Free Radical Biology and Medicine最新文献

{"title":"Energy metabolism rewiring following acute UVB irradiation is largely dependent on nuclear DNA damage.","authors":"Léa Dousset, Walid Mahfouf, Hadi Younes, Hala Fatrouni, Corinne Faucheux, Elodie Muzotte, Ferial Khalife, Rodrigue Rossignol, François Moisan, Muriel Cario, Stéphane Claverol, Laure Favot-Laforge, Anni I Nieminen, Seppo Vainio, Nsrein Ali, Hamid-Reza Rezvani","doi":"10.1016/j.freeradbiomed.2024.12.030","DOIUrl":"10.1016/j.freeradbiomed.2024.12.030","url":null,"abstract":"<p><p>Solar ultraviolet B (UVB) radiation-induced DNA damage is a well-known initiator of skin carcinomas. The UVB-induced DNA damage response (DDR) involves series of signaling cascades that are activated to maintain cell integrity. Among the different biological processes, little is known about the role of energy metabolism in the DDR. We sought to determine whether UVB-induced nuclear and/or mitochondrial cyclobutane pyrimidine dimers (CPDs) alter cellular energy metabolism. To gain insight into this question, we took advantage of keratinocytes expressing nuclear or mitochondrial CPD photolyase. Applying a quantitative proteomic approach and targeted metabolomics, we observed biphasic alterations in multiple metabolic pathways and in the abundance of various metabolites, largely influenced by the presence of genomic CPDs. The heightened oxygen consumption rate post-irradiation, along with mitochondrial structural rearrangements, was found to be dependent on both mitochondrial and nuclear CPDs. Understanding the influence of nuclear and mitochondrial DNA damage on keratinocyte responses to UVB irradiation deepens current knowledge regarding skin cancer prevention, initiation, and therapy.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"459-471"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the role of skin aging in pigmentary disorders.","authors":"Yiwen Yang, Yue Wu, Leihong Xiang, Mauro Picardo, Chengfeng Zhang","doi":"10.1016/j.freeradbiomed.2024.12.032","DOIUrl":"10.1016/j.freeradbiomed.2024.12.032","url":null,"abstract":"<p><p>Skin aging is a complex biological process involving intrinsic and extrinsic factors. Skin aging contains alterations at the tissue, cellular, and molecular levels. Currently, there is increasing evidence that skin aging occurs not only in time-dependent chronological aging but also plays a role in skin pigmentary disorders. This review provides an in-depth analysis of the impact of skin aging on different types of pigmentary disorders, including both hyperpigmentation disorders such as melasma and senile lentigo and hypopigmentation disorders such as vitiligo, idiopathic guttate hypomelanosis and graying of hair. In addition, we explore the mechanisms of skin aging on pigmentation regulation and suggest several potential therapeutic approaches for skin aging and aging-related pigmentary disorders.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"638-655"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinal AT1R contributes to neuroinflammation and neuropathic pain via NOX2-dependent redox signaling in microglia.","authors":"Wencui Zhang, Bo Jiao, Shangchen Yu, Kaiwen Zhang, Jiaoli Sun, Baowen Liu, Xianwei Zhang","doi":"10.1016/j.freeradbiomed.2024.12.004","DOIUrl":"10.1016/j.freeradbiomed.2024.12.004","url":null,"abstract":"<p><p>Microglia-mediated neuroinflammation demonstrates a crucial act in the progression of neuropathic pain. Oxidative damage induced by reactive oxygen species (ROS) derived from NADPH oxidase (NOX) in microglia drives proinflammatory microglia activation. Recent evidence points to the central renin angiotensin system (RAS) is involved in oxidative stress and neuroinflammation, with the angiotensin converting enzyme/angiotensin II/angiotensin receptor-1 (ACE/Ang II/AT1R) axis promoting inflammation through increased ROS production, counteracted by the ACE2/Ang (1-7)/Mas receptor (MasR) axis. While interventions targeting spinal AT1R have been shown to alleviate nociceptive hypersensitivity; yet the mechanisms remain elusive. Here, we discovered that spared nerve injury (SNI)-induced mechanical allodynia in rats were associated with M1-like microglia activation, oxidative stress and overactivity