BACKGROUND:Adeno-associated virus(AAV)gene therapy has been proven to be reliable and safe for the treatment of osteoarthritis in recent years.However,given the complexity of osteoarthritis pathogenesis,single gene ma...BACKGROUND:Adeno-associated virus(AAV)gene therapy has been proven to be reliable and safe for the treatment of osteoarthritis in recent years.However,given the complexity of osteoarthritis pathogenesis,single gene manipulation for the treatment of osteoarthritis may not produce satisfactory results.Previous studies have shown that nuclear factorκB could promote the inflammatory pathway in osteoarthritic chondrocytes,and bone morphogenetic protein 4(BMP4)could promote cartilage regeneration.OBJECTIVE:To test whether combined application of AAV-p65shRNA and AAV-BMP4 will yield the synergistic effect on chondrocytes regeneration and osteoarthritis treatment.METHODS:Viral particles containing AAV-p65-shRNA and AAV-BMP4 were prepared.Their efficacy in inhibiting inflammation in chondrocytes and promoting chondrogenesis was assessed in vitro and in vivo by transfecting AAV-p65-shRNA or AAV-BMP4 into cells.The experiments were divided into five groups:PBS group;osteoarthritis group;AAV-BMP4 group;AAV-p65shRNA group;and BMP4-p65shRNA 1:1 group.Samples were collected at 4,12,and 24 weeks postoperatively.Tissue staining,including safranin O and Alcian blue,was applied after collecting articular tissue.Then,the optimal ratio between the two types of transfected viral particles was further investigated to improve the chondrogenic potential of mixed cells in vivo.RESULTS AND CONCLUSION:The combined application of AAV-p65shRNA and AAV-BMP4 together showed a synergistic effect on cartilage regeneration and osteoarthritis treatment.Mixed cells transfected with AAV-p65shRNA and AAV-BMP4 at a 1:1 ratio produced the most extracellular matrix synthesis(P<0.05).In vivo results also revealed that the combination of the two viruses had the highest regenerative potential for osteoarthritic cartilage(P<0.05).In the present study,we also discovered that the combined therapy had the maximum effect when the two viruses were administered in equal proportions.Decreasing either p65shRNA or BMP4 transfected cells resulted in less collagen II synthesis.This implies that inhibiting inflammation by p65shRNA and promoting regeneration by BMP4 are equally important for osteoarthritis treatment.These findings provide a new strategy for the treatment of early osteoarthritis by simultaneously inhibiting cartilage inflammation and promoting cartilage repair.展开更多
Corrole,a representative branch of porphyrin,has recently gained popularity.These molecules,viewed as ring‑contracted porphyrinoids containing direct pyrrole‑pyrrole linkages due to the absence of a meso‑carbon atom,e...Corrole,a representative branch of porphyrin,has recently gained popularity.These molecules,viewed as ring‑contracted porphyrinoids containing direct pyrrole‑pyrrole linkages due to the absence of a meso‑carbon atom,exhibit significant photo‑physicochemical properties that make them attractive for various applications.Herein,this review comprehensively discusses the remarkable properties of corrole complexes,as well as related structures and chelation properties.It further explores the biological applications of corrole complexes for in vivo imaging and anticancer therapy.Additionally,it addresses common research bottlenecks and challenges,providing insights into future potential applications in disease diagnosis and treatment.Generally,this review aims to illuminate the significance of corrole complexes and their promising biological applications.展开更多
The realization of real-time thermal feedback for monitoring photothermal therapy(PTT)under near-infrared(NIR)light irradiation is of great interest and challenge for antitumor therapy.Herein,by assembling highly effi...The realization of real-time thermal feedback for monitoring photothermal therapy(PTT)under near-infrared(NIR)light irradiation is of great interest and challenge for antitumor therapy.Herein,by assembling highly efficient photothermal conversion gold nanorods and a temperature-responsive probe((E)-4-(4-(diethylamino)styryl)-1-methylpyridin-1-ium,PyS)within MOF-199,an intelligent nanoplatform(AMPP)was fabricated for simultaneous chemodynamic therapy and NIR light-induced temperature-feedback PTT.The fluorescence intensity and temperature of the PyS probe are linearly related due to the restriction of the rotation of the characteristic monomethine bridge.Moreover,the copper ions resulting from the degradation of MOF-199 in an acidic microenvironment can convert H_(2)O_(2)into•OH,resulting in tumor ablation through a Fenton-like reaction,and this process can be accelerated by increasing the temperature.This study establishes a feasible platform for fabricating highly sensitive temperature sensors for efficient temperature-feedback PTT.展开更多
