Biomedicine & Pharmacotherapy最新文献

{"title":"Multi-organ model assessment of neurotoxicity following exposure of liver spheroids to drugs","authors":"Wei Wu ,&nbsp;Faiza Anas ,&nbsp;Baran Koc ,&nbsp;Lipeng Tian ,&nbsp;Ryan Hasselkus ,&nbsp;Darian Rezania ,&nbsp;Sophia Sharareh ,&nbsp;Luba Farberov ,&nbsp;Dor Zlotnik ,&nbsp;Ariel Alon ,&nbsp;Guy Tenzer ,&nbsp;Isaac Bentwich ,&nbsp;Amir Bein","doi":"10.1016/j.biopha.2025.118021","DOIUrl":"10.1016/j.biopha.2025.118021","url":null,"abstract":"<div><div>Accurate prediction of drug toxicity is a major challenge for therapeutic development. The use of animal models for predicting toxicity has been a longstanding practice, but often falls short in accurately predicting human-specific responses. Human in vitro models, such as organoids and spheroids, provide alternative approaches to animal models. In this study, we employed primary human-derived liver spheroids (hLiSps) and human induced pluripotent stem cells (iPSC)-derived brain organoids (hiBOs) to create a combined Liver+Brain model for neurotoxicity assessment, to investigate the potential influence of incorporating a liver preconditioning component on toxic responses in the brain. Comparing the effect of six example drugs that are known to cause adverse clinical neurological effects, we observed that troglitazone (Trgl), tested at clinically relevant doses in the Liver+Brain model, caused a significantly greater reduction in cell viability compared to similar treatments in the Brain-only model. This was further confirmed across multiple donors and various stages of brain organoid development. In contrast, we found that high dose valproic acid treatment increased cell viability in the Liver+Brain model. Transcriptome analysis using RNA-seq revealed that liver-preconditioned Trgl elicited a more pronounced transcriptional response in hiBOs, identifying a 7-fold increase in the number of affected genes and over a 10-fold increase in affected pathways containing gene set components specifically associated with cell division and neurogenesis, which were not observed in the Brain model. Taken together, our data suggest that the addition of hLiSps to hiBOs is critical to accurately assess neurotoxicity using a comprehensive human in vitro model.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118021"},"PeriodicalIF":6.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug release from docetaxel-entrapped core-crosslinked polymeric micelles: A population pharmacokinetic modelling approach based on clinical data","authors":"Pascale C.S. Rietveld ,&nbsp;Stijn L.W. Koolen ,&nbsp;Stefan Zeiser ,&nbsp;Cristianne J.F. Rijcken ,&nbsp;Martijn van Noort ,&nbsp;Ruben A.G. van Eerden ,&nbsp;Florence Atrafi ,&nbsp;Iris H.C. Miedema ,&nbsp;C. Willemien Menke-van der Houven van Oordt ,&nbsp;Birgit C.P. Koch ,&nbsp;Ron H.J. Mathijssen ,&nbsp;Nelleke Snelder ,&nbsp;Sebastiaan D.T. Sassen","doi":"10.1016/j.biopha.2025.118028","DOIUrl":"10.1016/j.biopha.2025.118028","url":null,"abstract":"<div><div>CPC634 is a core-crosslinked polymeric micelle entrapping docetaxel (DTX) developed to improve tolerability and tumour drug accumulation compared to conventional DTX. A pH-responsive covalent sulfone ester linker allows for controlled native DTX release. Prior research has shown CPC634's dose-proportional clinical pharmacokinetics (PK) and enhanced tumour uptake. Through population PK modelling, we aimed to predict the plasma PK and intratumoural PK of CPC634 and released DTX, focusing on how varying pH levels affect DTX release. Concentration-time data in blood and tumour from three clinical studies were used to build a population PK model. <em>In vitro</em> release of DTX from CPC634 was examined across pH values (5–7.4), measuring cumulative release over time to create pH-specific models. The clinical PK analysis showed that elimination of CPC634 was described by linear kinetics whereas release of DTX was found to be time-dependent. The <em>in vitro</em> DTX release rate in buffer and