Biochemical pharmacology最新文献

{"title":"Abscisic acid, an evolutionary conserved hormone: Biosynthesis, therapeutic and diagnostic applications in mammals","authors":"Amir Gharib ,&nbsp;Carlee Marquez ,&nbsp;Maria Meseguer-Beltran ,&nbsp;Sandra Sanchez-Sarasua ,&nbsp;Ana M Sanchez-Perez","doi":"10.1016/j.bcp.2024.116521","DOIUrl":"10.1016/j.bcp.2024.116521","url":null,"abstract":"<div><p>Abscisic acid (ABA), a phytohormone traditionally recognized for its role in plant stress responses, has recently emerged as a significant player in mammalian defense mechanisms. Like plants, various mammalian cell types synthesize ABA in response to specific health challenges, although the precise pathways remain not fully elucidated. ABA is associated with the regulation of inflammation and insulin signaling, prompting extensive research into its potential as a therapeutic agent for various diseases.</p><p>ABA exerts its effects through its receptors, particularly PPAR-γ and LANCL-2, which serve as signaling hubs regulating numerous pathways. Through these interactions, ABA profoundly impacts mammalian health, and new ABA targets continue to be identified. Numerous studies in animal models demonstrate ABA’s benefit in managing conditions such as neurological and psychiatric disorders, cancer, and malaria infections, all of which involve significant inflammatory dysregulation.</p><p>In this manuscript we review the studies covering ABA synthesis and release in cell cultures, the signaling pathways regulated by ABA, and how these impact health in preclinical models. Furthermore, we highlight recent research suggesting that measuring ABA levels in human body fluids could serve as a useful biomarker for pathological conditions, providing insights into disease progression and treatment efficacy. This comprehensive review outlines the current understanding of ABA in mammalian pathophysiology, identifying gaps in knowledge, particularly concerning ABA biosynthesis and metabolism in mammals. In addition, this study emphasizes the need for clinical trials to validate the effectiveness of ABA-based therapies and its reliability as a biomarker for various diseases.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116521"},"PeriodicalIF":5.3,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142230277","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":"Gut microbiota-derived Metabolite, Shikimic Acid, inhibits vascular smooth muscle cell proliferation and migration","authors":"Sanjana Kumariya ,&nbsp;Arturo Grano de Oro ,&nbsp;Andrea L. Nestor-Kalinoski ,&nbsp;Bina Joe ,&nbsp;Islam Osman","doi":"10.1016/j.bcp.2024.116524","DOIUrl":"10.1016/j.bcp.2024.116524","url":null,"abstract":"<div><p>Gut microbiota dysbiosis is linked to vascular wall disease, but the mechanisms by which gut microbiota cross-talk with the host vascular cells remain largely unknown. Shikimic acid (SA) is a biochemical intermediate synthesized in plants and microorganisms, but not mammals. Surprisingly, recent metabolomic profiling data demonstrate that SA is detectable in human and murine blood. In this study, analyzing data from germ-free rats, we provide evidence in support of SA as a bona fide gut microbiota-derived metabolite, emphasizing its biological relevance. Since vascular cells are the first cells exposed to circulating metabolites, in this study, we examined, for the first time, the effects and potential underlying molecular mechanisms of SA on vascular smooth muscle cell (VSMC) proliferation and migration, which play a key role in occlusive vascular diseases, such as post-angioplasty restenosis and atherosclerosis. We found that SA inhibits the proliferation and migration of human coronary artery SMCs. At the molecular level, unexpectedly, we found that SA activates, rather than inhibits, multiple pro-mitogenic signaling pathways in VSMCs, such as ERK1/2, AKT, and mTOR/p70S6K. Conversely, we found that SA activates the anti-proliferative AMP-activated protein kinase (AMPK) in VSMCs, a key cellular energy sensor and regulator. However, loss-of-function experiments demonstrate that AMPK does not mediate the inhibitory effects of SA on VSMC proliferation. In conclusion, these studies demonstrate that a microbiota-derived metabolite, SA, inhibits VSMC proliferation and migration <em>in vitro</em> and prompt further evaluation of the possible underlying molecular mechanisms and the potential protective role in VSMC-related vascular wall disease <em>in vivo.