Pub Date : 2026-02-04DOI: 10.1016/j.biopha.2026.119021
Lihong Li , Wenqi Dai , Zhuwei Zhong , Qin Yang , Jiehuang Zheng , Yan Chen , Ziye Chen , Qinghe Liang , Chujiang Xu , Xiaojuan Li , Gang Huang
Osteoporosis is a chronic disorder marked by bone wasting and increased bone fragility. Targeted inhibition of osteoclastogensis is currently the core therapeutic strategy. Hexahydrocurcumin (HHC), derived from Zingiberis Rhizoma, has been shown to exhibit anti-inflammatory and antioxidant properties; however, its effects on osteoclasts regulation and osteoporosis pathogenesis remain unexplored. We conducted this study to observe the influence of HHC on RANKL-mediated osteoclast precursor differentiation and OVX-dependent osteoporotic mice. In this study, we revealed that HHC significantly attenuated the generation and bone resorptive function of osteoclasts induced by RANKL in vitro, which was achieved by targeting and inhibiting the phosphorylation of c-Src, a critical molecule in osteoclast differentiation. Next, HHC inhibited the subsequent Ca2+ influx and NFATc1 nuclear translocation, thereby suppressing the expression of osteoclastogenic regulators such as Acp5 and Mmp9. Furthermore, we validated that HHC inhibits osteoclastogenesis by targeting c-Src through siRNA-mediated silencing of c-Src. In the in vivo study, HHC notably alleviated bone loss in OVX-dependent osteoporotic mice. These findings suggest that HHC alleviates osteoporosis by inhibiting osteoclastogenesis via targeting c-Src, which provide preliminary evidence for the potential of HHC for the treatment of osteoporosis.
{"title":"Hexahydrocurcumin inhibits osteoclastogenesis and bone destruction in osteoporosis by targeting c-Src","authors":"Lihong Li , Wenqi Dai , Zhuwei Zhong , Qin Yang , Jiehuang Zheng , Yan Chen , Ziye Chen , Qinghe Liang , Chujiang Xu , Xiaojuan Li , Gang Huang","doi":"10.1016/j.biopha.2026.119021","DOIUrl":"10.1016/j.biopha.2026.119021","url":null,"abstract":"<div><div>Osteoporosis is a chronic disorder marked by bone wasting and increased bone fragility. Targeted inhibition of osteoclastogensis is currently the core therapeutic strategy. Hexahydrocurcumin (HHC), derived from <em>Zingiberis Rhizoma</em>, has been shown to exhibit anti-inflammatory and antioxidant properties; however, its effects on osteoclasts regulation and osteoporosis pathogenesis remain unexplored. We conducted this study to observe the influence of HHC on RANKL-mediated osteoclast precursor differentiation and OVX-dependent osteoporotic mice. In this study, we revealed that HHC significantly attenuated the generation and bone resorptive function of osteoclasts induced by RANKL in vitro, which was achieved by targeting and inhibiting the phosphorylation of c-Src, a critical molecule in osteoclast differentiation. Next, HHC inhibited the subsequent Ca<sup>2+</sup> influx and NFATc1 nuclear translocation, thereby suppressing the expression of osteoclastogenic regulators such as <em>Acp5</em> and <em>Mmp9</em>. Furthermore, we validated that HHC inhibits osteoclastogenesis by targeting c-Src through siRNA-mediated silencing of c-Src. In the in vivo study, HHC notably alleviated bone loss in OVX-dependent osteoporotic mice. These findings suggest that HHC alleviates osteoporosis by inhibiting osteoclastogenesis via targeting c-Src, which provide preliminary evidence for the potential of HHC for the treatment of osteoporosis.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"196 ","pages":"Article 119021"},"PeriodicalIF":7.5,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146127719","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}
Pub Date : 2026-02-04DOI: 10.1016/j.biopha.2026.119080
Maria Grazia Martina , Gregory Mathez , Daniele Rubini , Martina Eleonora Valenti , Paul Lachat , Sara Cristinelli , Carole Kebbi Beghdadi , Vincent Carlen , Emmanuele Crespan , Elena Bianchi , Onya Opota , Gilbert Greub , Angela Ciuffi , Jérôme Gouttenoire , Marco Radi , Valeria Cagno
Sexually transmitted infections (STIs) remain a major global health concern, contributing significantly to morbidity and facilitating the co-transmission of other pathogens. Recent outbreaks of Monkeypox virus (MPXV) have further underscored the urgent need for broad-spectrum antiviral agents effective against emerging and re-emerging sexually transmissible viruses. We report here the design and synthesis of a series of 3-cyanoquinoline-based Src inhibitors to evaluate their antimicrobial efficacy against sexually transmitted pathogens. Among them, compound 7d demonstrated potent inhibitory activity against MPXV, Herpes simplex virus types 1 and 2, Hepatitis C virus, Human immunodeficiency virus, and Chlamydia trachomatis at non-toxic concentrations. Owing to its broad-spectrum profile and favorable cytotoxicity profile, compound 7d represents a promising candidate for development as a topical microbicide for the prevention and treatment of STIs. Interestingly, the screening also identified compound 7g, which, despite lacking Src inhibitory activity, exhibited selective antiviral activity against members of the Poxviridae family, suggesting the involvement of alternative host-dependent mechanisms that can be further exploited. Both compounds were non-toxic in relevant epithelial and mucosal tissue models. Collectively, these findings highlight the therapeutic potential of 3-cyanoquinoline derivatives as scaffolds for the development of novel broad-spectrum microbicides targeting a range of sexually transmitted pathogens.
