Pub Date : 2026-01-21DOI: 10.1016/j.bcp.2026.117743
Peng Liu , Zhen-Yu Liu , Sui Mao , Li-Chan Lin , Ye Zhang , Jian-Yuan Zhao , Hui Tao
Cardiac fibrosis is regarded as a central mechanism by which different cardiovascular diseases react to a range of pathophysiological stimuli. The key features of cardiac fibrosis include the activation of fibroblasts, abnormal cellular proliferation, excessive extracellular matrix deposition, and an altered distribution of matrix components. As research on cardiac fibrosis advances, it has become increasingly clear that extracellular signals play a crucial role in regulating its initiation and progression. Hence, extracellular vesicles serve as pivotal mediators in intercellular communication, facilitating the transmission of a multitude of epigenetic signals and the conveyance of specific gene expression regulatory factors, thereby exerting a modulating influence on the development of cardiac fibrosis. Extracellular vesicles exhibit a dual role in cardiac fibrosis progression, as they can either promote or inhibit the fibrotic process. This review thoroughly explores the epigenetic regulatory mechanisms of extracellular vesicles (EVs) in mediating the process of cardiac fibrosis, and analyzes potential therapeutic intervention strategies. The research results indicate that extracellular vesicles have significant potential for treating cardiac fibrosis through epigenetic regulation, providing an important theoretical basis for the treatment and clinical application of related diseases.
{"title":"Extracellular vesicles are a double-edged sword in cardiac fibrosis: an epigenetic perspective","authors":"Peng Liu , Zhen-Yu Liu , Sui Mao , Li-Chan Lin , Ye Zhang , Jian-Yuan Zhao , Hui Tao","doi":"10.1016/j.bcp.2026.117743","DOIUrl":"10.1016/j.bcp.2026.117743","url":null,"abstract":"<div><div>Cardiac fibrosis is regarded as a central mechanism by which different cardiovascular diseases react to a range of pathophysiological stimuli. The key features of cardiac fibrosis include the activation of fibroblasts, abnormal cellular proliferation, excessive extracellular matrix deposition, and an altered distribution of matrix components. As research on cardiac fibrosis advances, it has become increasingly clear that extracellular signals play a crucial role in regulating its initiation and progression. Hence, extracellular vesicles serve as pivotal mediators in intercellular communication, facilitating the transmission of a multitude of epigenetic signals and the conveyance of specific gene expression regulatory factors, thereby exerting a modulating influence on the development of cardiac fibrosis. Extracellular vesicles exhibit a dual role in cardiac fibrosis progression, as they can either promote or inhibit the fibrotic process. This review thoroughly explores the epigenetic regulatory mechanisms of extracellular vesicles (EVs) in mediating the process of cardiac fibrosis, and analyzes potential therapeutic intervention strategies. The research results indicate that extracellular vesicles have significant potential for treating cardiac fibrosis through epigenetic regulation, providing an important theoretical basis for the treatment and clinical application of related diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117743"},"PeriodicalIF":5.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040177","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}
Psoriasis is an immune-mediated disease characterized with excessive keratinocyte proliferation and inflammation. In this review, we discuss the involvement of nitric oxide (NO) in the pathogenesis of psoriasis. NO is a molecule widely described in physiological and pathological contexts. One of the best-known functions of NO is its vasodilating activity, critical for a proper functioning of the cardiovascular system. Another important effect induced by NO is a regulation of immunity. Specifically, NO can act pro- and anti-inflammatory, regulating immune cell infiltration and secretion of inflammatory mediators. Furthermore, NO regulates proliferation and differentiation of keratinocytes, a major cell population actively involved in psoriasis development. Current evidence highlights involvement of NO synthase and NO itself in pathophysiological processes associated with psoriasis.