blood was described by first-order release (time-dependent) and (known) degradation processes. These findings were incorporated into the population PK model, allowing simulations to describe drug release behaviour. The <em>in vitro</em> findings indicated that DTX release rates of CPC634 increased with rising pH (positive correlation), as is expected from an ester linkage. The estimated clinical tumour DTX release rate from CPC634 was 1.23 * 10⁻³ h⁻¹ corresponding with pH 5–6. Achieving a balance between nanoparticle stability in the circulation and efficient intratumoural release is critical for improving therapeutic efficacy. This underscores the importance of pH in the design of nanoparticles with temporarily covalently bound drugs.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118028"},"PeriodicalIF":6.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of hypoxia-inducible factor-1 and 2 alpha inhibitory compounds in the oral cavity and pharyngeal cancer","authors":"Bianca Barbério Bogdan Tedeschi ,&nbsp;Tiago Henrique ,&nbsp;Ana Paula Simedan Vila ,&nbsp;Gabriela Helena Rodrigues ,&nbsp;Rosa Sayoko Kawasaki-Oyama ,&nbsp;Érika Cristina Pavarino ,&nbsp;Peterson de Jesus Morais ,&nbsp;Vitória Scavacini Possebon ,&nbsp;Vilson Serafim Júnior ,&nbsp;Márcia Maria Urbanin Castanhole-Nunes ,&nbsp;Eny Maria Goloni-Bertollo","doi":"10.1016/j.biopha.2025.118024","DOIUrl":"10.1016/j.biopha.2025.118024","url":null,"abstract":"<div><div>Hypoxia in the tumor environment leads to an activation of genotypes that favors the tumor, promoting angiogenesis, epithelial-mesenchymal transition, cell invasion, and metastasis. It is considered a prognostic factor related to the progression and aggressiveness of Head and Neck Cancer (HNC). Hypoxia-inducible factor (HIF) is the main gene activated by hypoxia and has been associated with tumor advancement. Thus, this work aims to evaluate the performance of the compounds Acriflavine, Resveratrol, Topotecan, and RNA interference (siRNA) as HIF inhibitors as well as a therapeutic approach. Molecular docking results have suggested that the evaluated compounds present potential interactions with HIF-1α and HIF-2α. In vitro analysis, they demonstrated that treatments with Acriflavine and Topotecan caused a decrease in the gene expression of HIFs in the HN13 cell line (carcinoma of the oral cavity). Furthermore, treatments performed with siRNAs effectively inhibited gene expression of HIFs in HN13 and FaDu (carcinoma of the pharynx) cell lines. Considering the role of hypoxia and HIFs in tumor aggressiveness; the present study shows the potential of the evaluated compounds as a therapeutic use for the prevention of tumor progression in head and neck cancer.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118024"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preparation and comprehensive preclinical study of Peramivir inhalation solution: Achieving accurate drug delivery","authors":"Chao Mei ,&nbsp;Xinyi Cai ,&nbsp;Pian Li ,&nbsp;Jingli Chen ,&nbsp;Wenting Lu ,&nbsp;Peipei Pi ,&nbsp;Jianfang Shi ,&nbsp;Wenlong Li ,&nbsp;Xiang Cai","doi":"10.1016/j.biopha.2025.118029","DOIUrl":"10.1016/j.biopha.2025.118029","url":null,"abstract":"<div><div>Peramivir, a Neuraminidase inhibitor used for influenza A or B treatment, is currently marketed in the form of injections globally. However, Peramivir injections result in widespread systemic distribution, with only 3–9 % of the drug reaching the nasal cavity and pharyngeal mucus (key sites of action). In contrast, inhaled formulations can directly reach the site of absorption or action, leading to rapid onset of effect. This approach circumvents the first-pass hepatic metabolism, reduces the dosage required, minimizes systemic exposure, and may mitigate or avoid certain adverse drug reactions. It is noteworthy that no Peramivir inhalation solution (PIS) products are currently available globally. In this study, we focused on the reformulation of Peramivir from intravenous to inhalation administration, conducting comprehensive research on its toxicity, tissue distribution, pharmacokinetics, and pharmacodynamics. We demonstrated that PIS, compared to intravenous administration, exhibited heightened local drug exposure in lung tissues, longer exposure duration, slower elimination, and exhibited good tolerability without specific safety concerns.