of ACE/Ang II/AT1R axis in the spinal cord. Increased AT1R and NOX2 expression were observed in activated dorsal horn microglia following SNI. Blockade of AT1R with losartan potassium (LOP) suppressed NOX2-mediated oxidative stress, and promoted a shift in microglia from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype in LPS-treated BV-2 cells. Additionally, NOX2 overexpression triggered the activation of the high-mobility group box 1/nuclear factor-kappa B (HMGB1/NF-κB) signaling pathway. Intrathecal administration of LOP effectively inhibited SNI-induced NOX2 overactivation in microglia and suppressed the HMGB1/NF-kB pathway, reducing oxidative stress and shifting the microglia polarization from M1 to M2 in the spinal cord, thereby attenuating neuroinflammation and pain hypersensitivity. Collectively, these findings underscore the neuroimmune-modulating effects of spinal AT1R in neuropathic pain, highlighting the regulation of redox homeostasis in microglia via a NOX2 dependent mechanism.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"143-156"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Giardia duodenalis flavohemoglobin is a target of 5-nitroheterocycle and benzimidazole compounds acting as enzymatic inhibitors or subversive substrates.","authors":"Edar Onam Pech-Santiago, Raúl Argüello-García, Guadalupe Arce-Cruz, Enrique Angeles, Guadalupe Ortega-Pierres","doi":"10.1016/j.freeradbiomed.2024.12.020","DOIUrl":"10.1016/j.freeradbiomed.2024.12.020","url":null,"abstract":"<p><p>Giardia duodenalis causes giardiasis in humans, companion, livestock and wild animals. Control of infection involves drugs as benzimidazoles (e.g., albendazole, ABZ) and 5-nitroheterocyclics [5-NHs: metronidazole (MTZ), furazolidone (FZD), nitazoxanide (NTZ)] as first-line agents. During infection, Giardia is exposed to immune and pro-oxidant host responses involving nitric oxide (NO). In Giardia, NO is detoxified by a flavohemoglobin (gFlHb), a heme-containing enzyme which is absent in mammals. gFlHb has NO dioxygenase and NADH oxidase activities converting NO into nitrate and producing a superoxide anion (O₂^•-) that causes oxidative stress and parasite death. The modulation of gFlHb activities may provide novel approaches for treatment of giardiasis. We investigated the capacity of selected benzimidazole-2-carbamates (BZCs: ABZ, oxibendazole, nocodazole), non-BZCs (thiabendazole), an ehtylphenylcarbamate (LQM-996) and 5-NHs (MTZ, NTZ, FZD and some derivatives) to bind to recombinant gFlHb at the heme group, modifying NADH consumption activity and/or inducing ROS production. Of these, BZCs and NTZ bind to heme and increased O₂^•- production (i.e. caused enzyme subversion), whereas MTZ binds to heme but inhibited NADH consumption. LQM-996 decreased NADH consumption and two out of four NTZ derivatives altered NADH oxidase activity. In silico docking and molecular dynamics studies suggested the interaction of distinct drug moieties in ABZ and NTZ with gFlHb sites involved in NADH and NO catalysis. These findings provide new insights on gFlHb as a novel target of BZCs, MTZ and NTZ, and provides a useful platform to assess the compounds binding capacity to gFlHb prior to experimental and clinical trials in giardiasis.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"355-366"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pleiotropic anti-cancer activities of novel non-covalent thioredoxin reductase inhibitors against triple negative breast cancer.","authors":"Brenna Flowers, Abigail Rullo, An Zhang, Keacha Chang, Valentina Z Petukhova, Sammy Y Aboagye, Francesco Angelucci, David L Williams, Steven Kregel, Pavel A Petukhov, Irida Kastrati","doi":"10.1016/j.freeradbiomed.2024.12.010","DOIUrl":"10.1016/j.freeradbiomed.2024.12.010","url":null,"abstract":"<p><p>Mounting evidence shows that tumor growth and progression rely on thioredoxin reductase 1 (TXNRD1)-mediated detoxification of oxidative stress that results from deregulated metabolism and mitogenic signaling in tumors. TXNRD1 levels are significant higher in triple negative breast cancer (TNBC) compared to normal tissue, making TXNRD1 a compelling TNBC therapeutic target. Despite the many attempts to generate TXNRD1 inhibitors, all