Pub Date : 2025-12-13DOI: 10.1016/j.biopha.2025.118869
Deepadarshan Urs , Abdul Rahman , H.S. Shuba , N.D. Satyanarayan , Rajkumar S. Meti , K.K. Dharmappa
Poultry farm workers are highly susceptible to developing lung inflammatory diseases (asthma, COPD, ARDS, and ALI) due to prolonged exposure to organic dust and other airborne irritants in confined poultry facilities. Secretory phospholipase A2 (sPLA2-IIA) is a vital proinflammatory enzyme play an important role in the production of inflammatory mediators. Hence, this study examined the regulatory role of secretory phospholipase A2 enzyme in poultry dust induced lung inflammation in in vitro and in vivo models. Lung epithelial A549 cells and BALB/c mice treated with poultry dust increased the sPLA2-IIA mRNA expression and stimulated the induction of inflammatory symptoms. Inhibition of sPLA2 enzyme activity by Tricyclic Dipyrido Diazepinone derivative 6 f (sPLA2 inhibitor) markedly ameliorated ODE-induced lung histopathological conditions, decreased lung edema, cellular infiltration, and protein secretion. Further, downregulated activation of cPLA2 via decreasing phosphorylation of ERK1/2 and p38. Suppressing cPLA2 signalling cascade significantly reduced the production of inflammatory cytokines (IL-6, IL-8, and TNF-α) and chemokines (MIP-1, MCP, and RANTES). Consequently, the activation of COX-2 and the production of prostaglandin E2 and thromboxane B2 were significantly decreased. Conclusively, these findings indicated that sPLA2-IIA could potentially serve as a novel therapeutic target for treating lung inflammation in disease conditions.
由于在密闭的家禽设施中长期接触有机粉尘和其他空气传播刺激物，家禽养殖场工人极易患肺部炎症性疾病（哮喘、慢性阻塞性肺病、急性呼吸窘迫综合征和急性呼吸道感染）。分泌型磷脂酶A2 （sPLA2-IIA）是一种重要的促炎酶，在炎症介质的产生中起重要作用。因此，本研究通过体外和体内模型研究了分泌磷脂酶A2在家禽粉尘诱导的肺部炎症中的调节作用。肺上皮A549细胞和BALB/c小鼠经禽尘处理后，sPLA2-IIA mRNA表达增加，刺激炎症症状的诱导。三环双嘧多二氮卓酮衍生物6 f （sPLA2抑制剂）抑制sPLA2酶活性可显著改善ode诱导的肺组织病理状况，减少肺水肿、细胞浸润和蛋白质分泌。此外，通过降低ERK1/2和p38的磷酸化，下调cPLA2的激活。抑制cPLA2信号级联可显著降低炎症因子（IL-6、IL-8和TNF-α）和趋化因子（MIP-1、MCP和RANTES）的产生。因此，COX-2的激活和前列腺素E2和血栓素B2的产生显著降低。总之，这些发现表明sPLA2-IIA可能作为治疗疾病条件下肺部炎症的新治疗靶点。
{"title":"sPLA2-IIA inhibitor Tricyclic Dipyrido Diazepinone derivative 6 f suppresses poultry organic dust-induced pulmonary inflammation by downregulating ERK1/2-cPLA2 pathway","authors":"Deepadarshan Urs , Abdul Rahman , H.S. Shuba , N.D. Satyanarayan , Rajkumar S. Meti , K.K. Dharmappa","doi":"10.1016/j.biopha.2025.118869","DOIUrl":"10.1016/j.biopha.2025.118869","url":null,"abstract":"<div><div>Poultry farm workers are highly susceptible to developing lung inflammatory diseases (asthma, COPD, ARDS, and ALI) due to prolonged exposure to organic dust and other airborne irritants in confined poultry facilities. Secretory phospholipase A2 (sPLA<sub>2</sub>-IIA) is a vital proinflammatory enzyme play an important role in the production of inflammatory mediators. Hence, this study examined the regulatory role of secretory phospholipase A2 enzyme in poultry dust induced lung inflammation in <em>in vitro</em> and <em>in vivo</em> models. Lung epithelial A549 cells and BALB/c mice treated with poultry dust increased the sPLA<sub>2</sub>-IIA mRNA expression and stimulated the induction of inflammatory symptoms. Inhibition of sPLA<sub>2</sub> enzyme activity by Tricyclic Dipyrido Diazepinone derivative 6 f (sPLA<sub>2</sub> inhibitor) markedly ameliorated ODE-induced lung histopathological conditions, decreased lung edema, cellular infiltration, and protein secretion. Further, downregulated activation of cPLA<sub>2</sub> via decreasing phosphorylation of ERK1/2 and p38. Suppressing cPLA<sub>2</sub> signalling cascade significantly reduced the production of inflammatory cytokines (IL-6, IL-8, and TNF-α) and chemokines (MIP-1, MCP, and RANTES). Consequently, the activation of COX-2 and the production of prostaglandin E2 and thromboxane B2 were significantly decreased. Conclusively, these findings indicated that sPLA<sub>2</sub>-IIA could potentially serve as a novel therapeutic target for treating lung inflammation in disease conditions.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"194 ","pages":"Article 118869"},"PeriodicalIF":7.5,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735767","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 : 2025-12-13DOI: 10.1016/j.biopha.2025.118903
Chunlian Song , Shengjia Sun , Ting Li , Ke Zhang , Xiong Zhao , Zee Zhu , Deng Pan , Huayi Bai , Ying Zhang , Deyan Cui , Limei Yang , Xiaoyu Liu , Xianghua Shu
