Objectives:Colorectal cancer(CRC)is a major global health burden,and Urolithin A(Uro-A)has emerged as a promising anticancer agent.This systematic review aims to synthesize current in vitro evidence on the anticancer ...Objectives:Colorectal cancer(CRC)is a major global health burden,and Urolithin A(Uro-A)has emerged as a promising anticancer agent.This systematic review aims to synthesize current in vitro evidence on the anticancer effects of Uro-A in CRC,highlighting effective concentration ranges,exposure times,relevant outcomes,and underlying molecular mechanisms.Methods:Following PRISMA 2020 guidelines,a systematic search was conducted in PubMed,Scopus,and Web of Science using the following strategy:(colorectal cancer)AND(urolithin a)OR(3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one).Eligibility criteria were defined by the PICO framework:(P)in vitro CRC cell models;(I)Uro-A alone or combined treatments;(C)No intervention,vehicle or other treatments;(O)Relevant anticancer outcomes of Uro-A in CRC.Only original,full-text,in vitro studies in English were included.Risk of bias was assessed using ToxRTool.A qualitative synthesis was performed due to the heterogeneity of the included studies.Results:Fifteen studies met inclusion criteria,involving CRC cell lines(Caco-2,HCT-116,HT-29,SW480,SW620)and normal colon fibroblasts(CCD18-Co).Uro-A inhibited CRC cell proliferation,clonogenic growth,cancer stem cells properties,migration,and invasion,and induced cell cycle arrest,apoptosis,autophagy,and senescence,through modulation of key signaling pathways and proteins.Co-treatments with conventional chemotherapeutics and microbiota-derived metabolites showed additive or synergistic effects.Discussion:The findings support UroA’s potential as a preventive or adjuvant agent in CRC treatment.However,preclinical nature of the evidence and methodological heterogeneity hinder clinical extrapolation to in vivo contexts.Human clinical trials are necessary to overcome these limitations.Other:This review was registered in PROSPERO(CRD420251070874)and supported by FCT/MCTES UIDP/05608/2020 and UIDB/05608/2020.Institutional.展开更多
Urolithin A(UA)is a natural metabolite produced from polyphenolics in foods such as pomegranates,berries,and nuts.UA is neuroprotective against Parkinson’s disease,Alzheimer’s disease,and cerebral hemorrhage.However...Urolithin A(UA)is a natural metabolite produced from polyphenolics in foods such as pomegranates,berries,and nuts.UA is neuroprotective against Parkinson’s disease,Alzheimer’s disease,and cerebral hemorrhage.However,its effect against traumatic brain injury remains unknown.In this study,we established adult C57BL/6J mouse models of traumatic brain injury by controlled cortical impact and then intraperitoneally administered UA.We found that UA greatly reduced brain edema;increased the expression of tight junction proteins in injured cortex;increased the immunopositivity of two neuronal autophagy markers,microtubule-associated protein 1A/B light chain 3A/B(LC3)and p62;downregulated protein kinase B(Akt)and mammalian target of rapamycin(mTOR),two regulators of the phosphatidylinositol 3-kinase(PI3K)/Akt/mTOR signaling pathway;decreased the phosphorylation levels of inhibitor of NFκB(IκB)kinase alpha(IKKα)and nuclear factor kappa B(NFκB),two regulators of the neuroinflammation-related Akt/IKK/NFκB signaling pathway;reduced blood-brain barrier permeability and neuronal apoptosis in injured cortex;and improved mouse neurological function.These findings suggest that UA may be a candidate drug for the treatment of traumatic brain injury,and its neuroprotective effects may be mediated by inhibition of the PI3K/Akt/mTOR and Akt/IKK/NFκB signaling pathways,thus reducing neuroinflammation and enhancing autophagy.展开更多