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118029"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nicotinamide derivatives protect the blood-brain barrier against oxidative stress","authors":"Antonio Zandona ,&nbsp;Anikó Szecskó ,&nbsp;Suzana Žunec ,&nbsp;Ivana Novak Jovanović ,&nbsp;Valentina Bušić ,&nbsp;Dajana Gašo Sokač ,&nbsp;Mária A. Deli ,&nbsp;Maja Katalinić ,&nbsp;Szilvia Veszelka","doi":"10.1016/j.biopha.2025.118018","DOIUrl":"10.1016/j.biopha.2025.118018","url":null,"abstract":"<div><div>Nicotinamides play a crucial role in energy metabolism and maintenance of the redox homeostasis counteracting oxidative stress and elevated reactive oxidative species (ROS) in human cells. The levels of nicotinamides decline with age and are associated with various pathologies, including ones linked with the blood-brain barrier disorder. Therefore, the investigation of the bioactivity of synthetic nicotinamide derivates (NAs) and evaluation of their potential to protect the blood-brain barrier (BBB) from oxidative stress is emerging as an important new strategy. In the current study, we tested different NAs as potential exogenous substitutes for such biological processes. All tested derivatives were non-toxic and attenuated elevation of ROS production in brain endothelial cells induced by <em>tert</em>-butyl hydroperoxide (tBHP), but one specifically was protective on the cell-cultured model of the BBB. The most promising NA was a derivative containing methoxy moiety (NA-4OCH₃), which not only increased cell impedance, but had a protective effect on brain endothelial cells barrier against tBHP-induced oxidative stress on several levels: reducing the ROS level and restoring the activity of glutathione, mitochondrial membrane potential, superoxide dismutase enzymes activity to the basal level. In addition, NA-4OCH₃ increased the integrity of both human and rat cell-based BBB model after tBHP-treatment seen by the elevated transendothelial electrical resistance, tight junction protein claudin-5 level as well as the decreased permeability of markers across the barrier. This study highlights novel approach to protect the BBB from oxidative stress-induced dysfunction, positioning NA-4OCH₃ as potential neuroprotective agent for ROS-mediated disease interventions, with implications for neurodegeneration and BBB.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118018"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the links between polyphenols, Nrf2, and diabetes: A review","authors":"Reza Ebrahimi ,&nbsp;Alireza Mohammadpour ,&nbsp;Alessandro Medoro ,&nbsp;Sergio Davinelli ,&nbsp;Luciano Saso ,&nbsp;Mehran Miroliaei","doi":"10.1016/j.biopha.2025.118020","DOIUrl":"10.1016/j.biopha.2025.118020","url":null,"abstract":"<div><div>Diabetes mellitus, a complex metabolic disorder, is marked by chronic hyperglycemia that drives oxidative stress and inflammation, leading to complications such as neuropathy, retinopathy, and cardiovascular disease. The Nrf2 pathway, a key regulator of cellular antioxidant defenses, plays a vital role in mitigating oxidative damage and maintaining glucose homeostasis. Dysfunction of Nrf2 has been implicated in the progression of diabetes and its related complications. Polyphenols, a class of plant-derived bioactive compounds, have shown potential in modulating the Nrf2 pathway. Numerous compounds have been found to activate Nrf2 through mechanisms including Keap1 interaction, transcriptional regulation, and epigenetic modification. Preclinical studies indicate their ability to reduce reactive oxygen species (ROS), improve insulin sensitivity, and attenuate inflammation in diabetic models. Clinical trials with certain polyphenols, such as resveratrol, have demonstrated improvements in glycemic parameters, though results remain inconsistent. While polyphenols show promise as a component of non-pharmacological approaches to diabetes management, challenges such as bioavailability, individual variability in response, and limited clinical evidence highlight the need for further investigation. Continued research could enhance understanding of their mechanisms and improve their practical application in mitigating diabetes-related complications.