Scutellarin, the active component of Erigeron breviscapus(Vant.)Hand.-Mazz, has therapeutic potential for neurological diseases but is limited by poor solubility, low bioavailability, and inability to cross the blood-brain barrier (BBB). This study used mouse brain tissue-derived exosomes as a delivery system for scutellarin. Exosomes were isolated via ultracentrifugation and loaded with scutellarin using ultrasonication, achieving a drug loading capacity of 31.86 ng/μg and a particle size of 90–120 nm. In an in vitro BBB model, exosome-loaded scutellarin showed significantly higher penetration (41 %) than the free drug (13.5 %). Confocal microscopy confirmed efficient cellular uptake, particularly by microglia (98 % efficiency). In vivo, exosomes accumulated and persisted in brain tissue for over 24 h. In a PRV-infected microglia model, exosome-delivered scutellarin significantly inhibited viral replication and modulated microglial polarization by downregulating the pro-inflammatory marker CD86 and upregulating the anti-inflammatory marker CD206. These findings demonstrate that brain-derived exosomes enhance scutellarin delivery across the BBB and improve its anti-neuroinflammatory effects, supporting their use as drug carriers for treating neuroinflammatory diseases.
{"title":"Exosome-mediated scutellarin delivery enhances BBB penetration and microglia targeting in antiviral neuroprotection","authors":"Chunlian Song , Shengjia Sun , Ting Li , Ke Zhang , Xiong Zhao , Zee Zhu , Deng Pan , Huayi Bai , Ying Zhang , Deyan Cui , Limei Yang , Xiaoyu Liu , Xianghua Shu","doi":"10.1016/j.biopha.2025.118903","DOIUrl":"10.1016/j.biopha.2025.118903","url":null,"abstract":"<div><div>Scutellarin, the active component of <em>Erigeron breviscapus(Vant.)Hand.-Mazz</em>, has therapeutic potential for neurological diseases but is limited by poor solubility, low bioavailability, and inability to cross the blood-brain barrier (BBB). This study used mouse brain tissue-derived exosomes as a delivery system for scutellarin. Exosomes were isolated via ultracentrifugation and loaded with scutellarin using ultrasonication, achieving a drug loading capacity of 31.86 ng/μg and a particle size of 90–120 nm. In an in vitro BBB model, exosome-loaded scutellarin showed significantly higher penetration (41 %) than the free drug (13.5 %). Confocal microscopy confirmed efficient cellular uptake, particularly by microglia (98 % efficiency). In vivo, exosomes accumulated and persisted in brain tissue for over 24 h. In a PRV-infected microglia model, exosome-delivered scutellarin significantly inhibited viral replication and modulated microglial polarization by downregulating the pro-inflammatory marker CD86 and upregulating the anti-inflammatory marker CD206. These findings demonstrate that brain-derived exosomes enhance scutellarin delivery across the BBB and improve its anti-neuroinflammatory effects, supporting their use as drug carriers for treating neuroinflammatory diseases.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"194 ","pages":"Article 118903"},"PeriodicalIF":7.5,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735768","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 : 2025-12-12DOI: 10.1016/j.biopha.2025.118891
Irati Aiestaran-Zelaia , María Jesús Sánchez-Guisado , Marta Beraza , Libe López-Arandia , Sandra Plaza-García , Irene Fernández-Folgueral , Antonio de Molina-Iracheta , Ian J. Holt , Jesus Ruiz-Cabello
Artificial sweeteners, such as aspartame, are widely used to reduce sugar intake to control body weight; however, their long-term metabolic and behavioral effects are unknown. To assess the long-term consequences, we evaluated the systemic effects of aspartame administration in male C57BL/6 mice over the course of one year, exposing them to a dose equivalent to one-sixth of the recommended maximum human daily intake. At this low dose, mice receiving aspartame showed decreased body weight, owing principally to a 20 % reduction in fat deposits, and this was associated with mild cardiac hypertrophy measured by MRI and histology, together with signs of altered neurobehavior, determined by the Barnes maze test. These findings indicate that while aspartame can help to achieve weight loss in mice, this is accompanied by pathophysiological changes in the heart and possibly in the brain. Thus, the study demonstrates that long-term exposure to artificial sweeteners can have a detrimental impact on organ function even at low doses, which suggests that current consumption guidelines should be critically re-examined.
