Background:Intrahepatic cholangiocarcinoma(iCCA)is a highly heteroge-neous and lethal hepatobiliary tumor with few therapeutic strategies.The metabolic reprogramming of tumor cells plays an essential role in the devel...Background:Intrahepatic cholangiocarcinoma(iCCA)is a highly heteroge-neous and lethal hepatobiliary tumor with few therapeutic strategies.The metabolic reprogramming of tumor cells plays an essential role in the develop-ment of tumors,while the metabolic molecular classification of iCCA is largely unknown.Here,we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients,hoping to provide a novel perspective to understand and treat iCCA.Methods:We performed integrated multiomics analysis in 116 iCCA samples,including whole-exome sequencing,bulk RNA-sequencing and proteome anal-ysis.Based on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models,the metabolic subtype of iCCA was determined.Survival and prognostic gene analy-ses were used to compare overall survival(OS)differences between metabolic subtypes.Cell proliferation analysis,5-ethynyl-2’-deoxyuridine(EdU)assay,colony formation assay,RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinaseα(DGKA)in iCCA cells.Results:Three metabolic subtypes(S1-S3)with subtype-specific biomarkers of iCCA were identified.These metabolic subtypes presented with distinct prog-noses,metabolic features,immune microenvironments,and genetic alterations.The S2 subtype with the worst survival showed the activation of some special metabolic processes,immune-suppressed microenvironment and Kirsten ratsar-coma viral oncogene homolog(KRAS)/AT-rich interactive domain 1A(ARID1A)mutations.Among the S2 subtype-specific upregulated proteins,DGKA was further identified as a potential drug target for iCCA,which promoted cell proliferation by enhancing phosphatidic acid(PA)metabolism and activating mitogen-activated protein kinase(MAPK)signaling.Conclusion:Viamultiomics analyses,we identified three metabolic subtypes of iCCA,revealing that the S2 subtype exhibited the poorest survival outcomes.We further identified DGKA as a potential target for the S2 subtype.展开更多
Pu-erh tea,a traditional Chinese beverage,performs an anti-obesity function,but the correlation between its components and efficacy remains unknown.Here,we screened two Pu-erh teas with significant anti-obesity effica...Pu-erh tea,a traditional Chinese beverage,performs an anti-obesity function,but the correlation between its components and efficacy remains unknown.Here,we screened two Pu-erh teas with significant anti-obesity efficacies from 11 teas.In vitro experiments revealed that lipid accumulation in L02 cells and lipid synthesis in 3T3-L1 cells were significantly better inhibited by Tea-B than Tea-A.Further in vivo experiments using model mice revealed that the differences in chemical components generated two pathways in the anti-obesity efficacy and mechanism of Pu-erh teas.Tea-A changes the histomorphology of brown adipose tissue(BAT)and increases the abundance of Coriobacteriaceae_UCG_002 and cyclic AMP in guts through high chemical contents of cyclopentasiloxane,decamethyl,tridecane and 1,2,3-trimethoxybenzene,eventually increasing BAT activation and fat browning gene expression;the high content of hexadecane and 1,2-dimethoxybenzene in Tea-B reduces white adipose tissue(WAT)accumulation and the process of fatty liver,increases the abundance of Odoribacter and sphinganine 1-phosphate,inhibits the expression of lipid synthesis and transport genes.These mechanistic findings on the association of the representative bioactive components in Pu-erh teas with the anti-obesity phenotypes,gut microbes,gut metabolite structure and anti-obesity pathways,which were obtained for the first time,provide foundations for developing functional Pu-erh tea.展开更多
Objective:Recurrence continues to be a pivotal challenge among hormone receptor-positive(HR^(+))/human epidermal growth factor receptor 2^(−)negative(HER2^(−))breast cancers.In the international consensus guidelines,H...Objective:Recurrence continues to be a pivotal challenge among hormone receptor-positive(HR^(+))/human epidermal growth factor receptor 2^(−)negative(HER2^(−))breast cancers.In the international consensus guidelines,HR^(+)/HER2^(−)breast cancer relapse patterns are divided into three distinct types:primary resistant,secondary resistant,and endocrine sensitive.However,owing to the lack of cohorts with treatment and follow-up data,the heterogeneity among different recurrence patterns remains uncharted.Current treatments still lack precision.Methods:This analysis included data from a large-scale multiomics study of a HR^(+)/HER2^(−)breast cancer cohort(n=314).Through the analysis of transcriptomics(n=312),proteomics(n=124),whole-exome sequencing(n=290),metabolomics(n=217),and