Macrophages,existed in almost all organs of the body,are responsible for detecting tissue injury,pathogens,playing a key role in host defense against a variety of invading pathogens triggering inflammatory responses.E...Macrophages,existed in almost all organs of the body,are responsible for detecting tissue injury,pathogens,playing a key role in host defense against a variety of invading pathogens triggering inflammatory responses.Emerging evidence suggests that macrophage-mediated immune responses are efficiently regulated by the ubiquitination modification,which is responsible for normal immune responses.However,numerous studies indicates that the aberrant activation or inhibition of macrophage-mediated immune responses occurs in inflammation,mainly caused by dysregulated ubiquitination modification due to E3 ubiquitin ligases mutations or abnormal expression.Notably,E3 ubiquitin ligases,responsible for recognizing the substrates,are key enzymes in the ubiquitin proteasome system(UPS)composed of ubiquitin(Ub),ubiquitin-activating E1 enzymes,ubiquitin-conjugating E2 enzymes,E3 ubiquitin ligases,26S proteasome,and deubiquitinating enzymes.Intriguingly,several E3 ubiquitin ligases are involved in the regulation of some common signal pathways in macrophage-mediated inflammation,including Toll-like receptors(TLRs),nucleotide-binding oligomerization domain(NOD)-like receptors(NLRs),RIG-I-like receptors(RLRs),C-type lectin receptors(CLRs)and the receptor for advanced glycation end products(RAGE).Herein,we summarized the physiological and pathological roles of E3 ligases in macrophage-mediated inflammation,as well as the inhibitors and agonists targeting E3 ligases in macrophage mediated inflammation,providing the new ideas for targeted therapies in macrophage-mediated inflammation caused aberrant function of E3 ligases.展开更多
Objective To observe changes of plain MR T1WI signal intensity of dentate nucleus in nasopharyngeal carcinoma patients after radiotherapy and multiple times of intravenous injection of gadolinium-based contrast agent(...Objective To observe changes of plain MR T1WI signal intensity of dentate nucleus in nasopharyngeal carcinoma patients after radiotherapy and multiple times of intravenous injection of gadolinium-based contrast agent(GBCA).Methods Fifty patients with pathologically confirmed nasopharyngeal carcinoma and received intensity-modulated radiotherapy were retrospectively enrolled as the nasopharyngeal carcinoma group,and 50 patients with other malignant tumors and without history of brain radiotherapy were retrospectively enrolled as the control group.All patients received yearly GBCA enhanced MR examinations for the nasopharynx or the head.T1WI signal intensities of the dentate nucleus and the pons on same plane were measured based on images in the year of confirmed diagnosis(recorded as the first year)and in the second to the fifth years.T1WI signal intensity ratio of year i(ranging from 1 to 5)was calculated with values of dentate nucleus divided by values of the pons(ΔSI i),while the percentage of relative changes of year j(ranging from 2 to 5)was calculated withΔSI j compared toΔSI 1(Rchange j).The values of these two parameters were compared,and the correlation ofΔSI and GBCA injection year-time was evaluated within each group.Results No significant difference of gender,age norΔSI 1 was found between groups(all P>0.05).The second to the fifth yearΔSI and Rchange in nasopharyngeal carcinoma group were all higher than those in control group(all P<0.05).Within both groups,ΔSI was positively correlated with GBCA injection year-time(both P<0.05).Conclusion Patients with nasopharyngeal carcinoma who underwent radiotherapy and multiple times of intravenous injection of GBCA tended to be found with gradually worsening GBCA deposition in dentate nucleus,for which radiotherapy might be a risk factor.展开更多
With the progress of aging,the incidence of vascular calcification(VC)gradually increases,which is correlated with cardiovascular events and all-cause death,aggravating global clinical burden.Over the past several dec...With the progress of aging,the incidence of vascular calcification(VC)gradually increases,which is correlated with cardiovascular events and all-cause death,aggravating global clinical burden.Over the past several decades,accumulating approaches targeting the underlying pathogenesis of VC have provided some possibilities for the treatment of VC.Unfortunately,none of the current interventions have achieved clinical effectiveness on reversing or curing VC.The purpose of this review is to make a summary of novel perspectives on the interventions of VC and provide reference for clinical decision-making.展开更多
The advent of gene editing represents one of the most transformative breakthroughs in life science,making genome manipulation more accessible than ever before.While traditional CRISPR/Cas-based gene editing,which invo...The advent of gene editing represents one of the most transformative breakthroughs in life science,making genome manipulation more accessible than ever before.While traditional CRISPR/Cas-based gene editing,which involves double-strand DNA breaks(DSBs),excels at gene disruption,it is less effective for accurate gene modification.The limitation arises because DSBs are primarily repaired via non-homologous end joining(NHEJ),which tends to introduce indels at the break site.While homology directed repair(HDR)can achieve precise editing when a donor DNA template is provided,the reliance on DSBs often results