Nucleos(t)ide analogs for hepatitis B virus infection differentially regulate the growth factor signaling in hepatocytes
Recent clinical studies have suggested that the risk of developing HCC might be lower in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate than in patients receiving entecavir, although there is no difference in biochemical and virological remission between the 2 drugs. The e...
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| creator | Shimizu, Ryogo Murai, Kazuhisa Tanaka, Kensuke Sato, Yuga Takeda, Naho Nakasyo, Saki Shirasaki, Takayoshi Kawaguchi, Kazunori Shimakami, Tetsuro Nio, Kouki Nakaya, Yuki Kagiwada, Harumi Horimoto, Katsuhisa Mizokami, Masashi Kaneko, Shuichi Murata, Kazumoto Yamashita, Taro Honda, Masao |
| description | Recent clinical studies have suggested that the risk of developing HCC might be lower in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate than in patients receiving entecavir, although there is no difference in biochemical and virological remission between the 2 drugs.
The effects of nucleoside analogs (NsAs; lamivudine and entecavir) or nucleotide analogs (NtAs; adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide) on cell growth and the expression of growth signaling molecules in hepatoma cell lines and PXB cells were investigated in vitro. The tumor inhibitory effects of NsAs or NtAs were evaluated using a mouse xenograft model, and protein phosphorylation profiles were investigated. The binding of NsAs or NtAs to the insulin receptor (INSR) was investigated by thermal shift assays.
NtAs, but not NsAs, showed direct growth inhibitory effects on hepatoma cell lines in vitro and a mouse model in vivo. A phosphoprotein array revealed that INSR signaling was impaired and the levels of phosphorylated (p)-INSRβ and downstream molecules phosphorylated (p)-IRS1, p-AKT, p-Gab1, and p-SHP2 were substantially reduced by NtAs. In addition, p-epidermal growth factor receptor and p-AKT levels were substantially reduced by NtAs. Similar findings were also found in PXB cells and nontumor lesions of liver tissues from patients with chronic hepatitis B. Prodrug NtAs, but not their metabolites (adefovir, adefovir monophosphate, adefovir diphosphate, tenofovir, tenofovir monophosphate, and tenofovir diphosphate), had such effects. A thermal shift assay showed the binding of NtAs to INSRβ.
NtAs (adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide), which are adenine derivative acyclic nucleotide analogs, potentially bind to the ATP-binding site of growth factor receptors and inhibit their autophosphorylation, which might reduce the risk of HCC in patients with chronic hepatitis B. |
| doi_str_mv | 10.1097/HC9.0000000000000351 |
| format | Article |
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The effects of nucleoside analogs (NsAs; lamivudine and entecavir) or nucleotide analogs (NtAs; adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide) on cell growth and the expression of growth signaling molecules in hepatoma cell lines and PXB cells were investigated in vitro. The tumor inhibitory effects of NsAs or NtAs were evaluated using a mouse xenograft model, and protein phosphorylation profiles were investigated. The binding of NsAs or NtAs to the insulin receptor (INSR) was investigated by thermal shift assays.
NtAs, but not NsAs, showed direct growth inhibitory effects on hepatoma cell lines in vitro and a mouse model in vivo. A phosphoprotein array revealed that INSR signaling was impaired and the levels of phosphorylated (p)-INSRβ and downstream molecules phosphorylated (p)-IRS1, p-AKT, p-Gab1, and p-SHP2 were substantially reduced by NtAs. In addition, p-epidermal growth factor receptor and p-AKT levels were substantially reduced by NtAs. Similar findings were also found in PXB cells and nontumor lesions of liver tissues from patients with chronic hepatitis B. Prodrug NtAs, but not their metabolites (adefovir, adefovir monophosphate, adefovir diphosphate, tenofovir, tenofovir monophosphate, and tenofovir diphosphate), had such effects. A thermal shift assay showed the binding of NtAs to INSRβ.
