Biochemical pharmacology最新文献

{"title":"The CDK9-targeting degrader PO-8 alleviates LPS-induced inflammation by inhibiting JAK-STAT signaling in vitro and in vivo","authors":"Ming-tao Ao ,&nbsp;Xiu-mei Wang ,&nbsp;Yin Cao ,&nbsp;Xiao-dan Li ,&nbsp;Yu-xiang Zhang ,&nbsp;Jia-yi Li ,&nbsp;Meng-yu Li ,&nbsp;Meng-xian Huang ,&nbsp;Ying-kun Qiu ,&nbsp;Hong-yu Hu ,&nbsp;Li-juan Wang ,&nbsp;Hua Fang ,&nbsp;Bai-cun Li ,&nbsp;Mei-juan Fang","doi":"10.1016/j.bcp.2025.117341","DOIUrl":"10.1016/j.bcp.2025.117341","url":null,"abstract":"<div><div>Cyclin-dependent kinase 9 (CDK9) emerges as a crucial activator of inflammatory responses, but the therapeutic potential of CDK9 degraders in inflammation remains largely unexplored. In this study, we demonstrated that <strong>iCDK9</strong>, a selective CDK9 inhibitor, effectively suppressed lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophages. Leveraging proteolysis-targeting chimera (PROTAC) technology, we designed and synthesized twelve <strong>iCDK9</strong>-based PROTAC molecules. Among them, <strong>PO-8</strong> was identified as an excellent CDK9 degrader with potent anti-inflammatory activity. Moreover, <strong>PO-8</strong> selectively induced CDK9 degradation <em>via</em> the ubiquitin–proteasome system, resulting in a significant attenuation of LPS-triggered inflammatory responses both <em>in vitro</em> and <em>in vivo</em>. Notably, <strong>PO-8</strong> exhibited an improved safety profile and a wider therapeutic window compared to its parent inhibitor, <strong>iCDK9</strong>. Mechanistic studies revealed that <strong>PO-8</strong>-mediated CDK9 degradation disrupts the JAK2-STAT3 signaling pathway, thereby mitigating inflammation. To the best of our knowledge, this study is the first to establish the anti-inflammatory efficacy of a small-molecule CDK9 degrader, highlighting PROTAC-based CDK9 targeting as a promising therapeutic strategy for inflammatory diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117341"},"PeriodicalIF":5.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111895","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":"Effects of G protein-coupled estrogen receptor on hydrogen sulfide production and cystathionine γ-lyase expression in human endothelial cells","authors":"Seung-Hwa Baek ,&nbsp;Seung Yeon Lee ,&nbsp;Sang Won Seo ,&nbsp;Hwi-Yeol Yun,&nbsp;Su Yeon Kim,&nbsp;Gi Ho Lee,&nbsp;Hye Gwang Jeong","doi":"10.1016/j.bcp.2025.117354","DOIUrl":"10.1016/j.bcp.2025.117354","url":null,"abstract":"<div><div>Hydrogen sulfide (H₂S) is an important regulator of cardiovascular homeostasis, along with nitric oxide (NO). In endothelial cells, H₂S is primarily synthesized by cystathionine γ-lyase (CSE) using L-cysteine and homocysteine as substrates. However, it has not been elucidated how G protein-coupled estrogen receptor 1 (GPER) affects H₂S production in endothelial cells. In this study, we investigated whether GPER activation enhances H₂S production by upregulating CSE expression in endothelial cells, and identified the underlying molecular mechanism. G-1 increased the phosphorylation of cAMP response element binding (CREB), protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (ERK1/2), AMP-activated protein kinase (AMPK), Ca²⁺/calmodulin protein kinase kinase β (CaMKKβ), and Ca²⁺/calmodulin-dependent protein kinase II α (CaMKIIα). Blockade of Akt, ERK1/2, AMPK, CaMKKβ, and CaMKIIα signaling pathways suppressed G-1-induced CSE expression by inhibiting CREB transcriptional activity. In addition, CSE expression was suppressed by inhibiting G protein alpha q subunit (Gαq) and G protein beta gamma subunit complex (Gβγ), which are subunits of GPER. In particular, G-1 induced CSE expression and increased H₂S production in human endothelial EA.hy926 cells, inhibited tumor necrosis factor-alpha (TNF-α)-induced expression of nuclear factor kappa B (NF-kB), and decreased the expression of intracellular adhesion molecules. These findings confirm that GPER affects H₂S production by regulating CSE expression through novel signaling mechanisms, which could be utilized as a potential therapeutic target to prevent endothelial dysfunction in cardiovascular disease.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117354"},"PeriodicalIF":5.