Glomerular filtration rate (GFR) is estimated by the abbreviated Modification of Diet in Renal Disease (MDRD) Study equation.11 Delayed graft function (DGF) was defined as the need for renal replacement therapy within 7 days post-transplant. Diagnosis of post-transplant DM was made according to international consensus guidelines.12 Hypercholesterolaemia was defined as total cholesterol greater than 5.8 mmol/L (224 mg/dL) or requiring a lipid-lowering agent. Ratio of donor kidney weight to recipient bodyweight (KW/BW) was used to estimate the donor/recipient size mismatch.13 The kidney weights (g) were recorded after a cold saline flush. The bodyweight (kg) of the recipient was measured on the morning

of the transplantation and recorded. Calculated KW/BW ratios were expressed as g/kg. Our patients were basically put on triple immunosuppressive therapy with either tacrolimus or Neoral cyclosporine (Novartis, learn more Basel, Switzerland), concomitantly with prednisolone and azathioprine therapy. All patients received 500 mg

of methylprednisolone at induction. This was followed by i.v. hydrocortisone 100 mg every 6 h for 3 days and followed by oral prednisolone 30 mg daily. The dose of prednisolone was gradually tapered after the first month at a rate of 2.5 mg every 2 weeks then maintained at 7.5 mg daily. Azathioprine was given at a dose of 1.5 mg/kg daily from day 1 after transplant. RGFP966 Cyclosporine (CsA) was initially given p.o. as a loading dose of 10 mg/kg within 12 h of surgery and then 5 mg/kg b.i.d. An abbreviated formula based on limited sampling strategy was used in this study to estimate the CsA area under 12 h concentration–time curve (AUC0–12). Calculation of CsA AUC0–12 was based on the formula: 452.4 + C0 × 17.5 + C1.5 × 1.89 (C0: CsA trough level; C1.5: 1.5 h post-dose CsA level).14 The dose of CsA was gradually titrated to maintain the abbreviated AUC0–12 at approximately 6000–8000 ng × h/mL

in the first 3 months post-transplant and 4000–6000 ng × h/mL from 3 months post-transplant onwards. On the other hand, tacrolimus was given p.o. with a loading dose of 0.3 mg/kg within 12 h of surgery and then 0.15 mg/kg b.i.d. Abbreviated tacrolimus AUC0–12 monitoring was used. Calculation of tacrolimus AUC0–12 was by the formula: 16.2 + C2 × 2.4 + C4 × 5.9 (C2: 2 h post-dose tacrolimus level; C4: 4 h post-dose tacrolimus Selleckchem Neratinib level). Based on a previous pilot study in stable patients on tacrolimus in our centre, AUC0–12 value was kept at approximately 100–150 ng × h/mL in the first 3 months and at approximately 80–100 ng × h/mL after 3 months.15 Some of our patients have received either basiliximab (Simulect; Novartis, Switzerland) or daclizumab (Zenapax; Roche Laboratories, Nutley, NJ, USA) during induction therapy since 2001. Basiliximab was given at a dose of 20 mg approximately 2 h before transplantation and the second dose was given 4 days after transplantation.

We did not find any association between CCR2 190 A/G polymorphism and ALD severity. In line with these results, it was demonstrated recently in an animal model that CCL2 plays

a role in alcoholic liver injury independently of CCR2 [16]. In conclusion, plasma levels and hepatic expression of CCL2 are increased in patients with ALD, GS-1101 mouse particularly in severe forms of AH. Our results further support the potential role of CCL2 in the pathogenesis of ALD, probably through neutrophil recruitment. CCL2 may in the future constitute an attractive therapeutic target in patients with severe AH. This study was supported in part by grants from the Erasme Foundation and from the Belgian National Fund for Scientific Research (FNRS). A. Lemmers is a post-doctoral researcher and R. Ouziel is a research fellow; D. Degré is an MD postdoctoral

fellow (FRSM). The authors thank I. Roland for help in treating pathological tissues. None of the authors has any potential financial conflict of interest related to this manuscript. Fig. S1. Evolution of CCL2 plasma levels after 7 days of steroids therapy in 16 patients with severe alcoholic hepatitis (AH). “
“Lorna MacLean, Drug Discovery Unit, College of Life Sciences, University of Dundee, Ensartinib research buy Dundee, UK Trypanosoma brucei are extracellular kinetoplastid parasites transmitted by the blood-sucking tsetse fly. They are responsible for the fatal disease human African trypanosomiasis (HAT),