known and reported compounds inhibiting TXNRD1 are problematic; they interact with TXNRD1 irreversibly and non-specifically resulting in numerous adverse side effects. Recently, a series of breakthrough studies identified a novel regulatory site, the 'doorstop pocket', in Schistosoma mansoni thioredoxin glutathione reductase, a TXNRD-like enzyme and an established drug target for the human parasitic infection, schistosomiasis. This discovery underpins the development of new first-in-class non-covalent inhibitors for this family of enzymes. Our data show that novel non-covalent TXNRD inhibitors (TXNRD(i)s) are potent dose-dependent inhibitors of viability in cellular models of TNBC. TXNRD(i)s attenuate several aggressive cancer phenotypes such as, clonogenic survival, mammosphere forming efficiency, invasion, and TXNRD-related gene expression in TNBC cells. TXNRD(i)s engage and inhibit TXNRD1 in live TNBC cells and xenograft tumors, thus supporting the mechanism of action at a cellular level. More importantly, TXNRD(i)s attenuated tumor growth in a preclinical MDA-MB-231 TNBC xenograft mouse model. Although additional optimization for TXNRD(i)s' potency is warranted, these results may open a new avenue for the development of novel small molecule therapeutics for TNBC.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"201-209"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The therapeutic potential of recombinant ANGPTL4 in Parkinson's disease: Evidence from in vivo and in vitro studies.","authors":"Hualing Li, Junjie Wei, Zhiyi Zheng, Rui Wang, Man Qu, Jiangbin Liu, Guotao Lu, Xiaobo Li, Weijuan Gong","doi":"10.1016/j.freeradbiomed.2024.12.009","DOIUrl":"10.1016/j.freeradbiomed.2024.12.009","url":null,"abstract":"<p><strong>Background: </strong>The established body of knowledge attests to the pivotal influence of ANGPTL4 on lipid metabolism and vascular biology. Nevertheless, its potential implication in neurodegenerative disease remains to be fully characterized.</p><p><strong>Methods: </strong>The present investigation delves into the involvement of ANGPTL4 in the pathological progression of PD, both in vitro and in vivo. PD models were induced by intraperitoneal administration of MPTP and LPS in WT and ANGPTL4^-/- mice. Additionally, rANGPTL4 was administered intravenously via the tail. Primary microglia cells cultured from the SNpc and Str regions of brains were exposed to LPS to induce neuroinflammation.</p><p><strong>Results: </strong>The observations unveiled that ANGPTL4 deficiency exacerbated behavioral aberrations, intensified dopaminergic neuron loss, and stimulated microglial activation along with p21-dependent senescence. There was an elevation in the expression of proinflammatory cytokines in the PD model. Furthermore, the administration of rANGPTL4 protein reversed the observed phenotypes in ANGPTL4^-/- mice, a phenomenon further validated in LPS-induced cells. Clinical specimens also manifested diminished levels of ANGPTL4 expression in PD patients. ANGPTL4 demonstrated the ability to alleviate neuroinflammation by suppressing EIF2-JNK-mediated ER stress and eliminating senescent cells.</p><p><strong>Conclusion: </strong>Our findings posit a salutary role for ANGPTL4 in counteracting PD, rendering it a prospective therapeutic target for the development of innovative drugs aimed at treating neuroinflammation-associated neurological diseases, including PD.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"190-200"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dimethyl labeling of N-terminal amines allows unambiguous identification of protein crosslinks.","authors":"Tina Nybo, Luke F Gamon, Eduardo Fuentes-Lemus, Daniel E Otzen, Michael J Davies, Per Hägglund","doi":"10.1016/j.freeradbiomed.2024.12.002","DOIUrl":"10.1016/j.freeradbiomed.2024.12.002","url":null,"abstract":"<p><p>Protein crosslinks induced through either deliberate enzymatic oxidation or reactive oxidants (oxidative eustress/distress), are associated with multiple human pathologies including atherosclerosis, Alzheimer's and Parkinson's diseases. In many cases, the nature of the crosslinks, their position(s) either within (intramolecular) or between (intermolecular) polypeptide chains, and concentrations