Article
Multidisciplinary Sciences
Atsushi Miura, Takashi Hosono, Taiichiro Seki
Summary: Depleting macrophages can suppress tissue remodeling and partially delay cell proliferation during regeneration after acute liver injury. Inhibiting tissue remodeling caused by depleted macrophages can delay the recovery of metabolic functions, indicating that liver injury affects liver metabolism.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Junmei Zhou, Chunbao Sun, Lu Yang, Jinhui Wang, Natacha Jn-Simon, Chen Zhou, Andrew Bryant, Qi Cao, Chenglong Li, Bryon Petersen, Liya Pi
Summary: YAP activation is involved in alcohol-related liver injury, and knocking out the Yap1 gene exacerbates liver damage. The regulation of ALDH1A1 by YAP plays an important role in liver regeneration and detoxification.
Article
Pharmacology & Pharmacy
Ming Li, Zhifeng Yang, Zhaoyuan Song, Cunxiang Bo, Shuo Wang, Qiang Jia
Summary: The aim of the study was to investigate the effects and potential mechanisms of ATM on the progression of liver fibrosis. The results showed that ATM deficiency exacerbated liver fibrosis development and was associated with the activation of the TGF-beta 1/Smad2 signaling pathway.
Article
Cell Biology
Meng Wang, Haoyu Liu, Xu Zhang, Wenbo Zhao, Danyang Li, Chengpeng Xu, Zhen Wu, Fei Xie, Xiangzhi Li
Summary: The study revealed that MOF is significantly overexpressed during ALI and can impact liver cell proliferation, fibrosis, and activation of certain signaling pathways. Knockdown of Mof attenuated ALI and promoted liver regeneration by activating the Insulin-like growth factor 1 signaling pathway. These findings suggest a potential therapeutic target for ALI.
JOURNAL OF CELLULAR PHYSIOLOGY
(2021)
Article
Medicine, Research & Experimental
Yu Sun, Hadrien Demagny, Adrien Faure, Francesca Pontanari, Antoine Jalil, Nadia Bresciani, Ece Yildiz, Melanie Korbelius, Alessia Perino, Kristina Schoonjans
Summary: The enzyme asparagine synthetase (ASNS) is responsible for the de novo synthesis of the nonessential amino acid asparagine. The expression of ASNS in pericentral hepatocytes, specialized liver cells in xenobiotic detoxification, is significantly increased in models of acute liver injury. Mice with hepatocyte-specific Asns deletion are more susceptible to pericentral liver damage, which can be reversed by intravenous administration of asparagine. The upregulation of ASNS in response to stress is mediated by the nuclear receptor, liver receptor homolog 1 (LRH-1; NR5A2) through an ATF4-independent, noncanonical pathway.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Review
Cell Biology
Robert S. Rogers, Annemarie Parker, Phill D. Vainer, Elijah Elliott, Dakota Sudbeck, Kaushal Parimi, Venkata P. Peddada, Parker G. Howe, Nick D'Ambrosio, Gregory Ruddy, Kaitlin Stackable, Megan Carney, Lauren Martin, Thomas Osterholt, Jeff L. Staudinger
Summary: Pregnane X receptor (PXR) is highly expressed in the enterohepatic system and regulates the expression of genes encoding key drug metabolizing enzymes and drug transporter proteins. Activation of PXR increases metabolism and clears drugs and xenobiotics from the body, mediating important drug interactions. PXR activation also transrepresses inflammatory- and nutrient-signaling pathways, connecting these pathways with drug biotransformation pathways. Research on post-translational modifications (PTMs) of PXR is still in its early stages.