in unintended genome damage.HDR is restricted to specific cell cycle phases,limiting its application.Currently,gene editing has evolved to unprecedented levels of precision without relying on DSB and HDR.The development of innovative systems,such as base editing,prime editing,and CRISPR-associated transposases(CASTs),now allow for precise editing ranging from single nucleotides to large DNA fragments.Base editors(BEs)enable the direct conversion of one nucleotide to another,and prime editors(PEs)further expand gene editing capabilities by allowing for the insertion,deletion,or alteration of small DNA fragments.The CAST system,a recent innovation,allows for the precise insertion of large DNA fragments at specific genomic locations.In recent years,the optimization of these precise gene editing tools has led to significant improvements in editing efficiency,specificity,and versatility,with advancements such as the creation of base editors for nucleotide transversions,enhanced prime editing systems for more efficient and precise modifications,and refined CAST systems for targeted large DNA insertions,expanding the range of applications for these tools.Concurrently,these advances are complemented by significant improvements in in vivo delivery methods,which have paved the way for therapeutic application of precise gene editing tools.Effective delivery systems are critical for the success of gene therapies,and recent developments in both viral and non-viral vectors have improved the efficiency and safety of gene editing.For instance,adeno-associated viruses(AAVs)are widely used due to their high transfection efficiency and low immunogenicity,though challenges such as limited cargo capacity and potential for immune responses remain.Non-viral delivery systems,including lipid nanoparticles(LNPs),offer an alternative with lower immunogenicity and higher payload capacity,although their transfection efficiency can be lower.The therapeutic potential of these precise gene editing technologies is vast,particularly in treating genetic disorders.Preclinical studies have demonstrated the effectiveness of base editing in correcting genetic mutations responsible for diseases such as cardiomyopathy,liver disease,and hereditary hearing loss.These technologies promise to treat symptoms and potentially cure the underlying genetic causes of these conditions.Meanwhile,challenges remain,such as optimizing the safety and specificity of gene editing tools,improving delivery systems,and overcoming off-target effects,all of which are critical for their successful application in clinical settings.In summary,the continuous evolution of precise gene editing technologies,combined with advancements in delivery systems,is driving the field toward new therapeutic applications that can potentially transform the treatment of genetic disorders by targeting their root causes.展开更多
文摘BACKGROUND:Adeno-associated virus(AAV)gene therapy has been proven to be reliable and safe for the treatment of osteoarthritis in recent years.However,given the complexity of osteoarthritis pathogenesis,single gene manipulation for the treatment of osteoarthritis may not produce satisfactory results.Previous studies have shown that nuclear factorκB could promote the inflammatory pathway in osteoarthritic chondrocytes,and bone morphogenetic protein 4(BMP4)could promote cartilage regeneration.OBJECTIVE:To test whether combined application of AAV-p65shRNA and AAV-BMP4 will yield the synergistic effect on chondrocytes regeneration and osteoarthritis treatment.METHODS:Viral particles containing AAV-p65-shRNA and AAV-BMP4 were prepared.Their efficacy in inhibiting inflammation in chondrocytes and promoting chondrogenesis was assessed in vitro and in vivo by transfecting AAV-p65-shRNA or AAV-BMP4 into cells.The experiments were divided into five groups:PBS group;osteoarthritis group;AAV-BMP4 group;AAV-p65shRNA group;and BMP4-p65shRNA 1:1 group.Samples were collected at 4,12,and 24 weeks postoperatively.Tissue staining,including safranin O and Alcian blue,was applied after collecting articular tissue.Then,the optimal ratio between the two types of transfected viral particles was further investigated to improve the chondrogenic potential of mixed cells in vivo.RESULTS AND CONCLUSION:The combined application of AAV-p65shRNA and AAV-BMP4 together showed a synergistic effect on cartilage regeneration and osteoarthritis treatment.Mixed cells transfected with AAV-p65shRNA and AAV-BMP4 at a 1:1 ratio produced the most extracellular matrix synthesis(P<0.05).In vivo results also revealed that the combination of the two viruses had the highest regenerative potential for osteoarthritic cartilage(P<0.05).In the present study,we also discovered that the combined therapy had the maximum effect when the two viruses were administered in equal proportions.Decreasing either p65shRNA or BMP4 transfected cells resulted in less collagen II synthesis.This implies that inhibiting inflammation by p65shRNA and promoting regeneration by BMP4 are equally important for osteoarthritis treatment.These findings provide a new strategy for the treatment of early osteoarthritis by simultaneously inhibiting cartilage inflammation and promoting cartilage repair.