</em></p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116524"},"PeriodicalIF":5.3,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0006295224005070/pdfft?md5=d7357872915a3c737207f195d9f6e6fc&pid=1-s2.0-S0006295224005070-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142167511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cutting-edge advances in nano/biomedicine: A review on transforming thrombolytic therapy","authors":"Chia-Hung Liu ,&nbsp;Lekshmi Rethi ,&nbsp;Pei-Wei Weng ,&nbsp;Hieu Trung Nguyen ,&nbsp;Andrew E.-Y. Chuang","doi":"10.1016/j.bcp.2024.116523","DOIUrl":"10.1016/j.bcp.2024.116523","url":null,"abstract":"<div><p>Thrombotic blockages within blood vessels give rise to critical cardiovascular disorders, including ischemic stroke, venous thromboembolism, and myocardial infarction. The current approach to the therapy of thrombolysis involves administering Plasminogen Activators (PA), but it is hindered by fast drug elimination, narrow treatment window, and the potential for bleeding complications. Leveraging nanomedicine to encapsulate and deliver PA offers a solution by improving the efficacy of therapy, safeguarding the medicine from proteinase biodegradation, and reducing unwanted effects in in vivo trials. In this review, we delve into the underlying venous as well as arterial thrombus pathophysiology and provide an overview of clinically approved PA used to address acute thrombotic conditions. We explore the existing challenges and potential directions within recent pivotal research on a variety of targeted nanocarriers, such as lipid, polymeric, inorganic, and biological carriers, designed for precise delivery of PA to specific sites. We also discuss the promising role of microbubbles and ultrasound-assisted Sono thrombolysis, which have exhibited enhanced thrombolysis in clinical studies. Furthermore, our review delves into approaches for the strategic development of nano-based carriers tailored for targeting thrombolytic action and efficient encapsulation of PA, considering the intricate interaction in biology systems as well as nanomaterials. In conclusion, the field of nanomedicine offers a valuable method for the exact and effective therapy of severe thrombus conditions, presenting a pathway toward improved patient outcomes and reduced complications.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116523"},"PeriodicalIF":5.3,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142272102","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":"Roxadustat alleviates metabolic traits in letrozole-induced PCOS mice","authors":"Nikke Virtanen ,&nbsp;Ulla Saarela ,&nbsp;Mikko Karpale ,&nbsp;Riikka K. Arffman ,&nbsp;Kari A. Mäkelä ,&nbsp;Karl-Heinz Herzig ,&nbsp;Peppi Koivunen ,&nbsp;Terhi Piltonen","doi":"10.1016/j.bcp.2024.116522","DOIUrl":"10.1016/j.bcp.2024.116522","url":null,"abstract":"<div><p>Polycystic ovary syndrome (PCOS) is a highly prevalent disorder in women that is commonly accompanied by metabolic syndrome. Activation of the hypoxia-inducible factor (HIF) pathway is known to alleviate metabolic defects. Hence, this study utilized a preclinical PCOS mouse model to investigate the effects of chemically induced HIF activation on the metabolic traits of PCOS. Prepubertal letrozole treatment was used to generate a PCOS mouse model in the C57Bl6/J strain, and PCOS mice were orally treated with vehicle or roxadustat for six weeks from age 12 weeks onwards to induce HIF activation. Although the PCOS mice showed impaired glucose tolerance, increased insulin resistance, elevated blood lipids, and reduced muscle glycogen content, there was no difference in histological evaluations of white adipose tissue (WAT) or liver or in organ weights. Roxadustat treatment resulted in significant improvement in glucose tolerance (27 % reduction in area under the curve (AUC) values, p &lt; 0.0001), fasting glucose levels (4.59 ± 0.83 mmol/l vs 3.05 ± 0.62 mmol/l, p &lt; 0.0001) and insulin resistance (46 % reduction in homeostasis model assessment–insulin resistance (HOMA-IR) values, 6.76 ± 3.72 vs 3.64 ± 2.44, p = 0.019) compared to vehicle-treated mice without altering the body weight. Gene expression analyses with real-time quantitative polymerase chain reaction (RT-qPCR) and RNA sequencing revealed significant differences in gene expression in the tissues of PCOS mice compared to control mice, whereas the transcriptomic effects of roxadustat were mainly transient. However, immunohistochemistry revealed increased uncoupling protein 1 (UCP1) expression in WAT, which may indicate WAT browning related to HIF pathway activation.