digital pathology(n=228)data,we explored distinctive molecular features and identified putative therapeutic targets for patients experiencing recurrence.Results:We explored distinct clinicopathological characteristics,biological heterogeneity,and potential therapeutic strategies for recurrence.Based on a shared relapse signature,we stratified patients into high-and lowrecurrence-risk groups.Patients with different relapse patterns presented unique molecular features in primary tumors.Specifically,receptor tyrosine kinase(RTK)pathway activation in the primary resistant group suggested the utility of RTK inhibitors,whereas mammalian target of rapamycin(mTOR)and cell cycle pathway activation in the secondary resistant group highlighted the potential of mTOR and CDK4/6 inhibitors.Interestingly,the endocrine-sensitive group displayed a quiescent state and high genomic instability,suggesting that targeting quiescent cells and using poly-ADP-ribose polymerase(PARP)inhibitors could be effective strategies.Conclusions:These findings illuminate the clinicopathological and molecular landscape of HR^(+)/HER2^(−)breast cancer patients with distinct recurrence patterns,highlighting potential targeted therapies.展开更多
Meniscal injury presents a formidable challenge and often leads to functional impairment and osteoarthritic progression.Meniscus tissue engineering(MTE)is a promising solution,as conventional strategies for modu-latin...Meniscal injury presents a formidable challenge and often leads to functional impairment and osteoarthritic progression.Meniscus tissue engineering(MTE)is a promising solution,as conventional strategies for modu-lating local immune responses and generating a conducive microenvironment for effective tissue repair are lacking.Recently,magnesium-containing bioactive glass nanospheres(Mg-BGNs)have shown promise in tissue regeneration.However,few studies have explored the ability of Mg-BGNs to promote meniscal regeneration.First,we verified the anti-inflammatory and fibrochondrogenic abilities of Mg-BGNs in vitro.A comprehensive in vivo evaluation of a rabbit critical-size meniscectomy model revealed that Mg-BGNs have multiple effects on meniscal reconstruction and effectively promote fibrochondrogenesis,collagen deposition,and cartilage pro-tection.Multiomics analysis was subsequently performed to further explore the mechanism by which Mg-BGNs regulate the regenerative microenvironment.Mechanistically,Mg-BGNs first activate the TRPM7 ion channel through the PI3K/AKT signaling pathway to promote the cellular function of synovium-derived mesenchymal stem cells and then activate the PPARγ/NF-κB axis to modulate macrophage polarization and inflammatory reactions.We demonstrated that Mg^(2+)is critical for the crosstalk among biomaterials,immune cells,and effector cells in Mg-BGN-mediated tissue regeneration.This study provides a theoretical basis for the application of Mg-BGNs as nanomedicines to achieve in situ tissue regeneration in complex intrajoint pathological microenvironments.展开更多
Although the tumor suppressor P53 is known to regulate a broad network of signaling pathways,it is still unclear how certain drugs influence these P53 signaling netw orks.Here,we used a comprehensive singlecell multio...Although the tumor suppressor P53 is known to regulate a broad network of signaling pathways,it is still unclear how certain drugs influence these P53 signaling netw orks.Here,we used a comprehensive singlecell multiomics view of the effects of ginsenosides on cancer cells.Transcriptome and proteome profiling revealed that the antitumor activity of ginsenosides is closely as sociated with P53 protein.A miRNA-proteome interaction network revealed that P53 controlled the transcription of at least 38 proteins,and proteomemetabolome profiling analysis revealed that P53 regulated proteins involved in nucleotide metabolism,amino acid metabolism and"Warburg effect".The results of integrative multiomics analysis revealed P53 protein as a potential key target that influences the anti-tumor activity of ginsenosides.Furthermore,by applying affinity mass spectrometry(MS)screening and surface plasmon resonance fragment library screening,we confirmed that 20(S)-protopanaxatriol directly targeted adj acent regions of the P53 DNA-binding pocket and promoted the stability of P53-DNA interactions,which further induced a series of omics changes.展开更多
