Andrew J McGovern, Maria Angeles Arevalo, Sergio Ciordia, Luis Miguel Garcia-Segura, George E Barreto
{"title":"Sex-specific gonadal status determines prefrontal cortex proteome response to tibolone.","authors":"Andrew J McGovern, Maria Angeles Arevalo, Sergio Ciordia, Luis Miguel Garcia-Segura, George E Barreto","doi":"10.1016/j.biopha.2025.118419","DOIUrl":"10.1016/j.biopha.2025.118419","url":null,"abstract":"<p><p>Sex differences in brain function and disease are influenced by gonadal hormones, which regulate protein expression in the prefrontal cortex (PFC) essential for cognition and emotional regulation. Clinical trials of menopausal hormone therapies for neurodegenerative diseases have resulted in conflicting therapeutic outcomes dependent on the timing of drug introduction after menopause. Tibolone, a synthetic steroid with estrogenic, progestogenic, and androgenic properties, shows promise for neuroprotection but its molecular mechanisms under different hormonal states remain unknown. We hypothesized that Tibolone efficacy on the prefrontal cortex proteome is dependent on gonads in male and female mice. Through proteomic analysis, we employed dimensionality reduction techniques to explore sex-specific and shared proteomic responses to gonadal hormone deprivation and Tibolone treatment. Our findings reveal that gonadectomy induces a functional convergence of the PFC proteome in both male and female mice, erasing many sex-specific differences in pathways associated with calcium regulation, cytoskeletal function, and mitochondrial metabolism. Tibolone induced distinct sex-specific proteomic trajectories, while in gonadectomized animals, responses converged toward shared molecular pathways. Functional enrichment analysis identified differential regulation of synaptic plasticity, neurotransmitter signalling, and cellular stress response pathways. These results provide novel insights into the critical window hypothesis of hormone therapy, demonstrating that the underlying neurosteroid environment alters hormone therapy efficacy. Our findings suggest that optimal neuroprotective strategies will require sex-specific and timing-specific approaches, establishing a molecular framework for precision hormone therapy in neurodegeneration.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"190 ","pages":"118419"},"PeriodicalIF":7.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Integrative systems biology, transcriptomic profiling, and experimental validation reveal enterolactone as a multi-target inhibitor of metastatic signalling in triple-negative breast cancer.","authors":"Akanksha Mahajan, Rajesh Patil, Ankita Jagtap, Ganesh Wagh, Akshay Deotare, Mahabaleshwar Hegde, Aniket Mali","doi":"10.1016/j.biopha.2025.118437","DOIUrl":"10.1016/j.biopha.2025.118437","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is characterized by aggressive metastatic behaviour and limited therapeutic options. Here, we present a multi-tiered systems biology framework to investigate the anti-metastatic potential of enterolactone (EL), integrating computational, transcriptomic, and experimental approaches in the MDA-MB-231 TNBC model. Network pharmacology identified 78 EL-metastatic TNBC (mTNBC) overlapping targets as potential therapeutic targets of EL against mTNBC, with PPI and GMFA network enrichment uncovering key metastasis-associated pathways including Notch, TGF-β, TNF, and ErbB signaling. Molecular docking and 100 ns molecular dynamics simulations revealed stable binding of EL to several core oncogenic proteins (e.g., EGFR, PARP1, AURKB, SMAD4, CDK4), suggesting poly-pharmacological engagement. Genome-wide transcriptomic profiling of EL-treated cells coupled with GSEA revealed coordinated downregulation of oncogenic programs including E2F, G2/M checkpoint, MYC targets, EMT, and metabolic plasticity, alongside induction of NRF2 signaling and ferroptosis. This study reports, for the first time, transcriptome-wide effects of EL in MDA-MB-231 cells, linking its activity to the repression of stemness, invasion, and immune-evasive traits. Experimental validation via qPCR confirmed EL-mediated suppression of key molecular targets of TGF-β and Notch signaling pathways. EL also impaired cortactin expression and disrupted cytoskeletal remodeling, validated by immunofluorescence and flow cytometry studies, indicating attenuation of invasive machinery. Furthermore, EL reduced metastatic dissemination in a zebrafish xenograft model, reinforcing its in vivo anti-metastatic potential. Together, our integrative study elucidates EL's multitarget mechanism against metastatic TNBC and highlights its translational promise as a systems-level modulator of oncogenic signaling. These findings warrant further in-depth mechanistic investigations to validate EL's therapeutic potential.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"190 ","pages":"118437"},"PeriodicalIF":7.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guanghai Nan, Lin Lin, Leejeong Kim, Kyeongmin Kim, Nari Kang, Hee Young Kim, Myeounghoon Cha, Bae Hwan Lee