{"title":"Aspartame decreases fat deposits in mice at a cost of mild cardiac hypertrophy and reduced cognitive performance","authors":"Irati Aiestaran-Zelaia , María Jesús Sánchez-Guisado , Marta Beraza , Libe López-Arandia , Sandra Plaza-García , Irene Fernández-Folgueral , Antonio de Molina-Iracheta , Ian J. Holt , Jesus Ruiz-Cabello","doi":"10.1016/j.biopha.2025.118891","DOIUrl":"10.1016/j.biopha.2025.118891","url":null,"abstract":"<div><div>Artificial sweeteners, such as aspartame, are widely used to reduce sugar intake to control body weight; however, their long-term metabolic and behavioral effects are unknown. To assess the long-term consequences, we evaluated the systemic effects of aspartame administration in male C57BL/6 mice over the course of one year, exposing them to a dose equivalent to one-sixth of the recommended maximum human daily intake. At this low dose, mice receiving aspartame showed decreased body weight, owing principally to a 20 % reduction in fat deposits, and this was associated with mild cardiac hypertrophy measured by MRI and histology, together with signs of altered neurobehavior, determined by the Barnes maze test. These findings indicate that while aspartame can help to achieve weight loss in mice, this is accompanied by pathophysiological changes in the heart and possibly in the brain. Thus, the study demonstrates that long-term exposure to artificial sweeteners can have a detrimental impact on organ function even at low doses, which suggests that current consumption guidelines should be critically re-examined.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"194 ","pages":"Article 118891"},"PeriodicalIF":7.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718562","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 : 2025-12-12DOI: 10.1016/j.biopha.2025.118894
Yasmine F. Ibrahim , Heba K. Alshaeri , Walaa Yehia Abdelzaher , Dina Moustafa Thabit , Ahmed Mohsen Faheem , Sara M. Ahmed
Cyclophosphamide (CYC) is an alkylating agent that is widely used in cancer chemotherapy and immunosuppressive therapy; however, its clinical application is limited because it causes multiple organ toxicities, including thyroid dysfunction. Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, possesses antioxidant, anti-inflammatory and anti-apoptotic properties, suggesting potential protective effects. This study aimed to evaluate the efficacy of OCA in reducing CYC-induced thyroid toxicity and to investigate its underlying molecular mechanisms in rats. Rats were randomly assigned to five groups: control, OCA, CYC, OCA10 + CYC and OCA20 + CYC. Serum thyroid hormones (T3, T4), oxidative stress markers (malondialdehyde [MDA] and total antioxidant capacity [TAC]) and histopathological changes were assessed. Molecular analyses included the measurement of myeloid differentiation primary response gene 88 (MYD88), toll-like receptor 4 (TLR4), nuclear factor κB (NF-κB), interleukin (IL)-1β, IL-18, thioredoxin-interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), caspase-1, B-cell lymphoma-2 (BCL-2), BAX and caspase-3 expression. CYC administration resulted in significant thyroid damage, reflected by increased serum T3 and T4 levels, histopathological alterations, enhanced oxidative stress and the activation of inflammatory and apoptotic pathways. OCA pre-treatment significantly mitigated these changes as evidenced by lowered MDA, higher TAC and improved thyroid architecture. Mechanistically, OCA suppressed inflammation via downregulation of TLR4/MYD88/NF-κB signalling, inhibited pyroptosis through TXNIP/NLRP3/ASC/caspase-1 pathway blockade and reduced p53-mediated apoptosis by modulating BAX, BCL-2 and cleaved caspase-3 expression. This study provides the first evidence that OCA confers protection against CYC-induced thyroid injury by reducing oxidative stress, inflammation, pyroptosis and apoptosis.