{"title":"The role of nitric oxide in skin inflammation and the pathogenesis of psoriasis","authors":"Marzena Staniszewska, Kajetan Kiełbowski, Estera Bakinowska, Paulina Plewa, Sylwia Słuczanowska-Głąbowska, Andrzej Pawlik","doi":"10.1016/j.bcp.2026.117742","DOIUrl":"10.1016/j.bcp.2026.117742","url":null,"abstract":"<div><div>Psoriasis is an immune-mediated disease characterized with excessive keratinocyte proliferation and inflammation. In this review, we discuss the involvement of nitric oxide (NO) in the pathogenesis of psoriasis. NO is a molecule widely described in physiological and pathological contexts. One of the best-known functions of NO is its vasodilating activity, critical for a proper functioning of the cardiovascular system. Another important effect induced by NO is a regulation of immunity. Specifically, NO can act pro- and anti-inflammatory, regulating immune cell infiltration and secretion of inflammatory mediators. Furthermore, NO regulates proliferation and differentiation of keratinocytes, a major cell population actively involved in psoriasis development. Current evidence highlights involvement of NO synthase and NO itself in pathophysiological processes associated with psoriasis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117742"},"PeriodicalIF":5.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040185","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 : 2026-01-21DOI: 10.1016/j.bcp.2026.117714
Mengdi Ma , Xin Xu , Kexun Yu , Xiongwei Yang , Weidong Qiang , Emre Dal , Yonghong Zhang , Jiangrun Zhu , Ruochuan Sun , Shangxin Zhang , Yongxiang Li
Gastric cancer (GC) is a major cause of morbidity and mortality worldwide; despite recent therapeutic advances, overall prognosis remains dismal due to late-stage diagnosis and therapeutic resistance. Among emerging mechanisms underlying tumor progression and therapeutic vulnerability, ferroptosis is defined as an iron-dependent form of regulated cell death that is characterised by the process of lipid peroxidation, has been increasingly implicated in the initiation and progression of diverse malignancies, including gastric cancer. In parallel, metabolic reprogramming has been recognized as a hallmark of cancer, with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) gaining attention as a key bifunctional metabolic enzyme. By modulating intracellular levels of fructose-2,6-bisphosphate, PFKFB4 orchestrates the balance between glycolysis and the pentose phosphate pathway (PPP), thereby supporting redox homeostasis and anabolic growth. Notably, recent studies have identified aberrant overexpression of PFKFB4 in a range of malignancies, implicating it in tumor progression. Building on this, in the present study, we demonstrated that PFKFB4 is markedly overexpressed in GC cells and modulates their sensitivity to ferroptosis through direct interaction with, and phosphorylation of, Heat Shock Protein Beta-1 (HSPB1), a critical negative regulator of ferroptotic signaling. Importantly, treatment with 5MPN, a specific inhibitor of PFKFB4, significantly potentiates ferroptotic cell death and suppresses GC tumor growth. These findings identify a previously unrecognized function of PFKFB4 in GC, extending beyond its canonical metabolic roles to include active regulation of ferroptosis, thereby promoting cancer progression. Consequently, pharmacological inhibition of PFKFB4 represents a promising therapeutic avenue for overcoming ferroptosis resistance and suppressing tumor progression in gastric cancer.
{"title":"PFKFB4-Mediated HSPB1 phosphorylation suppresses ferroptosis to Promote gastric cancer progression","authors":"Mengdi Ma , Xin Xu , Kexun Yu , Xiongwei Yang , Weidong Qiang , Emre Dal , Yonghong Zhang , Jiangrun Zhu , Ruochuan Sun , Shangxin Zhang , Yongxiang Li","doi":"10.1016/j.bcp.2026.117714","DOIUrl":"10.1016/j.bcp.2026.117714","url":null,"abstract":"<div><div>Gastric cancer (GC) is a major cause of morbidity and mortality worldwide; despite recent therapeutic advances, overall prognosis remains dismal due to late-stage diagnosis and therapeutic resistance. Among emerging mechanisms underlying tumor progression and therapeutic vulnerability, ferroptosis is defined as an iron-dependent form of regulated cell death that is characterised by the process of lipid peroxidation, has been increasingly implicated in the initiation and progression of diverse malignancies, including gastric cancer. In parallel, metabolic reprogramming has been recognized as a hallmark of cancer, with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) gaining attention as a key bifunctional metabolic enzyme. By modulating intracellular levels of fructose-2,6-bisphosphate, PFKFB4 orchestrates the balance between glycolysis and the pentose phosphate pathway (PPP), thereby supporting redox homeostasis and anabolic growth. Notably, recent studies have identified aberrant overexpression of PFKFB4 in a range of malignancies, implicating it in tumor progression. Building on this, in the present study, we demonstrated that PFKFB4 is markedly overexpressed in GC cells and modulates their sensitivity to ferroptosis through direct interaction with, and phosphorylation of, Heat Shock Protein Beta-1 (HSPB1), a critical negative regulator of ferroptotic signaling. Importantly, treatment with 5MPN, a specific inhibitor of PFKFB4, significantly potentiates ferroptotic cell death and suppresses GC tumor growth. These findings identify a previously unrecognized function of PFKFB4 in GC, extending beyond its canonical metabolic roles to include active regulation of ferroptosis, thereby promoting cancer progression. Consequently, pharmacological inhibition of PFKFB4 represents a promising therapeutic avenue for overcoming ferroptosis resistance and suppressing tumor progression in gastric cancer.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117714"},"PeriodicalIF":5.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024768","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 : 2026-01-20DOI: 10.1016/j.bcp.2026.117730
