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MK-0626,a selective DPP-4 inhibitor,attenuates hepatic steatosis in ob/ob mice

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World Journal of Gastroenterology 2014年第43期20卷 16227-16235页

作者： Tatsuya Ohyama Ken Sato Yuichi Yamazaki Hiroaki Hashizume norio horiguchi Satoru Kakizaki Masatomo Mori Motoyasu Kusano Masanobu Yamada Department of Medicine and Molecular Science Gunma University Graduate School of MedicineGunma 371-8511Japan Department of Endoscopy and Endoscopic Surgery Gunma University HospitalGunma 371-8511Japan

AIM: To investigate the mechanism and in vivo effects of MK-0626, a dipeptidyl peptidase-4 inhibitor, on hepatic steatosis using ob/ob mice.

关键词： Dipeptidyl peptidase-4 inhibitor Hepatic steatosis ob/ob mice AMP-activated protein kinase Microsomal triglyceride transfer protein Adiponectin

Combination therapy with daclatasvir and asunaprevir for dialysis patients infected with hepatitis C virus

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World Journal of Clinical Cases 2016年第3期4卷 88-93页

作者： Ken Sato Yuichi Yamazaki Tatsuya Ohyama Takeshi Kobayashi norio horiguchi Satoru Kakizaki Motoyasu Kusano Masanobu Yamada Department of Medicine and Molecular Science Gunma University Graduate School of Medicine Department of Gastroenterology Heisei Hidaka Clinic Department of Endoscopy and Endoscopic Surgery Gunma University Hospital

The standard antiviral therapy for dialysis patients infected with hepatitis C virus(HCV) is(pegylated) interferon monotherapy, but its efficacy is insufficient. Oral direct-acting antiviral agents(DAAs) have recently been developed for chronic hepatitis C patients. However, some DAAs have contraindications for chronic renal failure(CRF). Daclatasvir and asunaprevir are metabolized largely in the liver and are not contraindicated in CRF. Combination therapy with daclatasvir and asunaprevir was used for 4 dialysis patients infected with genotype 1b HCV. One patient had viral breakthrough, and the 3 others had sustained virological response 12. One patient was admitted for heart failure and percutaneous coronary intervention due to concomitant ischemic disease. Heart failure was unlikely to be caused by the combination therapy, as it was probably due to water overload. The patient continued to receive the combination therapy after the remission of the heart failure. The combination therapy was well tolerated in the other patients.

关键词： Hepatitis C Oral drug Daclatasvir Asunaprevir Dialysis

Overexpression of NK2 inhibits liver regeneration after partial hepatectomy in mice

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World Journal of Gastroenterology 2005年第47期11卷 7444-7449页

作者： Toshiyuki Otsuka norio horiguchi Daisuke Kanda Takashi Kosone Yuichi Yamazaki Kazuhisa Yuasa Naondo Sohara Satoru Kakizaki Ken Sato Hitoshi Takagi Glenn Merlino Masatomo Mori Department of Medicine and Molecular Science Gunma University Graduate School of Medicine3-39-15 ShowaMaebashiGunma 371-8511Japan Laboratory of Cell Regulation and Carinogenesis National Cancer InstituteBuilding 37Room 5002BethesdaMD 20892-4264United States

AIM： To investigate the in vivo effects of NK2 on liver regeneration after partial hepatectomy （PH）. METHODS： Survival after PH was observed with 21 NK2 transgenic mice and 23 wild-type （WT） mice over 10 d. Liver regeneration was analyzed using histology and immunohistochemistry. Expressions of genes were analyzed using Northern blot analysis, immunoprecipitation and immunoblotting, and reverse transcriptase polymerase chain reaction assay. Kaplan Meier method and the log-rank test were used for analyzing the survival after PH. Differences in the results of immunohistochemistry and percentage of liver regeneration was determined by the Student＇s t-test. RESULTS： More than half of NK2 transgenic mice died within 48 h after PH. After PH, increased deposition of small lipid droplets in hepatocytes was evident and hepatic proliferation was inhibited in NK2 transgenic mice. The hepatic expression and kinase activity of HGF receptor, c-Met, were unchanged among WT mice and NK2 transgenic mice after PH. The expression of tumor necrosis factor-co （TNF-c0 and interleukin-6 （IL-6） in liver tissues were prolonged in NK2 transgenic mice that died after PH. CONCLUSION： Our findings indicate that overexpression of NK2 inhibits liver regeneration after PH.