{"title":"Protective effect of obeticholic acid on cyclophosphamide-induced thyroid toxicity in rats by inhibiting TXNIP/NLRP3/ASC/caspase-1-dependent pyroptosis and p53/BAX/caspase-3-dependent apoptosis","authors":"Yasmine F. Ibrahim , Heba K. Alshaeri , Walaa Yehia Abdelzaher , Dina Moustafa Thabit , Ahmed Mohsen Faheem , Sara M. Ahmed","doi":"10.1016/j.biopha.2025.118894","DOIUrl":"10.1016/j.biopha.2025.118894","url":null,"abstract":"<div><div>Cyclophosphamide (CYC) is an alkylating agent that is widely used in cancer chemotherapy and immunosuppressive therapy; however, its clinical application is limited because it causes multiple organ toxicities, including thyroid dysfunction. Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, possesses antioxidant, anti-inflammatory and anti-apoptotic properties, suggesting potential protective effects. This study aimed to evaluate the efficacy of OCA in reducing CYC-induced thyroid toxicity and to investigate its underlying molecular mechanisms in rats. Rats were randomly assigned to five groups: control, OCA, CYC, OCA10 + CYC and OCA20 + CYC. Serum thyroid hormones (T3, T4), oxidative stress markers (malondialdehyde [MDA] and total antioxidant capacity [TAC]) and histopathological changes were assessed. Molecular analyses included the measurement of myeloid differentiation primary response gene 88 (MYD88), toll-like receptor 4 (TLR4), nuclear factor κB (NF-κB), interleukin (IL)-1β, IL-18, thioredoxin-interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), caspase-1, B-cell lymphoma-2 (BCL-2), BAX and caspase-3 expression. CYC administration resulted in significant thyroid damage, reflected by increased serum T3 and T4 levels, histopathological alterations, enhanced oxidative stress and the activation of inflammatory and apoptotic pathways. OCA pre-treatment significantly mitigated these changes as evidenced by lowered MDA, higher TAC and improved thyroid architecture. Mechanistically, OCA suppressed inflammation via downregulation of TLR4/MYD88/NF-κB signalling, inhibited pyroptosis through TXNIP/NLRP3/ASC/caspase-1 pathway blockade and reduced p53-mediated apoptosis by modulating BAX, BCL-2 and cleaved caspase-3 expression. This study provides the first evidence that OCA confers protection against CYC-induced thyroid injury by reducing oxidative stress, inflammation, pyroptosis and apoptosis.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"194 ","pages":"Article 118894"},"PeriodicalIF":7.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718563","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 : 2025-12-12DOI: 10.1016/j.biopha.2025.118902
Samuel Ruiz de Martín Esteban , M. Teresa Grande , Ana M. Martínez-Relimpio , Diego Herráez-Aguilar , Ricardo Mostany , Cecilia J. Hillard , William H. Hind , Julián Romero
The potential use of phytocannabinoids in neurodegenerative disorders is currently under intense investigation based on their potential anti-inflammatory, antioxidant, and neuroprotective effects. Here, we tested the effects of chronic (28 days) treatment with a complex botanical mixture of purified cannabidiol:Δ9-tetrahydrocannabinol (CBD:THC, 99:1) in male 5xFAD mice, a murine model of Alzheimer’s disease that recapitulates amyloid pathology. Effects of exposure to this cannabinoid mixture were evaluated using behavioral tests (elevated plus maze for anxiety, tail suspension for depression-like behavior, rotarod for motor coordination, open field for locomotor activity, and novel object recognition for memory), quantification of protein expression (IL-1β, CD40, TREM2, COX2), assessment of functional parameters (microglial phagocytic activity by flow cytometry), and in vivo multiphoton microscopy (time-course of changes of neuritic plaque structural features). Twice daily dosing with 50 mg/kg subcutaneously (s.c.) significantly reduced locomotion, increased anxiety- and depression-like behaviors and had no effect on memory and motor coordination. In vivo imaging experiments suggest that the CBD:THC treatment enhanced microglial phagocytic activity on amyloid plaques; this effect was observed both in plaque features (multiphoton microscopy measurements) as well as in microglia (flow cytometry data). Exposure to CBD:THC induced significant changes in in vivo microglia-amyloid interactions, increasing phagocytic activity and reducing the amyloid peptide accumulation in the neuritic plaques. Thus, CBD:THC (99:1) may be a promising treatment to reduce amyloid pathology, though caution should be noted due to the behavioral alterations observed, i.e., increased anxiety- and depression-like behaviors as well as decreased locomotion.