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118020"},"PeriodicalIF":6.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycosyl terpenoid-rich fraction of TeMac™ attenuates oxidative stress, inhibits cholinesterases enzyme activities, and protects brain against scopolamine-induced histopathological alterations in rats","authors":"Bruno Dupon Akamba Ambamba ,&nbsp;Ghislain Djiokeng Paka ,&nbsp;Guy Roussel Nguemto Takuissu ,&nbsp;Quentin Cicilien Piebeng Nongni ,&nbsp;Leonel Javeres Mbah Ntepe ,&nbsp;Fils Armand Ella ,&nbsp;Damaris Enyegue Mandob ,&nbsp;Martin Fonkoua ,&nbsp;Judith Laure Ngondi","doi":"10.1016/j.biopha.2025.118010","DOIUrl":"10.1016/j.biopha.2025.118010","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer's disease (AD) is the most commonly diagnosed form of senile dementia, with limited therapeutic options. Neuronal damage is caused by factors secreted by inflammatory cells but also, the lack of antioxidants to prevent oxidative stress and help maintain neuronal integrity, which is crucial for cognition and memory are mediators of AD. <em>Terminalia macroptera</em> barks contain glycosyl terpenoids, known for their strong antioxidant properties. This study investigated the antioxidant and neuroprotective effects of the glycosylic terpenoid-rich fraction of <em>Terminalia macroptera</em> (GT-TeMac™) in scopolamine-treated rats.</div></div><div><h3>Methods</h3><div>Glycosylic terpenoids were identified by LC-MS and antiradical activity tests (DPPH and ORAC) were performed. Cholinergic cognitive dysfunction and oxidative stress were induced in male <em>wistar</em> rats, by intraperitoneal injection of scopolamine (1 mg/kg BW/day) for seven consecutive days. GT-TeMac™ at 100 mg/kg and Donepezil at 5 mg/kg body weight were administered orally 60 min after scopolamine. After treatment, rat were sacrificed and brains were collected for the evaluation of cholinergic enzyme activity, oxidative stress markers and histopathological analysis. <em>In vitro</em> study was carried out to assess the ability of GT-TeMac™ to scavenge free radicals and suppress H₂O₂-induced ROS production in SK-N-SH cells. In addition, the ability of GT-TeMac™ to restore cell viability reduced by acrolein was performed.</div></div><div><h3>Results</h3><div>Chebuloside II, Sericoside, 24-deoxysericoside, arjunglucoside 1 and 23-galloylarjunolic acid 28-O-glucopyranosylester were identified by LC-MS. GT-TeMac™ has a SC₅₀ of 9.54 μg/mL and an ORAC value of 1130 µM Trolox equivalent per mg of GT-TeMac™. The administration of GT-TeMac™ protected against cognitive decline in AD by inhibiting cholinesterase metabolism, modulating oxidative stress parameters and protecting hippocampal areas. Additionally, GT-TeMac™ absorbed and eliminated ROS produced by hydrogen peroxide in SKNSH cells and restored cell viability reduced by acrolein.</div></div><div><h3>Conclusion</h3><div>These findings suggest that the active ingredients in GT-TeMac™ are promising drug candidates for the treatment of cognitive disorders associated with oxidative stress in AD.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118010"},"PeriodicalIF":6.