also known as sleeping sickness. In late-stage infection, trypanosomes cross the blood–brain barrier (BBB) and invade the central nervous system (CNS) invariably leading to coma and death if untreated. There is no available vaccine and current late-stage HAT chemotherapy consists of either melarsoprol, which is highly toxic causing up to 8% of deaths, or nifurtimox–eflornithine combination therapy (NECT), which is costly and difficult to administer. There is therefore an urgent need to identify new late-stage HAT drug candidates. Amobarbital Here, we review how current imaging tools, ranging from fluorescent confocal microscopy of live immobilized cells in culture to whole-animal imaging, are providing insight into T. brucei biology, parasite-host interplay, trypanosome CNS invasion and disease progression. We also consider how imaging tools can be used for candidate drug screening purposes that could lead to new chemotherapies. “
“The chemokine receptor CCR6 is expressed by dendritic cells, B and T cells predominantly within the organized structures of the gut-associated lymphatic tissue. Its ligand CCL20 is synthesized by the follicle-associated epithelium and is crucial for the development of M cells within Peyer’s patches. In addition, lineage-negative c-kit positive lymphocytes within cryptopatches (CP) express CCR6.

Among them apolipoprotein B-100, complement component 3, etc decreased in the last, indicating the association with nephrotic condition. On the other hand, complement component 9, apoprotein E increased probably suggesting of the association with clinical remission. Of interest is that apolipoprotein ACP-196 order E and serum amyloid P were high in both the first and last sessions. Moreover, serum apolipoprotein

E was also high in a non-responder group. Conclusion: The present proteomic analysis revealed that the increase in serum apolipoprotein E may predict the responsiveness of LDL-A in steroid-resistant nephrotic syndrome. Further study may clarify the more detailed mechanism of the LDL-A in an intractable setting of steroid-restant nephrotic syndrome. JEONG KYUNGHWAN1,2, ASANUMA KATSUHIKO2,3, LYDIA AIDA4, TAKAKI MIYUKI2, ASAO RIN2, KODAMA check details FUMIKO2, ASANUMA ETSUKO2, TOMINO YASUHIKO2 1Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Korea; 2Division of Nephrology, Department of Internal Medicine,Juntendo University, Faculty of Medicine, Tokyo, Japan; 3Laboratory for Kidney Research, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 4Division of Nephrology and Hypertension,

Department of Internal Medicine, Cipto Mangun Kusumo Hospital, University of Indonesia, Jakarta, Indonesia Introduction: Blockade of the renin-angiotensin system plays a key role in suppressing the progression of renal diseases. It has been well unknown whether this therapy provides additional effects when combined with vitamin D or its analog in an adriamycin (ADR)-induced nephropathy model. Methods: Here we evaluated the effect of applying the combination of an AT1 receptor blocker, telmisaltan, and a vitamin D analog, oxacalcitriol, in ADR-induced nephropathy mice and immortalized murine podocytes. Podocyte injury was assessed by podocyte apoptosis using the TUNEL assay, podocyte counting, and podocyte-specific expressed protein by immunofluorescence and

western blot analysis. Results: Mice with ADR-induced nephropathy (9.5 mg/kg single intravenous injection) developed progressive albuminuria and glomerulosclerosis within 30 days, accompanied by decreased expression of slit diaphragm-associated proteins (nephrin and podocin), reduced numbers of buy CHIR-99021 podocytes, and increased systolic blood pressure. Treatment with telmisartan (0.1 mg/kg ip injection, everyday) or oxacalcitriol (0.05 μg/Kg ip injection, three times per week) alone moderately ameliorated the kidney injury; the combined treatment most effectively reduced the albuminuria and glomerulosclerosis. These effects were accompanied by restoration of slit diaphragm-associated proteins (nephrin and podocin) and podocyte apoptosis and podocyte loss in the glomeruli. Cultured podocytes were exposed to 0.25 μg/ml of ADR with telmisartan (10−7 M) or oxacalcitriol (10−8 M) and combination.