Urolithin A(UA)is a metabolic compound generated during the biotransformation of ellagitannins by the intestinal bacteria.The physiologically relevant micromolar concentrations of UA,achieved in the plasma and gastroi...Urolithin A(UA)is a metabolic compound generated during the biotransformation of ellagitannins by the intestinal bacteria.The physiologically relevant micromolar concentrations of UA,achieved in the plasma and gastrointestinal tract(GI)after consumption of its dietary precursors,have been revealed to offer GI protection.The health benefit has been demonstrated to be principally related to anticancer and anti-inflammatory effects.UA has been shown to possess the capability to regulate multiple tumor and inflammatory signaling pathways and to modulate enzyme activity,including those involved in carcinogen biotransformation and antioxidant defense.The purpose of this review is to gather evidence from both in vitro and in vivo studies showing the potential of UA in GI protection alongside suggested mechanisms by which UA can protect against cancer and inflammatory diseases of the digestive tract.The data presented herein,covering both studies on the pure compound and in vivo generated UA form its natural precursor,support the potential of this metabolite in treatment interventions against GI ailments.展开更多
BACKGROUND In degenerative intervertebral disc(IVD),an unfavorable IVD environment leads to increased senescence of nucleus pulposus(NP)-derived mesenchymal stem cells(NPMSCs)and the inability to complete the differen...BACKGROUND In degenerative intervertebral disc(IVD),an unfavorable IVD environment leads to increased senescence of nucleus pulposus(NP)-derived mesenchymal stem cells(NPMSCs)and the inability to complete the differentiation from NPMSCs to NP cells,leading to further aggravation of IVD degeneration(IDD).Urolithin A(UA)has been proven to have obvious effects in delaying cell senescence and resisting oxidative stress.AIM To explore whether UA can alleviate NPMSCs senescence and to elucidate the underlying mechanism.METHODS In vitro,we harvested NPMSCs from rat tails,and divided NPMSCs into four groups:the control group,H2O2 group,H2O2+UA group,and H2O2+UA+SR-18292 group.Senescence-associatedβ-Galactosidase(SA-β-Gal)activity,cell cycle,cell proliferation ability,and the expression of senescence-related and silent information regulator of transcription 1/PPAR gamma coactivator-1α(SIRT1/PGC-1α)pathway-related proteins and mRNA were used to evaluate the protective effects of UA.In vivo,an animal model of IDD was constructed,and Xrays,magnetic resonance imaging,and histological analysis were used to assess whether UA could alleviate IDD in vivo.RESULTS We found that H2O2 can cause NPMSCs senescence changes,such as cell cycle arrest,reduced cell proliferation ability,increased SA-β-Gal activity,and increased expression of senescence-related proteins and mRNA.After UA pretreatment,the abovementioned senescence indicators were significantly alleviated.To further demonstrate the mechanism of UA,we evaluated the mitochondrial membrane potential and the SIRT1/PGC-1αpathway that regulates mitochondrial function.UA protected mitochondrial function and delayed NPMSCs senescence by activating the SIRT1/PGC-1αpathway.In vivo,we found that UA treatment alleviated an animal model of IDD by assessing the disc height index,Pfirrmann grade and the histological score.CONCLUSION In summary,UA could activate the SIRT1/PGC-1αsignaling pathway to protect mitochondrial function and alleviate cell senescence and IDD in vivo and vitro.展开更多
OBJECTIVE Mitochondrial dys⁃function contributes to the pathogenesis of neuro⁃degenerative diseases such as Parkinson dis⁃ease(PD).Therapeutic strategies targeting mito⁃chondrial dysfunction hold considerable promise ...OBJECTIVE Mitochondrial dys⁃function contributes to the pathogenesis of neuro⁃degenerative diseases such as Parkinson dis⁃ease(PD).Therapeutic strategies targeting mito⁃chondrial dysfunction hold considerable promise for the treatment of PD.Urolithin A(UA)is a gut metabolite produced from ellagic acid-containing foods such as pomegranates,berries,and wal⁃nuts.Recent reports have highlighted the protec⁃tive role of UA in several neurological disorders including Alzheimer disease and ischemic stroke.However,the potential role of UA in PD has not been characterized.In