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baicalin n-butyl ester alleviates inflammatory bowel disease and inhibits pyroptosis through the ROS/ERK/P-ERK/NLRP3 pathway in vivo and in vitro","authors":"Mengru Guo,&nbsp;Huining Wu,&nbsp;Jin Zhang,&nbsp;Linlu Zhao,&nbsp;Jieyi He,&nbsp;Zhichao Yu,&nbsp;Xingbin Ma,&nbsp;Yanhong Yong,&nbsp;Youquan Li,&nbsp;Xianghong Ju,&nbsp;Xiaoxi Liu","doi":"10.1016/j.biopha.2025.118012","DOIUrl":"10.1016/j.biopha.2025.118012","url":null,"abstract":"<div><h3>Background</h3><div>Baicalin is a flavonoid extracted from dried roots of the plant <em>Scutellariabaicalensis</em>. Baicalin n-butyl ester (BNE) is a flavonoid obtained by esterification of baicalin and has anti-inflammatory and antioxidant effects.</div></div><div><h3>Purpose</h3><div>The therapeutic efficacy and potential mechanism of BNE in inflammatory bowel disease remain unclear. This study investigated the effects and underlying mechanisms of BNE in ulcerative colitis.</div></div><div><h3>Methods</h3><div>Dextran sulfate sodium (DSS) was used to construct a mouse model of ulcerative colitis, and mice were given intragastric administration of BNE. During the experiment, the changes of body weight and hematochezia of mice were observed. At the end of administration, the levels of inflammatory factors, colonic microbial changes and pyroptosis of colonic cells were measured. Mouse intestinal epithelial cells were stimulated by lipopolysaccharide/adenosine-5′-triphosphate to establish an in vitro model. ELISA, qRT-PCR and immunoblotting were used to explore the effect and mechanism of BNE on pyroptosis.</div></div><div><h3>Results</h3><div>In vivo, BNE drastically attenuated ulcerative colitis symptoms by relieving body weight loss, a decline in colon length, and destruction of colon tissue structure. BNE also reduced the secretion of pro-inflammatory cytokines, including IL-1β, IL-18, and TNF-α, and reactive oxygen species (ROS). Furthermore, 16S rRNA sequencing analyses of gut microbiota revealed that BNE reversed gut microbiota dysbiosis by reducing the abundance of <em>unclassified-Clostridia-UCG-014</em> and increasing that of <em>Lachnospiraceae</em>. BNE also inhibited cell pyroptosis in mice with DSS-induced colitis. In vitro analyses showed that BNE decreased the secretion of IL-1β, IL-18, TNF-α, and ROS in lipopolysaccharide/adenosine-5′-triphosphate-stimulated mouse intestinal epithelial cells, and it inhibited pyroptosis mediated by oligomeric domain-like receptor protein 3 (NLRP3). Addition of ROS scavenger and ERK inhibitor further confirmed that BNE down-regulated ROS and inhibited the phosphorylation of ERK, thus inhibiting NLRP3-mediated cell pyroptosis. The magnetic beads pull-down assay showed that BNE had the capacity to bind directly to the ERK proteinin MODE-K cells.</div></div><div><h3>Conclusion</h3><div>BNE protects against colitis by increasing the abundance of <em>Lachnospiraceae</em> in vivo and suppressing pyroptosis via binding ERK protein and inhibiting ROS/ERK/P-ERK/NLRP3 in vivo and in vitro.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118012"},"PeriodicalIF":6.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin-mediated NRF2 induction limits inflammatory damage in, preclinical models of cystic fibrosis","authors":"Stephen A. Leon-Icaza ,&nbsp;Maxence Frétaud ,&nbsp;Sarahdja Cornélie ,&nbsp;Charlotte Bureau ,&nbsp;Laure Yatime ,&nbsp;R.Andres Floto ,&nbsp;Stephen A. Renshaw ,&nbsp;Jean-Louis Herrmann ,&nbsp;Christelle Langevin ,&nbsp;Céline Cougoule ,&nbsp;Audrey Bernut","doi":"10.1016/j.biopha.2025.117957","DOIUrl":"10.1016/j.biopha.2025.117957","url":null,"abstract":"<div><h3>Background</h3><div>Overactive neutrophilic inflammation causes damage to the airways and death in people with cystic fibrosis (CF), a genetic disorder resulting from mutations in the <em>CFTR</em> gene. Reducing the impact of inflammation is therefore a major concern in CF. Evidence indicates that dysfunctional NRF2 signaling in CF individuals may impair their ability to regulate their oxidative and inflammatory responses, although the role of NRF2 in neutrophil-dominated inflammation and tissue damage associated with CF has not been determined. Therefore, we examined whether curcumin, an activator of NRF2, might provide a beneficial effect in the context of CF.