Journal of Gastroenterology最新文献

{"title":"Quantitative measurements of M2BPGi depend on liver fibrosis and inflammation","authors":"Haruki Uojima, Kazumi Yamasaki, Masaya Sugiyama, Masayoshi Kage, Norihiro Ishii, Ken Shirabe, Hisashi Hidaka, Chika Kusano, Miyako Murakawa, Yasuhiro Asahina, Takashi Nishimura, Hiroko Iijima, Kazumasa Sakamoto, Kiyoaki Ito, Keisuke Amano, Takumi Kawaguchi, Nobuharu Tamaki, Masayuki Kurosaki, Takanori Suzuki, Kentaro Matsuura, Akinobu Taketomi, Satoru Joshita, Takeji Umemura, Sohji Nishina, Keisuke Hino, Hidenori Toyoda, Hiroshi Yatsuhashi, Masashi Mizokami","doi":"10.1007/s00535-024-02100-3","DOIUrl":"https://doi.org/10.1007/s00535-024-02100-3","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>The relationship between liver fibrosis and inflammation and Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with chronic liver disease (CLD) other than hepatitis C remains uncertain, owing to the limitations of qualitative methods. Here, we evaluated the influence of liver fibrosis and inflammation on quantitative M2BPGi (M2BPGi-Qt) in CLD, considering each etiology.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We recruited 1373 patients with CLD. To evaluate the influence of liver fibrosis and inflammation on M2BPGi-Qt levels, we assessed M2BPGi-Qt levels at each fibrosis and activity stage within different etiologies of CLD based on pathological findings. Subsequently, we evaluated if the accuracy of fibrosis staging based on M2BPGi-Qt could be improved by considering the influence of liver inflammation.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>In patients with viral hepatitis, non-alcoholic fatty liver disease, and primary biliary cholangitis, the median M2BPGi-Qt levels increased liver fibrosis progression. Median M2BPGi-Qt levels were not associated with the degree of fibrosis in patients with autoimmune hepatitis (AIH). Median M2BPGi-Qt levels increased with the progression of liver activity in all etiologies. A significant difference was found at each stage in AIH. Considering the liver inflammation, we established an algorithm, M2BPGi-Qt, to determine the alanine aminotransferase-to-platelet ratio (MAP-R) in liver cirrhosis (LC). The area under the receiver operating characteristic curve (AUC) of MAP-R was higher than that of the M2BPGi-Qt for detecting LC (AUC MAP-R = 0.759 and M2BPGi-Qt = 0.700,<i> p</i> &lt; 0.001).</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>The quantitative measurement system for M2BPGi depends on liver fibrosis and inflammation, regardless of etiology. Liver inflammation complicates the interpretation of M2BPGi-Qt results when assessing the fibrosis stage.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":"48 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140560950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The biochemical pattern defines MASLD phenotypes linked to distinct histology and prognosis","authors":"Javier Ampuero, Rocío Aller, Rocío Gallego-Durán, Javier Crespo, Jose Luis Calleja, Carmelo García-Monzón, Judith Gómez-Camarero, Joan Caballería, Oreste Lo Iacono, Luis Ibañez, Javier García-Samaniego, Agustín Albillos, Rubén Francés, Conrado Fernández-Rodríguez, Douglas Maya-Miles, Moisés Diago, Maria Poca, Raúl J. Andrade, Raquel Latorre, Francisco Jorquera, Rosa María Morillas, Desamparados Escudero, Manuel Hernández-Guerra, María Jesús Pareja-Megia, Jesús M. Banales, Patricia Aspichueta, Salvador Benlloch, José Miguel Rosales, Juan Turnes, Manuel Romero-Gómez","doi":"10.1007/s00535-024-02098-8","DOIUrl":"https://doi.org/10.1007/s00535-024-02098-8","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>MASLD can manifest as hepatocellular damage, which can result in mild elevation of aminotransferases. However, in some patients, MASLD presents with cholestatic pattern.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>To assess the impact of the biochemical pattern on the natural course of MASLD, including liver damage in histology, the accuracy of non-invasive tests(NITs), and prognosis.