Aging is a contributor to liver disease.Hence,the concept of liver aging has become prominent and has attracted considerable interest,but its underlying mechanism remains poorly understood.In our study,the internal me...Aging is a contributor to liver disease.Hence,the concept of liver aging has become prominent and has attracted considerable interest,but its underlying mechanism remains poorly understood.In our study,the internal mechanism of liver aging was explored via multi-omics analysis and molecular experiments to support future targeted therapy.An aged rat liver model was established with D-galactose,and two other senescent hepatocyte models were established by treating HepG2 cells with D-galactose and H2O2.We then performed transcriptomic and metabolomic assays of the aged liver model and transcriptome analyses of the senescent hepatocyte models.In livers,genes related to peroxisomes,fatty acid elongation,and fatty acid degradation exhibited down-regulated expression with aging,and the hepatokine Fgf21 expression was positively correlated with the down-regulation of these genes.In senescent hepatocytes,similar to the results found in aged livers,FGF21 expression was also decreased.Moreover,the expressions of cell cycle-related genes were significantly down-regulated,and the down-regulated gene E2F8 was the key cell cycle-regulating transcription factor.We then validated that FGF21 overexpression can protect against liver aging and that FGF21 can attenuate the declines in the antioxidant and regenerative capacities in the aging liver.We successfully validated the results from cellular and animal experiments using human liver and blood samples.Our study indicated that FGF21 is an important target for inhibiting liver aging and suggested that pharmacological prevention of the reduction in FGF21 expression due to aging may be used to treat liver aging-related diseases.展开更多
Omics data address key issues in liver transplantation(LT)as the most effective therapeutic means for end-stage liver disease.The purpose of this study was to review the current application and future direction for om...Omics data address key issues in liver transplantation(LT)as the most effective therapeutic means for end-stage liver disease.The purpose of this study was to review the current application and future direction for omics in LT.We reviewed the use of multiomics to elucidate the pathogenesis leading to LT and prognostication.Future directions with respect to the use of omics in LT are also described based on perspectives of surgeons with experience in omics.Significant molecules were identified and summarized based on omics,with a focus on post-transplant liver fibrosis,early allograft dysfunction,tumor recurrence,and graft failure.We emphasized the importance omics for clinicians who perform LTs and prioritized the directions that should be established.We also outlined the ideal workflow for omics in LT.In step with advances in technology,the quality of omics data can be guaranteed using an improved algorithm at a lower price.Concerns should be addressed on the translational value of omics for better therapeutic effects in patients undergoing LT.展开更多
Black phosphorus(BP)is a newly discovered two-dimensional material that has promising applications from bioelectronics to biomedicine.However,facile oxidation of BP leads to changes in surface chemical composition and...Black phosphorus(BP)is a newly discovered two-dimensional material that has promising applications from bioelectronics to biomedicine.However,facile oxidation of BP leads to changes in surface chemical composition and physical properties,often being referred to as the degradation process of BP.Degradation products of BP nanosheets,namely,oxidized BP nanosheets(oBPNSs),are routinely considered as by-products without many uses.Herein,we found that oBPNSs displayed excellent osteoclastogenesis inhibition effects without impairing cell viability.In contrast to the classic antiresorptive bisphosphonate drugs,oBPNSs showed a different mode of action by suppressing the maturation of osteoclasts.Bone resorption assays,osteoclast actin ring analysis,and tartrate-resistant acid phosphate activity assay results indicated that oBPNSs suppressed receptor activator of nuclear factor-κB(NF-κB)ligand(RANKL)-induced osteoclastogenesis in a dose-and oxidation-dependent manner.Transcriptomic and proteomic analyses indicated that oBPNSs inhibited the activation of the NF-κB signaling pathway and phosphorylation of mitogen-activated protein kinase(MAPK)in differentiated osteoclasts,as confirmed by Western blot analysis.Our results suggest that oBPNSs might be potential antiresorptive nanomaterials to treat osteoporosis.展开更多
基金This project was supported by grants from the National Natural Science Foundation of China(82273387,82273386,82073217,32270711,82073218 and 82003084)the National Key Research and Develop-ment Program of China(2018YFC1312100)+3 种基金Beijing Nova Program(20220484230)Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)Shanghai Municipal Key Clinical Specialty,CAMS Innovation Fund for Medical Sciences(CIFMS)(2019-I2M-5-058)the State Key Laboratory of Proteomics(SKLP-K202004).