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116522"},"PeriodicalIF":5.3,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0006295224005057/pdfft?md5=95c23946462ec8c82afcf3a22457bcda&pid=1-s2.0-S0006295224005057-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of human-specific amino acid residues governing atenolol transport via organic cation transporter 2","authors":"Akira Hosooka,&nbsp;Tomoya Yasujima,&nbsp;Ayano Murata,&nbsp;Takahiro Yamashiro,&nbsp;Hiroaki Yuasa","doi":"10.1016/j.bcp.2024.116514","DOIUrl":"10.1016/j.bcp.2024.116514","url":null,"abstract":"<div><p>Organic cation transporter 2 (OCT2/SLC22A2) is predominantly localized on the basolateral membranes of renal tubular epithelial cells and plays a crucial role in the renal secretion of various cationic drugs. Although variations in substrate selectivity among renal organic cation transport systems across species have been reported, the characteristics of OCT2 remain unclear. In this study, we demonstrated that atenolol, a β1-selective adrenergic antagonist, is transported almost exclusively by human OCT2, contrasting with OCT2s from other selected species. Using chimeric constructs between human OCT2 (hOCT2) and the highly homologous monkey OCT2 (monOCT2), along with site-directed mutagenesis, we identified non-conserved amino acids Val⁸, Ala³¹, Ala³⁴, Tyr²²², Tyr²⁴⁵, Ala²⁷⁰, Ile³⁹⁴, and Leu⁵⁰³ as pivotal for hOCT2-mediated atenolol transport. Kinetic analysis revealed that atenolol was transported by hOCT2 with a 12-fold lower affinity than MPP⁺, a typical OCT2 substrate. The inhibitory effect of atenolol on MPP⁺ transport was 6200-fold lower than that observed for MPP⁺ on atenolol transport. Additionally, we observed weaker inhibitory effects on MPP⁺ transport compared to atenolol transport with ten different OCT2 substrates. Altogether, this study suggests that eight hOCT2-specific amino acids constitute the low-affinity recognition site for atenolol transport, indicating differences in OCT2-mediated drug elimination between humans and highly homologous monkeys. Our findings underscore the importance of understanding species-specific differences in drug transport mechanisms, shedding light on potential variations in drug disposition and aiding in drug development.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116514"},"PeriodicalIF":5.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0006295224004970/pdfft?md5=1f7e8c312dc6c9a29d0aba9f56c8900d&pid=1-s2.0-S0006295224004970-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eicosatrienoic acid inhibits estradiol synthesis through the CD36/FOXO1/CYP19A1 signaling pathway to improve PCOS in mice","authors":"Jun Zhu ,&nbsp;Jun-Xia Wang ,&nbsp;Zheng-Yun Jin ,&nbsp;Dongxu Li ,&nbsp;Shaobo Qi ,&nbsp;Sheng-Zhong Han ,&nbsp;Shuang-Yan Chang ,&nbsp;Jin Yan ,&nbsp;Jin-Dan Kang ,&nbsp;Lin-Hu Quan","doi":"10.1016/j.bcp.2024.116517","DOIUrl":"10.1016/j.bcp.2024.116517","url":null,"abstract":"<div><p>Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder characterized by abnormal elevation in hormone levels, with currently lacking effective treatment options. N-3 polyunsaturated fatty acids (PUFA) have broad pharmacological activity and play a beneficial role in the development of PCOS. In this study, we observed that n-3 PUFA-eicosatrienoic acid (ETA) improves the estrous cycle and ovarian morphology in dehydroepiandrosterone (DHEA)-induced PCOS mice, particularly serum hormone levels. Additionally, it suppresses the expression of <em>CYP19A1</em> and E2 synthesis in human granulosa-like tumor cell line (KGN) cells. Further investigation revealed that ETA significantly upregulates the expression of CD36, cAMP, P-PKA, and FOXO1 in KGN cells and mouse ovaries to lower E2 levels. This conclusion was supported by inhibiting CD36 and FOXO1 at both the mouse and cellular levels. Additionally, ETA treatment decreased the expression of ESR1, <em>Kiss1</em>, <em>Gnrh</em> in the hypothalamus, and GnRHR, <em>Lhβ</em>, <em>Egr1</em>, <em>Pitx1</em>, <em>Sf1</em> in the pituitary of PCOS mice. No differences were observed after ETA treatment in the CD36 and FOXO1 inhibitor groups, indicating that ETA improves PCOS mice by regulating the hypothalamic-pituitary axis through E2 synthesis inhibition. In summary, we have elucidated for the first time the mechanism by which CD36 regulates E2 synthesis in ovarian granulosa cells and demonstrated that ETA activates the CD36 receptor to inhibit E2 synthesis through the cAMP/PKA/FOXO1/CYP19A1 signaling pathway, thereby improving hormonal imbalance and treating PCOS. This provides a new strategy for the effective prevention and treatment of PCOS.