{"title":"Vinpocetine alleviates chemotherapy-induced peripheral neuropathy by reducing oxidative stress and enhancing mitochondrial biogenesis in mice.","authors":"Guanghai Nan, Lin Lin, Leejeong Kim, Kyeongmin Kim, Nari Kang, Hee Young Kim, Myeounghoon Cha, Bae Hwan Lee","doi":"10.1016/j.biopha.2025.118434","DOIUrl":"10.1016/j.biopha.2025.118434","url":null,"abstract":"<p><p>Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of cancer treatment and is primarily driven by oxidative stress and mitochondrial dysfunction. Despite its clinical relevance, effective mechanism-based therapies remain limited. Vinpocetine, a neuroprotective compound, has shown antioxidant, anti-inflammatory, and mitochondrial function-preserving effects; however, its efficacy in CIPN remains unknown. This study aimed to evaluate the efficacy and underlying mechanisms of vinpocetine in a paclitaxel-induced CIPN mouse model. In behavioral tests, acute administration of vinpocetine alleviated mechanical hypersensitivity, whereas repeated treatment provided sustained relief from mechanical, thermal, and cold hypersensitivity. Mechanistically, vinpocetine reduced mitochondrial reactive oxygen species (ROS), restored SOD2 levels, and activated mitochondrial biogenesis via the PGC-1α-NRF1-TFAM pathway, as shown by Western blot analysis. In oxidative stress-induced pain models, vinpocetine also attenuated mechanical hypersensitivity, reinforcing its antioxidant properties. Voltage-sensitive dye imaging revealed reduced spinal neuronal hyperexcitability. Immunohistochemistry analysis further demonstrated reduced expression of AMPA and PKC-α in NeuN-positive neurons. This preclinical study is the first to demonstrate that vinpocetine alleviates CIPN by enhancing mitochondrial biogenesis, reducing oxidative stress, and suppressing neuronal excitability in the spinal cord. These results provide mechanistic insights into its effects on CIPN and support further translational research in this indication.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"190 ","pages":"118434"},"PeriodicalIF":7.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144801227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Seung-Yeon Lee, Eun-Ji Kwon, Dayeon Kim, Jumi Kim, Sang-Hun Lee, Young-Hyun Go, Hyuk-Jin Cha
{"title":"In silico chemical fingerprint screening identifies fisetin as a novel stemotoxic flavonoid.","authors":"Seung-Yeon Lee, Eun-Ji Kwon, Dayeon Kim, Jumi Kim, Sang-Hun Lee, Young-Hyun Go, Hyuk-Jin Cha","doi":"10.1016/j.biopha.2025.118369","DOIUrl":"10.1016/j.biopha.2025.118369","url":null,"abstract":"<p><p>Despite recent advances in stem cell therapy using human pluripotent stem cells (hPSCs), the risk of teratoma formation due to residual undifferentiated cells remains a significant safety concern. Numerous small molecules, termed stemotoxic agents, have been developed to eliminate these residual cells, such as the promising natural flavonoid quercetin (QC). Application of QC in clinical settings during the differentiation of dopaminergic neurons from hPSCs has demonstrated its safety and efficacy in selectively targeting residual hPSCs without affecting neural stem cells (NSCs). Interestingly, not all flavonoids with structural similarity to QC exhibit stemotoxic activity. This study conducted an in silico analysis of the common chemical fingerprints of QC, luteolin, and apigenin, three flavonoids known to possess stemotoxicity, and subsequently identified fisetin (FST) as a possible candidate among thousands of dietary flavonoids in PubChem. In vitro, FST selectively induced cell death in hPSCs (distinguished by high NANOG and POU5F1 expression) while sparing human dermal fibroblasts and hPSC-derived NSCs. Notably, by eliminating undifferentiated cells, FST treatment enriched PAX6-positive NSCs and DA neurons. These findings suggest that, in addition to QC, FST may serve as an effective stemotoxic flavonoid for promoting DA neurons enrichment and minimizing the risk of residual hPSC contamination.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"190 ","pages":"118369"},"PeriodicalIF":7.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hyeon Do Jeon, Insung Choi, Woojeung Song, Junyang Jung, Jaejung Park, Ja-Eun Kim, Ji Hyun Lee, Dong Keon Yon, Gi Bbeum Lee, Seong Hye Ahn, Hwajin Lee, Inwha Baek
