Comparison of the ethanolic and water extracts of saffron showed that the ethanolic extract had the highest phenolic content (67.62 mg gallic acid/g) and the best antioxidant activity. The ascorbic acid equivalent antioxidant capacities of the ethanolic extract were 0.253 and 0.304 mmol/g in the FRAP and ABTS assays,

respectively. Correspondingly, the best free radical scavenging activity, as measured by the DPPH assay, was exerted by ethanolic extract (median inhibitory concentration [IC50] = 2.0 mg/mL) (Table 1). The antioxidant activity of ethanolic saffron extract was also measured in vivo and is summarized in Table 2, which shows the antioxidant status of liver of control and experimental animals. Group 3 (HCC) animals exhibited significant increase Vemurafenib (P < 0.001) in MDA, P.Carbonyl, GSH levels, as well as in MPO and GST activities (P < 0.001) and decrease in CAT (P < 0.01) and SOD (P < 0.001) activities compared to group 1 (control). These findings are consistent with hepatic oxidative stress and damage caused by DEN-2-2AAF. However, as can be seen in Table 2, pretreatment with saffron (groups 4, 5 and 6) significantly attenuated the changes in these oxidative stress markers compared to control. Both medium and high doses of saffron abolished DEN-2-2AAF-induced oxidative stress more effectively than

the lower dose. Surprisingly, GSH levels remained elevated in groups pretreated with saffron and did not return to normal levels as opposed to other oxidative stress markers. Sirolimus in vitro It is well established that GSH synthesis is up-regulated during oxidative damage, inflammation and cell proliferation. It is possible that even in saffron-treated animals, DEN-2-2AAF causes a persistent low level of

oxidative stress as well as low levels of inflammation/proliferation, which in turn causes GSH levels to remain, elevated. Macroscopically, rats in group 3 (HCC) revealed enlarged liver with multiple nodules on the liver surface, the nodule incidence was 75% and the number of nodules per nodule-bearing animal (nodule multiplicity) was 2.33 in this group (Table 3). Groups 4-6, where animals treated with saffron and DEN-2-2AAF, showed a decrease in liver enlargement, nodule incidence and multiplicity. The protective effect of saffron was most dramatic in group 4 rats ZD1839 ic50 (highest dose of saffron), where saffron completely inhibited the appearance of hepatic nodule altogether. Serum activities of GGT, ALT, and AFP were significantly increased in group 3 (HCC) as compared to control rats (group 1), thus indicating liver damage. However, pretreatment with saffron (groups 4-6) caused a significant decrease in the elevation of these proteins (Table 4). Interestingly, higher doses of saffron caused a lesser decrease in the DEN-induced GGT and ALT levels, as opposed to the lowest doses almost reversed these DEN-induced enzyme increase.

CYP2E1 expression in the liver of patients with chronic hepatitis C correlated with the progression of hepatic disease (both lobular inflammation and fibrosis indices), and observed check details variations were consistent with the preferential distribution of CYP2E1 in the lobular zone.[42] The effect of alcohol metabolism on HCV replication and the antiviral action of IFN was studied in Huh-7 cells that harbor HCV replication and metabolize ethanol

via the introduced expression of CYP2E1. Alcohol (up to 100 mmol/L) significantly increased HCV replication, which was dependent on CYP2E1 expression and alcohol-induced oxidative stress, and attenuated the anti-HCV action of IFN.[43] In chronic hepatitis C patients,

cross-reactivity Copanlisib cell line between CYP2E1 and specific sequences in HCV-NS5b protein can promote the development of auto-antibodies targeting conformational epitopes on the CYP2E1 surface that might contribute to hepatic injury.[44] Alcohol’s elevation of HCV titer in patients and increase of HCV RNA in replicon cells suggest that HCV replication is increased in the presence and absence of the complete viral replication cycle. Seronello et al.[45] used Huh7 human hepatoma cells that naturally express comparable levels of CYP2E1 as human liver to demonstrate that ethanol, at physiologically relevant concentrations, enhances complete HCV replication. Acetaldehyde, the first metabolite of ethanol, also enhanced HCV replication. They reported that elevated NADH/NAD+ is required for the potentiation of HCV replication by ethanol, and inhibiting CYP2E1 or ALDH suppressed replication. Thus, alteration of cellular NADH/NAD ratio is likely to play a critical role in the potentiation of HCV replication by ethanol (Fig. 4). Chronic heavy alcohol consumption