are unclear. Although limited data are available from specific antibodies, detailed characterization of protein crosslinks is often performed by mass spectrometric analysis of peptides from proteolytic digestion. Such analyses are challenging due to the low concentration of these species, and the complexity of their fragment ion spectra when compared to non-crosslinked species. We hypothesized that highly efficient and specific chemical amine labeling of the two N-termini in crosslinked peptides (compared to the single N-terminus of linear peptides), using \"light\" and \"heavy\" isotope-labelled reagents would facilitate identification, validation and quantification of crosslinks. This method was compared to a previous enzyme-catalyzed ¹⁸O C-terminal carboxylate labeling approach. N-terminal amine dimethyl labeling is shown to have major advantages over the ¹⁸O-approach including high labeling yields (92-100 %) and well-defined mass spectrometric isotope distribution patterns. This approach has allowed identification of novel dityrosine crosslinks between pair of tyrosine (Tyr, Y) residues in photo-oxidized β-casein (Y195-Y195, Y195-Y208, Y208-Y208), and α-synuclein exposed to nitrosative stress (Y39-Y39, Y39-Y125, Y39-Y133, Y133-Y136). This approach is also applicable to disulfide bond mapping, with 15 of 17 disulfides in serum albumin readily detected. These data indicate that dimethyl labeling is a highly versatile and efficient approach for the site-specific identification of oxidation- and nitration-induced crosslinks in proteins.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"629-637"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles released by ALL patients contain HNE-adducted proteins: Implications of collateral damage.","authors":"Jenni Ho, Suriyan Sukati, Tamara Taylor, Sherry Carter, Brittany Fuller, Amy Marmo, Caryn Sorge, John D'Orazio, D Allan Butterfield, Subbarao Bondada, Heidi Weiss, Daret K St Clair, Luksana Chaiswing","doi":"10.1016/j.freeradbiomed.2024.12.006","DOIUrl":"10.1016/j.freeradbiomed.2024.12.006","url":null,"abstract":"<p><p>Off-target neuronal injury is a serious side-effect observed in cancer survivors. It has previously been shown that pediatric acute lymphoblastic leukemia (ALL) survivors have a decline in neurocognition compared to healthy age-matched counterparts. Elevated oxidative stress has been documented to be a mediator in off-target tissue damage in cancer survivors. Early detection of oxidative stress markers may provide an opportunity to prevent off-target tissue damage. Extracellular vesicles (EVs) have surfaced as a potential diagnostic tool due to molecular cargo they contain. We investigated the potential for EVs to be a sensitive indicator of oxidative stress and off-target tissue damage by isolating EVs from pediatric ALL patients throughout their first 2 months of treatment. EVs were measured throughout the collection points for: 1) number of EV particles generated using nanoparticle tracking analysis (NTA); 2) markers of neurons (NeuN), astrocyte activation (GFAP), neuronal stability (BDNF), 3) markers of pre-B cell ALL (CD19 and CD22); and) 4-hydroxy-2-nonenal (HNE) adducted proteins. HNE protein adductions were measured in the patient sera and CSF. Pro-inflammatory cytokine levels were also measured in patient sera because of their contribution to oxidative stress and neuronal injury. Our results: 1) demonstrate EVs are a sensitive indicator of oxidative damage; 2) suggest EVs as a marker of a decline in neuronal stability; and 3) show the presence of leukemia has a greater contribution to pro-inflammatory cytokine production in the patient's serum than the cancer treatment. Specifically, we observed a significant decrease in cytokine levels (e.g., TNF-α, IL-1β, IL-6, and IL-8) following the initiation of treatment, highlighting the influence of leukemia burden on systemic inflammation. The results support the utilization of EVs as a sensitive marker of oxidative stress and off-target tissue damage.