NtAs (adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide), which are adenine derivative acyclic nucleotide analogs, potentially bind to the ATP-binding site of growth factor receptors and inhibit their autophosphorylation, which might reduce the risk of HCC in patients with chronic hepatitis B.</description><identifier>ISSN: 2471-254X</identifier><identifier>EISSN: 2471-254X</identifier><identifier>DOI: 10.1097/HC9.0000000000000351</identifier><identifier>PMID: 38180972</identifier><language>eng</language><publisher>United States: Lippincott Williams & Wilkins</publisher><subject>Carcinoma, Hepatocellular - drug therapy ; Hepatitis B - complications ; Hepatitis B - drug therapy ; Hepatitis B virus ; Hepatitis B, Chronic - complications ; Hepatitis B, Chronic - drug therapy ; Hepatocytes ; Humans ; Intercellular Signaling Peptides and Proteins ; Liver Neoplasms - drug therapy ; Nucleotides ; Original ; Proto-Oncogene Proteins c-akt ; Tenofovir - pharmacology ; Tenofovir - therapeutic use</subject><ispartof>Hepatology communications, 2024-01, Vol.8 (1)</ispartof><rights>Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.</rights><rights>Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases. 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c358t-1dd718b5120fa2f5b526005f5100367a5481556d2aef0340778299339b1395123</cites><orcidid>0000-0003-3050-5854</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10781114/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10781114/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,27926,27927,53793,53795</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38180972$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shimizu, Ryogo</creatorcontrib><creatorcontrib>Murai, Kazuhisa</creatorcontrib><creatorcontrib>Tanaka, Kensuke</creatorcontrib><creatorcontrib>Sato, Yuga</creatorcontrib><creatorcontrib>Takeda, Naho</creatorcontrib><creatorcontrib>Nakasyo, Saki</creatorcontrib><creatorcontrib>Shirasaki, Takayoshi</creatorcontrib><creatorcontrib>Kawaguchi, Kazunori</creatorcontrib><creatorcontrib>Shimakami, Tetsuro</creatorcontrib><creatorcontrib>Nio, Kouki</creatorcontrib><creatorcontrib>Nakaya, Yuki</creatorcontrib><creatorcontrib>Kagiwada, Harumi</creatorcontrib><creatorcontrib>Horimoto, Katsuhisa</creatorcontrib><creatorcontrib>Mizokami, Masashi</creatorcontrib><creatorcontrib>Kaneko, Shuichi</creatorcontrib><creatorcontrib>Murata, Kazumoto</creatorcontrib><creatorcontrib>Yamashita, Taro</creatorcontrib><creatorcontrib>Honda, Masao</creatorcontrib><title>Nucleos(t)ide analogs for hepatitis B virus infection differentially regulate the growth factor signaling in hepatocytes</title><title>Hepatology communications</title><addtitle>Hepatol Commun</addtitle><description>Recent clinical studies have suggested that the risk of developing HCC might be lower in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate than in patients receiving entecavir, although there is no difference in biochemical and virological remission between the 2 drugs.
The effects of nucleoside analogs (NsAs; lamivudine and entecavir) or nucleotide analogs (NtAs; adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide) on cell growth and the expression of growth signaling molecules in hepatoma cell lines and PXB cells were investigated in vitro. The tumor inhibitory effects of NsAs or NtAs were evaluated using a mouse xenograft model, and protein phosphorylation profiles were investigated. The binding of NsAs or NtAs to the insulin receptor (INSR) was investigated by thermal shift assays.
NtAs, but not NsAs, showed direct growth inhibitory effects on hepatoma cell lines in vitro and a mouse model in vivo. A phosphoprotein array revealed that INSR signaling was impaired and the levels of phosphorylated (p)-INSRβ and downstream molecules phosphorylated (p)-IRS1, p-AKT, p-Gab1, and p-SHP2 were substantially reduced by NtAs. In addition, p-epidermal growth factor receptor and p-AKT levels were substantially reduced by NtAs. Similar findings were also found in PXB cells and nontumor lesions of liver tissues from patients with chronic hepatitis B. Prodrug NtAs, but not their metabolites (adefovir, adefovir monophosphate, adefovir diphosphate, tenofovir, tenofovir monophosphate, and tenofovir diphosphate), had such effects. A thermal shift assay showed the binding of NtAs to INSRβ.