in the presence of obesity and viral hepatitis could be damaging for the liver. While moderate alcohol consumption was associated with decreased prevalence of steatohepatitis in patients with NAFLD,[46] heavy alcohol consumption is discouraged whether an individual Lepirudin has NAFLD or not. The presence of common mechanisms for liver damage due to viruses, obesity, or chronic heavy alcohol consumption is relevant and may exacerbate damage to the liver when these three conditions exist. Further research is needed to clarify the interaction, if any, between moderate drinking, NAFLD, and viral hepatitis. The author does not have any conflicting interests to declare. “
“Murine models of autoimmunity allow the study of the earliest events in disease pathogenesis.

Corals hosting different genotypes Selleck Ulixertinib of Symbiodinium may have varying thermal bleaching thresholds, but changes in the symbiont’s antioxidant system that may accompany these differences have received less attention. This study shows that constitutive activity and up-regulation of different parts of the antioxidant network under thermal stress differs between four Symbiodinium types in culture and that thermal susceptibility

can be linked to glutathione redox homeostasis. In Symbiodinium B1, C1 and E, declining maximum quantum yield of PSII (Fv/Fm) and death at 33°C were generally associated with elevated superoxide dismutase (SOD) activity and a more oxidized glutathione pool. Symbiodinium F1 exhibited no decline in Fv/Fm or growth, but showed proportionally larger increases in ascorbate peroxidase (APX) activity and glutathione content (GSx), while maintaining GSx in a reduced state. Depressed growth in Symbiodinium B1 at a sublethal temperature

of 29°C was associated with transiently increased APX activity and glutathione pool size, and an overall increase in glutathione reductase (GR) activity. The collapse of GR activity at 33°C, together with increased SOD, APX and glutathione S-transferase activity, contributed to a strong oxidation of the glutathione pool with subsequent death. Integrating responses of multiple components of the antioxidant network highlights the importance of antioxidant plasticity in explaining type-specific temperature responses in Symbiodinium. “
“Macrocystis pyrifera is selleck compound a widely distributed, highly productive, seaweed. It is known to use bicarbonate (HCO3−) from seawater in photosynthesis and the main mechanism of utilization is attributed to the external catalyzed dehydration of HCO3− by the surface-bound enzyme carbonic anhydrase (CAext). Here, we examined other putative HCO3− uptake mechanisms in

M. pyrifera under pHT 9.00 (HCO3−: CO2 = 940:1) and pHT 7.65 (HCO3−: CO2 = 51:1). Rates of photosynthesis, Ribonuclease T1 and internal CA (CAint) and CAext activity were measured following the application of AZ which inhibits CAext, and DIDS which inhibits a different HCO3− uptake system, via an anion exchange (AE) protein. We found that the main mechanism of HCO3− uptake by M. pyrifera is via an AE protein, regardless of the HCO3−: CO2 ratio, with CAext making little contribution. Inhibiting the AE protein led to a 55%–65% decrease in photosynthetic rates. Inhibiting both the AE protein and CAext at pHT 9.00 led to 80%–100% inhibition of photosynthesis, whereas at pHT 7.65, passive CO2 diffusion supported 33% of photosynthesis. CAint was active at pHT 7.65 and 9.00, and activity was always higher than CAext, because of its role in dehydrating HCO3− to supply CO2 to RuBisCO. Interestingly, the main mechanism of HCO3− uptake in M.

“
“Drug-induced and indeterminate acute liver failure (ALF) might be due to an autoimmune-like hepatitis that is responsive to corticosteroid therapy. The aim of this study was to evaluate whether corticosteroids improve survival in fulminant autoimmune

hepatitis, drug-induced, or indeterminate ALF, and whether this benefit varies according to the severity of illness. We conducted a retrospective analysis of autoimmune, indeterminate, and drug-induced ALF patients in the Acute Liver Failure Selumetinib research buy Study Group from 1998-2007. The primary endpoints were overall and spontaneous survival (SS, survival without transplant). In all, 361 ALF patients were studied, 66 with autoimmune (25 steroids, 41 no steroids), 164 with indeterminate (21 steroids, 143 no steroids), and 131 with drug-induced (16 steroids, 115 no steroids) ALF. Steroid use was not associated with improved overall survival (61% versus 66%, P = 0.41), nor with improved survival in any diagnosis category. Steroid use was associated with diminished survival in certain subgroups of patients, including