关键词： Hepatocyte growth factor NK2 Transgenic mice Partial hepatectomy Liver regeneration

Sofosbuvir/Ribavirin therapy for patients experiencing failure of ombitasvir/paritaprevir/ritonavir + ribavirin therapy: Two cases report and review of literature

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World Journal of Clinical Cases 2019年第9期7卷 1043-1052页

作者： Ken Sato Yuichi Yamazaki Takeshi Kobayashi Satoshi Takakusagi norio horiguchi Satoru Kakizaki Masayasu Andou Yoshihiro Matsuda Toshio Uraoka Hiroshi Ohnishi Hiroaki Okamoto Department of Gastroenterology and Hepatology Gunma University Graduate School of Medicine Department of Nephrology and Rheumatology Gunma University Graduate School of Medicine Department of Diagnostic Radiology and Nuclear Medicine Gunma University Graduate School of Medicine Division of Virology Department of Infection and Immunity Jichi Medical University School of Medicine

BACKGROUND The effectiveness of sofosbuvir/ribavirin(SOF/RBV) combination therapy,which is one of the 1 st-choice therapeutic options for patients with hepatitis C virus(HCV) genotype 2(HCV-G2) in Japan according to the most recent version of the Japan Society of Hepatology guideline, for patients who experienced failure of the ombitasvir/paritaprevir/ritonavir plus ribavirin(OBV/PTV/r+RBV) combination therapy, which was another option for patients with HCV-G2, is *** SUMMARY We evaluated the effects of SOF/RBV combination therapy in two patients with genotype 2 a who could not achieve a sustained virological response(SVR) by OBV/PTV/r+RBV combination therapy. One patient was complicated with VogtKoyanagi-Harada(VKH) disease. Resistance-associated variations before SOF/RBV combination therapy were not detected in two patients. Both patients had an SVR at 12 wk after the treatment(SVR12). Regarding adverse events(AEs), itching, chill, a dull feeling in the throat and cough as well as increase of alanine transaminase level were shown in one patient, while a headache and deterioration of light aversion probably due to the recurrence of VKH disease were shown in the other patients. In addition, the latter patient developed arthralgia and morning stiffness approximately 7 wk after the therapy and turned out to be diagnosed with rheumatoid *** SOF/RBV therapy might be effective for patients experiencing failure of OBV/PTV/r+RBV therapy, but caution should be taken regarding the AEs.

关键词： Direct-acting antiviral agent failure Hepatitis C Genotype 2 Ribavirin Sofosbuvir Case report

Non-invasive prediction of non-alcoholic steatohepatitis in Japanese patients with morbid obesity by artificial intelligence using rule extraction technology

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World Journal of Hepatology 2018年第12期10卷 934-943页

作者： Daisuke Uehara Yoichi Hayashi Yosuke Seki Satoru Kakizaki norio horiguchi Hiroki Tojima Yuichi Yamazaki Ken Sato Kazuki Yasuda Masanobu Yamada Toshio Uraoka Kazunori Kasama Department of Medicine and Molecular Science Gunma University Graduate School of Medicine Department of Gastroenterology and Hepatology Gunma University Graduate School of Medicine Department of Computer Science Meiji University Tama-ku Weight Loss and Metabolic Surgery Center Yotsuya Medical Cube Department of Metabolic Disorder Diabetes Research Center Research Institute National Center for Global Health and Medicine Department of Internal Medicine Division of Endocrinology and Metabolism Gunma University Graduate School of Medicine

AIM To construct a non-invasive prediction algorithm for predicting non-alcoholic steatohepatitis(NASH), we investigated Japanese morbidly obese patients using artificial intelligence with rule extraction *** Consecutive patients who required bariatric surgery underwent a liver biopsy during the operation. Standard clinical, anthropometric, biochemical measurements were used as parameters to predict NASH and were analyzed using rule extraction technology. One hundred and two patients, including 79 NASH and 23 non-NASH patients were analyzed in order to create the predictionmodel, another cohort with 77 patients including 65 NASH and 12 non-NASH patients were analyzed to validate the *** Alanine aminotransferase, C-reactive protein, homeostasis model assessment insulin resistance, albumin were extracted as predictors of NASH using a recursive-rule extraction algorithm. When we adopted the extracted rules for the validation cohort using a highly accurate rule extraction algorithm, the predictive accuracy was 79.2%. The positive predictive value, negative predictive value,sensitivity and specificity were 88.9%, 35.7%, 86.2% and 41.7%, *** We successfully generated a useful model for predicting NASH in Japanese morbidly obese patients based on their biochemical profile using a rule extraction algorithm.