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Multicenter study enrolling 2156 patients with biopsy-proven MASLD, who were classified based on their[ALT/ULN)]/[(ALP/ULN)] levels at the time of biopsy: (a) hepatocellular pattern(H), &gt; 5; (b) mixed pattern(M),2–5; (c) cholestatic pattern(C), &lt; 2. Outcomes: (a) histological evaluation of the single components of NAS, MASH, and fibrosis; (b) NITs and transient elastography assessing advanced fibrosis; (c) prognosis determined by the appearance of decompensated cirrhosis and death.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Out of the 2156 patients, 22.9% exhibited the H-pattern, whilst 31.7% exhibited the C-pattern. Severe steatosis, ballooning, lobular inflammation, and MASH (56.4% H <i>vs.</i> 41.9% M <i>vs.</i> 31.9% C) were more common in H-pattern (<i>p</i> = 0.0001),whilst C-pattern was linked to cirrhosis (5.8% H <i>vs.</i> 5.6% M <i>vs.</i> 10.9% C; <i>p</i> = 0.0001). FIB-4(0.74(95% CI 0.69–0.79) <i>vs.</i> 0.83 (95% CI 0.80–0.85); <i>p</i> = 0.005) and Hepamet Fibrosis Score(0.77 (95% CI 0.69–0.85) <i>vs.</i> 0.84 (95% CI 0.80–0.87); <i>p</i> = 0.044)exhibited lower AUROCs in the H-pattern. The C-pattern[HR 2.37 (95% CI 1.12–5.02); <i>p</i> = 0.024], along with age, diabetes, and cirrhosis were independently associated with mortality. Most patients maintained their initial biochemical pattern during the second evaluation.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>The H-pattern exhibited greater necro-inflammation in the histology than the C-pattern, whereas the latter showed more cirrhosis. The accuracy of NITs in detecting fibrosis was decreased in H-pattern. The occurrence of decompensated events and mortality was predominant in C-pattern. Therefore, identifying MASLD phenotypes based on the biochemical presentation could be relevant for clinical practice.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":"5 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140560937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic change of metabolic dysfunction-associated steatotic liver disease in patients with hepatitis C virus infection after achieving sustained virologic response with direct-acting antivirals","authors":"Chen-Hua Liu, Yu-Ping Chang, Yu-Jen Fang, Pin-Nan Cheng, Chi-Yi Chen, Wei-Yu Kao, Chih-Lin Lin, Sheng-Shun Yang, Yu-Lueng Shih, Cheng-Yuan Peng, Ming-Chang Tsai, Shang-Chin Huang, Tung-Hung Su, Tai-Chung Tseng, Chun-Jen Liu, Pei-Jer Chen, Jia-Horng Kao","doi":"10.1007/s00535-024-02101-2","DOIUrl":"https://doi.org/10.1007/s00535-024-02101-2","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Information on the dynamics of metabolic dysfunction-associated steatotic liver disease (MASLD) among hepatitis C virus patients achieving sustained virologic response (SVR₁₂) with direct-acting antivirals (DAAs) is limited.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We enrolled 1512 eligible participants in this prospective study. MASLD was defined by a controlled attenuation parameter (CAP) of ≥248 dB/m utilizing vibration-controlled transient elastography in conjunction with presence of ≥1 cardiometabolic risk factor. The distribution of MASLD and the changes in CAP were evaluated before treatment and at SVR₁₂. Forward stepwise logistic regression analyses were performed to determine factors significantly associated with the regression or emergence of MASLD.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The prevalence of MASLD decreased from 45.0% before treatment to 36.1% at SVR₁₂. Among 681 participants with MASLD before treatment, 144 (21%) exhibited MASLD regression at SVR₁₂. Conversely, among 831 participants without MASLD before treatment, 9 (1.1%) developed MASLD at SVR₁₂. Absence of type 2 diabetes (T2D) [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.13–2.65, <i>p</i> = 0.011], age &gt; 50 years (OR: 1.73, 95% CI: 1.11–2.68, <i>p</i> = 0.015), and alanine transaminase (ALT) ≤ 2 times the upper limit of normal (ULN) (OR: 1.56; 95% CI: 1.03–2.37, <i>p</i> = 0.035) were associated with the regression of MASLD. Presence of T2D was associated with the emergence of MASLD (OR: 5.83, 95% CI: 1.51–22.56, <i>p</i> = 0.011).