Pub Date : 2026-01-31DOI: 10.1016/j.biopha.2026.119064
Yi Leng, Yuhang Gao, Jianzeng Zhang, Xin Qi
Osteoarthritis (OA) remains a formidable global health challenge, characterized by progressive articular cartilage degradation and a lack of effective disease-modifying interventions. Extracellular vesicles (EVs), previously categorized as mere cellular debris, have recently emerged as pivotal orchestrators of intercellular communication within the joint microenvironment. This review critically examines the dichotomous nature of EVs in OA. We characterize how endogenous EVs from stressed joint tissues drive pathology by disseminating pro-inflammatory and catabolic signals. Conversely, we highlight the therapeutic promise of exogenous EVs-particularly those derived from mesenchymal stem cells-as potent, cell-free regenerative agents capable of immunomodulation and cartilage repair. Beyond their biological roles, we discuss the emerging utility of synovial fluid EVs as liquid biopsies for early diagnosis and disease stratification. Finally, we address key translational bottlenecks, which demand standardization according to Minimal Information for Studies of Extracellular Vesicles 2023 (MISEV2023) to accelerate clinical application.
{"title":"The dual role of extracellular vesicles in OA: Pathological mediators, diagnostic biomarkers, and therapeutic targets","authors":"Yi Leng, Yuhang Gao, Jianzeng Zhang, Xin Qi","doi":"10.1016/j.biopha.2026.119064","DOIUrl":"10.1016/j.biopha.2026.119064","url":null,"abstract":"<div><div>Osteoarthritis (OA) remains a formidable global health challenge, characterized by progressive articular cartilage degradation and a lack of effective disease-modifying interventions. Extracellular vesicles (EVs), previously categorized as mere cellular debris, have recently emerged as pivotal orchestrators of intercellular communication within the joint microenvironment. This review critically examines the dichotomous nature of EVs in OA. We characterize how endogenous EVs from stressed joint tissues drive pathology by disseminating pro-inflammatory and catabolic signals. Conversely, we highlight the therapeutic promise of exogenous EVs-particularly those derived from mesenchymal stem cells-as potent, cell-free regenerative agents capable of immunomodulation and cartilage repair. Beyond their biological roles, we discuss the emerging utility of synovial fluid EVs as liquid biopsies for early diagnosis and disease stratification. Finally, we address key translational bottlenecks, which demand standardization according to Minimal Information for Studies of Extracellular Vesicles 2023 (MISEV2023) to accelerate clinical application.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"196 ","pages":"Article 119064"},"PeriodicalIF":7.5,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076944","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}
Calcimimetics such as etelcalcetide (ET) are used to manage secondary hyperparathyroidism patients with chronic kidney disease (CKD) on dialysis. While their cardiovascular benefits—including left ventricular hypertrophy (LVH) suppression—are recognized, the underlying mechanisms remain unclear. This study investigated how ET suppresses LVH using rat models.
Methods
LVH was induced via transverse aortic coarctation, and CKD by 5/6 nephrectomy. Rats were assigned to the sham, CKD, LVH, or CKD/LVH groups, with each pathological group further divided into vehicle- or ET-treated subgroups. After eight weeks of treatment, echocardiography, histological, biochemical, and molecular analyses were conducted.
Results
ET reduced serum parathyroid hormone and fibroblast growth factor 23 (FGF23) levels in the CKD and CKD/LVH groups but not in the LVH group, where these levels were not increased. ET did not affect serum calcium, phosphorus, or vitamin D levels in the LVH and CKD/LVH groups. Nonetheless, ET suppressed cardiac hypertrophy and cardiomyocyte enlargement in the LVH and CKD/LVH groups despite no changes in systemic mineral metabolism parameters. Mechanistically, ET attenuated cardiac hypertrophy, serum aldosterone levels, and cardiac renin-angiotensin-aldosterone system (RAAS) components in the LVH and CKD/LVH groups. Cardiac FGF23 expression, elevated in the LVH and CKD/LVH groups, was also decreased by ET. The calcineurin/nuclear factor of the activated T-cell signaling pathway was unaffected.
Conclusion
ET effectively suppressed LVH in the LVH and CKD/LVH groups. These findings suggest that ET’s cardioprotective effects are mediated via the modulation of the RAAS and cardiac FGF23 expression rather than solely through the correction of CKD-mineral bone disorder abnormalities.