{"title":"Single-cell transcriptomic and pharmacological studies of onvansertib for small cell lung cancer treatment.","authors":"Hyeon Do Jeon, Insung Choi, Woojeung Song, Junyang Jung, Jaejung Park, Ja-Eun Kim, Ji Hyun Lee, Dong Keon Yon, Gi Bbeum Lee, Seong Hye Ahn, Hwajin Lee, Inwha Baek","doi":"10.1016/j.biopha.2025.118307","DOIUrl":"10.1016/j.biopha.2025.118307","url":null,"abstract":"<p><p>Polo-like kinase 1 (PLK1), a serine/threonine protein kinase, plays a crucial role in essential biological processes such as cell division, DNA damage response, and cell death. Since its dysregulation is highly associated with tumor development and progression, PLK1 inhibitors, including onvansertib, have been developed as promising anti-cancer therapeutics. Onvansertib is currently under Phase II investigation to evaluate its safety and efficacy in patients with relapsed small cell lung cancer (SCLC). In this study, the efficacy, tolerability, and toxicity of onvansertib were comprehensively profiled using a large panel of 144 cancer cell lines and mouse models. We identified that SCLC cell lines are highly responsive to onvansertib. SCLC xenograft assays showed that daily oral administration of onvansertib at 60 mg/kg was more effective in tumor regression without inducing significant changes in body weight compared to a treatment cycle of 3 days of administration followed by 4 days of rest over a 3-week experimental period. However, in vivo toxicity studies revealed onvansertib-related mortality, clinical signs, and hematological adverse effects at the 60 mg/kg dose. Our findings collectively provide experimental evidence to support combination therapies or toxicity-salvaging low-dose regimens, as reflected in current clinical trials of onvansertib. Additionally, we conducted single-cell RNA-sequencing to elucidate the pharmacological mechanisms of onvansertib in SCLC with unprecedented resolution. Onvansertib impairs a normal cell cycle transition by downregulating the cell division process, leading to G2/M phase arrest. Altogether, this work demonstrates the therapeutic mechanisms and in vitro and in vivo pharmacological profiles of onvansertib in SCLC.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"190 ","pages":"118307"},"PeriodicalIF":7.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Synthesis and anti-inflammatory properties of glycosylated cinnamaldehyde derivatives in mice models of colitis and gout.","authors":"Wei-Ting Wong, Lan-Hui Li, Hsiao-Wen Chiu, Po-Yu Chiang, Hsueh-Chen Lu, Chun-Hsien Wu, Chen-Lung Ho, Lee-Chiang Lo, Kuo-Feng Hua","doi":"10.1016/j.biopha.2025.118441","DOIUrl":"10.1016/j.biopha.2025.118441","url":null,"abstract":"<p><p>Cinnamaldehyde, a natural compound with diverse biological activities, has limited biomedical application due to its potential cytotoxicity. In this study, we synthesized a series of novel glycosylated cinnamaldehyde derivatives by varying both the sugar moiety and its attachment position on the aromatic ring. Preliminary screening for cytotoxicity and anti-inflammatory activity revealed that these structural modifications critically influenced bioactivity. Among the derivatives, compound 1a, bearing a β-D-galactosyl group at the para-position of the cinnamaldehyde phenyl ring, exhibited the most promising therapeutic potential. In contrast, replacing the β-D-galactosyl group with β-D-glucosyl (1b) or α-D-mannosyl (1c) residues resulted in loss of anti-inflammatory activity. Similarly, shifting the β-D-galactosyl group to the meta (1d) or ortho (1e) positions also abolished activity, highlighting the importance of both sugar identity and its positional attachment in determining function. Subsequent mechanistic studies focused on compound 1a and its effect on the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, a central mediator in inflammatory disorders. Compound 1a effectively suppressed NLRP3 inflammasome activation by reducing mitochondrial damage and disrupting inflammasome complex assembly in macrophages. Furthermore, 1a promoted Sirt1-mediated autophagy, which contributed to additional inhibition of inflammasome activation. Notably, 1a inhibited not only the NLRP3 inflammasome but also the NLRC4 inflammasome in macrophages. In vivo, oral administration of 1a significantly alleviated both dextran sulfate sodium (DSS)-induced colitis and monosodium urate (MSU)-induced peritonitis in mice, primarily through NLRP3 inflammasome suppression. Collectively, these findings identify compound 1a as a promising lead compound for the treatment of inflammasome-driven inflammatory diseases and underscore the therapeutic potential of rational glycosylation-based modification of cinnamaldehyde.