</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>The prevalence of MASLD decreased after achieving SVR₁₂ with DAAs. Patients with pre-existing T2D showed a diminished probability of MASLD regression and a heightened risk of MASLD emergence post-SVR₁₂.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":"27 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140560860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study","authors":"Motoki Makuuchi, Yoichi Kakuta, Junji Umeno, Toshimitsu Fujii, Tetsuya Takagawa, Takashi Ibuka, Miki Miura, Yu Sasaki, Sakuma Takahashi, Hiroshi Nakase, Hiroki Kiyohara, Keiichi Tominaga, Yosuke Shimodaira, Sakiko Hiraoka, Nobuhiro Ueno, Shunichi Yanai, Takeo Yoshihara, Kazuki Kakimoto, Katsuyoshi Matsuoka, Ryohei Hayashi, Sohachi Nanjo, Itaru Iwama, Yoh Ishiguro, Hirofumi Chiba, Katsuya Endo, Takashi Kagaya, Tomohiro Fukuda, Yasuhisa Sakata, Takahiro Kudo, Tomohisa Takagi, Kenichi Takahashi, Makoto Naganuma, Masaru Shinozaki, Noriyuki Ogata, Hiroki Tanaka, Kazuyuki Narimatsu, Haruka Miyazaki, Takashi Ishige, Motoyuki Onodera, Yu Hashimoto, Hiroshi Nagai, Yusuke Shimoyama, Takeo Naito, Rintaro Moroi, Hisashi Shiga, Yoshitaka Kinouchi, Akira Andoh, Tadakazu Hisamatsu, Atsushi Masamune","doi":"10.1007/s00535-024-02099-7","DOIUrl":"https://doi.org/10.1007/s00535-024-02099-7","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with &lt; 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":"9 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140560859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical risk factors for portal hypertension-related complications in systemic therapy for hepatocellular carcinoma","authors":"","doi":"10.1007/s00535-024-02097-9","DOIUrl":"https://doi.org/10.1007/s00535-024-02097-9","url":null,"abstract":"<h3>Abstract</h3> <span> <h3>Background</h3> <p>During systemic therapy, the management of portal hypertension (PH)-related complications is vital. This study aimed to clarify factors associated with the incidence and exacerbation of PH-related complications, including the usefulness of contrast-enhanced computed tomography (CECT) in the management of PH-related complications during systemic therapy.</p> </span> <span> <h3>Methods</h3> <p>A total of 669 patients who received systemic therapy as first-line treatment (443 patients for sorafenib, 131 for lenvatinib, and 90 for atezolizumab/bevacizumab [ATZ/BEV]) were enrolled in this retrospective study. Additionally, the lower esophageal intramural vessel diameters (EIV) on CECT and endoscopic findings in 358 patients were compared.</p> </span> <span> <h3>Results</h3> <p>The cutoff values of the EIV diameter on CECT were 3.1 mm for small, 5.1 mm for medium, and 7.6 mm for large varices, demonstrating high concordance with the endoscopic findings. esophageal varices (EV) bleeding predictors include EIV ≥ 3.1 mm and portal vein tumor thrombosis (PVTT). In patients without EV before systemic therapy, factors associated with EV exacerbation after 3 months were EIV ≥ 1.9 mm and ATZ/BEV use. Predictors of hepatic encephalopathy (HE) include the ammonia level or portosystemic shunt diameter ≥ 6.8 mm. The incidence of HE within 2 weeks was significantly higher (18%) in patients with an ammonia level ≥ 73 μmol/L and a portosystemic shunt ≥ 6.8 mm. The exacerbating factors for ascites after 3 months were PVTT and low albumin levels.</p> </span> <span> <h3>Conclusions</h3> <p>Careful management is warranted for patients with risk factors for exacerbation of PH-related complications; moreover, the effective use of CECT is clinically important.