{"title":"The calcimimetic etelcalcetide attenuates pressure overload–induced cardiac hypertrophy in rats with and without chronic kidney disease","authors":"Hidehisa Okamoto, Shunsuke Goto, Yuma Nose, Hayaki Okamoto, Hideki Fujii","doi":"10.1016/j.biopha.2026.119054","DOIUrl":"10.1016/j.biopha.2026.119054","url":null,"abstract":"<div><h3>Introduction</h3><div>Calcimimetics such as etelcalcetide (ET) are used to manage secondary hyperparathyroidism patients with chronic kidney disease (CKD) on dialysis. While their cardiovascular benefits—including left ventricular hypertrophy (LVH) suppression—are recognized, the underlying mechanisms remain unclear. This study investigated how ET suppresses LVH using rat models.</div></div><div><h3>Methods</h3><div>LVH was induced via transverse aortic coarctation, and CKD by 5/6 nephrectomy. Rats were assigned to the sham, CKD, LVH, or CKD/LVH groups, with each pathological group further divided into vehicle- or ET-treated subgroups. After eight weeks of treatment, echocardiography, histological, biochemical, and molecular analyses were conducted.</div></div><div><h3>Results</h3><div>ET reduced serum parathyroid hormone and fibroblast growth factor 23 (FGF23) levels in the CKD and CKD/LVH groups but not in the LVH group, where these levels were not increased. ET did not affect serum calcium, phosphorus, or vitamin D levels in the LVH and CKD/LVH groups. Nonetheless, ET suppressed cardiac hypertrophy and cardiomyocyte enlargement in the LVH and CKD/LVH groups despite no changes in systemic mineral metabolism parameters. Mechanistically, ET attenuated cardiac hypertrophy, serum aldosterone levels, and cardiac renin-angiotensin-aldosterone system (RAAS) components in the LVH and CKD/LVH groups. Cardiac FGF23 expression, elevated in the LVH and CKD/LVH groups, was also decreased by ET. The calcineurin/nuclear factor of the activated T-cell signaling pathway was unaffected.</div></div><div><h3>Conclusion</h3><div>ET effectively suppressed LVH in the LVH and CKD/LVH groups. These findings suggest that ET’s cardioprotective effects are mediated via the modulation of the RAAS and cardiac FGF23 expression rather than solely through the correction of CKD-mineral bone disorder abnormalities.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"196 ","pages":"Article 119054"},"PeriodicalIF":7.5,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071122","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 : 2026-01-24DOI: 10.1016/j.biopha.2026.119027
Dan Chen , Chuanjun Lu , Meiling Wang , Xiaoyong Wei
Diabetic cataract (DC) is a major cause of vision impairment, partly driven by the pathological roles of aldose reductase (AR) and inducible nitric oxide synthase (iNOS). Gigantol, a bibenzyl compound derived from Dendrobium, has shown potential in preventing DC, yet its molecular mechanism remains incompletely understood. In this study, we investigated the modulation of conformational integrity and aggregation propensity of AR/iNOS by gigantol using fluorescent labeling, fluorescence resonance energy transfer (FRET), single-molecule imaging in living cells, fluorescence spectroscopy, confocal Raman spectroscopy, and atomic force microscopy (AFM). FRET analysis revealed interaction distances of 3.02 ± 0.22 nm for gigantol-AR and 5.07 ± 0.23 nm for gigantol-iNOS, with energy transfer efficiencies of 38.37 ± 4.76 % and 28.15 ± 3.52 %, respectively. Gigantol spontaneously bound to AR and iNOS via hydrogen bonds and van der Waals forces, inducing conformational changes in tyrosine and tryptophan microenvironments. Raman spectroscopy indicated significant alterations in α-helix and β-sheet structures, and AFM directly visualized protein aggregation upon gigantol treatment. These findings demonstrate that gigantol disrupts the conformational integrity of AR and iNOS and promotes their aggregation, thereby inhibiting their activity and providing a molecular basis for its anti-DC potential.
{"title":"Gigantol disrupts AR and iNOS conformation and promotes aggregation through direct molecular interaction to suppress diabetic cataract","authors":"Dan Chen , Chuanjun Lu , Meiling Wang , Xiaoyong Wei","doi":"10.1016/j.biopha.2026.119027","DOIUrl":"10.1016/j.biopha.2026.119027","url":null,"abstract":"<div><div>Diabetic cataract (DC) is a major cause of vision impairment, partly driven by the pathological roles of aldose reductase (AR) and inducible nitric oxide synthase (iNOS). Gigantol, a bibenzyl compound derived from <em>Dendrobium</em>, has shown potential in preventing DC, yet its molecular mechanism remains incompletely understood. In this study, we investigated the modulation of conformational integrity and aggregation propensity of AR/iNOS by gigantol using fluorescent labeling, fluorescence resonance energy transfer (FRET), single-molecule imaging in living cells, fluorescence spectroscopy, confocal Raman spectroscopy, and atomic force microscopy (AFM). FRET analysis revealed interaction distances of 3.02 ± 0.22 nm for gigantol-AR and 5.07 ± 0.23 nm for gigantol-iNOS, with energy transfer efficiencies of 38.37 ± 4.76 % and 28.15 ± 3.52 %, respectively. Gigantol spontaneously bound to AR and iNOS via hydrogen bonds and van der Waals forces, inducing conformational changes in tyrosine and tryptophan microenvironments. Raman spectroscopy indicated significant alterations in α-helix and β-sheet structures, and AFM directly visualized protein aggregation upon gigantol treatment. These findings demonstrate that gigantol disrupts the conformational integrity of AR and iNOS and promotes their aggregation, thereby inhibiting their activity and providing a molecular basis for its anti-DC potential.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119027"},"PeriodicalIF":7.5,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034974","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 : 2026-01-23DOI: 10.1016/j.biopha.2026.119031