Jinyu Hu , Haoxin Fu , Ruibin Li , Peiqi Wang , Jun Wu , Lu Cao , Chenjian Zhou , Ren-ai Xu
Fexinidazole is a ctirical treatment for Human African trypanosomiasis in Africa, but its metabolic characteristics are not fully understood. This study investigated the impacts of CYP3A4 genetic polymorphisms and (−)-epigallocatechin gallate (EGCG) on the metabolism of fexinidazole in vitro (rat liver microsomes (RLM), human liver mircosomes (HLM), and nine CYP3A4 variants) and in vivo (rat) models. Ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was utilized to quantify fexinidazole and its metabolites. The results showed that fexinidazole was metabolized mainly by CYP3A4, which was significantly modulated by CYP3A4 polymorphisms. In addition, EGCG significantly inhibited the metabolism of fexinidazole in both RLM (IC50 = 8.02 ± 0.28 μM) and HLM (IC50 = 9.97 ± 0.43 μM) via mixed-type inhibition mechanisms. In vivo, co-administration of EGCG significantly altered the pharmacokinetic parameters of fexinidazole, increasing the AUC and Cmax by approximately 1.46 and 1.44-fold, respectively, while decreasing clearance (CLz/F). Furthermore, continuous administration of EGCG significantly downregulated key hepatic CYP450 (CYP3a1, CYP2d1/2, CYP2b1/2, and CYP2c11) at both the protein and mRNA levels. This study elucidated the major metabolic pathways of fexinidazole and reported the effects of genetic polymorphisms and the drug EGCG on its metabolism for the first time.
{"title":"Effects of CYP3A4 variants and drug–drug interactions on the metabolism of fexinidazole","authors":"Jinyu Hu , Haoxin Fu , Ruibin Li , Peiqi Wang , Jun Wu , Lu Cao , Chenjian Zhou , Ren-ai Xu","doi":"10.1016/j.bcp.2026.117730","DOIUrl":"10.1016/j.bcp.2026.117730","url":null,"abstract":"<div><div>Fexinidazole is a ctirical treatment for Human African trypanosomiasis in Africa, but its metabolic characteristics are not fully understood. This study investigated the impacts of CYP3A4 genetic polymorphisms and (−)-epigallocatechin gallate (EGCG) on the metabolism of fexinidazole <em>in vitro</em> (rat liver microsomes (RLM), human liver mircosomes (HLM), and nine CYP3A4 variants) and <em>in vivo</em> (rat) models. Ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was utilized to quantify fexinidazole and its metabolites. The results showed that fexinidazole was metabolized mainly by CYP3A4, which was significantly modulated by CYP3A4 polymorphisms. In addition, EGCG significantly inhibited the metabolism of fexinidazole in both RLM (IC<sub>50</sub> = 8.02 ± 0.28 μM) and HLM (IC<sub>50</sub> = 9.97 ± 0.43 μM) via mixed-type inhibition mechanisms. <em>In vivo</em>, co-administration of EGCG significantly altered the pharmacokinetic parameters of fexinidazole, increasing the AUC and C<sub>max</sub> by approximately 1.46 and 1.44-fold, respectively, while decreasing clearance (CL<sub>z/F</sub>). Furthermore, continuous administration of EGCG significantly downregulated key hepatic CYP450 (CYP3a1, CYP2d1/2, CYP2b1/2, and CYP2c11) at both the protein and mRNA levels. This study elucidated the major metabolic pathways of fexinidazole and reported the effects of genetic polymorphisms and the drug EGCG on its metabolism for the first time.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117730"},"PeriodicalIF":5.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028337","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 : 2026-01-20DOI: 10.1016/j.bcp.2026.117724
Jia Li , Abdulkareem Qasem Moqbel , Yongzhao Wang , Erhu Zhao , Muhammad Usman Ghani , Ping Liang
Glioblastoma (GBM) is one of the most aggressive, fast-growing, and therapeutically challenging brain tumors. The difficulty in managing GBM stems from its genetic instability and the intricately complex tumor microenvironment (TME). Within the TME, intricate interactions between neoplastic cells and signaling mediators drive tumor progression. Despite advances in current treatments, obstacles such as the blood–brain barrier (BBB) and pronounced inter- and intratumoral heterogeneity continue to hinder therapeutic success. Consequently, research efforts have increasingly focused on immunotherapeutic strategies that combine immune checkpoint inhibitors (ICIs) with standard-of-care (SOC) treatments or other immune-remodeling modalities, which seek to reprogram the tumor landscape and restore robust, durable anti-tumor responses. In this context, chemoradiation and oncolytic viruses induce immunogenic cell death and activate innate immunity, creating opportunities for checkpoint inhibitors to amplify T-cell responses. Complementing these strategies, engineered CAR-T cells and myeloid-targeting agents address tumor antigen loss and macrophage-mediated suppression of the immune response. Together, by targeting these complementary resistance mechanisms, combination regimens hold the potential to transform the immunologically ‘cold’ GBM TME into an inflamed and treatment-responsive state. Collectively, these combinatorial approaches converge to remodel the GBM microenvironment, enhancing dendritic cell (DC) activation, promoting T-cell infiltration, and thereby promoting durable anti-tumor immunity, as well as extending survival. This review provides a comprehensive analysis of the TME’s role in GBM progression, highlighting the latest immunotherapeutic advances designed to address TME-related obstacles and enhance therapeutic efficacy and patient survival.