</p> </span>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":"56 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140560948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural history of lean and non-lean metabolic dysfunction-associated steatotic liver disease","authors":"","doi":"10.1007/s00535-024-02093-z","DOIUrl":"https://doi.org/10.1007/s00535-024-02093-z","url":null,"abstract":"<h3>Abstract</h3> <span> <h3>Background</h3> <p>Conflicting evidence regarding the prognosis of lean metabolic dysfunction-associated steatotic liver disease (MASLD) has raised substantial questions.</p> </span> <span> <h3>Aim</h3> <p>This study aimed to elucidate the prognosis of lean MASLD by conducting a comprehensive analysis of a vast Asian cohort.</p> </span> <span> <h3>Methods</h3> <p>This study used a nationwide, population-based database and analyzed 2.9 million patients. The primary endpoints were liver-related events (LREs) and cardiovascular events (CVEs) in patients with lean MASLD, non-lean MASLD, and normal liver control groups.</p> </span> <span> <h3>Results</h3> <p>The median observation period was 4.2 years. The 5-year incidence values of LREs in the lean MASLD, non-lean MASLD, and normal liver control groups were 0.065%, 0.039%, and 0.006%, respectively. The LRE risk of lean MASLD was significantly higher than that of normal liver control (adjusted hazard ratio [aHR]: 5.94, 95% confidence interval [CI]: 3.95–8.92) but comparable to that of non-lean MASLD (aHR: 1.35, 95% CI: 0.87–2.08). By contrast, for CVEs, the non-lean MASLD group exhibited a higher 5-year cumulative incidence rate (0.779%) than the lean MASLD (0.600%) and normal liver control (0.254%) groups. The lean MASLD group had a reduced risk of CVEs compared with the non-lean MASLD group (aHR, 0.73; 95% CI: 0.64–0.84), and comparable risk of CVEs to the normal liver control group (aHR, 0.99; 95% CI: 0.88–1.12).</p> </span> <span> <h3>Conclusion</h3> <p>Lean MASLD exhibits a similar LRE risk and a lower CVE risk to non-lean MASLD. Therefore, follow-up and treatment strategies should be tailored to the specific MASLD condition.</p> </span>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":"20 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to: Minocycline versus tetracycline in bismuth-containing quadruple therapy for Helicobacter pylori rescue treatment: a multicentre, randomized controlled trial.","authors":"Yu Huang, Hong Lu","doi":"10.1007/s00535-024-02085-z","DOIUrl":"10.1007/s00535-024-02085-z","url":null,"abstract":"","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"358"},"PeriodicalIF":6.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139729731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the side effects and resistance in H. pylori treatment: a discussion on minocycline versus tetracycline therapy.","authors":"Tomohiro Kurokawa, Tomoharu Kurokawa","doi":"10.1007/s00535-024-02084-0","DOIUrl":"10.1007/s00535-024-02084-0","url":null,"abstract":"","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"357"},"PeriodicalIF":6.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139983060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indoleamine 2,3-dioxygenase 1-mediated iron metabolism in macrophages contributes to lipid deposition in nonalcoholic steatohepatitis.","authors":"Chaofeng Wu, Junjie Li, Hui Jia, Jiamin Zhao, Mengchen Qin, Hao Shi, Chang Liu, Jiajie Lin, Min Cai, Yong Gu, Bin Liu, Lei Gao","doi":"10.1007/s00535-024-02082-2","DOIUrl":"10.1007/s00535-024-02082-2","url":null,"abstract":"<p><strong>Background: </strong>Non-alcoholic steatohepatitis (NASH) is a rapidly progressing chronic liver disease of global significance. However, the underlying mechanisms responsible for NASH remain unknown. Indoleamine 2,3-dioxygenase 1 (IDO1) has been recognized as essential factor in immune response and metabolic regulation. Here we aimed to investigate the functions and mechanisms of the IDO1 in macrophages on hepatic lipid deposition and iron metabolism in NASH.