关键词： Non-alcoholic steatohepatitis Artificial intelligence Rule extraction Morbid obesity Liver biopsy Non-invasive prediction

Ipragliflozin-induced improvement of liver steatosis in obese mice may involve sirtuin signaling

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World Journal of Hepatology 2020年第7期12卷 350-362页

作者： Takayoshi Suga Ken Sato Tatsuya Ohyama Sho Matsui Takeshi Kobayashi Hiroki Tojima norio horiguchi Yuichi Yamazaki Satoru Kakizaki Ayaka Nishikido Takashi Okamura Masanobu Yamada TadahiroKitamura Toshio Uraoka Department of Gastroenterology and Hepatology Gunma University Graduate School of MedicineMaebashi 371-8511GunmaJapan Metabolic Signal Research Center Institute for Molecular and Cellular RegulationGunma UniversityMaebashi 371-8512GunmaJapan Department of Medicine and Molecular Science Gunma Graduate School of MedicineMaebashi 371-8511GunmaJapan

BACKGROUND Sodium glucose cotransporter 2(SGLT2)inhibitors are newly developed oral antidiabetic ***2 is primarily expressed in the kidneys and reabsorbs approximately 90%of the glucose filtered by the renal ***2 inhibitors lower glucose levels independently of insulin action by facilitating urinary glucose *** SGLT2 inhibitor ipragliflozin has reportedly improved liver steatosis in animal models and clinical ***,the mechanisms by which SGLT2 inhibitors improve liver steatosis are not fully *** To investigate the ameliorative effects of ipragliflozin on liver steatosis and the mechanisms of these effects in obese *** We analyzed 8-wk-old male obese(ob/ob)mice that were randomly divided into a group receiving a normal chow diet and a group receiving a normal chow diet supplemented with ipragliflozin(3 mg/kg or 10 mg/kg)for 4 *** also analyzed their lean sex-matched littermates receiving a normal chow diet as another control group. Body weight and liver weight were evaluated, and liverhistology, immunoblotting, and reverse transcription-polymerase chain reactionanalyses were *** lipid accumulation was significantly ameliorated in ob/ob mice treatedwith 10 mg/kg ipragliflozin compared to untreated ob/ob mice irrespective ofbody weight changes. Ipragliflozin had no appreciable effects on hepatic oxidativestress-related gene expression levels or macrophage infiltration, but significantlyreduced hepatic interleukin-1β (IL-1β) mRNA expression levels. Ipragliflozinincreased both the mRNA and protein expression levels of sirtuin 1 (SIRT1) in theliver. The hepatic mRNA levels of peroxisome proliferator-activated receptor γcoactivator 1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα),and fibroblast growth factor-21 (FGF21) were also significantly higher inipragliflozin-treated ob/ob mice than in untreated ob/ob *** study suggests that the liver steatosis-ameliorati

关键词： Selective sodium glucose cotransporter 2 Nonalcoholic fatty liver disease Sirtuin 1 Peroxisome proliferator-activated receptorγcoactivator 1α Peroxisome proliferator-activated receptorα Fibroblast growth factor-21

Extended therapy duration for therapy-refractory hepatitis C patients with genotype 2

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World Journal of Gastroenterology 2013年第34期19卷 5754-5758页

作者： Ken Sato Masatoshi Yanagisawa Hiroaki Hashizume Yuichi Yamazaki norio horiguchi Satoru Kakizaki Masatomo Mori Department of Medicine and Molecular Science Gunma University Graduate School of Medicine

We devised an extended 72-wk peginterferon--2a/ribavirin therapy regimen for the retreatment of highly intractable cases,i.e.,48-wk peginterferon--2b/ribavirin therapy-intractable *** 2 cases achieved a rapid virological response to 72-wk peginterferon--2a/ribavirin therapy,1 case failed to achieve a sustained virological *** the reason for this difference in the effectiveness of 72-wk peginterferon--2a/ribavirin therapy between the cases was unclear,the rebound phenomenon of serum transaminase after48-wk peginterferon--2b/ribavirin therapy and the resultant lower viral load compared to that before 48-wk peginterferon--2b/ribavirin therapy might have influenced the treatment ***,it may be beneficial to consider the rebound phenomenon of serum transaminase and the changes in viral load resulting from previous interferon-based therapy and then cau-tiously determine the indication and the timing of the administration of 72-wk peginterferon--2a/ribavirin in highly intractable *** studies should be performed to confirm this strategy.