this study,the role of UA in 6-OHDA-induced neurotoxicity in cell cultures and mouse model of PD was investi⁃gated.METHODS In vitro,PC12 cells were exposed to 6-OHDA in the presence or absence of UA.For in vivo study,C57BL/6 mice were ste⁃reotactic injected with 6-OHDA to induce experi⁃mental PD model.UA(10 mg·kg-1)was intraperi⁃toneal injected for 7 d before surgery.RESULTS UA protected against 6-OHDA cytotoxicity and apoptosis in PC12 cells.Prior administration of UA to 6-OHDA lesioned mice ameliorated both motor deficits and nigral-straital dopaminergic neurotoxicity.Moreover,UA attenuated 6-OHDA-induced mitochondrial dysfunction in PC12 cells accompanied by enhanced mitochondrial biogen⁃esis.Mechanically,the neuroprotective effects of UA were mediated by SIRT1-PGC-1αsignaling-mediated mitochondrial biogenesis.CONCLU⁃SION These data provide new insights into the novel role of UA in promoting mitochondria bio⁃genesis and suggest that UA may have potential therapeutic applications for PD.展开更多
The gut microbial-derived metabolites of ellagitannins and ellagic acid,urolithins(Uros)are well-established anti-cancer metabolites according to preclinical studies.However,their efficacy is limited in systemic tissu...The gut microbial-derived metabolites of ellagitannins and ellagic acid,urolithins(Uros)are well-established anti-cancer metabolites according to preclinical studies.However,their efficacy is limited in systemic tissues,including the brain,by phase-II metabolism.Exosomes(EXOs),extracellular vesicles involved in cell signaling with the ability to cross the blood-brain barrier(BBB),could protect polyphenols from metabolism.Therefore,we loaded milk EXOs with Uro-A,Uro-B or IsoUro-A to evaluate their brain delivery and anticancer effects compared to non-encapsulated Uros.In Sprague-Dawley rats,perfused brain tissue analyses by UPLC-ESI-QTOF-MS showed higher Uro levels(~3-4-fold)at 5 min following intravenous administration of EXO-Uros compared to non-encapsulated Uros,except for Uro-B,using similar Uro concentrations(17-30μM).Experiments on neuro-blastoma SH-SY5Y cells revealed dose-dependent antiproliferative effects for all EXO-Uros(0.3-1.2μM),but not with non-encapsulated Uros(10μM).Flow cytometry analyses indicated that only EXO-Uros arrested the cell cycle and induced apoptosis.Finally,using fluorescent-labeled EXOs and selective inhibitors,the primary endocytic pathway was revealed to be clathrin-dependent.Overall,encapsulating Uros into EXOs is promising for enhancing brain delivery and anticancer activity.展开更多
Triphala is a traditional herbal formulation composed of Terminalia chebula,Terminalia bellirica,and Emblica officinalis,and is rich in polyphenols and tannins.However,the stability and metabolic fate of these compoun...Triphala is a traditional herbal formulation composed of Terminalia chebula,Terminalia bellirica,and Emblica officinalis,and is rich in polyphenols and tannins.However,the stability and metabolic fate of these compounds during gastrointestinal digestion and gut microbial fermentation remain incompletely understood.In the present study,the gastrointestinal stability,microbial biotransformation,and in vitro bioactivity of Triphala were investigated using simulated INFOGEST digestion followed by in vitro colonic fermentation.Substantial microbial metabolism was observed during fermentation,leading to approximately 50-55%degradation of native phe-nolics and the transient formation of urolithins,with maximal levels detected at 24 h.A total of 36 phytocon-stituents were tentatively identified in Triphala churna extract using UPLC-Q-ToF-MS/MS.Selected polyphenols and urolithins as urolithin C,and urolithin B including pyrogallol,gallic acid,epigallocatechin,corilagin,ellagic acid,chebulinic acid,were quantified by UPLC-PDA before and after digestion.Fermentation-induced compo-sitional changes were associated with increased total phenolic content and enhanced antioxidant capacity,as determined by ABTS,FRAP,and DPPH assays.Furthermore,fermented Triphala extracts attenuated palmitic acid/LPS-induced