{"title":"Treatment with a botanical mixture of cannabidiol:Δ9-tetrahydrocannabinol enhances microglial phagocytosis and shapes amyloid plaques in a mouse model of Alzheimer’s disease","authors":"Samuel Ruiz de Martín Esteban , M. Teresa Grande , Ana M. Martínez-Relimpio , Diego Herráez-Aguilar , Ricardo Mostany , Cecilia J. Hillard , William H. Hind , Julián Romero","doi":"10.1016/j.biopha.2025.118902","DOIUrl":"10.1016/j.biopha.2025.118902","url":null,"abstract":"<div><div>The potential use of phytocannabinoids in neurodegenerative disorders is currently under intense investigation based on their potential anti-inflammatory, antioxidant, and neuroprotective effects. Here, we tested the effects of chronic (28 days) treatment with a complex botanical mixture of purified cannabidiol:Δ<sup>9</sup>-tetrahydrocannabinol (CBD:THC, 99:1) in male 5xFAD mice, a murine model of Alzheimer’s disease that recapitulates amyloid pathology. Effects of exposure to this cannabinoid mixture were evaluated using behavioral tests (elevated plus maze for anxiety, tail suspension for depression-like behavior, rotarod for motor coordination, open field for locomotor activity, and novel object recognition for memory), quantification of protein expression (IL-1β, CD40, TREM2, COX2), assessment of functional parameters (microglial phagocytic activity by flow cytometry), and <em>in vivo</em> multiphoton microscopy (time-course of changes of neuritic plaque structural features). Twice daily dosing with 50 mg/kg subcutaneously (s.c.) significantly reduced locomotion, increased anxiety- and depression-like behaviors and had no effect on memory and motor coordination. <em>In vivo</em> imaging experiments suggest that the CBD:THC treatment enhanced microglial phagocytic activity on amyloid plaques; this effect was observed both in plaque features (multiphoton microscopy measurements) as well as in microglia (flow cytometry data). Exposure to CBD:THC induced significant changes in <em>in vivo</em> microglia-amyloid interactions, increasing phagocytic activity and reducing the amyloid peptide accumulation in the neuritic plaques. Thus, CBD:THC (99:1) may be a promising treatment to reduce amyloid pathology, though caution should be noted due to the behavioral alterations observed, i.e., increased anxiety- and depression-like behaviors as well as decreased locomotion.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"194 ","pages":"Article 118902"},"PeriodicalIF":7.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735824","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 : 2025-12-12DOI: 10.1016/j.biopha.2025.118892
María Arenas-Moreira , Alberto Ocaña , Iván Bravo , Carlos Alonso-Moreno
To date, several targeted therapies have been developed for their clinical use, exhibiting increased cancer cell specificity. PROteolysis TArgeting Chimeras (PROTACs) are small molecules designed to induce the degradation of target proteins via proteasome after their ubiquitination. These molecules represent the most recent strategy of targeting specific proteins for post-translational degradation rather than simply inhibiting them. Despite the promising efficacy of PROTAC-based targeted therapies, significant drawbacks remain regarding their clinical translation. Advances in drug delivery systems (DDS) and nanotechnology offer innovative strategies to overcome these limitations and optimize the therapeutic index of PROTACs, through the use of several nanocarriers including lipid-based nanoparticles, polymeric nanoparticles or metallic nanoparticles, among others. In light of the exponential growth of preclinical studies, this review summarizes key achievements in the development of PROTACs and nanoPROTACs, highlighting how DDS can improve their mechanism of action and facilitate future clinical applications. Furthermore, recent research has focused on addressing critical challenges related to the permeability, bioavailability, and toxicity of these molecules, paving the way for more effective and safer therapeutic options. Continued interdisciplinary efforts integrating medicinal chemistry, nanotechnology and oncology are essential to fully exploit the potential of PROTACs.