{"title":"Unraveling the glioblastoma (GBM) tumor microenvironment: future perspective on targeted immunotherapy","authors":"Jia Li , Abdulkareem Qasem Moqbel , Yongzhao Wang , Erhu Zhao , Muhammad Usman Ghani , Ping Liang","doi":"10.1016/j.bcp.2026.117724","DOIUrl":"10.1016/j.bcp.2026.117724","url":null,"abstract":"<div><div>Glioblastoma (GBM) is one of the most aggressive, fast-growing, and therapeutically challenging brain tumors. The difficulty in managing GBM stems from its genetic instability and the intricately complex tumor microenvironment (TME). Within the TME, intricate interactions between neoplastic cells and signaling mediators drive tumor progression. Despite advances in current treatments, obstacles such as the blood–brain barrier (BBB) and pronounced inter- and intratumoral heterogeneity continue to hinder therapeutic success. Consequently, research efforts have increasingly focused on immunotherapeutic strategies that combine immune checkpoint inhibitors (ICIs) with standard-of-care (SOC) treatments or other immune-remodeling modalities, which seek to reprogram the tumor landscape and restore robust, durable anti-tumor responses. In this context, chemoradiation and oncolytic viruses induce immunogenic cell death and activate innate immunity, creating opportunities for checkpoint inhibitors to amplify T-cell responses. Complementing these strategies, engineered CAR-T cells and myeloid-targeting agents address tumor antigen loss and macrophage-mediated suppression of the immune response. Together, by targeting these complementary resistance mechanisms, combination regimens hold the potential to transform the immunologically ‘cold’ GBM TME into an inflamed and treatment-responsive state. Collectively, these combinatorial approaches converge to remodel the GBM microenvironment, enhancing dendritic cell (DC) activation, promoting T-cell infiltration, and thereby promoting durable anti-tumor immunity, as well as extending survival. This review provides a comprehensive analysis of the TME’s role in GBM progression, highlighting the latest immunotherapeutic advances designed to address TME-related obstacles and enhance therapeutic efficacy and patient survival.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117724"},"PeriodicalIF":5.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028357","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 : 2026-01-20DOI: 10.1016/j.bcp.2026.117728
Seung Yeon Lee , Anh Thi Ngoc Bui , Tuyet Ngan Thai , Gi Ho Lee , Minseo Kim , Su Yeon Kim , Jeonghwan Maeng , Jae-Kyung Jung , Moo-Yeol Lee , Sang Ki Lee , Hwi-yeol Yun , Nam Doo Kim , Eun Hee Han , Hye Gwang Jeong
Humulus lupulus L. (hops), which is traditionally used in brewing, is a rich botanical source of prenylated flavonoids with potential cardiovascular protective properties. Of these, 8-prenylnaringenin (8-PN), a potent phytoestrogen formed from isoxanthohumol by the gut microbiota, has been implicated in vascular health. Nitric oxide (NO), which is produced by endothelial nitric oxide synthase (eNOS), exerts profound effects on vascular tone and endothelial integrity. This study examined the protective effects of 8-PN on endothelial signaling and vascular function using in vitro endothelial cell assays, ex vivo isolated artery preparations, and an in vivo mouse model of Angiotensin II (Ang II)-induced endothelial dysfunction. In endothelial cells, 8-PN increased phosphorylation of eNOS on Ser1177 and NO production through G-protein coupled estrogen receptor (GPER)-mediated Ca2+-dependent signaling pathways involving phosphorylation of Ca2+/calmodulin-dependent protein kinase β (CaMKKβ) and AMPK-activated protein kinase (AMPK). Furthermore, 8-PN activated eNOS via GPER-mediated epidermal growth factor receptor (EGFR) activation, with c-Src facilitating phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-related kinase (ERK) phosphorylation. Molecular docking results indicated that 8-PN could bind to GPER and facilitate the activation of downstream signaling cascades. Both of 8-PN-mediated eNOS phosphorylation are mediated through the Gβγ subunit. In vivo, 8-PN attenuated angiotensin II-induced endothelial dysfunction in mice and induced vasorelaxation in vivo. 8-PN stimulated eNOS phosphorylation and NO production via dual GPER-dependent pathways, supporting its potential as a therapeutic candidate for endothelial dysfunction-related vascular diseases.