{"title":"Identification of 3-cyanoquinolines as broad-spectrum inhibitors of Monkeypox virus and other sexually transmitted pathogens","authors":"Maria Grazia Martina , Gregory Mathez , Daniele Rubini , Martina Eleonora Valenti , Paul Lachat , Sara Cristinelli , Carole Kebbi Beghdadi , Vincent Carlen , Emmanuele Crespan , Elena Bianchi , Onya Opota , Gilbert Greub , Angela Ciuffi , Jérôme Gouttenoire , Marco Radi , Valeria Cagno","doi":"10.1016/j.biopha.2026.119080","DOIUrl":"10.1016/j.biopha.2026.119080","url":null,"abstract":"<div><div>Sexually transmitted infections (STIs) remain a major global health concern, contributing significantly to morbidity and facilitating the co-transmission of other pathogens. Recent outbreaks of Monkeypox virus (MPXV) have further underscored the urgent need for broad-spectrum antiviral agents effective against emerging and re-emerging sexually transmissible viruses. We report here the design and synthesis of a series of 3-cyanoquinoline-based Src inhibitors to evaluate their antimicrobial efficacy against sexually transmitted pathogens. Among them, compound <strong>7d</strong> demonstrated potent inhibitory activity against MPXV, Herpes simplex virus types 1 and 2, Hepatitis C virus, Human immunodeficiency virus, and <em>Chlamydia trachomatis</em> at non-toxic concentrations. Owing to its broad-spectrum profile and favorable cytotoxicity profile, compound <strong>7d</strong> represents a promising candidate for development as a topical microbicide for the prevention and treatment of STIs. Interestingly, the screening also identified compound <strong>7g</strong>, which, despite lacking Src inhibitory activity, exhibited selective antiviral activity against members of the <em>Poxviridae</em> family, suggesting the involvement of alternative host-dependent mechanisms that can be further exploited. Both compounds were non-toxic in relevant epithelial and mucosal tissue models. Collectively, these findings highlight the therapeutic potential of 3-cyanoquinoline derivatives as scaffolds for the development of novel broad-spectrum microbicides targeting a range of sexually transmitted pathogens.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"196 ","pages":"Article 119080"},"PeriodicalIF":7.5,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146127709","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}
Pub Date : 2026-02-03DOI: 10.1016/j.biopha.2026.119075
Sophie Tran, Anne-Laure Grindel, Dimitri Kereselidze, Laurène Jourdain, Caroline Denis, Benoit Jego, Soizic Martin-Aubert, Jean-Luc Gennisson, Jean-Michel Daugas, Anthony Novell , Charles Truillet
Radioligand therapy targeting prostate-specific membrane antigen (PSMA) has demonstrated promising clinical outcomes for patients with metastatic castration-resistant prostate cancer. However, accumulation in non-target organs can lead to significant radiotoxicity, affecting patient well-being and potentially requiring treatment discontinuation. Ultrasound combined with microbubbles (USMB) has been shown to transiently permeabilize biological barriers, enabling efficient and safe drug delivery to tumor tissues while minimizing dose-limiting toxicities. This study explores the impact of different conditions of USMB on the distribution of the diagnostic radiopharmaceutical [18F]F-PSMA-1007 as a preliminary step before applying therapeutic radiopharmaceuticals (RPs) in a preclinical subcutaneous model. Immunodeficient mice bearing human LNCaP tumors were treated with different ultrasound parameters (i.e., pulse length and pressure). Each mouse received an intravenous injection of [18F]F-PSMA-1007 (5.1 ± 1.7 MBq) and was imaged by PET/CT 2 h post-injection (p.i.). Additionally, an intravenous injection of TRITC Dextran (100 µL, 70 kDa, 5 mg/mL) was administered to quantify its extravasation into the tumor, correlated with PSMA and CD31 expression via immunofluorescence. Contrast-enhanced ultrasound imaging was also performed to assess tumor perfusion. Results showed a mild, though non-significant, trend toward increased [18 F]F-PSMA-1007 in most groups compared to the control, except for those exposed to short pulses associated with high-pressure. These findings highlight the potential of USMB to enhance drug delivery for PSMA uptake but also underscore the necessity for careful consideration of ultrasound parameters to prevent tissue damage.