文摘Background:Intrahepatic cholangiocarcinoma(iCCA)is a highly heteroge-neous and lethal hepatobiliary tumor with few therapeutic strategies.The metabolic reprogramming of tumor cells plays an essential role in the develop-ment of tumors,while the metabolic molecular classification of iCCA is largely unknown.Here,we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients,hoping to provide a novel perspective to understand and treat iCCA.Methods:We performed integrated multiomics analysis in 116 iCCA samples,including whole-exome sequencing,bulk RNA-sequencing and proteome anal-ysis.Based on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models,the metabolic subtype of iCCA was determined.Survival and prognostic gene analy-ses were used to compare overall survival(OS)differences between metabolic subtypes.Cell proliferation analysis,5-ethynyl-2’-deoxyuridine(EdU)assay,colony formation assay,RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinaseα(DGKA)in iCCA cells.Results:Three metabolic subtypes(S1-S3)with subtype-specific biomarkers of iCCA were identified.These metabolic subtypes presented with distinct prog-noses,metabolic features,immune microenvironments,and genetic alterations.The S2 subtype with the worst survival showed the activation of some special metabolic processes,immune-suppressed microenvironment and Kirsten ratsar-coma viral oncogene homolog(KRAS)/AT-rich interactive domain 1A(ARID1A)mutations.Among the S2 subtype-specific upregulated proteins,DGKA was further identified as a potential drug target for iCCA,which promoted cell proliferation by enhancing phosphatidic acid(PA)metabolism and activating mitogen-activated protein kinase(MAPK)signaling.Conclusion:Viamultiomics analyses,we identified three metabolic subtypes of iCCA,revealing that the S2 subtype exhibited the poorest survival outcomes.We further identified DGKA as a potential target for the S2 subtype.
基金The financial support received from the Shenzhen Science and Technology Innovation Commission(KCXFZ20201221173207022,WDZC20200821141349001)Shenzhen Bay Laboratory Startup Fund(21310041,S234602003)。
文摘Pu-erh tea,a traditional Chinese beverage,performs an anti-obesity function,but the correlation between its components and efficacy remains unknown.Here,we screened two Pu-erh teas with significant anti-obesity efficacies from 11 teas.In vitro experiments revealed that lipid accumulation in L02 cells and lipid synthesis in 3T3-L1 cells were significantly better inhibited by Tea-B than Tea-A.Further in vivo experiments using model mice revealed that the differences in chemical components generated two pathways in the anti-obesity efficacy and mechanism of Pu-erh teas.Tea-A changes the histomorphology of brown adipose tissue(BAT)and increases the abundance of Coriobacteriaceae_UCG_002 and cyclic AMP in guts through high chemical contents of cyclopentasiloxane,decamethyl,tridecane and 1,2,3-trimethoxybenzene,eventually increasing BAT activation and fat browning gene expression;the high content of hexadecane and 1,2-dimethoxybenzene in Tea-B reduces white adipose tissue(WAT)accumulation and the process of fatty liver,increases the abundance of Odoribacter and sphinganine 1-phosphate,inhibits the expression of lipid synthesis and transport genes.These mechanistic findings on the association of the representative bioactive components in Pu-erh teas with the anti-obesity phenotypes,gut microbes,gut metabolite structure and anti-obesity pathways,which were obtained for the first time,provide foundations for developing functional Pu-erh tea.
基金supported by the National Key Research and Development Program of China (No. 2020YFA0112304)the National Natural Science Foundation of China (No. 82373167, 82341003 and 92159301)+4 种基金the Natural Science Foundation of Shanghai (No. 22ZR1479200)the Shanghai Key Laboratory of Breast Cancer (No. 12DZ2260100)the SHDC Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (No. SHDC12 021103)Shanghai Medical Innovation Research Project (No. 22Y11912700)Shanghai Anticancer Association EYAS PROJECT (No. SACA-CY22A05)
文摘Objective:Recurrence continues to be a pivotal challenge among hormone receptor-positive(HR^(+))/human epidermal growth factor receptor 2^(−)negative(HER2^(−))breast cancers.In the international consensus guidelines,HR^(+)/HER2^(−)breast cancer relapse patterns are divided into three distinct types:primary resistant,secondary resistant,and endocrine sensitive.However,owing to the lack of cohorts with treatment and follow-up data,the heterogeneity among different recurrence patterns remains uncharted.Current treatments still lack precision.Methods:This analysis included data from a large-scale multiomics study of a HR^(+)/HER2^(−)breast cancer cohort(n=314).Through the analysis of transcriptomics(n=312),proteomics(n=124),whole-exome sequencing(n=290),metabolomics(n=217),and digital pathology(n=228)data,we explored distinctive molecular features and identified putative therapeutic targets for patients experiencing recurrence.Results:We explored distinct clinicopathological characteristics,biological heterogeneity,and potential therapeutic strategies for recurrence.Based on a shared relapse signature,we stratified patients into high-and lowrecurrence-risk groups.Patients with different relapse patterns presented unique molecular features in primary tumors.Specifically,receptor tyrosine kinase(RTK)pathway activation in the primary resistant group suggested the utility of RTK inhibitors,whereas mammalian target of rapamycin(mTOR)and cell cycle pathway activation in the secondary resistant group highlighted the potential of mTOR and CDK4/6 inhibitors.Interestingly,the endocrine-sensitive group displayed a quiescent state and high genomic instability,suggesting that targeting quiescent cells and using poly-ADP-ribose polymerase(PARP)inhibitors could be effective strategies.Conclusions:These findings illuminate the clinicopathological and molecular landscape of HR^(+)/HER2^(−)breast cancer patients with distinct recurrence patterns,highlighting potential targeted therapies.