{"title":"PROTAC delivery systems: Innovative approaches for cancer treatment","authors":"María Arenas-Moreira , Alberto Ocaña , Iván Bravo , Carlos Alonso-Moreno","doi":"10.1016/j.biopha.2025.118892","DOIUrl":"10.1016/j.biopha.2025.118892","url":null,"abstract":"<div><div>To date, several targeted therapies have been developed for their clinical use, exhibiting increased cancer cell specificity. PROteolysis TArgeting Chimeras (PROTACs) are small molecules designed to induce the degradation of target proteins via proteasome after their ubiquitination. These molecules represent the most recent strategy of targeting specific proteins for post-translational degradation rather than simply inhibiting them. Despite the promising efficacy of PROTAC-based targeted therapies, significant drawbacks remain regarding their clinical translation. Advances in drug delivery systems (DDS) and nanotechnology offer innovative strategies to overcome these limitations and optimize the therapeutic index of PROTACs, through the use of several nanocarriers including lipid-based nanoparticles, polymeric nanoparticles or metallic nanoparticles, among others. In light of the exponential growth of preclinical studies, this review summarizes key achievements in the development of PROTACs and nanoPROTACs, highlighting how DDS can improve their mechanism of action and facilitate future clinical applications. Furthermore, recent research has focused on addressing critical challenges related to the permeability, bioavailability, and toxicity of these molecules, paving the way for more effective and safer therapeutic options. Continued interdisciplinary efforts integrating medicinal chemistry, nanotechnology and oncology are essential to fully exploit the potential of PROTACs.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"194 ","pages":"Article 118892"},"PeriodicalIF":7.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718561","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 : 2025-12-12DOI: 10.1016/j.biopha.2025.118896
Yeonsoo Kim , Eunsol Seo , Anna Kang , Min-Geun Kang , Ki Beom Jang , Sangnam Oh , Younghoon Kim
The gut microbiota plays a pivotal role in maintaining host health and has increasingly been linked to the pathogenesis of neurodegenerative diseases through the microbiota-gut-brain axis. Parkinson’s disease (PD), characterized by dopaminergic dysfunction, neuro inflammation, and pathological alpha-synuclein (α-synuclein) aggregation, is frequently accompanied by gut microbial dysbiosis. Probiotics isolated from human infants could offer distinct neuroprotective and immunomodulatory benefits, yet their effects on integrated gut-brain axis models remain underexplored. In this study, we investigated the therapeutic potential of Lactobacillus acidophilus SLAM_LAA02 (L. acidophilus SLAM_LAA02), a novel infant-derived strain, in modulating PD-related behavioral and neuropathological features via modulation of the gut-brain axis. Following comprehensive safety and functional assessments, we first assessed L. acidophilus SLAM_LAA02 in Caenorhabditis elegans, where supplementation extended lifespan, enhanced antimicrobial defense, improved behavioral responses, and reduced α-synuclein expression in transgenic worms. We then evaluated its effects in a rotenone-induced mouse model that reflects early-stage PD-like features. L. acidophilus SLAM_LAA02 administration ameliorated motor dysfunction, modulated neuroinflammatory signaling, restored gut microbial diversity, and improved intestinal barrier-associated outcomes. These changes were accompanied by a notable reduction in α-synuclein expression and upregulated neuroprotective gene expression, including brain-derived neurotrophic factor (BDNF). Together, these findings suggest that L. acidophilus SLAM_LAA02 exhibits neuroprotective and gut-modulating properties across complementary model systems, supporting its potential as a promising probiotic candidate for alleviating early PD-related dysfunctions through the gut-brain axis.
{"title":"A neuroprotective effect of newly isolated probiotic bacterium Lactobacillus acidophilus SLAM_LAA02 in a rotenone-induced mouse model of Parkinson’s disease","authors":"Yeonsoo Kim , Eunsol Seo , Anna Kang , Min-Geun Kang , Ki Beom Jang , Sangnam Oh , Younghoon Kim","doi":"10.1016/j.biopha.2025.118896","DOIUrl":"10.1016/j.biopha.2025.118896","url":null,"abstract":"<div><div>The gut microbiota plays a pivotal role in maintaining host health and has increasingly been linked to the pathogenesis of neurodegenerative diseases through the microbiota-gut-brain axis. Parkinson’s disease (PD), characterized by dopaminergic dysfunction, neuro inflammation, and pathological alpha-synuclein (α-synuclein) aggregation, is frequently accompanied by gut microbial dysbiosis. Probiotics isolated from human infants could offer distinct neuroprotective and immunomodulatory benefits, yet their effects on integrated gut-brain axis models remain underexplored. In this study, we investigated the therapeutic potential of <em>Lactobacillus acidophilus</em> SLAM_LAA02 (<em>L. acidophilus</em> SLAM<em>_</em>LAA02), a novel infant-derived strain, in modulating PD-related behavioral and neuropathological features via modulation of the gut-brain axis. Following comprehensive safety and functional assessments, we first assessed <em>L. acidophilus</em> SLAM<em>_</em>LAA02 in <em>Caenorhabditis elegans</em>, where supplementation extended lifespan, enhanced antimicrobial defense, improved behavioral responses, and reduced α-synuclein expression in transgenic worms. We then evaluated its effects in a rotenone-induced mouse model that reflects early-stage PD-like features. <em>L. acidophilus</em> SLAM<em>_</em>LAA02 administration ameliorated motor dysfunction, modulated neuroinflammatory signaling, restored gut microbial diversity, and improved intestinal barrier-associated outcomes. These changes were accompanied by a notable reduction in α-synuclein expression and upregulated neuroprotective gene expression, including brain-derived neurotrophic factor (BDNF). Together, these findings suggest that <em>L. acidophilus</em> SLAM_LAA02 exhibits neuroprotective and gut-modulating properties across complementary model systems, supporting its potential as a promising probiotic candidate for alleviating early PD-related dysfunctions through the gut-brain axis.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"194 ","pages":"Article 118896"},"PeriodicalIF":7.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735825","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}