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116517"},"PeriodicalIF":5.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139198","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":"USP10-mediated deubiquitination of NR3C1 regulates bone homeostasis by controlling CST3 expression","authors":"Long Zhou ,&nbsp;Shuai Mu ,&nbsp;Yiqi Zhang ,&nbsp;Hanyi Song","doi":"10.1016/j.bcp.2024.116519","DOIUrl":"10.1016/j.bcp.2024.116519","url":null,"abstract":"<div><p>Dysregulated bone homeostasis contributes to multiple diseases including osteoporosis (OP). In this study, osteoporotic mice were successfully generated using ovariectomy to investigate the role of nuclear receptor subfamily 3 group C member 1 (NR3C1) in OP. NR3C1, identified as a significantly upregulated gene in OP using bioinformatic tools, was artificially downregulated in osteoporotic mice. NR3C1 expression was significantly elevated in the femoral tissues of osteoporotic patients, and downregulation of NR3C1 alleviated bone loss and restored bone homeostasis in osteoporotic mice, as manifested by increased ALP- and OCN-positive cells and reduced RANKL/OPG ratio. Downregulation of NR3C1 inhibited osteoclastic differentiation of RAW264.7 cells and mouse bone marrow-derived macrophages (BMDM) and promoted osteogenic differentiation of MC3T3-E1 cells. The transcription factor NR3C1 bound to the cystatin-3 (CST3) promoter to repress its transcription in both RAW264.7 and MC3T3-E1 cells. The downregulation of CST3 reversed the protective effect of NR3C1 downregulation against OP. Ubiquitin-specific-processing protease 10 (USP10)-mediated deubiquitination of NR3C1 improved NR3C1 stability. Downregulation of USP10 inhibited osteoclastic differentiation of RAW264.7 cells and BMDM while promoting osteogenic differentiation of MC3T3-E1 cells. Taken together, USP10-mediated deubiquitination of NR3C1 regulates bone homeostasis by controlling CST3 transcription, providing an attractive therapeutic strategy to alleviate OP.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116519"},"PeriodicalIF":5.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139201","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":"Piperlongumine, a natural alkaloid from Piper longum L. ameliorates metabolic-associated fatty liver disease by antagonizing the thromboxane A2 receptor","authors":"Yufeng Dai ,&nbsp;Jinxiang Chen ,&nbsp;Jialong Fang ,&nbsp;Shuxiao Liang ,&nbsp;Hao Zhang ,&nbsp;Haitao Li ,&nbsp;Wei Chen","doi":"10.1016/j.bcp.2024.116518","DOIUrl":"10.1016/j.bcp.2024.116518","url":null,"abstract":"<div><p>Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, including hyperglycemia, hepatic steatosis, and insulin resistance. Piperlongumine (PL), a natural amide alkaloid extracted from the fruits of <em>Piper longum</em> L., exhibited hepatoprotective effects in zebrafish and liver injury mice. This study aimed to investigate the therapeutic potential of PL on MAFLD and its underlying mechanisms. The findings demonstrate that PL effectively combats MAFLD induced by a high-fat diet (HFD) and improves metabolic characteristics in mice. Additionally, our results suggest that the anti-MAFLD effect of PL is attributed to the suppression of excessive hepatic gluconeogenesis, inhibition of de novo lipogenesis, and alleviation of insulin resistance. Importantly, the results indicate that, on the one hand, the hypoglycemic effect of PL is closely associated with CREB-regulated transcriptional coactivators (CRTC2)-dependent cyclic AMP response element binding protein (CREB) phosphorylation; on the other hand, the lipid-lowering effect of PL is attributed to reducing the nuclear localization of sterol regulatory element-binding proteins 1c (Srebp-1c). Mechanistically, PL could alleviate insulin resistance induced by endoplasmic reticulum stress by antagonizing the thromboxane A₂ receptor (TP)/Ca²⁺ signaling, and the TP receptor serves as the potential target for PL in the treatment of MAFLD. Therefore, our results suggested PL effectively improved the major hallmarks of MAFLD induced by HFD, highlighting a potential therapeutic strategy for MAFLD.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116518"},"PeriodicalIF":5.