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111868","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":"Asterosaponin CN-3 performs an anti-glioma effect by inhibiting the migration and invasion of glioma cells through the regulation of miR-4465/HMGA1/NF-κB signaling pathway","authors":"Yang Du ,&nbsp;Peng-Cheng Qiu ,&nbsp;Tian-Yi Li ,&nbsp;Qian Zhang ,&nbsp;Yun-Yang Lu ,&nbsp;Hai-Feng Tang ,&nbsp;Jing-Wen Wang","doi":"10.1016/j.bcp.2025.117355","DOIUrl":"10.1016/j.bcp.2025.117355","url":null,"abstract":"<div><div>Malignant gliomas are devastating tumors that frequently kill patients within 1 year of diagnosis. Diffuse invasion is a major obstacle to cure, which allows tumor to escape from complete surgical resection as well as chemotherapy and radiotherapy. Therefore, the development of new chemotherapeutic agent that inhibiting the infiltrative growth of glioma is urgently needed. Culcita novaeguineae-3 (CN-3) is a marine-derived steroidal saponin which exhibit significant cytotoxicity to glioma cells. This study was designed to confirm the effect of CN-3 on glioma and to further clarify its mechanism of action. The experimental results showed that CN-3 could significantly inhibit the proliferation, invasion and migration of glioma cells in vitro and in vivo. CN-3 could down-regulate the expression of high mobility group protein A1 (HMGA1), to inhibit the infiltrative growth of glioma cells. Furthermore, the metastatic mobility was significantly reduced in HMGA1 knockout glioma cells. Moreover, miR-4465 was confirmed to target and reduce HMGA1 expression. In addition, CN-3 could upregulate the expression of miR-4465 in cells, thereby inhibiting migration and invasion of glioma cells. These results elucidate the mechanism by which CN-3, a steroidal saponin from the sea, may inhibit the invasive behavior of glioma cells through the miRNA-4465/HMGA1/NF-κB pathway, which also raise the prospect of using CN-3 as a chemotherapeutic agent to prevent glioma invasive growth.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117355"},"PeriodicalIF":5.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111920","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":"Gestational morin administration attenuates prenatal stress-induced apoptotic and associated neurobehavioral alterations in F1 generation Wistar rats","authors":"Madhu Sharma ,&nbsp;Era Seth ,&nbsp;Aitizaz Ul Ahsan ,&nbsp;Sweety Mehra ,&nbsp;Muskan Budhwar ,&nbsp;Mani Chopra","doi":"10.1016/j.bcp.2025.117340","DOIUrl":"10.1016/j.bcp.2025.117340","url":null,"abstract":"<div><div>Stress during prenatal period can affect the young ones, increasing the risk of aberrations in gut-brain of neonates during critical developmental periods and serves as a risk factor for postnatal pathologies. Compelling data from animal studies has shown that gestational stress-induced hyperactivation of the hypothalamic–pituitary–adrenal (HPA) axis, marked by excessive corticosterone (CORT) release, underlies profound and lasting developmental deficits in the offspring. It is well-established that stress during the gestational period disrupts gut and brain homeostasis in the F1 generation of Wistar rats. However, morin (3, 5, 7, 2′, 4′-pentahydroxyflavone), a plant flavonoid, exerts neuroprotective and antioxidant potential which could be beneficial in management of prenatal stress (PNS). Hence, this study was designed to evaluate the mitigatory potential of morin against the detrimental effects of prenatal stress, including the early onset of apoptosis in the gut and brain of the F1 offspring. Morin treatment to the stressed dams significantly improved HPA axis mediated oxidative stress and gut &amp; brain barrier permeabilities. Furthermore, morin, due to its redox balancing and anti-inflammatory properties, prevented early onset of apoptosis, maintained the histoarchitecture and functions of gut &amp; brain in F1 progeny. These findings provide a favourable research basis that morin administration during gestational period can significantly help in regulation of stress induced transgenerational gut-brain axis pathologies.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117340"},"PeriodicalIF":5.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111898","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":"Inhibiting TIRAP-mediated inflammatory signaling: A promising therapeutic strategy against sepsis","authors":"Rajat Atre ,&nbsp;Alexander G. Obukhov ,&nbsp;Rahul Sharma ,&nbsp;Faaiza Siddiqi ,&nbsp;Fletcher A. White ,&nbsp;Syed M. Faisal ,&nbsp;Vivek P. Varma ,&nbsp;Gajanan N. Darwhekar ,&nbsp;Mirza S. Baig","doi":"10.1016/j.bcp.2025.117353","DOIUrl":"10.1016/j.bcp.2025.117353","url":null,"abstract":"<div><div>The timely therapeutic targeting of the dysregulated immune response in sepsis is essential to restore immune homeostasis and prevent progression to organ dysfunction. In this study, we investigated