Marta Portillo-Carrasquer , Arabela Sanz-Alcázar , Begoña Sánchez-López , Fabien Delaspre , Maria Pazos-Gil , Luiza Oliveira-Jorge , Laia Castells-Roca , Jordi Tamarit , Joaquim Ros , Elisa Cabiscol
Friedreich ataxia (FA) is a rare, multisystemic neurodegenerative disorder caused by a deficiency of the mitochondrial protein frataxin. It is characterized by degeneration of the large sensory neurons in the dorsal root ganglia (DRG) and spinocerebellar tracts, leading to progressive neurodegeneration and muscle weakness. Frataxin deficiency induces iron dyshomeostasis, defective energy production, and oxidative stress, all regulated by NRF2. Omaveloxolone, an NRF2 activator, is currently the only approved therapy for FA; however, its effects on DRG neurons remain unknown. Here we used frataxin-deficient DRG neurons to better understand the drug’s role in these sensory neurons. Omaveloxolone improved most of the analyzed parameters, including frataxin levels, cell survival, mitochondrial respiratory activity, iron homeostasis, oxidative stress, transferrin receptor 1 and glutathione peroxidase 4 levels, as well as the GSH/GSSG ratio. Moreover, lipid peroxidation, a key marker of ferroptosis that was increased in frataxin-deficient neurons, was almost completely rescued by omaveloxolone. Both total and nuclear NRF2 levels were decreased in frataxin-deficient neurons, and omaveloxolone treatment fully prevented this alteration. In addition, most of these results were validated in fibroblasts from FA patients. We also evaluated a combinatorial treatment using low doses of omaveloxolone together with honokiol, a SIRT3 activator with known neuroprotective properties. This combination enhanced cell survival and produced a synergistic effect increasing mitochondrial respiration in frataxin-deficient DRG neurons. In summary, these findings demonstrate the beneficial effects of omaveloxolone and further suggest that combination therapy with honokiol may provide an effective strategy for the treatment of FA, potentially mitigating adverse effects.
{"title":"Targeting frataxin deficiency in DRG neurons and fibroblasts: omaveloxolone restores metabolic and iron balance to reduce ferroptosis","authors":"Marta Portillo-Carrasquer , Arabela Sanz-Alcázar , Begoña Sánchez-López , Fabien Delaspre , Maria Pazos-Gil , Luiza Oliveira-Jorge , Laia Castells-Roca , Jordi Tamarit , Joaquim Ros , Elisa Cabiscol","doi":"10.1016/j.biopha.2026.119031","DOIUrl":"10.1016/j.biopha.2026.119031","url":null,"abstract":"<div><div>Friedreich ataxia (FA) is a rare, multisystemic neurodegenerative disorder caused by a deficiency of the mitochondrial protein frataxin. It is characterized by degeneration of the large sensory neurons in the dorsal root ganglia (DRG) and spinocerebellar tracts, leading to progressive neurodegeneration and muscle weakness. Frataxin deficiency induces iron dyshomeostasis, defective energy production, and oxidative stress, all regulated by NRF2. Omaveloxolone, an NRF2 activator, is currently the only approved therapy for FA; however, its effects on DRG neurons remain unknown. Here we used frataxin-deficient DRG neurons to better understand the drug’s role in these sensory neurons. Omaveloxolone improved most of the analyzed parameters, including frataxin levels, cell survival, mitochondrial respiratory activity, iron homeostasis, oxidative stress, transferrin receptor 1 and glutathione peroxidase 4 levels, as well as the GSH/GSSG ratio. Moreover, lipid peroxidation, a key marker of ferroptosis that was increased in frataxin-deficient neurons, was almost completely rescued by omaveloxolone. Both total and nuclear NRF2 levels were decreased in frataxin-deficient neurons, and omaveloxolone treatment fully prevented this alteration. In addition, most of these results were validated in fibroblasts from FA patients. We also evaluated a combinatorial treatment using low doses of omaveloxolone together with honokiol, a SIRT3 activator with known neuroprotective properties. This combination enhanced cell survival and produced a synergistic effect increasing mitochondrial respiration in frataxin-deficient DRG neurons. In summary, these findings demonstrate the beneficial effects of omaveloxolone and further suggest that combination therapy with honokiol may provide an effective strategy for the treatment of FA, potentially mitigating adverse effects.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119031"},"PeriodicalIF":7.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034914","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 : 2026-01-23DOI: 10.1016/j.biopha.2026.119052
Ángela Berlana , Esther Rey , Elena Fresno-Ventura , Patricia Gomez-Gutierrez , Miguel Vega , Carmelo García-Monzón , Águeda González-Rodríguez
Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the leading cause of chronic liver disease worldwide. The increasing MASLD burden and the lack of effective therapies underscore the urgent need for new therapeutic approaches. Interleukin 1 beta (IL1β) has been identified as a key mediator of MASLD progression, and is considered a promising therapeutic target. This study evaluated the efficacy of AIK3a305, a novel allosteric inhibitor of cJun N-terminal kinase (JNK), in preventing MASLD progression through a selective inhibition of IL1β synthesis. Macrophages were treated with LPS and palmitate to assess IL1β modulation, and hepatocytes with palmitic acid (PA) to explore lipid accumulation, lipoapoptosis, and inflammatory signaling, in the presence or absence of this compound. Mice fed a high-fat diet (HFD) or a choline-deficient, L-amino acid-defined (CDAA) diet were orally treated with AIK3a305 or vehicle, and livers were collected for histopathological and molecular analysis. AIK3a305 selectively inhibited LPS- and palmitate-induced IL1β expression in macrophages, while protecting hepatocytes from intracellular lipid accumulation and lipoapoptosis. These hepatic effects were associated with a suppression of JNK signaling, which triggered a decrease in IL1β expression, and a transient inhibition of the transcription factor NFκB and p38 pathways, and, thus, tumor necrosis factor α (TNFα) synthesis. In preclinical models of MASLD, treatment with AIK3a305 attenuated disease progression in animals fed either a HFD or a CDAA diet, as evidenced by improved liver histopathology, including reduced steatosis and inflammation. These findings position AIK3a305 as a promising therapeutic candidate for MASLD treatment.
代谢功能障碍相关脂肪变性肝病（MASLD）是目前世界范围内慢性肝病的主要原因。日益增加的MASLD负担和缺乏有效的治疗方法强调了迫切需要新的治疗方法。白细胞介素1β (il - 1β)已被确定为MASLD进展的关键介质，并被认为是一个有希望的治疗靶点。这项研究评估了AIK3a305（一种新型的cJun n -末端激酶（JNK）变构抑制剂）通过选择性抑制il - 1β合成来阻止MASLD进展的功效。用脂多糖和棕榈酸处理巨噬细胞以评估il - 1β的调节，用棕榈酸（PA）处理肝细胞以探索存在或不存在这种化合物的脂质积累、脂质凋亡和炎症信号。饲喂高脂肪饮食（HFD）或缺乏胆碱的l -氨基酸（CDAA）饮食的小鼠口服AIK3a305或载药，并收集肝脏进行组织病理学和分子分析。AIK3a305选择性抑制LPS和棕榈酸盐诱导的巨噬细胞中il - 1β的表达，同时保护肝细胞免受细胞内脂质积累和脂肪凋亡。这些肝脏效应与JNK信号的抑制有关，JNK信号的抑制引发il - 1β表达的降低，转录因子NFκB和p38通路的短暂抑制，从而抑制肿瘤坏死因子α (TNFα)的合成。在MASLD的临床前模型中，AIK3a305治疗减轻了饲喂HFD或CDAA饮食的动物的疾病进展，肝脏组织病理学改善，包括脂肪变性和炎症减少，证明了这一点。这些发现表明AIK3a305是一种有希望的MASLD治疗候选药物。
{"title":"The inhibition of Il1β synthesis mediated by a novel pyridine-sulfonamide compound protects against the progression of metabolic dysfunction-associated steatotic liver disease","authors":"Ángela Berlana , Esther Rey , Elena Fresno-Ventura , Patricia Gomez-Gutierrez , Miguel Vega , Carmelo García-Monzón , Águeda González-Rodríguez","doi":"10.1016/j.biopha.2026.119052","DOIUrl":"10.1016/j.biopha.2026.119052","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the leading cause of chronic liver disease worldwide. The increasing MASLD burden and the lack of effective therapies underscore the urgent need for new therapeutic approaches. Interleukin 1 beta (IL1β) has been identified as a key mediator of MASLD progression, and is considered a promising therapeutic target. This study evaluated the efficacy of AIK3a305, a novel allosteric inhibitor of cJun N-terminal kinase (JNK), in preventing MASLD progression through a selective inhibition of IL1β synthesis. Macrophages were treated with LPS and palmitate to assess IL1β modulation, and hepatocytes with palmitic acid (PA) to explore lipid accumulation, lipoapoptosis, and inflammatory signaling, in the presence or absence of this compound. Mice fed a high-fat diet (HFD) or a choline-deficient, <span>L</span>-amino acid-defined (CDAA) diet were orally treated with AIK3a305 or vehicle, and livers were collected for histopathological and molecular analysis. AIK3a305 selectively inhibited LPS- and palmitate-induced IL1β expression in macrophages, while protecting hepatocytes from intracellular lipid accumulation and lipoapoptosis. These hepatic effects were associated with a suppression of JNK signaling, which triggered a decrease in IL1β expression, and a transient inhibition of the transcription factor NFκB and p38 pathways, and, thus, tumor necrosis factor α (TNFα) synthesis. In preclinical models of MASLD, treatment with AIK3a305 attenuated disease progression in animals fed either a HFD or a CDAA diet, as evidenced by improved liver histopathology, including reduced steatosis and inflammation. These findings position AIK3a305 as a promising therapeutic candidate for MASLD treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119052"},"PeriodicalIF":7.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034913","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 : 2026-01-23DOI: 10.1016/j.biopha.2026.119050
Wenwen Zha , Minglei Wang , Yunlong Meng , Kangyu Liu , Lirong Huang , Haining Li , Nan Yin , Yuanhai Xie , Jiayi Du , Mingxia Song , Zigang Cao , Jianjun Chen , Zilin Zhong