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139200","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":"An inducible sphingosine kinase 1 in hepatic stellate cells potentiates liver fibrosis","authors":"Jin Sol Baek ,&nbsp;Ji Hyun Lee ,&nbsp;Ji Hye Kim ,&nbsp;Sam Seok Cho ,&nbsp;Yun Seok Kim ,&nbsp;Ji Hye Yang ,&nbsp;Eun Jin Shin ,&nbsp;Hyeon-Gu Kang ,&nbsp;Seok-Jun Kim ,&nbsp;Sang-Gun Ahn ,&nbsp;Eun Young Park ,&nbsp;Dong Jae Baek ,&nbsp;Sung-Kun Yim ,&nbsp;Keon Wook Kang ,&nbsp;Sung Hwan Ki ,&nbsp;Kyu Min Kim","doi":"10.1016/j.bcp.2024.116520","DOIUrl":"10.1016/j.bcp.2024.116520","url":null,"abstract":"<div><p>Hepatic stellate cells (HSCs) play a role in hepatic fibrosis and sphingosine kinase (SphK) is involved in biological processes. As studies on the regulatory mechanisms and functions of SphK in HSCs during liver fibrosis are currently limited, this study aimed to elucidate the regulatory mechanism and connected pathways of SphK upon HSC activation. The expression of SphK1 was higher in HSCs than in hepatocytes, and upregulated in activated primary HSCs. SphK1 was also increased in liver homogenates of carbon tetrachloride-treated or bile duct ligated mice and in transforming growth factor-β (TGF-β)-treated LX-2 cells. TGF-β-mediated SphK1 induction was due to Smad3 signaling in LX-2 cells. SphK1 modulation altered the expression of liver fibrogenesis-related genes. This SphK1-mediated profibrogenic effect was dependent on SphK1/sphingosine-1-phosphate/sphingosine-1-phosphate receptor signaling through ERK. Epigallocatechin gallate blocked TGF-β-induced SphK1 expression and hepatic fibrogenesis by attenuating Smad and MAPK activation. SphK1 induced by TGF-β facilitates HSC activation and liver fibrogenesis, which is reversed by epigallocatechin gallate. Accordingly, SphK1 and related signal transduction may be utilized to treat liver fibrosis.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116520"},"PeriodicalIF":5.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139197","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":"Dasatinib interferes with HIV-1 proviral integration and the inflammatory potential of monocyte-derived macrophages from people with HIV","authors":"Sara Rodríguez-Mora ,&nbsp;Clara Sánchez-Menéndez ,&nbsp;Guiomar Bautista-Carrascosa ,&nbsp;Elena Mateos ,&nbsp;Lucia Moreno-Serna ,&nbsp;Diego Megías ,&nbsp;Juan Cantón ,&nbsp;Valentín García-Gutiérrez ,&nbsp;María Aránzazu Murciano-Antón ,&nbsp;Miguel Cervero ,&nbsp;Adam Spivak ,&nbsp;Vicente Planelles ,&nbsp;Mayte Coiras","doi":"10.1016/j.bcp.2024.116512","DOIUrl":"10.1016/j.bcp.2024.116512","url":null,"abstract":"<div><p>HIV-1 infection is efficiently controlled by the antiretroviral treatment (ART) but viral persistence in long-lived reservoirs formed by CD4 + T cells and macrophages impedes viral eradication and creates a chronic inflammatory environment. Dasatinib is a tyrosine kinase inhibitor clinically used against chronic myeloid leukemia (CML) that has also showed an anti-inflammatory potential. We previously reported that dasatinib is very efficient at interfering with HIV-1 infection of CD4 + T cells by preserving the antiviral activity of SAMHD1, an innate immune factor that blocks T-cell activation and proliferation and that is inactivated by phosphorylation at T592 (pSAMHD1). We observed that short-term treatment in vitro with dasatinib significantly reduced pSAMHD1 in monocyte-derived macrophages (MDMs) isolated from people with HIV (PWH) and healthy donors, interfering with HIV-1 infection. This inhibition was based on low levels of 2-LTR circles and proviral integration, while viral reverse transcription was not affected. MDMs isolated from people with CML on long-term treatment with dasatinib also showed low levels of pSAMHD1 and were resistant to HIV-1 infection. In addition, dasatinib decreased the inflammatory potential of MDMs by reducing the release of M1-related cytokines like TNFα, IL-1β, IL-6, CXCL8, and CXCL9, but preserving the antiviral activity through normal levels of IL-12 and IFNγ. Due to the production of M2-related anti-inflammatory cytokines like IL-1RA and IL-10 was also impaired, dasatinib appeared to interfere with MDMs differentiation. The use of dasatinib along with ART could be used against HIV-1 reservoir in CD4 and macrophages and to alleviate the chronic inflammation characteristic of PWH.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116512"},"PeriodicalIF":5.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0006295224004957/pdfft?md5=5699eb7b00c118ce2031e8b50c7863b7&pid=1-s2.0-S0006295224004957-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}