CAT-354 has recently been shown to be safe for use in humans in a phase I clinical trial but its real clinical efficacy remains to be proven [148]. Over the past few years, some evidence suggests that the most effective approaches may be combination therapies interfering with several cytokines and pathways involved in asthma

pathogenesis, since anti-IL-4 treatment alone appears to be ineffective and similarly antagonizing IL-13 in mice requires additional suppression of eosinophillic inflammation [149]. IL-4 and IL-13 both use the IL-4R-α chain, and blocking this receptor has been developed as a therapeutic strategy. A human monoclonal anti-IL-4Rα antibody (AMG317) was developed but showed no clinical efficacy [150], whereas another fully humanized anti-IL-4R-α antibody (Dupilumab REGN668) showed clinical

efficacy in patients with high peripheral blood eosinophilia upon tapering of inhaled selleck chemicals llc steroids and bronchodilators [151]. Initial proof of concept studies in human asthmatics with anti-IL-5-specific antibody therapies, such as mepolizumab and reslizumab, showed an effective reduction of eosinophil numbers in the blood and sputum of both mild and severe asthmatics, but late allergen responses and BHR were not improved [152, 153]. However, improved efficacy was noticed in specific subgroups Sotrastaurin in vivo of patients with frequent asthma exacerbation and in these patients mepolizumab treatment significantly reduced blood and sputum eosinophil levels and allowed lower corticosteroid doses to be used to control the inflammation [12, 13]. It seems, however, that for the majority of asthmatic patients, the anti-IL-5 treatment will need to be administered in combination with other therapies that suppress asthma features through other mechanisms. Results of clinical trials targeting the IL-5R-α subunit to obtain long-term depletion of eosinophils and basophils are eagerly awaited [154]. Currently, clinical data on anti-IL-9 therapeutics are modest and larger clinical

trials are eagerly awaited to conclude whether this form of therapy can be used in the treatment of asthma [155]. Similarly, studies on the neutralization of IL-17 and/or IL-23 and the effect of such Fluorometholone Acetate neutralization on asthma still need to be reported in humans. Could ILC2s constitute a therapeutic target? Certainly, given the character of the ROR-α nuclear receptor, it might be a target amenable to modification by selective antagonists. Also the precise contribution of ILC2s to asthma pathogenesis in human asthma or in mice with a fully functional adaptive immune system has not been thoroughly explored, as strategies to selectively deplete these cells without affecting other cells of the innate and adaptive immune system have not yet been developed.

Methods:  Association studies were identified from the databases of PubMed, Embase and Cochrane Library on 1 October 2011, and eligible investigations were identified and synthesized using the meta-analysis method. Results were expressed using odds ratios (OR) for dichotomous data and 95% confidence intervals (CI) were also calculated. Results:  Twelve studies reporting the relation between ACE I/D gene polymorphism and ESRD risk in DN patients were identified. In overall populations,

there was a notable association between D allele or DD genotype and ESRD susceptibility (D: OR = 1.32, 95% CI: 1.11–1.56, P = 0.002; DD: OR = 1.67, 95% CI: 1.25–2.21, P = 0.0004). In the sub-group analysis according to ethnicity, D allele or DD genotype was associated with ESRD risk in Asians. Selleck Ulixertinib In Caucasians, the association of Adriamycin solubility dmso DD genotype with ESRD risk was observed, but the D allele was not. Furthermore,

ACE I/D gene polymorphism was associated with ESRD risk in patients with DN due to diabetes mellitus type 2, but the association was not found for patients with DN due to diabetes mellitus type-1. Conclusions:  Our results indicate that D allele or DD homozygous is associated with the ESRD susceptibility in DN patients. However, more investigations are required to further this association. “
“Aim:  Vascular stiffness is associated with cardiovascular mortality in dialysis patients

and related with vascular calcification and microvascular inflammation. The objective of this study is to compare predictability of two different vascular calcification scoring systems using plain radiographs in peritoneal dialysis (PD) patients. Methods:  Vascular stiffness was represented by heart-to-femoral pulse wave velocity (hfPWV) in our 79 PD patients. Peripheral vascular calcification score (PVCS) and abdominal aortic calcification score (AACS) were measured from plain radiographs. Microvascular inflammation was represented by peritoneal protein Inositol monophosphatase 1 clearance (PPC). Regression analysis and the receiver operating characteristic (ROC) curve analysis were used for analysis. Results:  The hfPWV revealed correlation with PVCS and AACS independently. In the ROC curve analysis, area under the curve (AUC) of PVC score was 0.7119 (P = 0.006), and AUC of AACS were 0.6960 (P = 0.011). After multiple linear regression analysis, PVCS remained as a predictor of vascular stiffness (R2 = 0.579, β = 0.210, P = 0.038). The combination of PVCS and PPC exhibited a trend toward better predictability for vascular stiffness (AUC 0.7738, P = 0.001) than any of the two parameters alone. Conclusion:  It is assumed that the PVCS system is more predictable for vascular stiffness in our study. Moreover, the combination of PVCS and PPC might be more useful as a screening test for vascular stiffness.