{"title":"Gut microbiota-derived isoxanthohumol metabolite, 8-prenylnaringenin, mitigates endothelial dysfunction in Angiotensin II-induced hypertension through G protein-coupled estrogen receptor-mediated eNOS activation","authors":"Seung Yeon Lee , Anh Thi Ngoc Bui , Tuyet Ngan Thai , Gi Ho Lee , Minseo Kim , Su Yeon Kim , Jeonghwan Maeng , Jae-Kyung Jung , Moo-Yeol Lee , Sang Ki Lee , Hwi-yeol Yun , Nam Doo Kim , Eun Hee Han , Hye Gwang Jeong","doi":"10.1016/j.bcp.2026.117728","DOIUrl":"10.1016/j.bcp.2026.117728","url":null,"abstract":"<div><div><em>Humulus lupulus</em> L. (hops), which is traditionally used in brewing, is a rich botanical source of prenylated flavonoids with potential cardiovascular protective properties. Of these, 8-prenylnaringenin (8-PN), a potent phytoestrogen formed from isoxanthohumol by the gut microbiota, has been implicated in vascular health. Nitric oxide (NO), which is produced by endothelial nitric oxide synthase (eNOS), exerts profound effects on vascular tone and endothelial integrity. This study examined the protective effects of 8-PN on endothelial signaling and vascular function using <em>in vitro</em> endothelial cell assays, <em>ex vivo</em> isolated artery preparations, and an <em>in vivo</em> mouse model of Angiotensin II (Ang II)-induced endothelial dysfunction. In endothelial cells, 8-PN increased phosphorylation of eNOS on Ser1177 and NO production through G-protein coupled estrogen receptor (GPER)-mediated Ca<sup>2+</sup>-dependent signaling pathways involving phosphorylation of Ca<sup>2+</sup>/calmodulin-dependent protein kinase β (CaMKKβ) and AMPK-activated protein kinase (AMPK). Furthermore, 8-PN activated eNOS via GPER-mediated epidermal growth factor receptor (EGFR) activation, with c-Src facilitating phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-related kinase (ERK) phosphorylation. Molecular docking results indicated that 8-PN could bind to GPER and facilitate the activation of downstream signaling cascades. Both of 8-PN-mediated eNOS phosphorylation are mediated through the Gβγ subunit. <em>In vivo</em>, 8-PN attenuated angiotensin II-induced endothelial dysfunction in mice and induced vasorelaxation <em>in vivo.</em> 8-PN stimulated eNOS phosphorylation and NO production via dual GPER-dependent pathways, supporting its potential as a therapeutic candidate for endothelial dysfunction-related vascular diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117728"},"PeriodicalIF":5.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024476","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 : 2026-01-20DOI: 10.1016/j.bcp.2026.117729
Yujie Li , Tingru Dong , Jiamin Wu , Fenglan Yang , Shiyu Jin , Renxue Xiong , Meiya Li , Xiuzu Song , Cuiping Guan
Androgenetic alopecia (AGA) is a progressive hair loss disorder characterized by follicular miniaturization primarily driven by dihydrotestosterone (DHT). Mitochondrial dysfunction in dermal papilla cells (DPCs) has emerged as a key pathological feature, yet the upstream regulatory mechanisms remain unclear. Our previous work revealed that the mitochondria-targeted antioxidant MitoQ upregulates CYP19A1 (aromatase) and alleviates AGA-like pathology. Here, we investigated whether CYP19A1 modulates mitochondrial function and mediates the protective effects of MitoQ. Using a DHT-induced AGA mouse model and DPCs with CYP19A1 knockdown or overexpression, we examined hormone profiles, mitochondrial activity, and hair growth–related factors. DHT markedly reduced CYP19A1 expression and increased inhibitory factors such as DKK1, TGF-β, and IL-6, whereas CYP19A1 overexpression or MitoQ pretreatment reversed these effects. Both CYP19A1 and MitoQ decreased mitochondrial reactive oxygen species (mtROS), improved respiratory capacity, and preserved mitochondrial morphology. Importantly, our findings reveal a previously unrecognized aromatase–mitochondria cross-talk in hair-follicle cells, whereby CYP19A1-derived estrogens sustain mitochondrial homeostasis under androgenic stress. MitoQ amplifies this cross-talk through CYP19A1 activation, restoring redox balance and mitochondrial integrity. Collectively, these results identify CYP19A1 as a pivotal regulator of mitochondrial resilience and suggest that the CYP19A1–mitochondrial axis represents a promising pharmacological target for treating AGA.