{"title":"Shifting the paradigm of PSMA delivery in prostate cancer for internal radiotherapy: An innovative ultrasound-mediated approach","authors":"Sophie Tran, Anne-Laure Grindel, Dimitri Kereselidze, Laurène Jourdain, Caroline Denis, Benoit Jego, Soizic Martin-Aubert, Jean-Luc Gennisson, Jean-Michel Daugas, Anthony Novell , Charles Truillet","doi":"10.1016/j.biopha.2026.119075","DOIUrl":"10.1016/j.biopha.2026.119075","url":null,"abstract":"<div><div>Radioligand therapy targeting prostate-specific membrane antigen (PSMA) has demonstrated promising clinical outcomes for patients with metastatic castration-resistant prostate cancer. However, accumulation in non-target organs can lead to significant radiotoxicity, affecting patient well-being and potentially requiring treatment discontinuation. Ultrasound combined with microbubbles (USMB) has been shown to transiently permeabilize biological barriers, enabling efficient and safe drug delivery to tumor tissues while minimizing dose-limiting toxicities. This study explores the impact of different conditions of USMB on the distribution of the diagnostic radiopharmaceutical [<sup>18</sup>F]F-PSMA-1007 as a preliminary step before applying therapeutic radiopharmaceuticals (RPs) in a preclinical subcutaneous model. Immunodeficient mice bearing human LNCaP tumors were treated with different ultrasound parameters (<em>i.e.</em>, pulse length and pressure). Each mouse received an intravenous injection of [<sup>18</sup>F]F-PSMA-1007 (5.1 ± 1.7 MBq) and was imaged by PET/CT 2 h post-injection (<em>p.i.</em>). Additionally, an intravenous injection of TRITC Dextran (100 µL, 70 kDa, 5 mg/mL) was administered to quantify its extravasation into the tumor, correlated with PSMA and CD31 expression via immunofluorescence. Contrast-enhanced ultrasound imaging was also performed to assess tumor perfusion. Results showed a mild, though non-significant, trend toward increased [18 F]F-PSMA-1007 in most groups compared to the control, except for those exposed to short pulses associated with high-pressure. These findings highlight the potential of USMB to enhance drug delivery for PSMA uptake but also underscore the necessity for careful consideration of ultrasound parameters to prevent tissue damage.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"196 ","pages":"Article 119075"},"PeriodicalIF":7.5,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146121303","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}
Pub Date : 2026-02-02DOI: 10.1016/j.biopha.2026.119084
Jiun-Yi Li , Kuan-Hung Lin , Ting-Yu Chen , Ray-Jade Chen , Hsueh-Hsiao Wang , Hsien-Yu Peng , Wan-Jung Lu
Platelets, which mediate hemostasis, have been implicated in cardiovascular diseases such as myocardial infarction and stroke. Calycosin, a flavonoid extracted from the root of Astragalus membranaceus, has diverse biological effects, including anticancer, anti-inflammatory, and antidiabetic effects. Whether calycosin inhibits platelet activation and thrombus formation is unclear. The present study explored the mechanisms underlying the potential antiplatelet and antithrombotic effects of calycosin. Platelet aggregation assays, flow cytometry, and Western blotting were performed to analyze the antiplatelet effects of calycosin. Thrombus formation in mouse mesenteric vessels was investigated to analyze the antithrombotic effects of calycosin. Calycosin selectively inhibited collagen-induced platelet aggregation and glycoprotein VI-mediated downstream signaling, including pathways involving phospholipase Cγ2 and protein kinase C. Additionally, calycosin attenuated the activation of protein kinase B and mitogen-activated protein kinase and further suppressed collagen-induced granule release, calcium mobilization, and glycoprotein IIb/IIIa activation. In vivo experiments revealed that calycosin prevented pulmonary thromboembolism and delayed thrombus formation in mouse mesenteric vessels, without affecting hemostasis. This study is the first to demonstrate that calycosin effectively prevents platelet activation and thrombus formation, partly by targeting glycoprotein VI-mediated signaling, without affecting hemostasis. These findings highlight the therapeutic potential of calycosin for cardiovascular diseases.