Winkelmayer et al. further looked at the effect of late referral on access to transplantation.75 A cohort of 3014 incident patients on RRT was studied. Due to the old age of this population, only 35 received a kidney transplant.

Thirty-two of these were matched with 197 controls with similar comorbidity and demographic data. Late referral (<90 days) in this retrospective case–control study was associated with a significant reduction in transplantation (OR 0.22, 95% CI: 0.05–0.97). Socioeconomic status and comorbidity were also significantly associated PD0332991 with a reduced rate of transplantation. Finally, Wu et al. analysed 52 type 2 diabetic patients commencing predialysis at his institution selleck screening library in Taiwan over a 2-year period.76 Late referral was defined as less than 6 months before starting dialysis (36 patients) versus 16 early referrals. Survival (extended out to 5 years) was better in the early referral group (RR 0.42, 95% CI: 0.152–0.666) and was independent of age, glycaemic control and residual renal function. Most data come from retrospective studies. Prospective studies are limited and RCT unlikely due to logistic and ethical concerns. A systemic review demonstrates that late referral leads to worse patient outcomes (mortality and increased duration of hospitalization). Early referral provides the opportunity for optimal care by a nephrologist-led multidisciplinary team. Kidney Disease Outcomes Quality Initiative:

In general patients with eGFR <30 should be referred, or earlier if the ‘clinical action plan’ cannot be carried out. UK Renal Association: GFR should be calculated using the four-variable Modification of Diet in Renal Disease equation. A GFR of <15 merits immediate referral, 15–29 urgent referral and 30–59 routine referral. Patients with stage IV and V kidney disease should be discussed with a nephrologist. Canadian Society of Nephrology: Measure or calculate creatinine clearance for patients with a serum creatinine Glutathione peroxidase of >200 µmol/L. Measure creatinine clearance by 24-hour urine collection with a concurrent serum creatinine

or calculate it using the Cockcroft–Gault formula. Refer patients with a creatinine clearance of <30 mL/min to a nephrologist for opinion regarding management of renal failure. European Best Practice Guidelines: No recommendation. International Guidelines: No recommendation. Estimated GFR at the time of referral should be correlated with the time interval between referral and initiation of dialysis to suggest an optimal eGFR range to allow adequate predialysis management. Grant Luxton has no relevant financial affiliations that would cause a conflict of interest according to the conflict of interest statement set down by CARI. "
“Aim:  Proliferation signal inhibitors (PSI) have demonstrated efficacy in prevention and treatment in an animal model of lupus nephritis (LN) but there are no data regarding the use of PSI in human LN.

3A and C). In contrast to females,

male mice exhibited a more severe form of EAE than nonstressed females (Fig. 3C), which was associated with about 17% mortality rate and did not, however, exacerbate under CVS conditions (Fig. 3B and C). The induction and progression of EAE were associated with an increase in CORT levels in both stressed and nonstressed mice (Fig. 3D). Throughout the experiment, CORT levels were persistently higher in female compared with male mice (Fig. 3D). Compared to nonstressed mice, stressed females but not stressed males, showed a lower CORT response to MOG35-55 immunization at the day of EAE onset (Fig. 3D). This suggests that an impaired CORT response may have contributed to the exacerbation of EAE in stressed female mice. We thus hereon focus on the mechanism whereby selleck products CVS increases

disease severity in female mice. To directly determine the role of CORT in stress-induced GDC-941 EAE exacerbation, female mice were injected daily with the glucocorticoid antagonist mifepristone 2 hours prior to stress induction (Fig. 4). Following the stress exposure period, mice were injected with MOG35-55 to induce EAE. Nonstressed and stressed mice were used as controls. As shown in Figure 4A, compared with nonstressed controls, disease incidence rate was significantly increased in stressed mice whereas no difference was observed in stressed mice administered with mifepristone. Notably, ANOVA test revealed a significant effect for treatment (F (2,38) = 3.0132, p < 0.05) and for time selleck inhibitor (F (12,456) = 30.9, p < 0.0001); Fisher post-hoc analysis confirmed that EAE severity did not exacerbate in stressed

mice injected with mifepristone compared to nonstressed control mice (Fig. 4B), and was partially ameliorated compared to stressed control mice (decreased clinical score, days 11–13 post MOG35-55 immunization; p < 0.05; Fig. 4B). The increased EAE susceptibility and severity observed in stressed female mice could have been mediated by CORT-induced alterations in certain innate and adaptive cell subsets. To examine whether the effector functions of lymphocytes were affected following CVS in female mice, cytokine production was measured following anti-CD3 stimulation of splenocytes derived from stressed and nonstressed female mice. As shown in Table 2, no differences were found between stressed and nonstressed mice in the levels of pro- and antiinflammatory cytokines or in the levels of the chemoattractant MCP-1, suggesting that CVS did not intrinsically affect T-cell function. Thus, and given that stress increased CORT levels for a long period of time (Fig. 2), we also tested whether stress-induced elevation in CORT levels may have desensitized the lymphocytes to the immunosuppressive effects of CORT.