</p><p><strong>Methods: </strong>The effect of IDO1 in NASH was evaluated by WT and IDO1^-/- mice model fed with methionine/choline-deficient (MCD) diet in vivo. Macrophages scavenger clodronate liposomes (CL) and overexpressing of IDO1 in macrophages by virus were employed as well. Lipid deposition was assessed through pathological examination and lipid droplet staining, while iron levels were measured using an iron assay kit and western blotting. Primary hepatocytes and bone marrow-derived macrophages were treated with oleic acid/palmitic acid (OA/PA) to assess IDO1 expression via Oil Red O staining and immunofluorescence staining in vitro.</p><p><strong>Results: </strong>Pathological images demonstrated that the increase of IDO1 exacerbated lipid accumulation in the livers of mice with MCD diet, while reduction of iron accumulation was observed in the liver and the serum of MCD-fed mice. Scavenging of macrophages effectively mitigated both lipid and iron accumulation. In addition, the deficiency of IDO1 in macrophages significantly mitigated lipid accumulation and iron overload in hepatic parenchymal cells. Finally, lentivirus-mediated overexpression of IDO1 in liver macrophages exacerbated hepatic steatosis and iron deposition in NASH.</p><p><strong>Conclusions: </strong>Our results demonstrated that effective inhibition of IDO1 expression in macrophages in NASH alleviated hepatic parenchymal cell lipid accumulation and iron deposition, which provided new insights for the future treatment of NASH.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"342-356"},"PeriodicalIF":6.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139944177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel, small anti-HBV compound reduces HBsAg and HBV-DNA by destabilizing HBV-RNA.","authors":"Takehisa Watanabe, Sanae Hayashi, Yan Zhaoyu, Hiroki Inada, Katsuya Nagaoka, Masakuni Tateyama, Yasuhito Tanaka","doi":"10.1007/s00535-023-02070-y","DOIUrl":"10.1007/s00535-023-02070-y","url":null,"abstract":"<p><strong>Background: </strong>Currently, standard treatments for chronic hepatitis B such as nucleos(t)ide analogs (NAs), effectively reduce hepatitis B virus (HBV) loads but rarely result in a functional cure (defined as sustained HBsAg loss). We report the discovery of a novel, 4-pyridone compound, SAG-524, a potent and orally bioavailable small molecule inhibitor of HBV replication.</p><p><strong>Methods: </strong>The antiviral characteristics and selectivity of SAG-524 and its derivative compound against HBV were evaluated in HBV-infection assays and HBV-infected chimeric urokinase-type plasminogen activator/severe combined immunodeficiency mice with humanized livers (PXB mice), alone or in combination with entecavir. Toxicity studies were conducted in mice and monkeys.</p><p><strong>Results: </strong>SAG-524 reduced HBV-DNA (IC₅₀ = 0.92 nM) and HBsAg (IC₅₀ = 1.4 nM) in the supernatant of the HepG2.2.15 cells. SAG-524 selectively destabilized HBV-RNA via PAPD5, but not GAPDH or albumin mRNA, by shortening the poly(A) tail. PAPD5 may also be involved in HBV regulation via ELAVL1. In a study of HBV-infected PXB mice, SAG-524 produced potent reductions of serum HBsAg and HBcrAg, and the minimum effective dose was estimated to be 6 mg/kg/day. The combination therapy with entecavir greatly reduced HBsAg and cccDNA in the liver due to reduction of human hepatocytes with good tolerability. Administration of SAG-524 to monkeys, up to 1000 mg/kg/day for two weeks, led to no significant toxicity, as determined by blood tests and pathological images.</p><p><strong>Conclusions: </strong>We have identified SAG-524 as novel and orally bioavailable HBV-RNA destabilizers which can reduce HBsAg and HBV-DNA levels, and possibly contribute a functional cure.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"315-328"},"PeriodicalIF":6.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139692028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}