{"title":"Calycosin extracted from Astragalus membranaceus root inhibits platelet activation and thrombus formation: Insights from in vivo and in vitro experiments","authors":"Jiun-Yi Li , Kuan-Hung Lin , Ting-Yu Chen , Ray-Jade Chen , Hsueh-Hsiao Wang , Hsien-Yu Peng , Wan-Jung Lu","doi":"10.1016/j.biopha.2026.119084","DOIUrl":"10.1016/j.biopha.2026.119084","url":null,"abstract":"<div><div>Platelets, which mediate hemostasis, have been implicated in cardiovascular diseases such as myocardial infarction and stroke. Calycosin, a flavonoid extracted from the root of <em>Astragalus membranaceus</em>, has diverse biological effects, including anticancer, anti-inflammatory, and antidiabetic effects. Whether calycosin inhibits platelet activation and thrombus formation is unclear. The present study explored the mechanisms underlying the potential antiplatelet and antithrombotic effects of calycosin. Platelet aggregation assays, flow cytometry, and Western blotting were performed to analyze the antiplatelet effects of calycosin. Thrombus formation in mouse mesenteric vessels was investigated to analyze the antithrombotic effects of calycosin. Calycosin selectively inhibited collagen-induced platelet aggregation and glycoprotein VI-mediated downstream signaling, including pathways involving phospholipase Cγ2 and protein kinase C. Additionally, calycosin attenuated the activation of protein kinase B and mitogen-activated protein kinase and further suppressed collagen-induced granule release, calcium mobilization, and glycoprotein IIb/IIIa activation. In vivo experiments revealed that calycosin prevented pulmonary thromboembolism and delayed thrombus formation in mouse mesenteric vessels, without affecting hemostasis. This study is the first to demonstrate that calycosin effectively prevents platelet activation and thrombus formation, partly by targeting glycoprotein VI-mediated signaling, without affecting hemostasis. These findings highlight the therapeutic potential of calycosin for cardiovascular diseases.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"196 ","pages":"Article 119084"},"PeriodicalIF":7.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115219","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}
Pub Date : 2026-02-02DOI: 10.1016/j.biopha.2026.119076
Jinyeong Heo , Soonju Park , Honggun Lee , Yeonguk Jeon , Sangeun Jeon , Dawoon Lee , Inhee Choi , Young Mi Kim , Ju Hwan Jeong , Seong Cheol Min , Min-Suk Song , Seungtaek Kim , David Shum , Jiho Kim
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need for broad and potent antiviral agents. Although overall disease severity has diminished, the persistent risk of reinfection highlights the continued demand for novel therapeutic options.
In this study, we performed an image-based high-throughput screening campaign of 11,030 small molecules—including nucleoside analogs, known antivirals, and diverse bioactives—to identify inhibitors of SARS-CoV-2 infection. Using an immunofluorescence assay that quantified viral proteins and assessed cell viability by Hoechst nuclear staining, we identified 97 primary hits in infected Vero cells. Dose–response evaluation confirmed 18 compounds active against both ancestral and Omicron variants, and subsequent validation in human lung cell lines (A549-hACE2-TMPRSS2 and Calu-3) highlighted multiple cysteine protease inhibitors as strong antiviral candidates.
Among these, MG-101 emerged as a potent cysteine protease inhibitor with favorable pharmacokinetics, metabolic stability, and robust in vivo antiviral efficacy. Docking analysis and enzymatic assays demonstrated that MG-101 inhibits the SARS-CoV-2 3CL protease, and combination studies revealed in vitro synergistic antiviral activity with remdesivir.
Together, these findings establish MG-101 as a potential therapeutic lead for COVID-19 and illustrate the value of image-based high-throughput screening for accelerating antiviral drug discovery.