those with the highest quartile of the Model for Endstage Liver Disease (MELD) (>40, survival 30% versus 57%, P = 0.03). In multivariate analysis controlling for steroid use and diagnosis, age (odds ratio [OR] 1.37 per decade), coma grade (OR 2.02 grade 2, 2.65 grade 3, 5.29 grade 4), MELD (OR 1.07), and pH < 7.4 (OR 3.09) were significantly associated with mortality. Although steroid use was associated with a marginal benefit in SS overall (35% versus 23%, P = 0.047), this benefit did not persistent in multivariate analysis; mechanical ventilation KU-57788 manufacturer (OR 0.24), MELD (OR 0.93), and alanine aminotransferase (1.02) were the only significant predictors of SS. Conclusion: Corticosteroids did not improve overall survival or SS in drug-induced, indeterminate, or autoimmune ALF and were associated with lower survival in patients with the highest

MELD scores. (Hepatology 2014;59:612–621) “
“Dietary fat has multiple roles on human Dapagliflozin health, and some dietary fat is used to treat organic diseases because of its anti-inflammatory effect. It is commonly accepted that omega-3 polyunsaturated fatty acid (PUFA) is beneficial on ischemic heart disease or rheumatic arthritis. On the contrary, effect of omega-3-PUFA on Crohn’s disease remained controversial. That effect of omega-3 PUFA differs according to the location of inflamed intestine was hypothesized. To elucidate this hypothesis, to investigate the role of dietary fat on disease activity in different kind of murine models of intestinal inflammatory diseases was planned. The effect of omega-3 PUFA on small intestinal Crohn’s disease model and large intestinal Crohn’s disease model of mice. Chronic colitis model C57BL/6 mice received two cycles of dextran sodium sulfate solution treatment to induce chronic colitis.

Two independent reviewers then reviewed the complete text, and a paper was selected if both reviewers agreed that it was suitable for this adaptation. If the two reviewers could not reach an agreement, a chairperson Seliciclib molecular weight helped them reach consensus. Ultimately, six existing guidelines were selected as seed guidelines (Fig. 1). AGREE II was used to evaluate the quality of the seed guidelines. AGREE II has six domains including scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. It comprises 23 structured key items and two items for general assessment, all of

which are scored using a 7-point Likert scale. Each seed guideline was evaluated by two reviewers based upon the Korean-AGREE II developed by the Steering Committee for Clinical Practice Guidelines of the Korean Academy of Medical Science. The Korean-AGREE II was tested for its validity through a formal consensus, and its practicality was demonstrated through the actual guideline assessment.[14] Prior to the evaluation in this study, a workshop for the implementation

of AGREE II was held during which guideline development expert Ein Soon Shin reduced point modifications between reviewers as much as possible. During the workshop, one guideline was selected for practice, and all evaluators assessed the guideline using AGREE II. The practice assessments KU-60019 were then compared with an assessment by an experienced member of the Steering Committee for Clinical Practice Guidelines of the Korean Academy of Medical Science and adjusted based on the member’s feedback. Finally, two individuals assessed each guideline, and a re-assessment was performed if there were five or more items with a score difference of three or higher. A standardized score for each domain was calculated and a distribution chart was created, and then six seed guidelines were selected by comparing the

scores of each domain (Fig. 2). Rigor of development was considered the most important selection criteria, and only guidelines with a rigor score greater than the scaled final score of 50% ADAPTE were selected. Although all 2009 guidelines from AMP deaminase Canada, the American College of Gastroenterology, and Korea scored less than 50 in terms of rigor, two guidelines from each source were included as representatives of each country.[4, 15, 16] Upon final selection of the seed guidelines, a recommendation matrix for data extraction was created to extract recommendations from each subheading based on the clinical questions (PICO) (Table 1). These recommendations were then unified into a single recommendation proposal. A level of evidence evaluation was conducted for the planning method, quality and consistency of the study based on Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria for high overall quality of evidence across outcomes (Table 2) and consisted of three levels as follows.