{"title":"MitoQ upregulates CYP19A1 to protect dermal papilla cells from DHT-induced mitochondrial dysfunction and apoptosis in androgenetic alopecia","authors":"Yujie Li , Tingru Dong , Jiamin Wu , Fenglan Yang , Shiyu Jin , Renxue Xiong , Meiya Li , Xiuzu Song , Cuiping Guan","doi":"10.1016/j.bcp.2026.117729","DOIUrl":"10.1016/j.bcp.2026.117729","url":null,"abstract":"<div><div>Androgenetic alopecia (AGA) is a progressive hair loss disorder characterized by follicular miniaturization primarily driven by dihydrotestosterone (DHT). Mitochondrial dysfunction in dermal papilla cells (DPCs) has emerged as a key pathological feature, yet the upstream regulatory mechanisms remain unclear. Our previous work revealed that the mitochondria-targeted antioxidant MitoQ upregulates CYP19A1 (aromatase) and alleviates AGA-like pathology. Here, we investigated whether CYP19A1 modulates mitochondrial function and mediates the protective effects of MitoQ. Using a DHT-induced AGA mouse model and DPCs with <em>CYP19A1</em> knockdown or overexpression, we examined hormone profiles, mitochondrial activity, and hair growth–related factors. DHT markedly reduced <em>CYP19A1</em> expression and increased inhibitory factors such as DKK1, TGF-β, and IL-6, whereas <em>CYP19A1</em> overexpression or MitoQ pretreatment reversed these effects. Both CYP19A1 and MitoQ decreased mitochondrial reactive oxygen species (mtROS), improved respiratory capacity, and preserved mitochondrial morphology. Importantly, our findings reveal a previously unrecognized aromatase–mitochondria cross-talk in hair-follicle cells, whereby CYP19A1-derived estrogens sustain mitochondrial homeostasis under androgenic stress. MitoQ amplifies this cross-talk through CYP19A1 activation, restoring redox balance and mitochondrial integrity. Collectively, these results identify CYP19A1 as a pivotal regulator of mitochondrial resilience and suggest that the CYP19A1–mitochondrial axis represents a promising pharmacological target for treating AGA.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117729"},"PeriodicalIF":5.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024709","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 : 2026-01-20DOI: 10.1016/j.bcp.2026.117733
Hongwei Lu , Weifeng Liu , Yanfang Zhu, Ting Wen, Yan Deng, Chunhong Yu, Zhuotao Zheng, Shiyu Liu, Xiaolong Yin, Yunwei Hu
Ginkgolide B (GB) protects against diabetes complications, yet its role in diabetic retinopathy (DR) and the underlying mechanisms remain poorly understood. This study aims to elucidate the therapeutic mechanisms of GB in DR.
A high-fat diet (HFD) combined with streptozotocin (STZ)-induced diabetic mouse model and a high-glucose-treated human retinal microvascular endothelial cell (hRMEC) model were used to explore the effects of GB on diabetes-induced retinal dysfunction. Both of them were treated with GB or the ferroptosis inhibitor ferrostatin-1 (Fer-1). Our in vitro and in vivo experiments demonstrated that glucolipotoxicity impairs vascular endothelial function and elevates ferroptosis levels. GB treatment improved retinal thickness and vascular barrier function in DR mice by suppressing ferroptosis. Furthermore, GB treatment improved hRMECs cell viability, proliferation, migration, and tube formation activity also by attenuating ferroptosis. Utilizing a network pharmacology (NP) approach, we identified translocator protein (TSPO) as a key target of GB in protection of DR, inhibition of TSPO markedly abolished the therapeutic benefits of GB in DR. Mechanistically, glucolipotoxicity suppressed the TSPO/nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway, whereas GB treatment restored its activity, ultimately leading to the inhibition of ferroptosis.
GB protects cells and tissues from glucolipotoxicity in DR models by inhibiting ferroptosis through promoting TSPO/Nrf2 signaling. Administration of GB in diabetic patients may delay the onset of retinopathy or alleviate the progression of diabetic retinopathy.