whether a combination therapy with an antibiotic exhibiting anti-inflammatory properties and the anti-inflammatory compound dorzolamide will improve the bacterial sepsis outcome. Using an in-silico approach, we screened a structure library of FDA-approved antibiotics to identify those that can interact with the Toll/interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP), a protein regulating proinflammatory cytokine production in immune cells. Our virtual screening identified a broad-spectrum antibiotic, levofloxacin, as a candidate. We subsequently employed the cecum slurry (CS) septic mouse model to validate the candidates in vivo, while monitoring survival of mice, tissue mRNA expression, cell morphology, cytokine levels, and other biochemical markers. The in vivo studies confirmed that the combination of levofloxacin and dorzolamide (LeDoz) increased the survival rate of septic mice. Hematoxylin and eosin (H&amp;E) tissue staining, cytokine levels, as well as immunofluorescence dual staining and serum biomarkers, all showed the reestablishment of homeostatic conditions in the LeDoz-treated group of septic mice compared to untreated septic mice. In vitro analyses also confirmed the ability of LeDoz to attenuate TIRAP-mediated inflammatory signaling. Thus, the combination of levofloxacin and dorzolamide exhibits both an antibacterial effect and a strong potential for synergistically reducing chronic inflammation in the host by inhibiting the activation of TIRAP.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117353"},"PeriodicalIF":5.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102628","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 pregnane X receptor is a novel host target for dengue virus infection that reprograms lipid metabolism and suppresses the immune response","authors":"Carlos Daniel Bautista-Olivier ,&nbsp;Fátima E. Murillo-González ,&nbsp;Jorge Limón-Pacheco ,&nbsp;Felipe Hernández-Cázares ,&nbsp;Selvin Noé Palacios-Rápalo ,&nbsp;Carlos Daniel Cordero-Rivera ,&nbsp;Carlos Noe Farfan-Morales ,&nbsp;Rosa María del Ángel ,&nbsp;Guillermo Elizondo","doi":"10.1016/j.bcp.2025.117347","DOIUrl":"10.1016/j.bcp.2025.117347","url":null,"abstract":"<div><div>Dengue virus (DENV) is the main mosquito-transmitted virus in the world, with approximately 500,000 people developing severe DENV infection (dengue hemorrhagic fever or dengue shock syndrome) annually. DENV is localized principally to tropical and subtropical regions, but its range is expanding north and south due to climate change and urbanization. Therapeutic options are currently limited, and the identification of new antiviral targets is urgently needed. Here, we demonstrated that, in macrophages, DENV2 increases lipid droplet biogenesis and the expression of genes involved in triglyceride and cholesterol synthesis and accumulation while decreasing the immune response through the activation of the pregnane X receptor (PXR), a nuclear ligand–dependent transcription factor. PXR inhibition with okadaic acid or ketoconazole (KTZ) partially restored interleukin (IL)-1β, IL-6, tumor necrosis factor-α, IL-12, interferon (IFN)-γ, and IFN-α levels and blocked the DENV2 infection–induced expression of <em>Srebp2</em>, <em>Pparγ</em>, <em>Cd36</em>, and <em>Sqle</em>. KTZ, a PXR antagonist and United States Food and Drug Administration–approved antimycotic drug, also reduced viral replication <em>in vitro</em> and <em>in vivo</em>. We additionally determined that the DENV2 capsid protein drives PXR activation. Thus, the present investigation led to the characterization of the PXR-dependent reprogramming of fatty-acid and cholesterol metabolism and immune suppression promoted by DENV2 to facilitate its replication. Taken together, our data position PXR as a new druggable target for dengue treatment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117347"},"PeriodicalIF":5.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102589","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":"Diversity of human choline transporters: substrate specificity, kinetic properties, and inhibitor sensitivity","authors":"Kyra-Elisa Maria Redeker,&nbsp;Jürgen Brockmöller","doi":"10.1016/j.bcp.2025.117343","DOIUrl":"10.1016/j.bcp.2025.117343","url":null,"abstract":"<div><div>Carrier-mediated uptake of choline is rate-limiting for acetylcholine biosynthesis and various other biological processes. To date, 16 solute carrier (SLC) proteins have been identified that may facilitate choline permeation across the outer cell membrane. However, their biochemical functions have not yet been experimentally compared.