基金grants from Natural Science Foundation of China(82272481,323B2043).
文摘Meniscal injury presents a formidable challenge and often leads to functional impairment and osteoarthritic progression.Meniscus tissue engineering(MTE)is a promising solution,as conventional strategies for modu-lating local immune responses and generating a conducive microenvironment for effective tissue repair are lacking.Recently,magnesium-containing bioactive glass nanospheres(Mg-BGNs)have shown promise in tissue regeneration.However,few studies have explored the ability of Mg-BGNs to promote meniscal regeneration.First,we verified the anti-inflammatory and fibrochondrogenic abilities of Mg-BGNs in vitro.A comprehensive in vivo evaluation of a rabbit critical-size meniscectomy model revealed that Mg-BGNs have multiple effects on meniscal reconstruction and effectively promote fibrochondrogenesis,collagen deposition,and cartilage pro-tection.Multiomics analysis was subsequently performed to further explore the mechanism by which Mg-BGNs regulate the regenerative microenvironment.Mechanistically,Mg-BGNs first activate the TRPM7 ion channel through the PI3K/AKT signaling pathway to promote the cellular function of synovium-derived mesenchymal stem cells and then activate the PPARγ/NF-κB axis to modulate macrophage polarization and inflammatory reactions.We demonstrated that Mg^(2+)is critical for the crosstalk among biomaterials,immune cells,and effector cells in Mg-BGN-mediated tissue regeneration.This study provides a theoretical basis for the application of Mg-BGNs as nanomedicines to achieve in situ tissue regeneration in complex intrajoint pathological microenvironments.
基金supported by International Cooperation and Exchange of the National Natural Science Foundation of China(No.81761168039)Macao Science and TechnologyDevelopment 345 Fund(No.015/2017/AFJ,China)National Key Research and Development Program of China(Nos.2018YFC1704800 and 2018YFC1704805)
文摘Although the tumor suppressor P53 is known to regulate a broad network of signaling pathways,it is still unclear how certain drugs influence these P53 signaling netw orks.Here,we used a comprehensive singlecell multiomics view of the effects of ginsenosides on cancer cells.Transcriptome and proteome profiling revealed that the antitumor activity of ginsenosides is closely as sociated with P53 protein.A miRNA-proteome interaction network revealed that P53 controlled the transcription of at least 38 proteins,and proteomemetabolome profiling analysis revealed that P53 regulated proteins involved in nucleotide metabolism,amino acid metabolism and"Warburg effect".The results of integrative multiomics analysis revealed P53 protein as a potential key target that influences the anti-tumor activity of ginsenosides.Furthermore,by applying affinity mass spectrometry(MS)screening and surface plasmon resonance fragment library screening,we confirmed that 20(S)-protopanaxatriol directly targeted adj acent regions of the P53 DNA-binding pocket and promoted the stability of P53-DNA interactions,which further induced a series of omics changes.
基金the Research Unit Project of the Chinese Academy of Medical Sciences(No.2019-I2M-5-030)the Research Project of Jinan Microecological Biomedicine Shandong Laboratory(China)(No.JNL2022002A)the Fundamental Research Funds for the Central Universities(China)(No.226-2023-00107).