文摘Corrole,a representative branch of porphyrin,has recently gained popularity.These molecules,viewed as ring‑contracted porphyrinoids containing direct pyrrole‑pyrrole linkages due to the absence of a meso‑carbon atom,exhibit significant photo‑physicochemical properties that make them attractive for various applications.Herein,this review comprehensively discusses the remarkable properties of corrole complexes,as well as related structures and chelation properties.It further explores the biological applications of corrole complexes for in vivo imaging and anticancer therapy.Additionally,it addresses common research bottlenecks and challenges,providing insights into future potential applications in disease diagnosis and treatment.Generally,this review aims to illuminate the significance of corrole complexes and their promising biological applications.
基金supported by the National Natural Science Foundation of China(22171001,22305001,51972001,52372073)the Natural Science Foundation of Anhui Province of China(2108085MB49).
文摘The realization of real-time thermal feedback for monitoring photothermal therapy(PTT)under near-infrared(NIR)light irradiation is of great interest and challenge for antitumor therapy.Herein,by assembling highly efficient photothermal conversion gold nanorods and a temperature-responsive probe((E)-4-(4-(diethylamino)styryl)-1-methylpyridin-1-ium,PyS)within MOF-199,an intelligent nanoplatform(AMPP)was fabricated for simultaneous chemodynamic therapy and NIR light-induced temperature-feedback PTT.The fluorescence intensity and temperature of the PyS probe are linearly related due to the restriction of the rotation of the characteristic monomethine bridge.Moreover,the copper ions resulting from the degradation of MOF-199 in an acidic microenvironment can convert H_(2)O_(2)into•OH,resulting in tumor ablation through a Fenton-like reaction,and this process can be accelerated by increasing the temperature.This study establishes a feasible platform for fabricating highly sensitive temperature sensors for efficient temperature-feedback PTT.
文摘Macrophages,existed in almost all organs of the body,are responsible for detecting tissue injury,pathogens,playing a key role in host defense against a variety of invading pathogens triggering inflammatory responses.Emerging evidence suggests that macrophage-mediated immune responses are efficiently regulated by the ubiquitination modification,which is responsible for normal immune responses.However,numerous studies indicates that the aberrant activation or inhibition of macrophage-mediated immune responses occurs in inflammation,mainly caused by dysregulated ubiquitination modification due to E3 ubiquitin ligases mutations or abnormal expression.Notably,E3 ubiquitin ligases,responsible for recognizing the substrates,are key enzymes in the ubiquitin proteasome system(UPS)composed of ubiquitin(Ub),ubiquitin-activating E1 enzymes,ubiquitin-conjugating E2 enzymes,E3 ubiquitin ligases,26S proteasome,and deubiquitinating enzymes.Intriguingly,several E3 ubiquitin ligases are involved in the regulation of some common signal pathways in macrophage-mediated inflammation,including Toll-like receptors(TLRs),nucleotide-binding oligomerization domain(NOD)-like receptors(NLRs),RIG-I-like receptors(RLRs),C-type lectin receptors(CLRs)and the receptor for advanced glycation end products(RAGE).Herein,we summarized the physiological and pathological roles of E3 ligases in macrophage-mediated inflammation,as well as the inhibitors and agonists targeting E3 ligases in macrophage mediated inflammation,providing the new ideas for targeted therapies in macrophage-mediated inflammation caused aberrant function of E3 ligases.