{"title":"MG-101, a cysteine protease inhibitor identified through high-throughput screening, exhibits in vivo efficacy and synergy with remdesivir against SARS-CoV-2","authors":"Jinyeong Heo , Soonju Park , Honggun Lee , Yeonguk Jeon , Sangeun Jeon , Dawoon Lee , Inhee Choi , Young Mi Kim , Ju Hwan Jeong , Seong Cheol Min , Min-Suk Song , Seungtaek Kim , David Shum , Jiho Kim","doi":"10.1016/j.biopha.2026.119076","DOIUrl":"10.1016/j.biopha.2026.119076","url":null,"abstract":"<div><div>The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need for broad and potent antiviral agents. Although overall disease severity has diminished, the persistent risk of reinfection highlights the continued demand for novel therapeutic options.</div><div>In this study, we performed an image-based high-throughput screening campaign of 11,030 small molecules—including nucleoside analogs, known antivirals, and diverse bioactives—to identify inhibitors of SARS-CoV-2 infection. Using an immunofluorescence assay that quantified viral proteins and assessed cell viability by Hoechst nuclear staining, we identified 97 primary hits in infected Vero cells. Dose–response evaluation confirmed 18 compounds active against both ancestral and Omicron variants, and subsequent validation in human lung cell lines (A549-hACE2-TMPRSS2 and Calu-3) highlighted multiple cysteine protease inhibitors as strong antiviral candidates.</div><div>Among these, MG-101 emerged as a potent cysteine protease inhibitor with favorable pharmacokinetics, metabolic stability, and robust <em>in vivo</em> antiviral efficacy. Docking analysis and enzymatic assays demonstrated that MG-101 inhibits the SARS-CoV-2 3CL protease, and combination studies revealed <em>in vitro</em> synergistic antiviral activity with remdesivir.</div><div>Together, these findings establish MG-101 as a potential therapeutic lead for COVID-19 and illustrate the value of image-based high-throughput screening for accelerating antiviral drug discovery.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"196 ","pages":"Article 119076"},"PeriodicalIF":7.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115250","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}
Breast cancers are characterized by complex energy metabolisms involving the Warburg effect but also mitochondria, although this area is not yet well understood. Tumor cells are particularly flexible by choosing oxidative phosphorylation (OXPHOS) or glycolysis depending on the needs and aggressiveness. Within the mitochondria, a HSP90-chaperone protein, TRAP1, exerts regulatory effects on several vital functions such as OXPHOS, production of reactive oxygen species and apoptosis by interacting with members of the respiratory chain or the mPTP. However, not all of its roles have yet been elucidated. Here, we propose to modulate TRAP1 functions using a mitochondriotropic molecule (containing triphenylphosphonium) targeting its C-terminal domain, 6BrCaQ-C10-TPP, in breast tumor cells. Its blocks proliferation with no massive apoptosis, after 24 h of treatment, and induces dissipation of the mitochondrial membrane potential. 6BrCaQ-C10-TPP also appears to modulate regulators of epithelial-mesenchymal transition (Snail and ZEB1) without a common response in all cell lines. Furthermore, the chaperone machinery is affected with a decrease of HSF1 and HSP70, but without degradation of HSP90 or TRAP1, while decreasing the levels of SDH-A and/or SDH-B, partner of TRAP1. Finally, short-term treatments (1 and 3 h) with 6BrCaQ-C10-TPP modify energy metabolism by promoting glycolysis. In conclusion, modulation of TRAP1 on the C-terminal domain by 6BrCaQ-C10-TPP exerts a cell-line dependent anti-tumor effect by modulating major mitochondrial functions in vitro. The differences between cell types need to be clarified. This study confirms that TRAP1 is a target of interest in breast cancer cells, but some of its functions still need to be elucidated.
{"title":"Inhibition of TRAP1 in the C-terminal domain influences mitochondria properties and breast cancer cell metabolism","authors":"Clélia Mathieu , Jessica Ristow Branco , Patricia Zancan , Catherine Brenner , Samir Messaoudi , Elias Fattal , Juliette Vergnaud","doi":"10.1016/j.biopha.2026.119060","DOIUrl":"10.1016/j.biopha.2026.119060","url":null,"abstract":"<div><div>Breast cancers are characterized by complex energy metabolisms involving the Warburg effect but also mitochondria, although this area is not yet well understood. Tumor cells are particularly flexible by choosing oxidative phosphorylation (OXPHOS) or glycolysis depending on the needs and aggressiveness. Within the mitochondria, a HSP90-chaperone protein, TRAP1, exerts regulatory effects on several vital functions such as OXPHOS, production of reactive oxygen species and apoptosis by interacting with members of the respiratory chain or the mPTP. However, not all of its roles have yet been elucidated. Here, we propose to modulate TRAP1 functions using a mitochondriotropic molecule (containing triphenylphosphonium) targeting its C-terminal domain, 6BrCaQ-C<sub>10</sub>-TPP, in breast tumor cells. Its blocks proliferation with no massive apoptosis, after 24 h of treatment, and induces dissipation of the mitochondrial membrane potential. 6BrCaQ-C<sub>10</sub>-TPP also appears to modulate regulators of epithelial-mesenchymal transition (Snail and ZEB1) without a common response in all cell lines. Furthermore, the chaperone machinery is affected with a decrease of HSF1 and HSP70, but without degradation of HSP90 or TRAP1, while decreasing the levels of SDH-A and/or SDH-B, partner of TRAP1. Finally, short-term treatments (1 and 3 h) with 6BrCaQ-C<sub>10</sub>-TPP modify energy metabolism by promoting glycolysis. In conclusion, modulation of TRAP1 on the C-terminal domain by 6BrCaQ-C<sub>10</sub>-TPP exerts a cell-line dependent anti-tumor effect by modulating major mitochondrial functions <em>in vitro</em>. The differences between cell types need to be clarified. This study confirms that TRAP1 is a target of interest in breast cancer cells, but some of its functions still need to be elucidated.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"196 ","pages":"Article 119060"},"PeriodicalIF":7.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115290","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}