NtAs (adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide), which are adenine derivative acyclic nucleotide analogs, potentially bind to the ATP-binding site of growth factor receptors and inhibit their autophosphorylation, which might reduce the risk of HCC in patients with chronic hepatitis B.</description><subject>Carcinoma, Hepatocellular - drug therapy</subject><subject>Hepatitis B - complications</subject><subject>Hepatitis B - drug therapy</subject><subject>Hepatitis B virus</subject><subject>Hepatitis B, Chronic - complications</subject><subject>Hepatitis B, Chronic - drug therapy</subject><subject>Hepatocytes</subject><subject>Humans</subject><subject>Intercellular Signaling Peptides and Proteins</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Nucleotides</subject><subject>Original</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>Tenofovir - pharmacology</subject><subject>Tenofovir - therapeutic use</subject><issn>2471-254X</issn><issn>2471-254X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkVFPHCEUhUlTU436DxrDo31Yy4VhB55Mu9HaxNiXNukbYWcusxh2WIGx3X8vzVqzygsk95zvHnII-QjsAphuP98s9AXbP0LCO3LEmxZmXDa_3--9D8lpzvdVA5oDaPaBHAoFqmL4Efl7N3UBYz4vn3yP1I42xCFTFxNd4cYWX3ymX-mjT1OmfnTYFR9H2nvnMOFYvA1hSxMOU7AFaVkhHVL8U1bU2a5USvZDZfpxqO4dMnbbgvmEHDgbMp4-38fk1_XVz8XN7PbHt--LL7ezTkhVZtD3LailBM6c5U4uJZ8zJp2E-ud5a2WjQMp5zy06JhrWtoprLYRegtDVJY7J5Y67mZZr7LuaOdlgNsmvbdqaaL15PRn9ygzx0QBrFQA0lXD-TEjxYcJczNrnDkOwI8YpG64BVCOZVFXa7KRdijkndC97gJl_xZlanHlbXLWd7Wd8Mf2vSTwBRdKUzg</recordid><startdate>20240101</startdate><enddate>20240101</enddate><creator>Shimizu, Ryogo</creator><creator>Murai, Kazuhisa</creator><creator>Tanaka, Kensuke</creator><creator>Sato, Yuga</creator><creator>Takeda, Naho</creator><creator>Nakasyo, Saki</creator><creator>Shirasaki, Takayoshi</creator><creator>Kawaguchi, Kazunori</creator><creator>Shimakami, Tetsuro</creator><creator>Nio, Kouki</creator><creator>Nakaya, Yuki</creator><creator>Kagiwada, Harumi</creator><creator>Horimoto, Katsuhisa</creator><creator>Mizokami, Masashi</creator><creator>Kaneko, Shuichi</creator><creator>Murata, Kazumoto</creator><creator>Yamashita, Taro</creator><creator>Honda, Masao</creator><general>Lippincott Williams & Wilkins</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3050-5854</orcidid></search><sort><creationdate>20240101</creationdate><title>Nucleos(t)ide analogs for hepatitis B virus infection differentially regulate the growth factor signaling in hepatocytes</title><author>Shimizu, Ryogo ; Murai, Kazuhisa ; Tanaka, Kensuke ; Sato, Yuga ; Takeda, Naho ; Nakasyo, Saki ; Shirasaki, Takayoshi ; Kawaguchi, Kazunori ; Shimakami, Tetsuro ; Nio, Kouki ; Nakaya, Yuki ; Kagiwada, Harumi ; Horimoto, Katsuhisa ; Mizokami, Masashi ; Kaneko, Shuichi ; Murata, Kazumoto ; Yamashita, Taro ; Honda, Masao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c358t-1dd718b5120fa2f5b526005f5100367a5481556d2aef0340778299339b1395123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Carcinoma, Hepatocellular - drug therapy</topic><topic>Hepatitis B - complications</topic><topic>Hepatitis B - drug therapy</topic><topic>Hepatitis B virus</topic><topic>Hepatitis B, Chronic - complications</topic><topic>Hepatitis B, Chronic - drug therapy</topic><topic>Hepatocytes</topic><topic>Humans</topic><topic>Intercellular Signaling Peptides and Proteins</topic><topic>Liver Neoplasms - drug therapy</topic><topic>Nucleotides</topic><topic>Original</topic><topic>Proto-Oncogene Proteins c-akt</topic><topic>Tenofovir - pharmacology</topic><topic>Tenofovir - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shimizu, Ryogo</creatorcontrib><creatorcontrib>Murai, Kazuhisa</creatorcontrib><creatorcontrib>Tanaka, Kensuke</creatorcontrib><creatorcontrib>Sato, Yuga</creatorcontrib><creatorcontrib>Takeda, Naho</creatorcontrib><creatorcontrib>Nakasyo, Saki</creatorcontrib><creatorcontrib>Shirasaki, Takayoshi</creatorcontrib><creatorcontrib>Kawaguchi, Kazunori</creatorcontrib><creatorcontrib>Shimakami, Tetsuro</creatorcontrib><creatorcontrib>Nio, Kouki</creatorcontrib><creatorcontrib>Nakaya, Yuki</creatorcontrib><creatorcontrib>Kagiwada, Harumi</creatorcontrib><creatorcontrib>Horimoto, Katsuhisa</creatorcontrib><creatorcontrib>Mizokami, Masashi</creatorcontrib><creatorcontrib>Kaneko, Shuichi</creatorcontrib><creatorcontrib>Murata, Kazumoto</creatorcontrib><creatorcontrib>Yamashita, Taro</creatorcontrib><creatorcontrib>Honda, Masao</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Hepatology communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shimizu, Ryogo</au><au>Murai, Kazuhisa</au><au>Tanaka, Kensuke</au><au>Sato, Yuga</au><au>Takeda, Naho</au><au>Nakasyo, Saki</au><au>Shirasaki, Takayoshi</au><au>Kawaguchi, Kazunori</au><au>Shimakami, Tetsuro</au><au>Nio, Kouki</au><au>Nakaya, Yuki</au><au>Kagiwada, Harumi</au><au>Horimoto, Katsuhisa</au><au>Mizokami, Masashi</au><au>Kaneko, Shuichi</au><au>Murata, Kazumoto</au><au>Yamashita, Taro</au><au>Honda, Masao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nucleos(t)ide analogs for hepatitis B virus infection differentially regulate the growth factor signaling in hepatocytes</atitle><jtitle>Hepatology communications</jtitle><addtitle>Hepatol Commun</addtitle><date>2024-01-01</date><risdate>2024</risdate><volume>8</volume><issue>1</issue><issn>2471-254X</issn><eissn>2471-254X</eissn><abstract>Recent clinical studies have suggested that the risk of developing HCC might be lower in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate than in patients receiving entecavir, although there is no difference in biochemical and virological remission between the 2 drugs.
The effects of nucleoside analogs (NsAs; lamivudine and entecavir) or nucleotide analogs (NtAs; adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide) on cell growth and the expression of growth signaling molecules in hepatoma cell lines and PXB cells were investigated in vitro. The tumor inhibitory effects of NsAs or NtAs were evaluated using a mouse xenograft model, and protein phosphorylation profiles were investigated. The binding of NsAs or NtAs to the insulin receptor (INSR) was investigated by thermal shift assays.
NtAs, but not NsAs, showed direct growth inhibitory effects on hepatoma cell lines in vitro and a mouse model in vivo. A phosphoprotein array revealed that INSR signaling was impaired and the levels of phosphorylated (p)-INSRβ and downstream molecules phosphorylated (p)-IRS1, p-AKT, p-Gab1, and p-SHP2 were substantially reduced by NtAs. In addition, p-epidermal growth factor receptor and p-AKT levels were substantially reduced by NtAs. Similar findings were also found in PXB cells and nontumor lesions of liver tissues from patients with chronic hepatitis B. Prodrug NtAs, but not their metabolites (adefovir, adefovir monophosphate, adefovir diphosphate, tenofovir, tenofovir monophosphate, and tenofovir diphosphate), had such effects. A thermal shift assay showed the binding of NtAs to INSRβ.
NtAs (adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide), which are adenine derivative acyclic nucleotide analogs, potentially bind to the ATP-binding site of growth factor receptors and inhibit their autophosphorylation, which might reduce the risk of HCC in patients with chronic hepatitis B.</abstract><cop>United States</cop><pub>Lippincott Williams & Wilkins</pub><pmid>38180972</pmid><doi>10.1097/HC9.0000000000000351</doi><orcidid>https://orcid.org/0000-0003-3050-5854</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Carcinoma, Hepatocellular - drug therapy Hepatitis B - complications Hepatitis B - drug therapy Hepatitis B virus Hepatitis B, Chronic - complications Hepatitis B, Chronic - drug therapy Hepatocytes Humans Intercellular Signaling Peptides and Proteins Liver Neoplasms - drug therapy Nucleotides Original Proto-Oncogene Proteins c-akt Tenofovir - pharmacology Tenofovir - therapeutic use |
| title | Nucleos(t)ide analogs for hepatitis B virus infection differentially regulate the growth factor signaling in hepatocytes |
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