{"title":"Ginkgolide B alleviates diabetic retinopathy by inhibiting ferroptosis in retinal vascular endothelial cells via the TSPO/Nrf2 pathway","authors":"Hongwei Lu , Weifeng Liu , Yanfang Zhu, Ting Wen, Yan Deng, Chunhong Yu, Zhuotao Zheng, Shiyu Liu, Xiaolong Yin, Yunwei Hu","doi":"10.1016/j.bcp.2026.117733","DOIUrl":"10.1016/j.bcp.2026.117733","url":null,"abstract":"<div><div>Ginkgolide B (GB) protects against diabetes complications, yet its role in diabetic retinopathy (DR) and the underlying mechanisms remain poorly understood. This study aims to elucidate the therapeutic mechanisms of GB in DR.</div><div>A high-fat diet (HFD) combined with streptozotocin (STZ)-induced diabetic mouse model and a high-glucose-treated human retinal microvascular endothelial cell (hRMEC) model were used to explore the effects of GB on diabetes-induced retinal dysfunction. Both of them were treated with GB or the ferroptosis inhibitor ferrostatin-1 (Fer-1). Our in vitro and in vivo experiments demonstrated that glucolipotoxicity impairs vascular endothelial function and elevates ferroptosis levels. GB treatment improved retinal thickness and vascular barrier function in DR mice by suppressing ferroptosis. Furthermore, GB treatment improved hRMECs cell viability, proliferation, migration, and tube formation activity also by attenuating ferroptosis. Utilizing a network pharmacology (NP) approach, we identified translocator protein (TSPO) as a key target of GB in protection of DR, inhibition of TSPO markedly abolished the therapeutic benefits of GB in DR. Mechanistically, glucolipotoxicity suppressed the TSPO/nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway, whereas GB treatment restored its activity, ultimately leading to the inhibition of ferroptosis.</div><div>GB protects cells and tissues from glucolipotoxicity in DR models by inhibiting ferroptosis through promoting TSPO/Nrf2 signaling. Administration of GB in diabetic patients may delay the onset of retinopathy or alleviate the progression of diabetic retinopathy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117733"},"PeriodicalIF":5.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024710","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 : 2026-01-20DOI: 10.1016/j.bcp.2026.117731
Yanwei Wang , Ziwei Han , Shanshan Pan , Minsong Guo , Meihong Wu , Xuesong Liu , Yuan Zhou , Jiahui Zhao , Yong Chen , Tengfei Xu
Diabetes significantly increases the risk of Parkinson’s disease (PD), and mitochondrial dysfunction is considered a shared pathological mechanism between diabetes and PD. Although our previous research indicated that shikonin ameliorates hyperglycemia-driven PD progression through dual regulation of glycolysis (via inhibition of pyruvate kinase muscle isozyme 2) and mitochondrial function, its mitochondrial repair mechanism remains unclear. Here, we demonstrate that shikonin repairs neuronal damage induced by high glucose and 6-hydroxydopamine via a PKM2-independent, p53/Solute Carrier Family 25 Member 28 (SLC25A28)-dependent mitochondrial iron shuttle. Proteomic analysis revealed that shikonin activates the SLC25A28–cytochrome c axis, maintaining mitochondrial Fe2+ homeostasis. Molecular validation confirmed that shikonin directly binds to p53 (isothermal titration calorimetry KD = 6.3 μM), promotes mitochondrial translocation of p53, and subsequently activates SLC25A28. This process facilitates Fe2+-dependent assembly of the cytochrome c/cytochrome c oxidase subunit 4 complex, restoring oxidative phosphorylation. Our work uncovers the p53/SLC25A28 axis as a target for shikonin-mediated mitochondrial iron homeostasis, providing a therapeutic strategy for diabetes-associated PD.
{"title":"Shikonin attenuates diabetic Parkinsonian neuronal injury by facilitating p53/SLC25A28-mediated iron shuttling","authors":"Yanwei Wang , Ziwei Han , Shanshan Pan , Minsong Guo , Meihong Wu , Xuesong Liu , Yuan Zhou , Jiahui Zhao , Yong Chen , Tengfei Xu","doi":"10.1016/j.bcp.2026.117731","DOIUrl":"10.1016/j.bcp.2026.117731","url":null,"abstract":"<div><div>Diabetes significantly increases the risk of Parkinson’s disease (PD), and mitochondrial dysfunction is considered a shared pathological mechanism between diabetes and PD. Although our previous research indicated that shikonin ameliorates hyperglycemia-driven PD progression through dual regulation of glycolysis (via inhibition of pyruvate kinase muscle isozyme 2) and mitochondrial function, its mitochondrial repair mechanism remains unclear. Here, we demonstrate that shikonin repairs neuronal damage induced by high glucose and 6-hydroxydopamine via a PKM2-independent, p53/Solute Carrier Family 25 Member 28 (SLC25A28)-dependent mitochondrial iron shuttle. Proteomic analysis revealed that shikonin activates the SLC25A28–cytochrome <em>c</em> axis, maintaining mitochondrial Fe<sup>2+</sup> homeostasis. Molecular validation confirmed that shikonin directly binds to p53 (isothermal titration calorimetry K<sub>D</sub> = 6.3 μM), promotes mitochondrial translocation of p53, and subsequently activates SLC25A28. This process facilitates Fe<sup>2+</sup>-dependent assembly of the cytochrome <em>c</em>/cytochrome <em>c</em> oxidase subunit 4 complex, restoring oxidative phosphorylation. Our work uncovers the p53/SLC25A28 axis as a target for shikonin-mediated mitochondrial iron homeostasis, providing a therapeutic strategy for diabetes-associated PD.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117731"},"PeriodicalIF":5.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024711","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 : 2026-01-20DOI: 10.1016/j.bcp.2026.117725