关键词： Hepatitis C Genotype 2 and high viral loads Interferon-based therapy Highly intractable case Extended therapy duration

Probable case of drug reaction with eosinophilia and systemic symptom syndrome due to combination therapy with daclatasvir and asunaprevir

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World Journal of Clinical Cases 2015年第12期3卷 1005-1010页

作者： Takayoshi Suga Ken Sato Yuichi Yamazaki Tatsuya Ohyama norio horiguchi Satoru Kakizaki Motoyasu Kusano Masanobu Yamada Department of Medicine and Molecular Science Gunma University Graduate School of Medicine Department of Endoscopy and Endoscopic Surgery Gunma University Hospital

A 66-year-old, interferon-ineligible, treatment-naive man who was diagnosed with chronic hepatitis C due to hepatitis C virus genotype 1b began combination therapy with daclatasvir and asunaprevir. On day 14 of treatment, hepatic reserve and renal function deterioration was observed, while his transaminase levels were normal. Both daclatasvir and asunaprevir were discontinued on day 18 of treatment, because the patient complained of dark urine and a rash on his trunk and four limbs. After discontinuing antiviral therapy, the abnormal laboratory finding and clinical manifestations gradually improved, without recurrence. Our case fulfilled the diagnostic criteria of probable drug reaction with eosinophilia and systemic symptom(DRESS) syndrome. Despite the 18-d treatment, sustained virological response 12 was achieved. Based on the clinical course, we concluded that there was a clear cause-and-effect relationship between the treatment and adverse events. To our knowledge, this patient represents the first case of probable DRESS syndrome that includes concomitant deterioration of hepatic reserve and renal function due to combination therapy with daclatasvir and asunaprevir, regardless of normalization of transaminase levels. Our case suggests that we should pay attention not only to the transaminase levels but also to allergic symptoms associated with organ involvement during combination therapy with daclatasvir and asunaprevir.

关键词： Hepatitis C Daclatasvir Renal dysfunction Asunaprevir Hepatic reserve deterioration

Clinical characteristics of null responders to Peg-IFNα2b/ ribavirin therapy for chronic hepatitis C

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World Journal of Hepatology 2010年第11期2卷 401-405页

作者： Hideyuki Suzuki Satoru Kakizaki norio horiguchi Takeshi Ichikawa Ken Sato Hitoshi Takagi Masatomo Mori Department of Medicine and Molecular Science Gunma Univ ersity Graduate School of Medicine

AIM: To predict which chronic hepatitis C patients are likely to be late-responders, we herein investigated the clinical characteristics of null-responders at 36 wk with hepatitis C virus (HCV) genotype Ib and a high viral load during the course of pegylated interferon (Peg-IFN)/ ribavirin ther apy. METHODS: One hundred forty-two patients with genotype Ib HCV and a high viral load were included in this study. Peg-IFNα2b (1.5 μg/kg once a week) and ribavirin (600-1000 mg per day according to body weight) were administered for 48 wk. We def ined nullresponders as the cases that never cleared serum HCV RNA as determined using RT-PCR until 36 wk. Other patients were def ined as responders. We compared the clinical characteristics (age, gender, body mass index, previous treatment) and HCV RNA titer during the therapy between null-responders and ***: The HCV RNA clearance rate was 17.9% (24/134), 46.3% (62/134), 60.6% (86/142), 86.6% (123/142), and 88.0% (125/142) at 4, 8, 12, 24, and 36 wk, respectively. There were 17 patients (12.0%) who were still null-responders at 36 wk. There were no differences in the clinical characteristics between the responders and null-responders except for the titer and decline rates of HCV RNA at 1 wk and 4 wk. The HCV RNA titers at 1 wk and after 4 wk of treatment were significantly higher in the null-responders in comp arison to the responders (P <0.01). The serum HCV RNA titers of the responders decreased by 1.3 log after 1 wk of treatment, and 1.6 log after 4 wk of treatm ent, respectively. On the other hand, the titers of the null responders decreased by only 0.5 log after 1 wk, and 0.7 log after 4 wk of treatment, respectively. The decrease rates of HCV RNA after 1 and 4 wk of treatm ent were signif icantly worse for null responders than for the responders (P <0.01). CONCLUSION: The HCV RNA titer at 1 wk and 4 wk after initiating treatment may be useful for predicting null-responders to Peg-IFNα2b/ribavirin therapy. Howe

关键词： Null responder Pegylated interferon α2b Ribavirin Chronic hepatitis C