Article
Immunology
Naresh Naik Ramavath, Laila Lavanya Gadipudi, Alessia Provera, Luca C. Gigliotti, Elena Boggio, Cristina Bozzola, Emanuele Albano, Umberto Dianzani, Salvatore Sutti
Summary: The study investigated the role of ICOS/ICOSL signaling in liver repair, finding that CD8(+) T-lymphocytes play a key role in supporting the survival of reparative MoMFs during liver healing.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Huma Hameed, Muhammad Farooq, Celine Vuillier, Claire Piquet-Pellorce, Annaig Hamon, Marie-Therese Dimanche-Boitrel, Michel Samson, Jacques Le Seyec
Summary: This study reveals that RIPK1 plays a protective role in preventing hepatocyte apoptosis caused by acute liver injury. TNF-alpha and FasL have emerged as factors promoting hepatocyte survival.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Ho Rim Oh, Min Kyung Ko, Daehee Son, Young Wook Ki, Shin-Il Kim, Seok-Yong Lee, Keon Wook Kang, Gi Jeong Cheon, Do Won Hwang, Hyewon Youn
Summary: Activated hepatic stellate cells (HSCs) play a detrimental role in liver fibrosis progression. Natural killer (NK) cells have therapeutic effects in a CCl4-induced liver cirrhosis mouse model by reducing collagen deposition, HSC marker activation, and macrophage infiltration. The repetitive administration of NK cells alleviates liver fibrosis through anti-fibrotic and anti-inflammatory mechanisms.
Article
Medicine, Research & Experimental
Tomislav Kostic, Dejan Popovic, Zoran Perisic, Dragana Stanojevic, Sonja Dakic, Sandra Saric, Danijela Djordjevic Radojkovic, Svetlana Apostolovic, Nenad Bozinovic, Snezana Ciric Zdravkovic, Stefan Milutinovic, Bojan Maricic, Nikola Zivkovic, Mladjan Golubovic, Miodrag Djordjevic, Radomir Damjanovic, Abraham Bell, Boris Dindic
Summary: The study demonstrates that aminoguanidine has a significant hepatoprotective effect in acute liver damage induced by CCl4, attributed to its antioxidant effects, inhibition of pro-oxidative and pro-inflammatory mediators, and induction of damaged hepatocytes into apoptosis.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Review
Biochemistry & Molecular Biology
Elke Burgermeister
Summary: This review summarizes the expression and function of the nuclear receptor superfamily (NRSF) in human solid tumors and hematopoietic malignancies, as well as their modulatory effects on immune cells. The study suggests that targeting these receptors may provide new opportunities for combination therapies with existing cancer medications.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Xinran Cai, Ye Feng, Meishu Xu, Chaohui Yu, Wen Xie
Summary: Activation of the xenobiotic receptor CAR has been shown to inhibit obesity and improve insulin sensitivity, but its metabolic benefits may depend partly on the inducible coactivator Gadd45b.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Biochemistry & Molecular Biology
Andrew D. Huber, William C. Wright, Wenwei Lin, Kinjal Majumder, Jonathan A. Low, Jing Wu, Cameron D. Buchman, David J. Pintel, Taosheng Chen
Summary: This study found that mutating a single residue in the PXR receptor can convert the antagonist SPA70 into an agonist. Molecular dynamics simulations revealed that in certain cases, the action of SPA70 is similar to that of agonists, further elucidating the relationship between the structure and activity of the PXR receptor.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Multidisciplinary Sciences
Abbie E. Fearon, Coenraad F. Slabber, Andrii Kuklin, Marc Bachofner, Luigi Tortola, Lea Pohlmeier, Sophia Pantasis, Thorsten Hornemann, Lin Chen, Manfred Kopf, Sabine Werner
Summary: The study showed that Fgfr3 is expressed by hepatocytes in the healthy liver, while its major ligand Fgf9 is mainly expressed by non-parenchymal cells and upregulated upon injury. Mice lacking Fgfr3 in hepatocytes exhibited increased tissue necrosis after acute toxin treatment and more excessive fibrosis after long-term injury, suggesting a potential use of FGFR3 ligands for therapeutic purposes in protecting the liver from toxin-induced cell death and fibrosis.
Article
Gastroenterology & Hepatology
Juhoon So, Minwook Kim, Seung-Hoon Lee, Sungjin Ko, Daniel A. Lee, Hyewon Park, Mizuki Azuma, Michael J. Parsons, David Prober, Donghun Shin
Summary: The differentiation of liver progenitor cells (LPCs) into hepatocytes is crucial for reducing inflammation and fibrosis in chronic liver diseases. Inhibition of the epidermal growth factor receptor (EGFR) signaling pathway promotes LPC-to-hepatocyte differentiation and may serve as a proregenerative therapeutic approach for patients with advanced liver disease. This study provides insights into the mechanisms underlying LPC-mediated liver regeneration and suggests the potential of EGFR inhibitors as a treatment option.