One important area of uncertainty is whether the term CHE, which was introduced to expand MHE toward grade I of oriented patients, is informative and clinically valuable. This needs to be evaluated by a data-driven approach. Likewise, the distinction between isolated liver failure and ACLF-associated HE should be evaluated by independent data. A closer scientific collaboration between clinical hepatologists and dedicated brain researchers, including functional brain

imaging experts, is needed. Likewise, neuropsychologists and psychiatrists are needed to clarify the broad spectrum of neuropsychiatric symptoms that can be observed in patients with liver disease. Syndrome diagnoses should be more precisely classified and transformed into classifiable entities based on pathophysiology and responding to the requirements of clinical hepatology practice and research. Future studies should fill our gaps in knowledge. They should buy ACP-196 be focused on assessing the effects of HE on individuals and society, how to use diagnostic tools appropriately, and define the therapeutic goals in each clinical scenario (Table 7). 1. Studies on economic and social burden

among different societies 2. Studies on cultural aspects on therapy and compliance with treatment 3. Long-term natural history studies 1. Studies on clinically applicable high-sensitivity screening tests that can guide which patients may benefit from dedicated testing 2.

Development of algorithms to decide when and how to apply the diagnostic process 3. Studies on competing factors (i.e., selleck kinase inhibitor HCV, delirium, depression, and narcotic use on diagnosis) 4. Studies on biomarkers for presence and progression of neurological dysfunction 1. Studies on selecting who will benefit from preventing the first OHE episode 2. Studies for >6 months to evaluate compliance and continued effects on cognitive improvement 3. Develop protocols focused on how to diagnose and treat precipitating factors 4. Determine what should be the standard protocol to investigate new therapies 5. Decide which therapies have been adequately studied and are not a priority for additional studies The existing literature suffers from a lack Dehydratase of standardization, and this heterogeneity makes pooling of data difficult or meaningless. Recommendations to promote consistency across the field have been published by ISHEN.[66] Following is a synopsis of the recommendations. Patients who are not expected to survive the hospitalization, who are terminally ill or have ACLF should be excluded. A detailed standard-of-care algorithm must be agreed upon a priori and must be instituted and monitored diligently throughout the trial. Patients should not be entered into trials until after the institution of optimal standard-of-care therapy and only if their mental state abnormalities persist.

We elucidate clinical feature of appendiceal tumors. Methods: From September 1999 to May 2013, 39 appendiceal 3-MA order tumors were resected and diagnosed histologically at Ehime Prefectural Central Hospital. We evaluated their clinical features

and histological findings, retrospectively. Results: Average age was 68.0 ± 16.1 years old (range: 27–91, male: female = 10:29). The frequent symptoms were right lower quadrant pain (32.1%) and abdominal distension (17.8%). Only 21.4% of patients were diagnosed with appendiceal tumor and 14.3% were with cecal tumor preoperatively. Eleven (39.3%) had been diagnosed with appendicitis preoperatively, and 7 (25.0%) were accidentaly found in resection for other diseases. Of all 39 cases, tumor markers (CEA and CA 19-9) were examined in 19 cases. Cases that showed elevation of serum levels of CEA were 36.8% (7/19), and those showed elevation of serum levels of CA19-9 were 15.8% (3/19). Pathological findings showed benign epithelial neoplasms in 17 cases (43.6%), malignant epithelial neoplasms in 18 cases (46.1%), and carcinoid tumors in 4 cases (10.3%). Among 17 cases with benign tumors, 16 were diagnosed with mucinous cystadenoma and 1 was with tubular adenoma. Among 18 cases with malignant tumors, 14 were with adenocarcinoma, and 4 were with mucinous cystadenocarcinoma. Survival rates of malignant

cases were 83.3%/ 1 year, 66.7%/2 years, and 66.7%/3 years. Conclusion: Preoperative Bafilomycin A1 clinical trial diagnosis for appendiceal tumors was difficult. Especially in elderly patients who showed the physical and laboratory findings of appendicitis, appendiceal tumors including malignancy should be kept in mind. Key Word(s): 1. appendiceal tumors Presenting Author: KYUNG BO YOO Additional Authors: CHANG HUN LEE, BUM SU CHOUNG, SEUNG YOUNG SEO, SEONG HUN KIM, SEUNG OK LEE, SOO TEIK LEE, IN HEE KIM, DAE GHON KIM, SANG WOOK KIM Corresponding Author: KYUNG BO YOO Affiliations: Chonbuk National University Hospital, Chonbuk National RANTES University Hospital, Chonbuk National University Hospital, Chonbuk

National University Hospital, Chonbuk National University Hospital, Chonbuk National University Hospital, Chonbuk National University Hospital, Chonbuk National University Hospital, Chonbuk National University Hospital Objective: Combination therapy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and other anticancer agents is a promising strategy to overcome TRAIL resistance in malignant cells. Parthenolide (PT) has proven to be a promising anticancer agent recently, and several studies have explored its use in combination therapy. Here, we aimed to analyze the effects of the combination treatment using PT and TRAIL. Methods: We investigated the molecular mechanisms by which PT sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis.