Bexarotene is a retinoid X receptor (RXR) agonist that plays a crucial role in cell growth and differentiation. It has shown potential in treating both early- and late-stage cutaneous T-cell lymphoma (CTCL). However, the impact of Bexarotene on the neurodevelopment of aquatic organisms, particularly aquatic vertebrates, remains poorly understood. This study aimed to investigate the effects of various concentrations of bexarotene (3 μg/L, 6 μg/L, and 9 μg/L) on the development of the zebrafish embryonic nervous system, using zebrafish as a model organism. The underlying molecular mechanisms were explored through a combination of pharmacological interventions, molecular biology, histopathology, and transcriptomics. Studies have shown that zebrafish embryos exposed to Bex show significant changes in development, including morphological abnormalities, head malformations, significantly shortened head length and width, reduced fluorescent area, cell apoptosis, shortened spinal motor neuron axon length, abnormal myelin development, decreased oligodendrocytes, cerebellar developmental damage, and abnormal behavior. Transcriptomics and qPCR results showed abnormal expression of neurodevelopmental genes (olig2, mbpa, atoh1a, gfap, ngn1, gap43, etc.). In addition, exposure to medium and high concentrations of bexarotene significantly increased acetylcholinesterase (AChE) activity. Bexarotene activates the Wnt signaling pathway, and treatment with the Wnt inhibitor IWR-1 can partially rescue the neurodevelopmental impairments in embryos. In summary, bexarotene offers new insights into the potential neurodevelopmental risks in zebrafish embryos, emphasizing the importance of preventing drug side effects and ensuring the safe and rational use of medications to protect the health of living organisms.
{"title":"Potential effects of bexarotene on neural development and function in zebrafish embryos","authors":"Wenwen Zha , Minglei Wang , Yunlong Meng , Kangyu Liu , Lirong Huang , Haining Li , Nan Yin , Yuanhai Xie , Jiayi Du , Mingxia Song , Zigang Cao , Jianjun Chen , Zilin Zhong","doi":"10.1016/j.biopha.2026.119050","DOIUrl":"10.1016/j.biopha.2026.119050","url":null,"abstract":"<div><div>Bexarotene is a retinoid X receptor (RXR) agonist that plays a crucial role in cell growth and differentiation. It has shown potential in treating both early- and late-stage cutaneous T-cell lymphoma (CTCL). However, the impact of Bexarotene on the neurodevelopment of aquatic organisms, particularly aquatic vertebrates, remains poorly understood. This study aimed to investigate the effects of various concentrations of bexarotene (3 μg/L, 6 μg/L, and 9 μg/L) on the development of the zebrafish embryonic nervous system, using zebrafish as a model organism. The underlying molecular mechanisms were explored through a combination of pharmacological interventions, molecular biology, histopathology, and transcriptomics. Studies have shown that zebrafish embryos exposed to Bex show significant changes in development, including morphological abnormalities, head malformations, significantly shortened head length and width, reduced fluorescent area, cell apoptosis, shortened spinal motor neuron axon length, abnormal myelin development, decreased oligodendrocytes, cerebellar developmental damage, and abnormal behavior. Transcriptomics and qPCR results showed abnormal expression of neurodevelopmental genes (<em>olig2</em>, <em>mbpa</em>, <em>atoh1a</em>, <em>gfap</em>, <em>ngn1</em>, <em>gap43</em>, etc.). In addition, exposure to medium and high concentrations of bexarotene significantly increased acetylcholinesterase (AChE) activity. Bexarotene activates the Wnt signaling pathway, and treatment with the Wnt inhibitor IWR-1 can partially rescue the neurodevelopmental impairments in embryos. In summary, bexarotene offers new insights into the potential neurodevelopmental risks in zebrafish embryos, emphasizing the importance of preventing drug side effects and ensuring the safe and rational use of medications to protect the health of living organisms.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119050"},"PeriodicalIF":7.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034955","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}
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, and repetitive behaviours. Numerous studies have associated ASD with immune dysregulation and inflammation, with neuroinflammatory processes reported in ASD individuals and mouse models. Altered immune cell profiles and cytokine levels have been observed in the peripheral blood (PB), supporting systemic immune dysfunction. Recently we showed that the administration of antioxidant molecule N-acetylcysteine (NAC) reduced oxidative stress and inflammation and counteracted behavioural deficits in two mouse models of ASD, providing a rationale for exploring other redox-active compounds. Here, we investigated the effects of astaxanthin (AST), potent antioxidant and anti-inflammatory molecule, in the Shank3b model (Shank3b-/- mice). AST treatment significantly improved core ASD-like behaviours, including social interaction deficits, motor incoordination, and repetitive grooming. In the cerebellum, AST reduced pro-inflammatory cytokines and counteracted microglial hyperactivation. In peripheral immune compartments, AST modulated cytokine expression. Pro-inflammatory markers were downregulated in Shank3b-/- mice in the bone marrow and spleen while they were elevated in Shank3b controls, suggesting immune rebalancing (i.e. adaptive modulation suppressing harmful inflammation while supporting protective immunity). As a limitation, oxidative stress assays were not performed here. Receiver operating characteristic (ROC) analysis suggests that TNF and IFNγ expression in peripheral immune cells may be promising biomarkers of treatment response. Notably, unlike NAC, AST did not induce pro-inflammatory effects in Shank3b+/+ animals. These findings show that AST administration may counteract behavioural deficits and immune dysfunction in Shank3b-/- mice, therefore suggesting its potential as a safe immunomodulatory therapy for ASD.