Pub Date : 2026-02-02DOI: 10.1016/j.biopha.2026.119042
Eun Yi Oh , Soo Hwan Suh , Seonhee Byeon , Jooyong Lee , Young-Ho Lee , Soo-Kyoung Choi
Endothelial dysfunction is a hallmark of type 2 diabetes mellitus (T2DM) and a major contributor to cardiovascular complications. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycemic control and cardiovascular outcomes, the mechanisms linking GLP-1RA therapy, gut microbiome modulation, and endothelial function remain incompletely understood. In this study, we investigated whether the GLP-1RA liraglutide improves endothelial dysfunction in T2DM through microbiome-associated mechanisms that support vascular homeostasis. Male db/db mice and non-diabetic controls were treated with liraglutide (300 μg/kg/day, intraperitoneally) or saline for two weeks. Vascular function was assessed in mesenteric resistance arteries using wire myography. Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose with or without liraglutide or the short chain fatty acid (SCFA), butyrate. Endothelial nitric oxide (NO) signaling was evaluated by eNOS (at Ser1177) phosphorylation and nitrite production. Gut microbiota composition was analyzed by 16S rRNA gene sequencing. Liraglutide significantly improved endothelium-dependent relaxation in db/db mice and restored high glucose-induced impairment of eNOS phosphorylation and NO production in HUVECs. In vivo, diabetes was associated with marked gut dysbiosis characterized by reduced alpha diversity and depletion of SCFA-producing taxa. Liraglutide treatment substantially restored microbial diversity and enriched beneficial genera, including Lachnospiraceae and Lactobacillus. Consistently, low-dose butyrate modestly enhanced NO production in endothelial cells. These findings support the concept of a GLP-1RA–microbiome–vascular axis, in which liraglutide-associated remodeling of the gut microbiota may contribute to improved endothelial NO signaling and vascular function in diabetes.
{"title":"Liraglutide alters gut microbiota and improves endothelium-dependent relaxation in db/db mice","authors":"Eun Yi Oh , Soo Hwan Suh , Seonhee Byeon , Jooyong Lee , Young-Ho Lee , Soo-Kyoung Choi","doi":"10.1016/j.biopha.2026.119042","DOIUrl":"10.1016/j.biopha.2026.119042","url":null,"abstract":"<div><div>Endothelial dysfunction is a hallmark of type 2 diabetes mellitus (T2DM) and a major contributor to cardiovascular complications. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycemic control and cardiovascular outcomes, the mechanisms linking GLP-1RA therapy, gut microbiome modulation, and endothelial function remain incompletely understood. In this study, we investigated whether the GLP-1RA liraglutide improves endothelial dysfunction in T2DM through microbiome-associated mechanisms that support vascular homeostasis. Male db/db mice and non-diabetic controls were treated with liraglutide (300 μg/kg/day, intraperitoneally) or saline for two weeks. Vascular function was assessed in mesenteric resistance arteries using wire myography. Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose with or without liraglutide or the short chain fatty acid (SCFA), butyrate. Endothelial nitric oxide (NO) signaling was evaluated by eNOS (at Ser1177) phosphorylation and nitrite production. Gut microbiota composition was analyzed by 16S rRNA gene sequencing. Liraglutide significantly improved endothelium-dependent relaxation in db/db mice and restored high glucose-induced impairment of eNOS phosphorylation and NO production in HUVECs. <em>In vivo</em>, diabetes was associated with marked gut dysbiosis characterized by reduced alpha diversity and depletion of SCFA-producing taxa. Liraglutide treatment substantially restored microbial diversity and enriched beneficial genera, including Lachnospiraceae and <em>Lactobacillus</em>. Consistently, low-dose butyrate modestly enhanced NO production in endothelial cells. These findings support the concept of a GLP-1RA–microbiome–vascular axis, in which liraglutide-associated remodeling of the gut microbiota may contribute to improved endothelial NO signaling and vascular function in diabetes.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"196 ","pages":"Article 119042"},"PeriodicalIF":7.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115303","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}
Pub Date : 2026-02-01DOI: 10.1016/j.biopha.2026.119059
Monisha Yadav H S , Young Yun Jung , Narasimha M. Beeraka , Bhoomika B R , Doddahosuru M. Gurudatt , Keshav Kumar Harish , Mahendra Madegowda , Santosh L. Gaonkar , Shreeja Basappa , Vladimir N. Nikolenko , Riyaz Ali M. Osmani , Kanchugarakoppal S. Rangappa , Basappa Basappa , Kwang Seok Ahn
Background
The development of targeted anticancer agents capable of selectively eliminating breast cancer cells while sparing normal tissues remains a critical therapeutic challenge. MCB-04, a novel dihydropyrimidinone (DHPM)-tethered piperazine derivative synthesized via a TiO₂ nanoparticle-mediated catalytic strategy, demonstrates promising anticancer potential.