oxidative stress and inflammatory responses in Caco-2 cells,as evidenced by reduced intra-cellular ROS levels,restoration of antioxidant enzyme activities,preservation of epithelial integrity,and sup-pression of pro-inflammatory cytokines(IL-6,TNF-α,and IL-1β).Gut microbiota analysis indicated that fermentation modulated microbial composition,with a reduction in Ruminococcus abundance,no significant change in Bifidobacterium levels,and an increase in Lactobacillus compared to the glucose-supplemented group.Overall,these findings underscore the role of gut microbial biotransformation in influencing the metabolic profile and in vitro bioactivity of Triphala.展开更多
As one of fruit waste by-products,the pomegranate peel is rich in bioactive compounds such as ellagic acid.Ellagic acid and its main gut microbial metabolite urolithin B have been reported to exhibit numerous biologic...As one of fruit waste by-products,the pomegranate peel is rich in bioactive compounds such as ellagic acid.Ellagic acid and its main gut microbial metabolite urolithin B have been reported to exhibit numerous biological activities and widely used as dietary supplements in the past decades.Interaction of these two compounds to serum albumin(SA)might affect their metabolism,efficacy,and body distribution.The interaction of ellagic acid and urolithin B with SA was investigated and BSA interference on the anti-cancer activity of these two compounds was also evaluated.Results of spectra experiments showed that ellagic acid and urolithin B could form complexes with bovine serum albumin(BSA)and urolithin B has a higher binding force and number of binding sites than ellagic acid when forming a complex with BSA.The results of molecular docking and molecular dynamics simulations suggested that ellagic acid and urolithin B tended to bind in site I rather than site II.The MTT assay results indicated that the IC_(50) value of ellagic acid decreased from 123.58μM to 55.91μM,while the IC_(50) value of urolithin B decreased from 83.67μM to 47.40μM.Ellagic acid and urolithin B can form complexes with serum albumin and the anti-cancer activity of ellagic acid and urolithin B was enhanced when combined with BSA.展开更多
Consumers are growing interest in foods that promote health and offer improved nutritional benefits.Berries,including raspberry,blackberry,and mulberry,are rich in bioactive compounds,such as polyphenols and flavonoid...Consumers are growing interest in foods that promote health and offer improved nutritional benefits.Berries,including raspberry,blackberry,and mulberry,are rich in bioactive compounds,such as polyphenols and flavonoids,which are recognized for their antioxidant and anti-inflammatory properties.Nonetheless,the bioavailability of these compounds,particularly ellagitannins(ETs)and ellagic acid(EA),is often restricted.To overcome this challenge,Limosilactobacillus fermentum FUA033 was employed to ferment raspberry,blackberry,and mulberry juices,with the objective of enhancing bioactivity and improving flavor.Headspace solid-phase microextraction gas chromatography-mass spectrometry(HS-SPME-GC-MS)was utilized to identify changes in volatile organic compounds(VOCs)that contribute to the flavor profiles of the fermented juices.The results indicated that fermentation with L.fermentum FUA033 significantly elevated the levels of polyphenols and flavonoids,thereby increasing antioxidant activity and facilitating the conversion of EA to urolithin A.Additionally,HS-SPME-GC-MS analysis demonstrated that fermentation improved the flavor characteristics of berry juices by increasing the content of VOCs,such as terpenes and esters.These findings provide a systematic illustration of the potential of L.fermentum FUA033 to enhance the functional properties of berry juices and offer novel insights for the development of innovative functional foods.展开更多
基金supported by FCT/MCTES UIDP/05608/2020(https://doi.org/10.54499/UIDP/05608/2020,accessed on 01 July 2025)UIDB/05608/2020(https://doi.org/10.54499/UIDB/05608/2020,accessed on 01 July 2025).Institutional.