{"title":"Astaxanthin improves behavioural and immune dysfunction in the Shank3b mouse model of autism spectrum disorder","authors":"Anjana Madhavan , Martina Schiano-Visconte , Lauren Dutton , Mattia Cantalupo , Luigi Balasco , Alessia Mavillonio , Gabriele Chelini , Yuri Bozzi , Luca Pangrazzi","doi":"10.1016/j.biopha.2026.119051","DOIUrl":"10.1016/j.biopha.2026.119051","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, and repetitive behaviours. Numerous studies have associated ASD with immune dysregulation and inflammation, with neuroinflammatory processes reported in ASD individuals and mouse models. Altered immune cell profiles and cytokine levels have been observed in the peripheral blood (PB), supporting systemic immune dysfunction. Recently we showed that the administration of antioxidant molecule N-acetylcysteine (NAC) reduced oxidative stress and inflammation and counteracted behavioural deficits in two mouse models of ASD, providing a rationale for exploring other redox-active compounds. Here, we investigated the effects of astaxanthin (AST), potent antioxidant and anti-inflammatory molecule, in the Shank3b model (<em>Shank3b</em><sup><em>-/-</em></sup> mice). AST treatment significantly improved core ASD-like behaviours, including social interaction deficits, motor incoordination, and repetitive grooming. In the cerebellum, AST reduced pro-inflammatory cytokines and counteracted microglial hyperactivation. In peripheral immune compartments, AST modulated cytokine expression. Pro-inflammatory markers were downregulated in <em>Shank3b</em><sup><em>-/-</em></sup> mice in the bone marrow and spleen while they were elevated in Shank3b controls, suggesting immune rebalancing (<em>i.e.</em> adaptive modulation suppressing harmful inflammation while supporting protective immunity). As a limitation, oxidative stress assays were not performed here. Receiver operating characteristic (ROC) analysis suggests that TNF and IFNγ expression in peripheral immune cells may be promising biomarkers of treatment response. Notably, unlike NAC, AST did not induce pro-inflammatory effects in <em>Shank3b</em><sup><em>+/+</em></sup> animals. These findings show that AST administration may counteract behavioural deficits and immune dysfunction in <em>Shank3b</em><sup><em>-/-</em></sup> mice, therefore suggesting its potential as a safe immunomodulatory therapy for ASD.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119051"},"PeriodicalIF":7.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034903","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 : 2026-01-23DOI: 10.1016/j.biopha.2026.119046
Juan Wang , Ying Wang , Rongmei Shi , Shaojun Xu , Shaorui Li , Xinxia Li , Yuduan Wang , Ruiting Liu , Le Zhao , Jinyan Zhang
Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive increase in pulmonary vascular pressure and resistance, which subsequently leads to right ventricular dysfunction and is the main cause of death for patients. Most drugs used for treating PAH focus on blood vessels, but no definitive treatment for PAH-induced right ventricular dysfunction is known. Recent studies have shown that allicin has a beneficial effect on PAH; however, whether allicin has a protective effect on right ventricular dysfunction caused by PAH and its specific mechanism of action are still unclear. In this study, we established a model by injecting monocrotaline. We examined the function of the pulmonary artery and right ventricle via right heart catheterization and a small animal cardiac ultrasound system, as well as HE and Masson staining. We also detected the calcium transport process and the expression of key proteins involved in calcium transport in right ventricular cells to reveal the role of the calcium communication mechanism in the treatment of PAH with right ventricular dysfunction by allicin. The results showed that allicin not only significantly improved pulmonary artery function but also improved right heart dysfunction in rats with PAH. Additionally, allicin significantly improved the calcium transport function of cardiomyocytes, increased mitochondrial ATP production, and decreased the generation of intracellular ROS. Conclusion: Allicin protects against PAH-induced right ventricular dysfunction by regulating calcium communication between the SR and mitochondria, providing a new theoretical basis for the clinical intervention of PAH-related right heart failure.