Results: There were 223 cases with SAS or SDS score ≥50 in 318 FGIDs check details (70.4%).

The difference of Anxiety Scale and Depression Scale between disease groups and the normal controls group had statistical significance (P < 0.05), but among disease groups, it had no statistical significance (P > 0.05). Conclusion: Patients with FGIDs are accompanied with depression and anxiety psychological obstacle, and doctors should fucuse on it. Key Word(s): 1. FGIDs; 2. anxiety; 3. depression; 4. psychological test; Presenting Author: SAYED ABBAS- HAGHAYEGH Additional Authors: PEIMAN- ADIBI Corresponding Author: PEIMAN- ADIBI Objective: Sleep Disorders are one of most common of comorbid problem in irritable bowel syndrome (IBS) patients The purpose of this research, was the determine the efficacy of Dialectical Behavioral Group Therapy on sleep

problems (early, maintain and wake-up) of IBS patients. Methods: Therefore, 52 IBS patients who received this diagnosis, according the Rome Fluorouracil ic50 II criteria, were selected and assigned to two experimental and control groups with 26 IBS patients in each group-according to Mooshine s manual-. The experimental group received 8 weekly sessions in the clinic of gastroentology in in Isfahan. The questionnaire of sleep problems was used as the pretest, post-test, follow-up). Results: Results of multi analysis of variance (MANOVA)

showed that there is significant difference the mean post-test scores of beginning of sleep problems between two groups. There was also significant difference in beginning of sleep problems and wake-up in follow-up. (p < 0.005). There was no significant difference in mean score of maintain sleep. Conclusion: Findings support rather the efficacy of Rebamipide Dialectical Behavioral Group Therapy in improvement of sleep problems IBS patients. Key Word(s): 1. IBS; 2. DBT; 3. sleep problems; Presenting Author: JUNYING XU Additional Authors: WEI DING Corresponding Author: JUNYING XU Affiliations: no Objective: To investigate the therapeutic effects of deanxit combined with proton pump inhibitors in treating non-erosive gastroesophageal reflux disease (NERD) with anxiety and depression. Methods: Totally 54 NERD patients were diagnosed with NERD accompanied with mild anxiety and/or depression according to HAD score, HAMA score, and HAMD score. They were randomly divided into two groups: 18 patients in Group A (proton pump inhibitor group) and 36 patients in Group B (deanxit combined with proton pump inhibitor group). Patients in Group A were treated with Esomeprazole 20 mg twice daily for 8 weeks, while those in Group B were treated with Esomeprazole 20 mg and deanxit 10 mg twice daily for 8 weeks.

As shown in Fig. 2C, C/EBPα activated the reporter gene through the E2 fragment. Next, we performed mutational analyses on predicted HNF binding sites. Because the multiple putative C/EBPα target sites were arranged in a tandem array, we did not perform mutation analysis on these sites. As shown in Fig. 2D, mutagenesis of certain conserved Selleckchem 5-Fluoracil sites (F4A-3, F3B-1, and F1A-3) abolished the effects of HNFs on the reporter, but mutations of all nonconserved sites made no difference. Remarkably, the F4A-3 site was a crucial site, because its mutation completely abolished the miR-122 promoter function. The F3B-1 and F1A-3 sites overlapped (Table 1), and mutations in these sites eliminated the effects