Gonadotropin-releasing hormone (GnRH) therapy, widely used in the management of reproductive and oncological disorders in adult humans, has been increasingly linked to metabolic and cardiovascular complications. This review focuses on the human clinical evidence, highlighting the interplay between GnRH-induced metabolic dysregulation and cardiotoxicity, particularly through mechanisms involving insulin resistance, dyslipidemia, and adipose tissue dysfunction. Suppression of sex steroid hormones by GnRH agonists and antagonists disrupts glucose and lipid metabolism, leading to heightened risks of type 2 diabetes, atherosclerosis, and cardiovascular disease (CVD). Long-term therapy promotes visceral adiposity—a metabolically active depot that amplifies systemic inflammation and endothelial dysfunction—further accelerating vascular injury. While substantial data exist in adult populations, evidence in youth remains extremely limited. The use of GnRH agonists in conditions such as central precocious puberty and gender dysphoria raises critical unanswered questions regarding whether early-life suppression of sex steroids produces similar or distinct cardiometabolic effects compared with adults. Given this uncertainty, extrapolation from adult data must be approached with caution. This review underscores the urgent need for proactive cardiovascular risk management in adults undergoing long-term GnRH therapy and highlights the importance of future longitudinal studies in younger populations. Integrating pharmacologic interventions (e.g., insulin sensitizers, statins, antihypertensives) with lifestyle strategies and precision-medicine approaches will be key to optimizing long-term metabolic and cardiovascular outcomes.
{"title":"Effects of GnRH agonists and antagonists on cardiovascular and metabolic systems in adults: Mechanistic pathways and risk management","authors":"Atoosa Etezadi , Seyed Mehdi Marashi , Leila Nazari , Mozhgan Sina , Fatemeh Samadi Nasab , Shahrzad Amirlatifi , Somaye Zamanifard , Ziba Zahiri , Farnaz Khodaparast","doi":"10.1016/j.biopha.2025.118860","DOIUrl":"10.1016/j.biopha.2025.118860","url":null,"abstract":"<div><div>Gonadotropin-releasing hormone (GnRH) therapy, widely used in the management of reproductive and oncological disorders in adult humans, has been increasingly linked to metabolic and cardiovascular complications. This review focuses on the human clinical evidence, highlighting the interplay between GnRH-induced metabolic dysregulation and cardiotoxicity, particularly through mechanisms involving insulin resistance, dyslipidemia, and adipose tissue dysfunction. Suppression of sex steroid hormones by GnRH agonists and antagonists disrupts glucose and lipid metabolism, leading to heightened risks of type 2 diabetes, atherosclerosis, and cardiovascular disease (CVD). Long-term therapy promotes visceral adiposity—a metabolically active depot that amplifies systemic inflammation and endothelial dysfunction—further accelerating vascular injury. While substantial data exist in adult populations, evidence in youth remains extremely limited. The use of GnRH agonists in conditions such as central precocious puberty and gender dysphoria raises critical unanswered questions regarding whether early-life suppression of sex steroids produces similar or distinct cardiometabolic effects compared with adults. Given this uncertainty, extrapolation from adult data must be approached with caution. This review underscores the urgent need for proactive cardiovascular risk management in adults undergoing long-term GnRH therapy and highlights the importance of future longitudinal studies in younger populations. Integrating pharmacologic interventions (e.g., insulin sensitizers, statins, antihypertensives) with lifestyle strategies and precision-medicine approaches will be key to optimizing long-term metabolic and cardiovascular outcomes.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"193 ","pages":"Article 118860"},"PeriodicalIF":7.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673113","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 : 2025-12-01DOI: 10.1016/j.biopha.2025.118882
Arkadiusz Grzeczka , Szymon Graczyk , Xutong Gong , Jan Gröschel , Sebastian Spethmann , Pawel Kordowitzki
Sirtuins are NAD⁺-dependent enzymes involved in metabolic regulation, aging, oxidative stress response, and inflammation, all of which are pivotal in the development of myocardial fibrosis. SIRT1, SIRT3, and SIRT6 are shown to exert protective effects by inhibiting fibroblast activation and reducing oxidative and inflammatory damage, while SIRT4 may promote fibrosis depending on context. This review article explores the multifaceted role of sirtuins (SIRT1–SIRT7) in cardiac fibrosis, a key pathological feature of heart failure characterized by excessive extracellular matrix accumulation. The article sheds light on the regulatory influence of non-coding RNAs and histone modifications on sirtuin expression, and illustrates the complex feedback between sirtuins and mitochondrial homeostasis, AMPK activation, and endothelial-to-mesenchymal transition (EndoMT). This review positions sirtuins as both markers and potential therapeutic targets for cardiac fibrosis, acknowledging their dual roles and context-specific effects. Herein, we highlight the importance of understanding the complex regulatory networks involving sirtuins to inform future anti-fibrotic interventions.