Review
Pharmacology & Pharmacy
Kouichi Yoshinari, Ryota Shizu
Summary: PXR and CAR are transcription factors highly expressed in the liver and play important roles in xenobiotic metabolism and liver functions. PXR activation enhances hepatocyte proliferation, while CAR activation is associated with liver tumorigenesis. Additionally, PXR may have antitumor effects by targeting inflammatory cytokine signals, angiogenesis, and epithelial-mesenchymal transition.
DRUG METABOLISM AND DISPOSITION
(2022)
Article
Pharmacology & Pharmacy
Daigo Asano, Syoya Hamaue, Hamim Zahir, Hideyuki Shiozawa, Yumi Nishiya, Takako Kimura, Miho Kazui, Naotoshi Yamamura, Marie Ikeguchi, Takahiro Shibayama, Shin-Ichi Inoue, Tsuyoshi Shinozuka, Toshiyuki Watanabe, Chizuko Yahara, Nobuaki Watanabe, Kouichi Yoshinari
Summary: This study assessed the human metabolites of DS-1971a and identified a human disproportionate metabolite M1 formed by CYP2C8-mediated metabolism. Species differences in the formation of M1 provide new insights into the metabolism of cyclohexane-containing substrates by CYP2C8.
DRUG METABOLISM AND DISPOSITION
(2022)
Article
Pharmacology & Pharmacy
Yasushi Yamazoe, Yoshiya Yamamura, Kouichi Yoshinari
Summary: A ligand-accessible space in the CYP2C9 active site was reconstituted as a fused grid-based template, and the interaction between CYP2C9 and its ligands was studied. The results suggest that contacts with the template walls stabilize the ligand binding, and trigger-residue movement initiates CYP2C9 reactions.
DRUG METABOLISM AND PHARMACOKINETICS
(2022)
Article
Chemistry, Medicinal
Yuki Hagiwara, Harumi Kumagai, Niels Ouwerkerk, Linda Gijzen, Rumaisha Annida, Marleen Bokkers, Remko van Vught, Kouichi Yoshinari, Yoshifumi Katakawa, Kei Motonaga, Tomokazu Tajiri
Summary: The aim of this study was to develop an in vitro drug permeability methodology that accurately mimics the gastrointestinal environment using a three-dimensional (3D) Caco-2 tubules and a microphysiological system. The methodology was confirmed by measuring the permeability of propranolol and subsequently applied to solifenacin and bile acids. This model provides an alternative testing system for drug absorption in a closely resembling environment to the human gastrointestinal tract.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Daigo Asano, Koichi Nakamura, Yumi Nishiya, Hideyuki Shiozawa, Hideo Takakusa, Takahiro Shibayama, Shin-Ichi Inoue, Tsuyoshi Shinozuka, Takakazu Hamada, Chizuko Yahara, Nobuaki Watanabe, Kouichi Yoshinari
Summary: This study assessed the pharmacokinetics of the human disproportionate metabolite M1 in PXB-mice and showed that the metabolite profile in PXB-mice is remarkably similar to that in humans. Furthermore, the PBPK model incorporating parameters from PXB-mice provided a more accurate prediction of exposure to M1 compared to the observed value in PXB-mice. This study highlights the usefulness of PBPK modeling in predicting exposure to human disproportionate metabolites.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Food Science & Technology
Takumi Sato, Ryota Shizu, Yoshie Miura, Takuomi Hosaka, Yuichiro Kanno, Takamitsu Sasaki, Kouichi Yoshinari
Summary: This study identified possible direct and indirect activators of rCAR by measuring Cyp2b1 mRNA levels and performing reporter assays. It demonstrated the usefulness of these methods in evaluating rCAR activation by chemicals.