文摘Objective To observe changes of plain MR T1WI signal intensity of dentate nucleus in nasopharyngeal carcinoma patients after radiotherapy and multiple times of intravenous injection of gadolinium-based contrast agent(GBCA).Methods Fifty patients with pathologically confirmed nasopharyngeal carcinoma and received intensity-modulated radiotherapy were retrospectively enrolled as the nasopharyngeal carcinoma group,and 50 patients with other malignant tumors and without history of brain radiotherapy were retrospectively enrolled as the control group.All patients received yearly GBCA enhanced MR examinations for the nasopharynx or the head.T1WI signal intensities of the dentate nucleus and the pons on same plane were measured based on images in the year of confirmed diagnosis(recorded as the first year)and in the second to the fifth years.T1WI signal intensity ratio of year i(ranging from 1 to 5)was calculated with values of dentate nucleus divided by values of the pons(ΔSI i),while the percentage of relative changes of year j(ranging from 2 to 5)was calculated withΔSI j compared toΔSI 1(Rchange j).The values of these two parameters were compared,and the correlation ofΔSI and GBCA injection year-time was evaluated within each group.Results No significant difference of gender,age norΔSI 1 was found between groups(all P>0.05).The second to the fifth yearΔSI and Rchange in nasopharyngeal carcinoma group were all higher than those in control group(all P<0.05).Within both groups,ΔSI was positively correlated with GBCA injection year-time(both P<0.05).Conclusion Patients with nasopharyngeal carcinoma who underwent radiotherapy and multiple times of intravenous injection of GBCA tended to be found with gradually worsening GBCA deposition in dentate nucleus,for which radiotherapy might be a risk factor.
基金supported by the Peking University Baidu Fund (2019BD019)
文摘With the progress of aging,the incidence of vascular calcification(VC)gradually increases,which is correlated with cardiovascular events and all-cause death,aggravating global clinical burden.Over the past several decades,accumulating approaches targeting the underlying pathogenesis of VC have provided some possibilities for the treatment of VC.Unfortunately,none of the current interventions have achieved clinical effectiveness on reversing or curing VC.The purpose of this review is to make a summary of novel perspectives on the interventions of VC and provide reference for clinical decision-making.
文摘The advent of gene editing represents one of the most transformative breakthroughs in life science,making genome manipulation more accessible than ever before.While traditional CRISPR/Cas-based gene editing,which involves double-strand DNA breaks(DSBs),excels at gene disruption,it is less effective for accurate gene modification.The limitation arises because DSBs are primarily repaired via non-homologous end joining(NHEJ),which tends to introduce indels at the break site.While homology directed repair(HDR)can achieve precise editing when a donor DNA template is provided,the reliance on DSBs often results in unintended genome damage.HDR is restricted to specific cell cycle phases,limiting its application.Currently,gene editing has evolved to unprecedented levels of precision without relying on DSB and HDR.The development of innovative systems,such as base editing,prime editing,and CRISPR-associated transposases(CASTs),now allow for precise editing ranging from single nucleotides to large DNA fragments.Base editors(BEs)enable the direct conversion of one nucleotide to another,and prime editors(PEs)further expand gene editing capabilities by allowing for the insertion,deletion,or alteration of small DNA fragments.The CAST system,a recent innovation,allows for the precise insertion of large DNA fragments at specific genomic locations.In recent years,the optimization of these precise gene editing tools has led to significant improvements in editing efficiency,specificity,and versatility,with advancements such as the creation of base editors for nucleotide transversions,enhanced prime editing systems for more efficient and precise modifications,and refined CAST systems for targeted large DNA insertions,expanding the range of applications for these tools.Concurrently,these advances are complemented by significant improvements in in vivo delivery methods,which have paved the way for therapeutic application of precise gene editing tools.Effective delivery systems are critical for the success of gene therapies,and recent developments in both viral and non-viral vectors have improved the efficiency and safety of gene editing.For instance,adeno-associated viruses(AAVs)are widely used due to their high transfection efficiency and low immunogenicity,though challenges such as limited cargo capacity and potential for immune responses remain.Non-viral delivery systems,including lipid nanoparticles(LNPs),offer an alternative with lower immunogenicity and higher payload capacity,although their transfection efficiency can be lower.The therapeutic potential of these precise gene editing technologies is vast,particularly in treating genetic disorders.Preclinical studies have demonstrated the effectiveness of base editing in correcting genetic mutations responsible for diseases such as cardiomyopathy,liver disease,and hereditary hearing loss.These technologies promise to treat symptoms and potentially cure the underlying genetic causes of these conditions.Meanwhile,challenges remain,such as optimizing the safety and specificity of gene editing tools,improving delivery systems,and overcoming off-target effects,all of which are critical for their successful application in clinical settings.In summary,the continuous evolution of precise gene editing technologies,combined with advancements in delivery systems,is driving the field toward new therapeutic applications that can potentially transform the treatment of genetic disorders by targeting their root causes.