{"title":"Allicin ameliorates right heart dysfunction in rats suffering from pulmonary arterial hypertension by regulating Ca2+ communication between the sarcoplasmic reticulum and mitochondria","authors":"Juan Wang , Ying Wang , Rongmei Shi , Shaojun Xu , Shaorui Li , Xinxia Li , Yuduan Wang , Ruiting Liu , Le Zhao , Jinyan Zhang","doi":"10.1016/j.biopha.2026.119046","DOIUrl":"10.1016/j.biopha.2026.119046","url":null,"abstract":"<div><div>Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive increase in pulmonary vascular pressure and resistance, which subsequently leads to right ventricular dysfunction and is the main cause of death for patients. Most drugs used for treating PAH focus on blood vessels, but no definitive treatment for PAH-induced right ventricular dysfunction is known. Recent studies have shown that allicin has a beneficial effect on PAH; however, whether allicin has a protective effect on right ventricular dysfunction caused by PAH and its specific mechanism of action are still unclear. In this study, we established a model by injecting monocrotaline. We examined the function of the pulmonary artery and right ventricle via right heart catheterization and a small animal cardiac ultrasound system, as well as HE and Masson staining. We also detected the calcium transport process and the expression of key proteins involved in calcium transport in right ventricular cells to reveal the role of the calcium communication mechanism in the treatment of PAH with right ventricular dysfunction by allicin. The results showed that allicin not only significantly improved pulmonary artery function but also improved right heart dysfunction in rats with PAH. Additionally, allicin significantly improved the calcium transport function of cardiomyocytes, increased mitochondrial ATP production, and decreased the generation of intracellular ROS. Conclusion: Allicin protects against PAH-induced right ventricular dysfunction by regulating calcium communication between the SR and mitochondria, providing a new theoretical basis for the clinical intervention of PAH-related right heart failure.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119046"},"PeriodicalIF":7.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034904","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}
Dengue virus (DENV) infection represents a significant public health concern in tropical and subtropical areas, with increasing cases in parts of Europe. Currently, licensed vaccines, Dengvaxia® and Qdenga®, rely on live-attenuated platforms but show limited efficacy due to imbalanced immune responses and risks associated with antibody-dependent enhancement (ADE). In this study, we developed and evaluated nucleoside-modified mRNA vaccine encoding the dengue virus serotype 1 (DENV1) pre-membrane and envelope (prME) proteins. To reduce the potential for ADE, we incorporated the F108A mutation in the fusion loop, substituted the pr region with that from Japanese encephalitis virus (JEV), and incorporated a consensus envelope domain III (cEDIII) sequence to broaden neutralizing antibody responses. Immunogenicity was assessed in BALB/C mice immunized twice at three-week intervals with 1, 2.5, or 10 μg doses. The WT prME construct induced the highest DENV1 neutralizing antibody (NtAb) titers in a dose-dependent manner and robust T cell responses, particularly with the 2.5 μg dose. While the F108A and cEDIII modifications modulated antigen expression and broadened cross-reactivity, they also slightly reduced DENV-1-specific neutralizing titers. Among constructs, F108A+cEDIII demonstrated reduced ADE activity with improved cross-neutralization, especially against DENV3. However, the prJEV chimera exhibited low immunogenicity, likely due to prM-E domain incompatibility. Overall, the WT prME construct showed the most favorable balance of immunogenicity and safety, supporting its advancement as a prototype for future tetravalent dengue mRNA vaccine development.