FOOD AND CHEMICAL TOXICOLOGY
(2022)
Article
Biochemistry & Molecular Biology
You-Ran Luo, Tada-aki Kudo, Kanako Tominami, Satoshi Izumi, Takakuni Tanaka, Yohei Hayashi, Takuya Noguchi, Atsushi Matsuzawa, Junichi Nakai, Guang Hong, Hang Wang
Summary: This study evaluated the mechanism of temperature-controlled repeated thermal stimulation (TRTS)-mediated neuronal differentiation. The researchers found that SP600125, a JNK inhibitor, can enhance TRTS-induced neuritogenesis by attenuating the negative feedback loop of BMP signaling. This study is important for the future development of regenerative neuromedicine.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Ryota Shizu, Yuta Otsuka, Chizuru Ishii, Kanako Ezaki, Kouichi Yoshinari
Summary: The nuclear receptor PPAR alpha controls fatty acid metabolism and can be inhibited by the xenobiotic receptor CAR, preventing lipid metabolism. Activation of PPAR alpha increases gene expression related to fatty acid metabolism. PPAR alpha binds to the promoter region of the CAR gene and induces its activity. CAR functions as a negative feedback factor for PPAR alpha activation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Immunology
Yuto Sekiguchi, Saya Takano, Takuya Noguchi, Tomohiro Kagi, Ryuto Komatsu, Maoko Tan, Yusuke Hirata, Atsushi Matsuzawa
Summary: In this study, gefitinib was found to activate the NLRP3 inflammasome through the activation of mitochondrial Src family kinases (mSFKs). All tested tyrosine kinase inhibitors were found to activate the NLRP3 inflammasome in human monocytic THP-1 cells and bone marrow-derived macrophages. These TKIs also exhibited off-target activity against mSFKs, such as c-Src, Fgr, and Fyn. These findings suggest that NLRP3 senses hypoactivity of mSFKs, resulting in mitochondrial dysfunction.
JOURNAL OF IMMUNOLOGY
(2023)
Article
Hematology
Koki Nagai, Tetsuya Niihori, Akihiko Muto, Yoshikazu Hayashi, Taiki Abe, Kazuhiko Igarashi, Yoko Aoki
Summary: Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an inherited bone marrow failure syndrome caused by missense mutations in the MECOM gene. Knockin mice harboring RUSAT-associated MECOM mutations recapitulate the bone marrow dysfunction observed in RUSAT patients.
Article
Cell Biology
Taiki Abe, Shin-ichiro Kanno, Tetsuya Niihori, Miho Terao, Shuji Takada, Yoko Aoki
Summary: Leucine zipper-like transcriptional regulator 1 (LZTR1) plays a crucial role in the proteostasis of the RAS subfamily. Deficiency of LZTR1 increases tumor growth and metastasis by promoting cell proliferation, invasion, and collagen secretion. The lack of LZTR1 also affects signaling pathways related to tumor progression and alters the expression of genes involved in epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) remodeling.
CELL DEATH & DISEASE
(2023)
Article
Toxicology
Tomomi Yoda, Tomoaki Tochitani, Toru Usui, Mami Kouchi, Hiroshi Inada, Takuomi Hosaka, Yuichiro Kanno, Izuru Miyawaki, Kouichi Yoshinari
Summary: In this study, the researchers investigated the mechanism of hepatotoxicity caused by DSP-0640 and found that CYP1A1 inhibition-mediated AHR activation is involved in the hepatotoxicity. This discovery reveals a novel mechanism for drug-induced hepatotoxicity.
JOURNAL OF TOXICOLOGICAL SCIENCES
(2022)
Meeting Abstract
Oncology
Yuichiro Kanno, Nao Saito, Naoya Yamashita, Kouichi Yoshinari
Article
Toxicology
Hideaki Yokoyama, Taku Masuyama, Yuki Tanaka, Iori Tsubakihara, Kazuma Kondo, Kouichi Yoshinari
Summary: This study found that pharmacological inhibition of DGAT1 increased plasma ALT and AST activity in rats, and the accumulation of DAG and resultant PKC activation in enterocytes played a key role in this elevation.
JOURNAL OF TOXICOLOGICAL SCIENCES
(2022)