</div></div><div><h3>Methods</h3><div>Combining Cftr-depleted zebrafish as an innovative biomedical model with CF patient-derived airway organoids (AOs), we aimed to understand how NRF2 dysfunction leads to abnormal inflammatory status and tissue remodeling and determine the effects of curcumin in reducing inflammation and tissue damage in CF.</div></div><div><h3>Results</h3><div>We demonstrate that NFR2 is instrumental in regulating neutrophilic inflammation and repair processes <em>in vivo</em>, thereby preventing inflammatory damage. Importantly, curcumin treatment restores NRF2 activity in both CF zebrafish and AOs. Curcumin reduces neutrophilic inflammation in CF context, by rebalancing the production of epithelial ROS and pro-inflammatory cytokines. Furthermore, curcumin improves tissue repair by reducing CF-associated fibrosis. Our findings demonstrate that curcumin prevents CF-mediated inflammation <em>via</em> activating the NRF2 pathway.</div></div><div><h3>Conclusions</h3><div>This work highlights the protective role of NRF2 in limiting inflammation and injury and show that therapeutic strategies to normalize NRF2 activity, using curcumin or others NRF2 activators, might simultaneously reduce airway inflammation and damage in CF.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117957"},"PeriodicalIF":6.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclosporine combined with dexamethasone regulates hepatic Abca1 and PPARα expression and lipid metabolism via butyrate derived from the gut microbiota","authors":"Yongping Shi ,&nbsp;Mi Jiang ,&nbsp;Wenzhong Zhu ,&nbsp;Ke Chang ,&nbsp;Xukai Cheng ,&nbsp;Haijun Bao ,&nbsp;Zuojie Peng ,&nbsp;Yuan Hu ,&nbsp;Chao Li ,&nbsp;Feifei Fang ,&nbsp;Jia Song ,&nbsp;Chenxing Jian ,&nbsp;Jinhuang Chen ,&nbsp;Xiaogang Shu","doi":"10.1016/j.biopha.2025.118017","DOIUrl":"10.1016/j.biopha.2025.118017","url":null,"abstract":"<div><div>Immunosuppression often leads to drastic metabolic, hormonal, and physiological disorders. Changes in the gut microbiota are believed to be one of the factors contributing to these disorders, but the association remains uncertain. Clinical studies can be complicated by confounding variables, such as diet and other drivers of heterogeneity in human microbiomes. In this study, we identified pronounced gut microbiome signatures in rhesus macaques (RMs) with immunosuppression-induced lipid metabolism disorders following cyclosporine combined with dexamethasone. Furthermore, we observed similar changes in the gut microbiota of mice with immunosuppression-induced lipid metabolism disorders, which were associated with short-chain fatty acid metabolism. ELISA showed that immunosuppression significantly reduced the levels of butyric acid in both feces and serum of mice. Spearman correlation analysis identified a significant correlation between serum butyric acid levels and gut microbial dysbiosis induced by immunosuppression, particularly in relation to <em>f_Lachnospiraceae</em>, <em>g_unidentified_Ruminococcaceae</em>, and s_<em>Clostridium leptum</em>. Additionally, mice transplanted with gut microbiota from immunosuppressed mice exhibited hepatic lipid metabolism disorders, and RNA sequencing revealed significant downregulation of ABC transporters and PPARα in the liver, which was closely associated with lipid transport and metabolism, particularly Abca1. Moreover, butyric acid supplementation alleviated hepatic lipid metabolism disorders and upregulated the expression of Abca1 and PPARα in mice transplanted with immunosuppression-induced gut microbiota. Thus, we propose that the combination of cyclosporine and dexamethasone regulates the expression of hepatic Abca1 and PPARα by modulating the gut microbiota and its derived butyrate, particularly <em>Lachnospiraceae</em> and <em>Clostridium leptum</em>, further regulating hepatic lipid metabolism.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118017"},"PeriodicalIF":6.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}