Objectives
This study aimed to synthesize DHPM-tethered piperazine derivatives using a TiO₂-catalyzed approach and to comprehensively evaluate the cytotoxic efficacy of the lead compound MCB-04 against human breast cancer cells, with particular emphasis on elucidating its underlying molecular mechanisms of cell death.
Methods
A library of DHPM-tethered piperazine derivatives was synthesized and characterized, and MCB-04 was identified as the lead compound. Cytotoxicity was assessed using the MTT assay in MDA-MB-231, MCF-7, BT-474, and SK-BR-3 breast cancer cell lines, as well as normal MCF-10A cells. Apoptosis and autophagy were analyzed by live/dead assays, Annexin V/PI staining, immunocytochemistry, and Western blotting. Mitochondrial dysfunction and oxidative stress were evaluated by measuring mitochondrial membrane potential (Δψm) and intracellular ROS levels using flow cytometry. The involvement of paraptosis and c-Met–mediated signaling pathways was further investigated.
Results
MCB-04 exhibited potent and selective cytotoxicity toward breast cancer cells, with the highest sensitivity observed in MDA-MB-231 cells (IC50 = 20 µM), while exerting minimal toxicity in normal MCF-10A cells. MCB-04 treatment significantly increased intracellular ROS levels and disrupted Δψm, indicating mitochondrial dysfunction. Mechanistically, MCB-04 induced apoptosis through activation of cleaved PARP and cleaved caspase-3, an increased Bax/Bcl-2 ratio, and upregulation of p53 and phosphorylated p53. Concurrently, autophagy was evidenced by LC3-II accumulation and increased Atg5 and Beclin-1 expression. Markers of ER stress-mediated paraptosis, including ATF4 and CHOP, were also elevated with concomintant decline in Alix. Furthermore, MCB-04 markedly suppressed phosphorylated c-Met, EMT-related VEGF, MMP-9 expression and downstream PI3K/Akt/mTOR/MEK signaling pathways.
Conclusion
MCB-04 exerts robust anti-breast cancer activity by triggering multiple programmed cell death pathways include apoptosis, autophagy, and paraptosis primarily through ROS-mediated mitochondrial dysfunction and inhibition of c-Met-dependent oncogenic signaling. These findings position MCB-04 as a promising multi-targeted therapeutic candidate, warranting further in vivo validation and preclinical development for breast cancer treatment.
{"title":"Targeting c-Met and EMT, PI3K/Akt/mTOR/MEK signaling with Dihydropyrimidinone-Piperazine-based scaffold that triggers apoptosis, autophagy, and paraptosis in breast carcinomas","authors":"Monisha Yadav H S , Young Yun Jung , Narasimha M. Beeraka , Bhoomika B R , Doddahosuru M. Gurudatt , Keshav Kumar Harish , Mahendra Madegowda , Santosh L. Gaonkar , Shreeja Basappa , Vladimir N. Nikolenko , Riyaz Ali M. Osmani , Kanchugarakoppal S. Rangappa , Basappa Basappa , Kwang Seok Ahn","doi":"10.1016/j.biopha.2026.119059","DOIUrl":"10.1016/j.biopha.2026.119059","url":null,"abstract":"<div><h3>Background</h3><div>The development of targeted anticancer agents capable of selectively eliminating breast cancer cells while sparing normal tissues remains a critical therapeutic challenge. MCB-04, a novel dihydropyrimidinone (DHPM)-tethered piperazine derivative synthesized via a TiO₂ nanoparticle-mediated catalytic strategy, demonstrates promising anticancer potential.</div></div><div><h3>Objectives</h3><div>This study aimed to synthesize DHPM-tethered piperazine derivatives using a TiO₂-catalyzed approach and to comprehensively evaluate the cytotoxic efficacy of the lead compound MCB-04 against human breast cancer cells, with particular emphasis on elucidating its underlying molecular mechanisms of cell death.</div></div><div><h3>Methods</h3><div>A library of DHPM-tethered piperazine derivatives was synthesized and characterized, and MCB-04 was identified as the lead compound. Cytotoxicity was assessed using the MTT assay in MDA-MB-231, MCF-7, BT-474, and SK-BR-3 breast cancer cell lines, as well as normal MCF-10A cells. Apoptosis and autophagy were analyzed by live/dead assays, Annexin V/PI staining, immunocytochemistry, and Western blotting. Mitochondrial dysfunction and oxidative stress were evaluated by measuring mitochondrial membrane potential (Δψm) and intracellular ROS levels using flow cytometry. The involvement of paraptosis and c-Met–mediated signaling pathways was further investigated.