{"title":"Aging hearts, fibrotic fears: The sirtuin connection","authors":"Arkadiusz Grzeczka , Szymon Graczyk , Xutong Gong , Jan Gröschel , Sebastian Spethmann , Pawel Kordowitzki","doi":"10.1016/j.biopha.2025.118882","DOIUrl":"10.1016/j.biopha.2025.118882","url":null,"abstract":"<div><div>Sirtuins are NAD⁺-dependent enzymes involved in metabolic regulation, aging, oxidative stress response, and inflammation, all of which are pivotal in the development of myocardial fibrosis. SIRT1, SIRT3, and SIRT6 are shown to exert protective effects by inhibiting fibroblast activation and reducing oxidative and inflammatory damage, while SIRT4 may promote fibrosis depending on context. This review article explores the multifaceted role of sirtuins (SIRT1–SIRT7) in cardiac fibrosis, a key pathological feature of heart failure characterized by excessive extracellular matrix accumulation. The article sheds light on the regulatory influence of non-coding RNAs and histone modifications on sirtuin expression, and illustrates the complex feedback between sirtuins and mitochondrial homeostasis, AMPK activation, and endothelial-to-mesenchymal transition (EndoMT). This review positions sirtuins as both markers and potential therapeutic targets for cardiac fibrosis, acknowledging their dual roles and context-specific effects. Herein, we highlight the importance of understanding the complex regulatory networks involving sirtuins to inform future anti-fibrotic interventions.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"193 ","pages":"Article 118882"},"PeriodicalIF":7.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681204","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 : 2025-12-01DOI: 10.1016/j.biopha.2025.118872
Yixiao Zhu , Andi Chen , Chenglin Gai , Li Lin , Chengqian Teng , Jianjie Wei , Yanping Yang , Xiaoxia Wei , Xiaohui Chen
Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist extensively used for sedation in clinical anesthesia, has recently attracted significant attention for its neuroprotective properties. These effects are mediated through multiple mechanisms, including anti-inflammatory and antioxidative stress responses, inhibition of apoptosis and autophagy, preservation of mitochondrial function, and maintenance of blood-brain barrier integrity. Brain injury, encompassing neonatal hypoxic-ischemic encephalopathy, ischemic stroke, traumatic brain injury, and other related cerebral pathologies, remains a leading cause of global neurological disability. Despite advances in critical care, effective interventions to prevent secondary neuronal damage and long-term neurological dysfunction remain limited. The neuroprotective actions of DEX suggest its potential as a therapeutic candidate for mitigating neurological deficits following brain injury. This review synthesizes preclinical and clinical evidence on DEX across various forms of brain injury, spanning molecular mechanisms, animal models, and clinical applications, thereby providing a foundation for exploring its therapeutic strategies in neurocritical care.
{"title":"Dexmedetomidine in ischemic and hemorrhagic brain injury: Neuroprotection from mechanisms to therapy","authors":"Yixiao Zhu , Andi Chen , Chenglin Gai , Li Lin , Chengqian Teng , Jianjie Wei , Yanping Yang , Xiaoxia Wei , Xiaohui Chen","doi":"10.1016/j.biopha.2025.118872","DOIUrl":"10.1016/j.biopha.2025.118872","url":null,"abstract":"<div><div>Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist extensively used for sedation in clinical anesthesia, has recently attracted significant attention for its neuroprotective properties. These effects are mediated through multiple mechanisms, including anti-inflammatory and antioxidative stress responses, inhibition of apoptosis and autophagy, preservation of mitochondrial function, and maintenance of blood-brain barrier integrity. Brain injury, encompassing neonatal hypoxic-ischemic encephalopathy, ischemic stroke, traumatic brain injury, and other related cerebral pathologies, remains a leading cause of global neurological disability. Despite advances in critical care, effective interventions to prevent secondary neuronal damage and long-term neurological dysfunction remain limited. The neuroprotective actions of DEX suggest its potential as a therapeutic candidate for mitigating neurological deficits following brain injury. This review synthesizes preclinical and clinical evidence on DEX across various forms of brain injury, spanning molecular mechanisms, animal models, and clinical applications, thereby providing a foundation for exploring its therapeutic strategies in neurocritical care.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"193 ","pages":"Article 118872"},"PeriodicalIF":7.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681205","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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