</div><div>We overexpressed 16 SLC proteins with known choline-transporting capacity and compared their choline transport kinetics. Additionally, we evaluated their capacity to transport choline analogues as well as metabolites involved in its biosynthesis and degradation or modulators of cholinergic neurotransmission to gain insight into the biological functions of the SLCs. Furthermore, we investigated whether the transporters could be distinguished by their sensitivity to inhibition by hemicholinium-3 and other substances.</div><div>Of the 16 SLCs tested, seven (SLC5A7, SLC35F2, SLC35F3, SLC35F4, SLC25F5, SLC35G4, and SLC44A5) exhibited K_M values for choline transport in the range of 12 to 50 µM, closely aligning with physiological plasma choline concentrations. Among them, SLC5A7 displayed over tenfold higher intrinsic clearance than any of the others. SLC22A1-3 were confirmed as choline transporters, albeit with low affinity. Hemicholinium-3 most strongly inhibited SLC5A7 and also significantly inhibited SLC35F2-5 and SLC35G4. Choline transport by these six transporters was inhibited by about 50 % at 100 µM decynium-22 and verapamil..</div><div>In humans, multiple SLCs may contribute to cellular choline uptake, depending on physiologic conditions and their yet incompletely characterized expression patterns. The present data may also enhance our understanding of inherited and environmental modulation of these transporters with possible consequence, for instance, on motor and cognitive functions.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117343"},"PeriodicalIF":5.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091138","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":"Modulation of bioenergetic metabolism by PDIA3 inhibition prevents breast cancer cell adhesion to endothelial cells","authors":"Marta Stojak ,&nbsp;Kamila Wojnar-Lason ,&nbsp;Anna Kurpinska ,&nbsp;Patrycja Kaczara ,&nbsp;Filip A Fedak ,&nbsp;Joanna Suraj-Prazmowska ,&nbsp;Martyna Stachowicz-Suhs ,&nbsp;Joanna Rossowska ,&nbsp;Magdalena Milczarek ,&nbsp;Ivars Kalviņš ,&nbsp;Joanna Wietrzyk ,&nbsp;Stefan Chlopicki","doi":"10.1016/j.bcp.2025.117344","DOIUrl":"10.1016/j.bcp.2025.117344","url":null,"abstract":"<div><div>Increased expression of protein disulphide isomerase (PDI), particularly PDIA3, is associated with breast cancer cell aggressiveness. However, it has not been explored whether PDIA3 modulates cancer cell phenotypes by altering cancer cell metabolism. Here, we investigated the effects of C-3399, a novel PDIA3 inhibitor, on the adhesion of breast cancer cells to the extracellular matrix (ECM) and pulmonary microvascular endothelial cells (hLMVEC). Additionally, we explored whether the anti-adhesive effect of PDIA3 inhibition by C-3399 could be mediated by changes in cellular bioenergetics. We found that PDIA3 inhibition modifies adhesive interactions of two human breast cancer lines, representing the luminal (MCF-7) and basal (MDA-MB-231) subtypes, to ECM and hLMVEC. We confirmed that the anti-adhesive effect of C-3399 was due to the inhibition of PDIA3, as the effect was lost in cancer cells with silenced PDIA3. MCF-7 and MDA-MB-231 cells displayed distinct metabolic profiles, with higher levels of tricarboxylic acid (TCA) cycle metabolites in MCF-7. Interestingly, the anti-adhesive effect of PDIA3 inhibition was associated with the downregulation of TCA metabolites (malate, fumarate, alpha-ketoglutarate, isocitrate) and increased lactate production, particularly in MCF-7 cells. Treatment with mitochondrial respiration inhibitors phenocopied the anti-adhesive effect in MCF-7 but had weaker effects in MDA-MB-231 cells. Quantification of C-3399 and its major metabolite (C-3399-B) revealed the extracellular metabolism of the active compound. In conclusion, the inhibition of extracellular PDIA3 represents a novel approach to inhibit the mitochondrial bioenergetic metabolism of cancer cells and to limit adhesion of cancer cells to the pulmonary endothelium.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117344"},"PeriodicalIF":5.