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"190 ","pages":"118441"},"PeriodicalIF":7.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144818654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhifang Zhang, Annie Yang, Anthony K Park, Shyambabu Chaurasiya, Jianming Lu, Sang-In Kim, Hannah Valencia, Courtney Chen, Supriya Deshpande, Yuman Fong, Yanghee Woo
{"title":"CF33-hNIS-antiPDL1 enhances immunogenicity and anti-tumor efficacy in an orthotopic syngeneic pancreatic cancer mouse model.","authors":"Zhifang Zhang, Annie Yang, Anthony K Park, Shyambabu Chaurasiya, Jianming Lu, Sang-In Kim, Hannah Valencia, Courtney Chen, Supriya Deshpande, Yuman Fong, Yanghee Woo","doi":"10.1016/j.biopha.2025.118408","DOIUrl":"10.1016/j.biopha.2025.118408","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by a tumor-protective immune microenvironment that limits the efficacy of current immunotherapeutic agents, underscoring the need for novel strategies. We previously demonstrated that CF33-hNIS-antiPDL1 possesses potent oncolytic properties against human PDAC in vitro and in immunocompromised mouse models. In this study, we investigated the immunogenic properties and therapeutic efficacy of CF33 derivatives in murine pancreatic cancer KPC cells in vitro and in an orthotopic syngeneic mouse model. CF33 derivatives replicated in and killed KPC cells in a dose- and time-dependent manner. KPC cells stained negative for surface PD-L1 but positive for intracellular PD-L1. Treatment with IFNγ and IFNβ1, cytokines involved in viral response and immune regulation, significantly upregulated cell surface PD-L1 expression on KPC cells. Notably, infected KPC cells produced virus-encoded anti-PD-L1 single-chain variable fragment (scFv) that blocked IFNγ/β1-induced surface PD-L1 binding. In vivo, intraperitoneal administration of CF33-hNIS-antiPDL1 significantly prolonged survival in mice bearing orthotopic KPC tumors. This benefit was associated with a notable increase in CD45<sup>+</sup> leukocytes and CD8<sup>+</sup> T cells. In conclusion, CF33-hNIS-antiPDL1 showed both immunogenic and anti-tumor activity against mouse KPC cells in vitro and in vivo, with functional expression of active anti-PD-L1 scFv. These findings support the clinical translation of CF33-hNIS-antiPDL1 as an intraperitoneal therapy in PDAC patients.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"190 ","pages":"118408"},"PeriodicalIF":7.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mariana Neves Amaral, Pradeep Kumar, Pedro Faísca, Hugo Alexandre Ferreira, João M P Coelho, M Manuela Gaspar, Catarina Pinto Reis
{"title":"Gold nanoparticle-mediated photothermal therapy: Expanding the frontiers of cancer treatment and theragnostics.","authors":"Mariana Neves Amaral, Pradeep Kumar, Pedro Faísca, Hugo Alexandre Ferreira, João M P Coelho, M Manuela Gaspar, Catarina Pinto Reis","doi":"10.1016/j.biopha.2025.118399","DOIUrl":"10.1016/j.biopha.2025.118399","url":null,"abstract":"<p><p>Gold nanoparticle (AuNP)-mediated photothermal therapy (PTT) has emerged as a promising approach for cancer treatment, offering high precision, minimal invasiveness, and selective tumor ablation through localized hyperthermia. This review explores the fundamental principles of AuNP-mediated PTT, including the design of AuNPs, synthesis strategies, and surface modifications that enhance their biocompatibility and targeting efficiency. Additionally, the integration of AuNPs with other therapeutic modalities is also discussed, such as chemotherapy, radiotherapy, and immunotherapy, to achieve synergistic treatment outcomes. The theragnostic potential of AuNPs, combining diagnostic imaging with therapeutic applications, is also highlighted, emphasizing their role in personalized medicine. But, despite significant advancements, challenges such as biodistribution, long-term safety, and regulatory approval remain key barriers to clinical translation. Ongoing research is expected to refine AuNP-based PTT, paving the way for its widespread clinical application in cancer treatment.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"190 ","pages":"118399"},"PeriodicalIF":7.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144818649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}