文摘Objectives:Colorectal cancer(CRC)is a major global health burden,and Urolithin A(Uro-A)has emerged as a promising anticancer agent.This systematic review aims to synthesize current in vitro evidence on the anticancer effects of Uro-A in CRC,highlighting effective concentration ranges,exposure times,relevant outcomes,and underlying molecular mechanisms.Methods:Following PRISMA 2020 guidelines,a systematic search was conducted in PubMed,Scopus,and Web of Science using the following strategy:(colorectal cancer)AND(urolithin a)OR(3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one).Eligibility criteria were defined by the PICO framework:(P)in vitro CRC cell models;(I)Uro-A alone or combined treatments;(C)No intervention,vehicle or other treatments;(O)Relevant anticancer outcomes of Uro-A in CRC.Only original,full-text,in vitro studies in English were included.Risk of bias was assessed using ToxRTool.A qualitative synthesis was performed due to the heterogeneity of the included studies.Results:Fifteen studies met inclusion criteria,involving CRC cell lines(Caco-2,HCT-116,HT-29,SW480,SW620)and normal colon fibroblasts(CCD18-Co).Uro-A inhibited CRC cell proliferation,clonogenic growth,cancer stem cells properties,migration,and invasion,and induced cell cycle arrest,apoptosis,autophagy,and senescence,through modulation of key signaling pathways and proteins.Co-treatments with conventional chemotherapeutics and microbiota-derived metabolites showed additive or synergistic effects.Discussion:The findings support UroA’s potential as a preventive or adjuvant agent in CRC treatment.However,preclinical nature of the evidence and methodological heterogeneity hinder clinical extrapolation to in vivo contexts.Human clinical trials are necessary to overcome these limitations.Other:This review was registered in PROSPERO(CRD420251070874)and supported by FCT/MCTES UIDP/05608/2020 and UIDB/05608/2020.Institutional.
基金supported by the National Natural Science Foundation of China,Nos.81974189(to HLT),81801236(to QYG and LC),82001310(to DXY).
文摘Urolithin A(UA)is a natural metabolite produced from polyphenolics in foods such as pomegranates,berries,and nuts.UA is neuroprotective against Parkinson’s disease,Alzheimer’s disease,and cerebral hemorrhage.However,its effect against traumatic brain injury remains unknown.In this study,we established adult C57BL/6J mouse models of traumatic brain injury by controlled cortical impact and then intraperitoneally administered UA.We found that UA greatly reduced brain edema;increased the expression of tight junction proteins in injured cortex;increased the immunopositivity of two neuronal autophagy markers,microtubule-associated protein 1A/B light chain 3A/B(LC3)and p62;downregulated protein kinase B(Akt)and mammalian target of rapamycin(mTOR),two regulators of the phosphatidylinositol 3-kinase(PI3K)/Akt/mTOR signaling pathway;decreased the phosphorylation levels of inhibitor of NFκB(IκB)kinase alpha(IKKα)and nuclear factor kappa B(NFκB),two regulators of the neuroinflammation-related Akt/IKK/NFκB signaling pathway;reduced blood-brain barrier permeability and neuronal apoptosis in injured cortex;and improved mouse neurological function.These findings suggest that UA may be a candidate drug for the treatment of traumatic brain injury,and its neuroprotective effects may be mediated by inhibition of the PI3K/Akt/mTOR and Akt/IKK/NFκB signaling pathways,thus reducing neuroinflammation and enhancing autophagy.
基金Supported by the National Science Centre,No.2017/26/D/NZ7/00748。
文摘Urolithin A(UA)is a metabolic compound generated during the biotransformation of ellagitannins by the intestinal bacteria.The physiologically relevant micromolar concentrations of UA,achieved in the plasma and gastrointestinal tract(GI)after consumption of its dietary precursors,have been revealed to offer GI protection.The health benefit has been demonstrated to be principally related to anticancer and anti-inflammatory effects.UA has been shown to possess the capability to regulate multiple tumor and inflammatory signaling pathways and to modulate enzyme activity,including those involved in carcinogen biotransformation and antioxidant defense.The purpose of this review is to gather evidence from both in vitro and in vivo studies showing the potential of UA in GI protection alongside suggested mechanisms by which UA can protect against cancer and inflammatory diseases of the digestive tract.The data presented herein,covering both studies on the pure compound and in vivo generated UA form its natural precursor,support the potential of this metabolite in treatment interventions against GI ailments.