of both HNF1α and HNF3β. These data

demonstrate that the HNFs could directly bind to the miR-122 promoter. This conclusion was further confirmed by way of chromatin immunoprecipitation assay. As shown in Fig. 2E, the three HNFs directly bind to the miR-122 promoter in Huh7 cells. To test whether the LETFs could up-regulate miR-122 expression in HCC cells, we performed overexpression studies. As shown in Fig. 2F, cells transfected with LETF-expressing vectors display an obvious up-regulation of miR-122, selleck compound especially for C/EBPα. Moreover, this finding is consistently observed in the three cell lines used. Together, these results show that C/EBPα, HNF1α, HNF3β, and HNF4α are involved in the transcriptional regulation of miR-122, which also suggests that miR-122 functions as an effector of these LETFs during liver development. Cellular proliferation and differentiation are the two most important processes for organ development.23 Numerous studies have established the pivotal roles of LETFs in the regulation of both processes during liver development.17-19 To search for the functional targets of miR-122, we primarily focused on candidate target genes with the potential to suppress differentiation and/or promote proliferation, which are contrary to the roles of LETFs. Eleven

candidate targets were arbitrarily selected from the results predicted by Targetscan 4.2 for further confirmation (Table 2). In addition, CCNG1 and BCL2L2, two known targets of miR-122, were Cediranib (AZD2171) employed as positive controls.16, 24 The 3′-UTR segments of each target were synthesized and subcloned downstream of the Renilla luciferase in the psiCHECK-2 dual luciferase reporter vector (Fig. 3A), and reporter assays were performed as indicated. Surprisingly, as shown in Fig. 3B, 11 reporters were significantly repressed by miR-122 to different degrees (30%-70% reduction), including the two known targets. MSN (moesin) and serum response factor (SRF) were not significant in this group. These data indicate that most candidate genes could be directly repressed by miR-122. To further confirm this hypothesis, we performed mutational analyses on each predicted site.

Therefore, Selinexor in vitro we fed the mice HFHFr or ATRA-supplemented HFHFr (ATRA

+ HFHFr) diets for another 4 weeks to investigate the effects of ATRA on NAFLD-associated insulin resistance (Fig. 2A). Although daily consumption did not differ between mice fed the HFHFr and ATRA + HFHFr diets, consumption was significantly lower in these two groups than in the control group (Fig. 2B), indicating that ATRA does not induce an anorexigenic effect and that leptin therefore likely does not affect the central nervous system in NAFLD mice. ATRA significantly decreased body weight, liver-to-body weight ratio, visceral fat tissue weight, serum alanine aminotransferase and aspartate aminotransferase levels in NAFLD mice (Fig. 2C-E, Supporting Fig. 3A,B). In agreement with a significant decrease in hepatic lipid levels

in the ATRA + HFHFr group as shown by biochemical assays, quantitative real-time polymerase chain reaction (qPCR) demonstrated that ATRA significantly up-regulated the lipolytic transcription factors PPARα and PPARβ, with concomitant down-regulation of lipogenic transcription factors, PPARγ and sterol regulatory element-binding protein 1 (SREBP1), and fatty acid synthase, as described24 (Fig. 3A, Supporting Fig. 3C-E). Note that the primers for detecting SREBP1 were designed to detect splicing variants SREBP1a and SREBP1c, both of which play central roles in regulating lipid synthesis, although each variant differs Olopatadine in some aspects.28 Moreover, ATRA significantly improved hepatic

histology as indicated GSK126 mouse by decreased numbers and area of lipid droplets, and ballooned hepatocytes (Supporting Fig. 3F, Supporting Table 1). The histological study also revealed remarkably diminished periportal macrovesicular steatosis, suggesting enhanced lipid metabolism in the livers of the ATRA + HFHFr group. This finding was consistent with the expression of lipid metabolism-related genes (Fig 3A-E). However, the efficacy of ATRA for treating patients with nonalcoholic steatohepatitis remains to be determined, as the mice in our present study did not develop severe inflammation and fibrosis (Supporting Table 1). We then explored the effect of ATRA on insulin resistance in a mouse model of HFHFr diet-induced NAFLD. As observed in KK-Ay mice, ATRA significantly normalized hyperglycemia, hyperinsulinemia, glucose intolerance, insulin resistance (homeostatic model assessment of insulin resistance and intraperitoneal insulin tolerance test), as well as hyperleptinemia (Fig. 4A-D, Supporting Fig. 4). In contrast to leptin, the HFHFr diet did not affect circulating levels of adiponectin, another antidiabetic adipokine, or tumor necrosis factor-α, which is known to impair insulin sensitivity (data not shown). IRS1 expression was significantly increased in association with increased tyrosine phosphorylation in ATRA + HFHFr group, compared with those in the HFHFr group (Fig. 4E, Supporting Fig. 5A,B).