文摘Aging is a contributor to liver disease.Hence,the concept of liver aging has become prominent and has attracted considerable interest,but its underlying mechanism remains poorly understood.In our study,the internal mechanism of liver aging was explored via multi-omics analysis and molecular experiments to support future targeted therapy.An aged rat liver model was established with D-galactose,and two other senescent hepatocyte models were established by treating HepG2 cells with D-galactose and H2O2.We then performed transcriptomic and metabolomic assays of the aged liver model and transcriptome analyses of the senescent hepatocyte models.In livers,genes related to peroxisomes,fatty acid elongation,and fatty acid degradation exhibited down-regulated expression with aging,and the hepatokine Fgf21 expression was positively correlated with the down-regulation of these genes.In senescent hepatocytes,similar to the results found in aged livers,FGF21 expression was also decreased.Moreover,the expressions of cell cycle-related genes were significantly down-regulated,and the down-regulated gene E2F8 was the key cell cycle-regulating transcription factor.We then validated that FGF21 overexpression can protect against liver aging and that FGF21 can attenuate the declines in the antioxidant and regenerative capacities in the aging liver.We successfully validated the results from cellular and animal experiments using human liver and blood samples.Our study indicated that FGF21 is an important target for inhibiting liver aging and suggested that pharmacological prevention of the reduction in FGF21 expression due to aging may be used to treat liver aging-related diseases.
基金supported by Innovative Research Groups of National Natural Science Foundation of China(81721091)Major Program of National Natural Science Foundation of China(91542205)+8 种基金National S&T Major Project(2017ZX 10203205)National Natural Science Foundation of China(81902813)Zhejiang International Science and Technology Cooperation Project(2016C04003)Zhejiang Provincial Natural Science Foundation of China(LY18H030002)Zhejiang Medical Association(grant no.2019ZYC-A81)International Youth Exchange Programme by China Association for Science and Technology(2019),Tianqing Liver Diseases Research Fund(TQGB20200114)Medical Health Science and Technology Project of Zhejiang Provincial Health Commission(2021KY145)Organ Transplantation Overseas Training for Youth Talents from Shulan Excellent Talent Project,CSCO(Chinese Society Of Clinical Oncology)-Bayer Tumor Research Funding(Y-bayer202001/zb-0003)Open Fund of Key laboratory of High-Incidence-Tumor Prevention&Treatment(Guangxi Medical University)belonged to Ministry of Education.
文摘Omics data address key issues in liver transplantation(LT)as the most effective therapeutic means for end-stage liver disease.The purpose of this study was to review the current application and future direction for omics in LT.We reviewed the use of multiomics to elucidate the pathogenesis leading to LT and prognostication.Future directions with respect to the use of omics in LT are also described based on perspectives of surgeons with experience in omics.Significant molecules were identified and summarized based on omics,with a focus on post-transplant liver fibrosis,early allograft dysfunction,tumor recurrence,and graft failure.We emphasized the importance omics for clinicians who perform LTs and prioritized the directions that should be established.We also outlined the ideal workflow for omics in LT.In step with advances in technology,the quality of omics data can be guaranteed using an improved algorithm at a lower price.Concerns should be addressed on the translational value of omics for better therapeutic effects in patients undergoing LT.
基金Financial support was provided by the National Science Foundation of China(nos.21671099 and 91753121)the Shenzhen Basic Research Program(no.JCYJ20170413150538897)supported by the Fundamental Research Funds for the Central Universities(no.020514380139).
文摘Black phosphorus(BP)is a newly discovered two-dimensional material that has promising applications from bioelectronics to biomedicine.However,facile oxidation of BP leads to changes in surface chemical composition and physical properties,often being referred to as the degradation process of BP.Degradation products of BP nanosheets,namely,oxidized BP nanosheets(oBPNSs),are routinely considered as by-products without many uses.Herein,we found that oBPNSs displayed excellent osteoclastogenesis inhibition effects without impairing cell viability.In contrast to the classic antiresorptive bisphosphonate drugs,oBPNSs showed a different mode of action by suppressing the maturation of osteoclasts.Bone resorption assays,osteoclast actin ring analysis,and tartrate-resistant acid phosphate activity assay results indicated that oBPNSs suppressed receptor activator of nuclear factor-κB(NF-κB)ligand(RANKL)-induced osteoclastogenesis in a dose-and oxidation-dependent manner.Transcriptomic and proteomic analyses indicated that oBPNSs inhibited the activation of the NF-κB signaling pathway and phosphorylation of mitogen-activated protein kinase(MAPK)in differentiated osteoclasts,as confirmed by Western blot analysis.Our results suggest that oBPNSs might be potential antiresorptive nanomaterials to treat osteoporosis.