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"312-321"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Puerarin reduces susceptibility to ventricular arrhythmias and inhibits ferroptosis via Sirt1/Nrf2 signaling in high-fat-diet rats.","authors":"Shuang Jiang, Suhua Qiu, Yu Mu, Chilu Liu, Yanxing Han, Jiandong Jiang, Yuhong Wang","doi":"10.1016/j.freeradbiomed.2024.12.005","DOIUrl":"10.1016/j.freeradbiomed.2024.12.005","url":null,"abstract":"<p><p>Obesity is a significant risk factor for cardiac arrhythmias, and the ferroptosis is closely related to cardiac arrhythmias. This study aimed to investigate whether puerarin (Pue), a natural isoflavone, could reduce the susceptibility to ventricular arrhythmias (VAs) associated with obesity and inhibit ferroptosis, with a particular focus on the Sirt1/Nrf2 signaling pathway. Male rats were randomly divided into three groups: normal chow diet (NC), high-fat diet (HFD), and HFD with Pue treatment (100mg/kg, HFD + Pue). After 16 weeks, electrophysiological, structural, and molecular analysis were performed. Compared to the NC group, HFD rats exhibited prolonged QT interval and Tpeak-Tend interval, amplified transmural dispersion of ventricular repolarization, and increased susceptibility to VAs. Pue treatment significantly ameliorated these electrophysiological abnormalities and reduced VAs susceptibility. HFD rats showed cardiac hypertrophy, fibrosis, and inflammation, which were alleviated by Pue application. Cardiac lipid peroxidation, iron deposition, mitochondrial abnormality, and ferroptosis marker induction were observed in HFD rats. Further, treatment with Pue improved these alterations. Additionally, molecular docking analysis confirmed the interaction of Pue with Sirt1 and Nrf2. Furthermore, Pue treatment upregulated Sirt1 and Nrf2 expression in HFD rats, thereby reducing reactive oxygen species (ROS) generation and ferroptosis. Moreover, Pue protected cardiomyocytes against palmitic acid (PA)-induced injury by inhibiting ferroptosis via the Sirt1/Nrf2 pathway in H9c2 cells. Overall, our study shows for the first time that Pue reduces susceptibility to VAs and inhibits ferroptosis in HFD rats by modulating the Sirt1/Nrf2 signaling pathway, offering a potential therapeutic strategy for obesity-related cardiac arrhythmias.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"472-484"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Static and dynamic in vitro colonic models reveal the spatiotemporal production of flavan-3-ol catabolites.","authors":"Yongkai Ma, Lucia Ghiretti, Vincenzo Castellone, Pedro Mena, Josep Rubert","doi":"10.1016/j.freeradbiomed.2024.12.034","DOIUrl":"10.1016/j.freeradbiomed.2024.12.034","url":null,"abstract":"<p><p>Flavan-3-ols are the most found flavonoid compounds in the human diet. Polymeric and monomeric flavan-3-ols reach the colonic region intact, where the gut microbiota utilizes them as substrates. In this research work, we investigated the pattern of colonic metabolites associated with flavan-3-ols, conducting a comprehensive analysis that combined (un)targeted metabolomics and in vitro colonic models. Firstly, the proposed flavan-3-ol metabolic pathway was investigated in-depth using a static in vitro model inoculated with different fecal donors. An apple, (-)-epicatechin, and procyanidin C1 were employed as feeding conditions. Small phenolic acids, such as phenylpropanoic acid and 3,4-dihydroxybenzoic acid, were positively associated with the apple feeding condition. In contrast, 5-(3',4'-dihydroxyphenyl)-γ-valerolactone and other specific early intermediates like phenylvaleric acids were positively associated with (-)-epicatechin. Secondly, by employing a dynamic in vitro simulator model of the human digestion system (SHIME), we reconstructed the flavan-3-ol metabolic pathway regionally. In the proximal colon region, we localized catabolites, such as 5-(3',4'-dihydroxyphenyl)-γ-valerolactone, while in the distal region, we identified mainly small phenolics. Combining static and dynamic in vitro models, we observed differences in the release of flavan-3-ol catabolites, influenced by both the food structure (isolated compounds and a food matrix) and the colonic region. This study sheds light on the colonic catabolism of one of the main dietary (poly)phenols and localizes microbial metabolites.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"582-592"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}