CD10+CD27− immature transitional B cells were classified as T1 and T2 cells based on CD21 expression to mark distinct stages of differentiation. Based on reports of clonal B cell expansions, we expected an increased B cell frequency

in the presence of MC. However, whereas white blood cell counts and absolute lymphocyte counts did not differ among patients Midostaurin purchase and uninfected controls (Supporting Fig. 1A,B), the frequency of CD19+ B cells was significantly lower in HCV-infected patients with MC (7.7 ± 1.3%) than in those without MC (13.6 ± 2.4%; P < 0.05) and uninfected controls (12.3 ± 1.4%; P < 0.05) (Fig. 2A). HCV-infected patients with and without MC also differed in absolute numbers of CD19+ B cells (103.6 ± 26.9/μL versus 299.2 ± 58.8/μL; P < 0.05)

(Supporting Fig. 1C). In addition to the reduced size of the CD19+ B cell population, the frequency of CD19+CD10− mature B cells was lower in HCV-infected patients with MC (97.5 ± 0.4%) than in HCV-infected patients without MC (98.7 ± 0.3%; P = 0.07), uninfected controls (99.3 ± 0.1%; P < 0.001) and HBV-infected patients (98.9 ± 0.3%; P < 0.001; Fig. 2B). This was consistent with a decreased absolute number of CD19+CD10- mature B cells CCI-779 clinical trial in the blood of HCV-infected patients with MC (101.5 ± 26.5/μL) compared with HCV-infected patients without MC (294.1 ± 58.3/μL; P = 0.05; Supporting Fig. 1D). We next studied the size of individual mature B cell subsets and detected no change in the percentage or absolute number of resting memory cells, tissue-like memory cells, or plasmablasts. However, HCV-infected patients with MC displayed a significantly reduced frequency of naïve B cells (53.9 ± 4.7%), the largest mature B cell subset, compared with HBV-infected patients (75 ± 5.4%; P < 0.001) and uninfected controls (74.3 ± 1.6%; P < 0.05; Figs. 3 and 4A). This was recapitulated in a reduction of the absolute number of naïve mature B cells in HCV-infected patients with MC (50.6 ± 17.7/μL) compared with those without MC (221.8 ± 48.7/μL; P < 0.001) and those with HBV infection (151.9 ± 33.3/μL; P < 0.05; Supporting Fig. 1E). NADPH-cytochrome-c2 reductase In

contrast to the decreased frequency and number of naïve B cells, the relative size of the activated mature B cell subset was increased in HCV-infected patients with MC (10.6 ± 2.1%) compared with HCV-infected patients without MC (4.3 ± 0.8%; P < 0.05), HBV-infected patients (2.6 ± 0.5%; P < 0.001), and uninfected controls (2.7 ± 0.3%; P < 0.0001; Figs. 3 and 4B). This result was expected, because cryoglobulins are produced by clonally expanded activated B cells.8 However, this increased frequency did not result in an increased absolute number of activated B cells (Supporting Fig. 1F). To investigate the reasons for the decreased frequency and number of naïve B cells, we examined their susceptibility to apoptosis.

The resultant biofilms were shown to have equivalent AZD0530 biomass to those formed on

polystyrene microtiter plates (results not shown). Therefore, for simplicity and the potential to investigate the large quantity of permutations required within this study, the 96-well microtiter plate high throughput model was used. The ability to remove C. albicans biofilm from the substrate was investigated following treatment with each of the four denture cleansers, either as recommended by the manufacturer or following overnight incubation (Fig 1). Overall, the most effective product tested was Dentural, which reduced the biomass by greater than 90% after 20 minutes and 18 hours immersion, with no significant differences observed between Napabucasin mw them. This exhibited significantly improved biomass removal capacity than did the other three products when used as per the manufacturer’s instructions (p < 0.001). Steradent Active Plus showed a significant difference between recommended and overnight immersion, with improved biofilm removal at 10 minutes (84%) compared to overnight (76%) (p < 0.001). Medical™ Interporous® produced a mean reduction of 80% and 75% after 15 minutes and 18 hours

