Zucker and HF/MCD+leptin-lean rat livers were significantly greater than in the normal-lean, normal-Zucker, and HF/MCD-lean rat livers (Fig. 5E). Additionally, the concomitant administration of leptin with endothelin-1 significantly enhanced the endothelin-1-induced increase in IHR of HF/MCD-Zucker and HF/MCD+leptin-lean rat livers (Fig. 5E). Simultaneous preincubation with the ETAR antagonist BQ123 abolished the leptin-enhanced endothelin-1-induced increase in IHR of HF/MCD-Zucker and HF/MCD+leptin-lean rat livers. Nevertheless, concomitant preincubation of the ETBR antagonist (BQ788) with leptin and endothelin-1 did not modify the leptin-induced increased in IHR of the HF/MCD-Zucker and HF/MCD+leptin-lean rat livers. Figure 6A and Supporting Fig. 2A shows that, when compared with a gel exposed to buffer only, incubation of endothelin-1 induced a significant decrease in the collagen gel surface area.