基金National Natural Science Foundation of China,No.81972136Young Medical Scholars Major Program of Jiangsu Province,No.QNRC2016342+1 种基金Key Funding Project of Maternal and Child Health Research of Jiangsu Province,No.F201801and Highlevel Health Professionals"Six projects"Top-notch Talent Research Program of Jiangsu Province,No.LGY2019035.
文摘BACKGROUND In degenerative intervertebral disc(IVD),an unfavorable IVD environment leads to increased senescence of nucleus pulposus(NP)-derived mesenchymal stem cells(NPMSCs)and the inability to complete the differentiation from NPMSCs to NP cells,leading to further aggravation of IVD degeneration(IDD).Urolithin A(UA)has been proven to have obvious effects in delaying cell senescence and resisting oxidative stress.AIM To explore whether UA can alleviate NPMSCs senescence and to elucidate the underlying mechanism.METHODS In vitro,we harvested NPMSCs from rat tails,and divided NPMSCs into four groups:the control group,H2O2 group,H2O2+UA group,and H2O2+UA+SR-18292 group.Senescence-associatedβ-Galactosidase(SA-β-Gal)activity,cell cycle,cell proliferation ability,and the expression of senescence-related and silent information regulator of transcription 1/PPAR gamma coactivator-1α(SIRT1/PGC-1α)pathway-related proteins and mRNA were used to evaluate the protective effects of UA.In vivo,an animal model of IDD was constructed,and Xrays,magnetic resonance imaging,and histological analysis were used to assess whether UA could alleviate IDD in vivo.RESULTS We found that H2O2 can cause NPMSCs senescence changes,such as cell cycle arrest,reduced cell proliferation ability,increased SA-β-Gal activity,and increased expression of senescence-related proteins and mRNA.After UA pretreatment,the abovementioned senescence indicators were significantly alleviated.To further demonstrate the mechanism of UA,we evaluated the mitochondrial membrane potential and the SIRT1/PGC-1αpathway that regulates mitochondrial function.UA protected mitochondrial function and delayed NPMSCs senescence by activating the SIRT1/PGC-1αpathway.In vivo,we found that UA treatment alleviated an animal model of IDD by assessing the disc height index,Pfirrmann grade and the histological score.CONCLUSION In summary,UA could activate the SIRT1/PGC-1αsignaling pathway to protect mitochondrial function and alleviate cell senescence and IDD in vivo and vitro.
文摘OBJECTIVE Mitochondrial dys⁃function contributes to the pathogenesis of neuro⁃degenerative diseases such as Parkinson dis⁃ease(PD).Therapeutic strategies targeting mito⁃chondrial dysfunction hold considerable promise for the treatment of PD.Urolithin A(UA)is a gut metabolite produced from ellagic acid-containing foods such as pomegranates,berries,and wal⁃nuts.Recent reports have highlighted the protec⁃tive role of UA in several neurological disorders including Alzheimer disease and ischemic stroke.However,the potential role of UA in PD has not been characterized.In this study,the role of UA in 6-OHDA-induced neurotoxicity in cell cultures and mouse model of PD was investi⁃gated.METHODS In vitro,PC12 cells were exposed to 6-OHDA in the presence or absence of UA.For in vivo study,C57BL/6 mice were ste⁃reotactic injected with 6-OHDA to induce experi⁃mental PD model.UA(10 mg·kg-1)was intraperi⁃toneal injected for 7 d before surgery.RESULTS UA protected against 6-OHDA cytotoxicity and apoptosis in PC12 cells.Prior administration of UA to 6-OHDA lesioned mice ameliorated both motor deficits and nigral-straital dopaminergic neurotoxicity.Moreover,UA attenuated 6-OHDA-induced mitochondrial dysfunction in PC12 cells accompanied by enhanced mitochondrial biogen⁃esis.Mechanically,the neuroprotective effects of UA were mediated by SIRT1-PGC-1αsignaling-mediated mitochondrial biogenesis.CONCLU⁃SION These data provide new insights into the novel role of UA in promoting mitochondria bio⁃genesis and suggest that UA may have potential therapeutic applications for PD.