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091112","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 tocopherol derivative suppresses obesity in high-fat diet-induced obese mice","authors":"S.M. Tafsirul Alam Tapu ,&nbsp;Kinari Hayashi ,&nbsp;Michiyasu Nakao ,&nbsp;Shintaro Yoneda ,&nbsp;Shigeki Sano ,&nbsp;Kentaro Kogure","doi":"10.1016/j.bcp.2025.117345","DOIUrl":"10.1016/j.bcp.2025.117345","url":null,"abstract":"<div><div>Lipid accumulation plays a pivotal role in obesity pathogenesis, aggravating the metabolic and inflammatory burden. However, drugs targeting lipid accumulation inhibition remains limited. α-Tocopheryl succinate (TS), a succinic ester of α-tocopherol (T), inhibits lipid accumulation but exhibits cytotoxicity (Majima et al., Biol. Pharm. Bull 2021). We previously developed α-tocopheryl adipate (Tadi) as a potential anti-obesity drug candidate. Tadi is an adipic acid ester of T, and was found to inhibit lipid accumulation without cytotoxicity (Yamasaki et al., Biochem Biophys Rep 2022). However, hydrolysis of its ester moiety attached to the phenolic hydroxyl group of T raises concerns about its chemical stability and oral administration. Herein, we synthesized deoxo α-tocopheryl adipate (dTadi), a novel α-tocopherol derivative, which is an ether analog of Tadi, in which the ester bond is replaced by an ether bond. Structural modification enhances the stability of dTadi over Tadi. dTadi significantly reduced lipid accumulation without cytotoxicity <em>in vitro</em>. Moreover, oral administration of dTadi dose-dependently suppressed body weight increase (by 13 %-20 %) in high-fat diet (HFD)-fed C57BL/6J mice without altering food intake <em>in vivo</em>. Additionally, dTadi significantly reduced blood glucose levels and serum triglyceride concentrations in a dose-dependent manner. dTadi treatment reduced epididymal and retroperitoneal fat mass while also attenuating adipose hypertrophy and reducing lipid accumulation in the liver. Safety studies revealed that dTadi produced no adverse effects. Lastly, dTadi treatment significantly increased glycerol release, uncoupling protein1 (UCP1), and fatty acid β-oxidation <em>in vitro</em>. These results demonstrate that dTadi may be a potential candidate for an oral anti-obesity drug.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117345"},"PeriodicalIF":5.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091147","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":"Melatonin attenuates high-fat diet- and particulate matter-induced cardiac injury: involvement of mitochondrial quality and miR-221/222 expression","authors":"Ya-Chun Chen ,&nbsp;Ming-Hsueh Lee ,&nbsp;Szu-Ju Fu ,&nbsp;Chiang-Wen Lee ,&nbsp;Wen-Chi Shen ,&nbsp;Tsai-Chun Lai ,&nbsp;Shu-Rung Lin ,&nbsp;Shu-Wha Lin ,&nbsp;I-Shing Yu ,&nbsp;Tzu-Yi Chuang ,&nbsp;Jaw-Shiun Tsai ,&nbsp;Yuh-Lien Chen","doi":"10.1016/j.bcp.2025.117346","DOIUrl":"10.1016/j.bcp.2025.117346","url":null,"abstract":"<div><div>Previous studies have shown that exposure to hyperlipidemia or particulate matter (PM) individually affects the progression of cardiovascular disease (CVD), but the combined effects of these factors remain understudied. This study investigated whether combined treatment with a high-fat diet (HFD)/palmitate (PA) and PM exacerbates cardiomyocyte injury and proposed using the antioxidant melatonin. Furthermore, we explored the role of mitochondria and <em>miR-221/222</em> in melatonin-mediated reduction of HFD- and PM-exacerbated cardiomyocyte injury. H9c2 cells were treated with or without 50 μM PA, 10 μg/mL PM, and 100 μM melatonin for 24 h. In the <em>in vivo</em> experiments, 8–12-week-old wild-type (WT) mice, <em>miR-221/222</em> knockout (<em>miR-221/222^–/-</em>) mice, and <em>miR-221/222</em> overexpression (<em>miR-221/222</em>^o/e) mice were treated with HFD for 4 weeks. PM was injected intratracheally at the end of the second and third weeks, and melatonin 20 mg/kg was administered orally daily starting at the end of the second week. Combined PA/HFD and PM induced mitochondrial ROS accumulation, subsequent mitochondrial fission, and excessive mitophagy in cardiomyocytes and cardiac tissues. This cascade increases cardiomyocyte apoptosis and fibrosis, leading to cardiac dysfunction. Melatonin treatment reduced mitochondrial ROS accumulation and improved HFD- and PM-induced cardiac dysfunction. Further exploration of the molecular mechanism highlighted that <em>miR-221/222</em> upregulation is a downstream effect of melatonin, revealing a novel regulatory pathway for HFD- and PM-induced cardiac injury. This study showed that simultaneous exposure to HFD/PA and PM exacerbated cardiomyocyte apoptosis and fibrosis. These effects could be ameliorated by melatonin-mediated ROS scavenging, maintenance of mitochondrial function, and cardioprotection associated with <em>miR-221/222</em>.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117346"},"PeriodicalIF":5.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091114","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}