immersion, respectively, and was more significantly active than Steradent Active Plus at either time point. Boots Smile was the poorest denture cleanser overall, with a mean reduction of 73% at both 15 minutes and 18 hours following immersion, which appeared to have decreased biofilm removal activity at 15 minutes in comparison to Medical™ Interporous® (p < 0.05), but the difference was not statistically significant after a Bonferroni correction was applied. In comparison to Steradent Active Plus and Dentural, Boots Smile had significantly decreased biofilm removal activity at 15 minutes (p < 0.001), but was significantly different only from Dentural following overnight immersion (p < 0.001). Metabolic activity of C. albicans biofilms was also determined following treatment Chloroambucil with each of the four denture cleansers, either as recommended by the manufacturer

or following overnight incubation (Fig 2). No significant differences in reduction of biofilm activity were observed between Medical™ Interporous® (86%), Steradent Active Plus (83%), and Dentural (86%); however, Boots Smile was significantly less effective (66%) (p < 0.0001). Following overnight immersion, all four cleansers showed no significant difference from one another, demonstrating metabolic reductions in the range of 85 to 87%. Boots Smile (p < 0.001) was significantly more effective at reducing the metabolism following an 18-hour immersion compared to disinfection times recommended by the manufacturer. The biofilms were also examined on three clinically relevant denture base acrylics treated with Dentural, the most effective denture-cleansing agent.

4A). In contrast, choline supplementation to MCD diet treatment, i.e., methionine-deficient (MD) diet treatment, produced no abnormalities in the liver (Fig. 4A,B). Interestingly, the decreases in serum LPC and the increases in Lpcat1-4 mRNA levels were detected in mice with MCD diet treatment, but GPCR Compound Library supplier not in mice with CD treatment (Figs. 4C, 5). Similarly, the increases in serum tauro-β-muricholate and taurocholate and the changes in hepatic expression of Abcc1/4, Slc10a1, and Slco1a1 were found in MCD-treated mice only (Figs. 4C, 5). However, there was no significant difference

in serum 12-HETE and hepatic Alox12 mRNA levels between the mice treated with MCD and MD diets (Figs. 4C, 5). Overall, these results clearly demonstrate that decreased

LPC and increased tauro-β-muricholate and taurocholate in serum were not a consequence of dietary choline deficiency or steatosis and were closely associated with steatohepatitis. Proinflammatory cytokines, such as TNF-α, IL-6, and TGF-β1, are among the major contributors to the pathogenesis of NASH.8-11, 23 Indeed, hepatic mRNA levels of TNF-α and TGF-β1 were increased in a time-dependent manner by MCD diet treatment, but not by CD or MD treatment (Supporting Fig. 6). To examine the direct contribution of these cytokines to serum LPC decreases, the mRNAs encoding Lpcat1-4 were measured in this website primary hepatocytes treated with TNF-α and TGF-β1. TNF-α through significantly induced the expression of Lpcat2/4 mRNA, whereas TGF-β1 markedly up-regulated the Lpcat4 mRNA levels (Fig. 6A). Thus, hepatic up-regulation of TNF-α and TGF-β1 and the accompanying induction of Lpcat2/4 were considered to be among causes of steatohepatitis-specific decreases in serum LPC. The relationship between these cytokines and the expression of bile acid transporters was also examined. TNF-α markedly enhanced the mRNA levels of Abcc1/4, but TGF-β1 had the opposite effect (Fig. 6B). Furthermore, TNF-α down-regulated the expression of

Slc10a1, and TGF-β1 also significantly suppressed the mRNAs encoding Slc10a1 and Slco1a1 (Fig. 6B). These results suggest a close relationship between increases in serum bile acid levels and these proinflammatory cytokines. Oxidative stress is another key mediator of NASH development.8-11 Hepatic mRNA encoding NADPH oxidase 2 (NOX2, also designated Cybb), a representative reactive oxygen species–generating enzyme, was significantly induced in a time-dependent manner and by MCD diet treatment (Supporting Fig. 7A,B). However, treatment of primary hepatocytes with H2O2 did not increase the mRNAs encoding Lpcat1-4 and Abcc1/4 or decrease those of Slc10a1 and Slco1a1 (Supporting Fig. 7C). To determine whether similar metabolite changes were seen in another steatosis/steatohepatitis model, genetically obese ob/ob mice were treated with GalN.