基金supported by the by the grants TED 2021-130962B-C21 and TED 2021-130962B-C22 funded byMICIU/AEI/10.13039/501100011033 and by the“European Union"or by the"Eu-ropean Union NextGenerationEU/PRTR",PID 2022-136419OB-100,and PID 2022-1431000B-I00funded byMICIU/AEI/10.13039/501100011033 and"ERDF A way of making Europe",the grant 22030/PI/22 funded by the Programa Regional de Fomento de la Investigación Cientifica y Técnica(Plan de Actuación 2022)de la Fundación SénecaAgencia de Cienciay Tecnología de la Región de Murcia(Murcia,Spain),and the AGROALNEXT program supported by MCIN with funding from the European Union NextGenerationEU(PRTR-C17.I1)and Fundación Séneca.M.C.L.-H.is a recipient of a Juan de la Cierva Grant IJC 2020-044353-/MCIN/AEI/10.13039/501100011033/EU/PRTR.A.S.-L.is supported by a predoctoral fellowship(N°2021-01-PhD GRANT)from the International Olive Council.CIBEROBN(CB22/03/00068)is an initiative of the Instituto de Salud Carlos Ⅲ,Spain.
文摘The gut microbial-derived metabolites of ellagitannins and ellagic acid,urolithins(Uros)are well-established anti-cancer metabolites according to preclinical studies.However,their efficacy is limited in systemic tissues,including the brain,by phase-II metabolism.Exosomes(EXOs),extracellular vesicles involved in cell signaling with the ability to cross the blood-brain barrier(BBB),could protect polyphenols from metabolism.Therefore,we loaded milk EXOs with Uro-A,Uro-B or IsoUro-A to evaluate their brain delivery and anticancer effects compared to non-encapsulated Uros.In Sprague-Dawley rats,perfused brain tissue analyses by UPLC-ESI-QTOF-MS showed higher Uro levels(~3-4-fold)at 5 min following intravenous administration of EXO-Uros compared to non-encapsulated Uros,except for Uro-B,using similar Uro concentrations(17-30μM).Experiments on neuro-blastoma SH-SY5Y cells revealed dose-dependent antiproliferative effects for all EXO-Uros(0.3-1.2μM),but not with non-encapsulated Uros(10μM).Flow cytometry analyses indicated that only EXO-Uros arrested the cell cycle and induced apoptosis.Finally,using fluorescent-labeled EXOs and selective inhibitors,the primary endocytic pathway was revealed to be clathrin-dependent.Overall,encapsulating Uros into EXOs is promising for enhancing brain delivery and anticancer activity.