</div></div><div><h3>Results</h3><div>MCB-04 exhibited potent and selective cytotoxicity toward breast cancer cells, with the highest sensitivity observed in MDA-MB-231 cells (IC50 = 20 µM), while exerting minimal toxicity in normal MCF-10A cells. MCB-04 treatment significantly increased intracellular ROS levels and disrupted Δψm, indicating mitochondrial dysfunction. Mechanistically, MCB-04 induced apoptosis through activation of cleaved PARP and cleaved caspase-3, an increased Bax/Bcl-2 ratio, and upregulation of p53 and phosphorylated p53. Concurrently, autophagy was evidenced by LC3-II accumulation and increased Atg5 and Beclin-1 expression. Markers of ER stress-mediated paraptosis, including ATF4 and CHOP, were also elevated with concomintant decline in Alix. Furthermore, MCB-04 markedly suppressed phosphorylated c-Met, EMT-related VEGF, MMP-9 expression and downstream PI3K/Akt/mTOR/MEK signaling pathways.</div></div><div><h3>Conclusion</h3><div>MCB-04 exerts robust anti-breast cancer activity by triggering multiple programmed cell death pathways include apoptosis, autophagy, and paraptosis primarily through ROS-mediated mitochondrial dysfunction and inhibition of c-Met-dependent oncogenic signaling. These findings position MCB-04 as a promising multi-targeted therapeutic candidate, warranting further in vivo validation and preclinical development for breast cancer treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119059"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074238","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}
Toad-based therapies (Chansu) are a part of traditional Chinese medicine (TCM) in which toad venom is used for the treatment of cancers. Toad venom is a complex mixture of steroid-based compounds called bufadienolides, which have good anticancer potential. Arenobufagin is a toad venom-derived bufadienolide that has been endowed with strong antitumor activity. Most of the studies have demonstrated that arenobufagin shows potent cytotoxicity in cell-based assay systems (IC50 value: <100 nM) and significant antitumor efficacy in preclinical cancer models at lower doses (between 3 and 5 mg/kg). Arenobufagin has been reported to target signaling axes such as the PI3K/Akt/mTOR, Nrf2, ATM/ATR, NF-κB, MAPKs, and Jagged1/Notch in various types of cancer cells. Pharmacokinetic studies have shown that arenobufagin has rapid absorption and gradual elimination from the system compared to many other bufadienolides. In the present article, we have comprehensively reviewed the literature related to the in vitro and in vivo anticancer properties of the arenobufagin. We have discussed the mechanism of the arenobufagin-induced cytotoxicity in different types of cancer cells and xenograft models, pharmacokinetics, and toxicity associated with its administration. Overall, the present article provides up-to-date information about arenobufagin in connection with its anticancer potential.
{"title":"The multifaceted antineoplastic effects of arenobufagin against human cancers","authors":"Gulafsha Siddiqui , Aditya Bhushan Pant , Chakrabhavi Dhananjaya Mohan","doi":"10.1016/j.biopha.2026.119062","DOIUrl":"10.1016/j.biopha.2026.119062","url":null,"abstract":"<div><div>Toad-based therapies (Chansu) are a part of traditional Chinese medicine (TCM) in which toad venom is used for the treatment of cancers. Toad venom is a complex mixture of steroid-based compounds called bufadienolides, which have good anticancer potential. Arenobufagin is a toad venom-derived bufadienolide that has been endowed with strong antitumor activity. Most of the studies have demonstrated that arenobufagin shows potent cytotoxicity in cell-based assay systems (IC<sub>50</sub> value: <100 nM) and significant antitumor efficacy in preclinical cancer models at lower doses (between 3 and 5 mg/kg). Arenobufagin has been reported to target signaling axes such as the PI3K/Akt/mTOR, Nrf2, ATM/ATR, NF-κB, MAPKs, and Jagged1/Notch in various types of cancer cells. Pharmacokinetic studies have shown that arenobufagin has rapid absorption and gradual elimination from the system compared to many other bufadienolides. In the present article, we have comprehensively reviewed the literature related to the <em>in vitro</em> and <em>in vivo</em> anticancer properties of the arenobufagin. We have discussed the mechanism of the arenobufagin-induced cytotoxicity in different types of cancer cells and xenograft models, pharmacokinetics, and toxicity associated with its administration. Overall, the present article provides up-to-date information about arenobufagin in connection with its anticancer potential.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119062"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069521","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}