Benedetta Barzon , Federica Marchiotto , Sofia Nasini , Antonino Casile , Sabina Peluso , Carlo Cifani , Nikolaos Pitsikas , Gabriella Gobbi , Marco Cambiaghi , Stefano Comai
Schizophrenia (SCZ) is a chronic psychiatric disorder characterized by positive, negative, and cognitive symptoms that remain insufficiently controlled by current dopamine- and serotonin-based antipsychotics. Emerging evidence implicates melatonin MT2 receptors in the regulation of the sleep-wake cycle, circadian rhythms and cortical inhibition, both altered in SCZ. Here, we investigated the neuropharmacological effects of the selective MT2 partial agonist UCM924 in the MK-801 model of SCZ-like dysfunctions in male mice. UCM924 (10 mg/kg, intraperitoneally) was selected as a dose not affecting basal locomotion. Acute administration of MK-801 (0.3 mg/kg) induced hyperlocomotion, social interaction abnormalities, and impaired spatial working memory. UCM924 normalized MK-801-induced hyperactivity and social deficits but did not improve cognitive performance. Immunofluorescence analysis revealed that UCM924 increased c-Fos activation in parvalbumin-positive interneurons of the prefrontal cortex, with no effect on tyrosine hydroxylase-positive neurons in the ventral tegmental area. Local field potential recordings showed that UCM924 alone reduced gamma-band power (12–90 Hz) in both regions, whereas MK-801 markedly enhanced it. Co-administration of MK-801 and UCM924 resulted in MK-801-dominant oscillatory patterns, suggesting limited efficacy of MT2 activation in restoring network synchronization. These findings indicate that MT2 receptor stimulation selectively enhances prefrontal inhibitory tone and ameliorates behavioral abnormalities related to positive-like and negative-like symptoms, without normalizing cognitive and electrophysiological deficits. Overall, MT2 receptor-selective drugs may represent promising candidates for targeting specific symptom domains in SCZ through mechanisms distinct from current antipsychotics.
{"title":"Neurophysiological and neuropharmacological effects of melatonin MT2 receptors activation in MK-801-induced schizophrenia-like dysfunctions","authors":"Benedetta Barzon , Federica Marchiotto , Sofia Nasini , Antonino Casile , Sabina Peluso , Carlo Cifani , Nikolaos Pitsikas , Gabriella Gobbi , Marco Cambiaghi , Stefano Comai","doi":"10.1016/j.bcp.2026.117725","DOIUrl":"10.1016/j.bcp.2026.117725","url":null,"abstract":"<div><div>Schizophrenia (SCZ) is a chronic psychiatric disorder characterized by positive, negative, and cognitive symptoms that remain insufficiently controlled by current dopamine- and serotonin-based antipsychotics. Emerging evidence implicates melatonin MT2 receptors in the regulation of the sleep-wake cycle, circadian rhythms and cortical inhibition, both altered in SCZ. Here, we investigated the neuropharmacological effects of the selective MT2 partial agonist UCM924 in the MK-801 model of SCZ-like dysfunctions in male mice. UCM924 (10 mg/kg, intraperitoneally) was selected as a dose not affecting basal locomotion. Acute administration of MK-801 (0.3 mg/kg) induced hyperlocomotion, social interaction abnormalities, and impaired spatial working memory. UCM924 normalized MK-801-induced hyperactivity and social deficits but did not improve cognitive performance. Immunofluorescence analysis revealed that UCM924 increased c-Fos activation in parvalbumin-positive interneurons of the prefrontal cortex, with no effect on tyrosine hydroxylase-positive neurons in the ventral tegmental area. Local field potential recordings showed that UCM924 alone reduced gamma-band power (12–90 Hz) in both regions, whereas MK-801 markedly enhanced it. Co-administration of MK-801 and UCM924 resulted in MK-801-dominant oscillatory patterns, suggesting limited efficacy of MT2 activation in restoring network synchronization. These findings indicate that MT2 receptor stimulation selectively enhances prefrontal inhibitory tone and ameliorates behavioral abnormalities related to positive-like and negative-like symptoms, without normalizing cognitive and electrophysiological deficits. Overall, MT2 receptor-selective drugs may represent promising candidates for targeting specific symptom domains in SCZ through mechanisms distinct from current antipsychotics.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117725"},"PeriodicalIF":5.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028303","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}
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