{"title":"Preclinical evaluation of DENV1 mRNA vaccines in mice: Toward improved neutralizing antibody and T cell responses","authors":"Chirayus Khawsang , Eakachai Prompetchara , Supichcha Saithong , Kittipan Tharakhet , Papatsara Kaewpang , Nongnaphat Yostrerat , Pachara Wangsoontorn , Patrawadee Pitakpolrat , Supranee Buranapraditkun , Chunya Puttikhunt , Kieu Lam , James Heyes , Chutitorn Ketloy , Drew Weissman , Kiat Ruxrungtham","doi":"10.1016/j.biopha.2026.119037","DOIUrl":"10.1016/j.biopha.2026.119037","url":null,"abstract":"<div><div>Dengue virus (DENV) infection represents a significant public health concern in tropical and subtropical areas, with increasing cases in parts of Europe. Currently, licensed vaccines, Dengvaxia® and Qdenga®, rely on live-attenuated platforms but show limited efficacy due to imbalanced immune responses and risks associated with antibody-dependent enhancement (ADE). In this study, we developed and evaluated nucleoside-modified mRNA vaccine encoding the dengue virus serotype 1 (DENV1) pre-membrane and envelope (prME) proteins. To reduce the potential for ADE, we incorporated the F108A mutation in the fusion loop, substituted the pr region with that from Japanese encephalitis virus (JEV), and incorporated a consensus envelope domain III (cEDIII) sequence to broaden neutralizing antibody responses. Immunogenicity was assessed in BALB/C mice immunized twice at three-week intervals with 1, 2.5, or 10 μg doses. The WT prME construct induced the highest DENV1 neutralizing antibody (NtAb) titers in a dose-dependent manner and robust T cell responses, particularly with the 2.5 μg dose. While the F108A and cEDIII modifications modulated antigen expression and broadened cross-reactivity, they also slightly reduced DENV-1-specific neutralizing titers. Among constructs, F108A+cEDIII demonstrated reduced ADE activity with improved cross-neutralization, especially against DENV3. However, the prJEV chimera exhibited low immunogenicity, likely due to prM-E domain incompatibility. Overall, the WT prME construct showed the most favorable balance of immunogenicity and safety, supporting its advancement as a prototype for future tetravalent dengue mRNA vaccine development.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119037"},"PeriodicalIF":7.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034912","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 : 2026-01-22DOI: 10.1016/j.biopha.2026.119023
Yiming Jin , Khiem Nguyen , Sidra Bashir , Girija Pawge , Reagan M. Strand , Chia-Hung Christine Hsiao , Olga Vinogradova , Andrew J. Wiemer
Phosphoantigens (pAgs) are phosphate-containing small molecules that elicit an immune response. The pAgs bind to the intracellular domain of butyrophilin 3 (BTN3), enabling interactions with other butyrophilins to form complexes that trigger the T cell receptor (TCR) of Vγ9Vδ2 (γ9δ2) T cells. Despite multiple reports on this process, the conditions that regulate pAg levels leading to their detection remain unclear. Here we reveal a novel stress detection pathway, a type of lymphoid stress-surveillance response, in which mild cold stress triggers endogenous pAgs to engage with BTN family proteins, leading to the activation of γ9δ2 T cells. This stress response is dependent upon endogenous pAgs, as inhibition of HMG-CoA reductase abrogates the effect. It is also dependent upon BTN proteins, as depletion of BTN3A1 reduces the response. The ability of BTN2A1/BTN3A1 to respond is enhanced by the presence of BTN3A2 or BTN3A3. Furthermore, the internal domains of BTN2A1, BTN3A1, and BTN3A3 display differing abilities to dimerize, with BTN2A1 a constitutive dimer, BTN3A1 a monomer, and BTN3A3 a concentration dependent dimer. Full length BTN2A1/3A1 hybrid proteins additionally reveal that appropriately spaced multimers of BTN2A1 and BTN3A1 are critical in engaging the γ9δ2 TCR. In summary, our study uncovers a novel γ9δ2 T cell activation pathway mediated by cell stress and mevalonate pathway intermediates and highlights the critical roles of the BTN family members and their spacing in this process.
{"title":"Cell stress activates γ9δ2 T cells via endogenous phosphoantigens and butyrophilin complex dynamics","authors":"Yiming Jin , Khiem Nguyen , Sidra Bashir , Girija Pawge , Reagan M. Strand , Chia-Hung Christine Hsiao , Olga Vinogradova , Andrew J. Wiemer","doi":"10.1016/j.biopha.2026.119023","DOIUrl":"10.1016/j.biopha.2026.119023","url":null,"abstract":"<div><div>Phosphoantigens (pAgs) are phosphate-containing small molecules that elicit an immune response. The pAgs bind to the intracellular domain of butyrophilin 3 (BTN3), enabling interactions with other butyrophilins to form complexes that trigger the T cell receptor (TCR) of Vγ9Vδ2 (γ9δ2) T cells. Despite multiple reports on this process, the conditions that regulate pAg levels leading to their detection remain unclear. Here we reveal a novel stress detection pathway, a type of lymphoid stress-surveillance response, in which mild cold stress triggers endogenous pAgs to engage with BTN family proteins, leading to the activation of γ9δ2 T cells. This stress response is dependent upon endogenous pAgs, as inhibition of HMG-CoA reductase abrogates the effect. It is also dependent upon BTN proteins, as depletion of BTN3A1 reduces the response. The ability of BTN2A1/BTN3A1 to respond is enhanced by the presence of BTN3A2 or BTN3A3. Furthermore, the internal domains of BTN2A1, BTN3A1, and BTN3A3 display differing abilities to dimerize, with BTN2A1 a constitutive dimer, BTN3A1 a monomer, and BTN3A3 a concentration dependent dimer. Full length BTN2A1/3A1 hybrid proteins additionally reveal that appropriately spaced multimers of BTN2A1 and BTN3A1 are critical in engaging the γ9δ2 TCR. In summary, our study uncovers a novel γ9δ2 T cell activation pathway mediated by cell stress and mevalonate pathway intermediates and highlights the critical roles of the BTN family members and their spacing in this process.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119023"},"PeriodicalIF":7.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034905","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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