文摘Triphala is a traditional herbal formulation composed of Terminalia chebula,Terminalia bellirica,and Emblica officinalis,and is rich in polyphenols and tannins.However,the stability and metabolic fate of these compounds during gastrointestinal digestion and gut microbial fermentation remain incompletely understood.In the present study,the gastrointestinal stability,microbial biotransformation,and in vitro bioactivity of Triphala were investigated using simulated INFOGEST digestion followed by in vitro colonic fermentation.Substantial microbial metabolism was observed during fermentation,leading to approximately 50-55%degradation of native phe-nolics and the transient formation of urolithins,with maximal levels detected at 24 h.A total of 36 phytocon-stituents were tentatively identified in Triphala churna extract using UPLC-Q-ToF-MS/MS.Selected polyphenols and urolithins as urolithin C,and urolithin B including pyrogallol,gallic acid,epigallocatechin,corilagin,ellagic acid,chebulinic acid,were quantified by UPLC-PDA before and after digestion.Fermentation-induced compo-sitional changes were associated with increased total phenolic content and enhanced antioxidant capacity,as determined by ABTS,FRAP,and DPPH assays.Furthermore,fermented Triphala extracts attenuated palmitic acid/LPS-induced oxidative stress and inflammatory responses in Caco-2 cells,as evidenced by reduced intra-cellular ROS levels,restoration of antioxidant enzyme activities,preservation of epithelial integrity,and sup-pression of pro-inflammatory cytokines(IL-6,TNF-α,and IL-1β).Gut microbiota analysis indicated that fermentation modulated microbial composition,with a reduction in Ruminococcus abundance,no significant change in Bifidobacterium levels,and an increase in Lactobacillus compared to the glucose-supplemented group.Overall,these findings underscore the role of gut microbial biotransformation in influencing the metabolic profile and in vitro bioactivity of Triphala.
基金This work was supported by the National Natural Science Foundation of China(31972160)the Scientific Research Fund for Doctoral Start-up Project of Anyang Institute of Technology(BSJ2020016 and BSJ2020014).
文摘As one of fruit waste by-products,the pomegranate peel is rich in bioactive compounds such as ellagic acid.Ellagic acid and its main gut microbial metabolite urolithin B have been reported to exhibit numerous biological activities and widely used as dietary supplements in the past decades.Interaction of these two compounds to serum albumin(SA)might affect their metabolism,efficacy,and body distribution.The interaction of ellagic acid and urolithin B with SA was investigated and BSA interference on the anti-cancer activity of these two compounds was also evaluated.Results of spectra experiments showed that ellagic acid and urolithin B could form complexes with bovine serum albumin(BSA)and urolithin B has a higher binding force and number of binding sites than ellagic acid when forming a complex with BSA.The results of molecular docking and molecular dynamics simulations suggested that ellagic acid and urolithin B tended to bind in site I rather than site II.The MTT assay results indicated that the IC_(50) value of ellagic acid decreased from 123.58μM to 55.91μM,while the IC_(50) value of urolithin B decreased from 83.67μM to 47.40μM.Ellagic acid and urolithin B can form complexes with serum albumin and the anti-cancer activity of ellagic acid and urolithin B was enhanced when combined with BSA.
基金supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions,the Key Natural Science Foundation of the Jiangsu Higher Education Institutions of China(20KJA550001)Project“333”of Jiangsu Province,Open-end Funds of Jiangsu Key Laboratory of Marine Bioresources and Environment(SH20191204)the College Students’Innovation and Entrepreneurship Training Program of Jiangsu Province(SY202311641638001).
文摘Consumers are growing interest in foods that promote health and offer improved nutritional benefits.Berries,including raspberry,blackberry,and mulberry,are rich in bioactive compounds,such as polyphenols and flavonoids,which are recognized for their antioxidant and anti-inflammatory properties.Nonetheless,the bioavailability of these compounds,particularly ellagitannins(ETs)and ellagic acid(EA),is often restricted.To overcome this challenge,Limosilactobacillus fermentum FUA033 was employed to ferment raspberry,blackberry,and mulberry juices,with the objective of enhancing bioactivity and improving flavor.Headspace solid-phase microextraction gas chromatography-mass spectrometry(HS-SPME-GC-MS)was utilized to identify changes in volatile organic compounds(VOCs)that contribute to the flavor profiles of the fermented juices.The results indicated that fermentation with L.fermentum FUA033 significantly elevated the levels of polyphenols and flavonoids,thereby increasing antioxidant activity and facilitating the conversion of EA to urolithin A.Additionally,HS-SPME-GC-MS analysis demonstrated that fermentation improved the flavor characteristics of berry juices by increasing the content of VOCs,such as terpenes and esters.These findings provide a systematic illustration of the potential of L.fermentum FUA033 to enhance the functional properties of berry juices and offer novel insights for the development of innovative functional foods.
