AIM:To evaluate the relationship between gene polymorphism(BclI,ER22/23EK,N363S)and the occurrence,progression and sensitivity to glucocorticoid of lacrimal gland benign lymphoepithelial lesion(LGBLEL).METHODS:Clinica...AIM:To evaluate the relationship between gene polymorphism(BclI,ER22/23EK,N363S)and the occurrence,progression and sensitivity to glucocorticoid of lacrimal gland benign lymphoepithelial lesion(LGBLEL).METHODS:Clinical peripheral blood samples of 52 LGBLEL patients and 10 normal volunteers were collected for DNA extraction and polymerase chain reaction sequencing to analyze single nucleotide polymorphism(SNP)genotypes.The lacrimal tissues of LGBLEL were surgically removed and made into paraffin sections for subsequent hematoxylin-eosin(HE)and Masson staining analysis.The duration of disease and hormone use of LGBLEL patients from diagnosis to surgery were also analyzed.The Meta-analysis follows PRISMA guidelines to conducted a systematic review of human studies investigating the relationship between the NR3C1 BclI polymorphism and glucocorticoids(GCs)sensitivity.RESULTS:There was no association between ER22/23EK or N363S and the occurrence of LGBLEL or GCs sensitivity(P>0.05);BclI GC genotype was closely related to GCs resistance(P=0.03)as is the minor allele C(P=0.0017).The HE staining and Masson staining showed that the GC genotype of BclI remarkably slowed down the disease progression and reduced fibrosis(P<0.05),especially for GCs-dependent patients(P<0.0001).Meta-analysis showed that BclI was not significantly associated with GCs responsiveness.CONCLUSION:The LGBLEL patients who carry the NR3C1 BclI allele C may be more sensitive to GCs and associated with lower fibrosis and slower disease progression.The results may guide the clinical treatment strategy for the LGBLEL patients.展开更多
BACKGROUND Tooth avulsion is one of the most severe types of dental trauma.Most avulsed teeth undergo long-term ankylosis and replacement resorption after delayed reimplantation and exhibit a poor prognosis.The aim of...BACKGROUND Tooth avulsion is one of the most severe types of dental trauma.Most avulsed teeth undergo long-term ankylosis and replacement resorption after delayed reimplantation and exhibit a poor prognosis.The aim of this work was to improve the success rate of avulsed teeth after delayed reimplantation using autologous platelet-rich fibrin(PRF).CASE SUMMARY Case 1 was a 14-year-old boy who fell and knocked out his left upper central incisor 18 h prior to his arrival at the department.The diagnoses were avulsion of tooth 21,lateral luxation of tooth 11 and alveolar fracture of teeth 11 and 21.In case 2,a 17-year-old boy fell 2 h prior to his presentation to the hospital,and his left upper lateral incisor was completely knocked out of the alveolar socket.The diagnoses included avulsion of tooth 22,complicated crown fracture of tooth 11and complicated crown-root fracture of tooth 21.The avulsed teeth were reimplanted along with autologous PRF granules and splinted using a semiflexible titanium preshaped labial arch.The root canals of the avulsed teeth were filled with calcium hydroxide paste,and root canal filling was performed 4 wk after reimplantation.The reimplanted teeth showed no symptoms of inflammatory root resorption or ankylosis at the 3-,6-,and 12-mo follow-up examinations after reimplantation with autologous PRF.In addition to the avulsed teeth,the other injured teeth were treated using corresponding conventional treatment methods.CONCLUSION These cases provide examples of the successful use of PRF to reduce pathological root resorption of the avulsed teeth,and the application of PRF may provide new healing opportunities for traditionally“hopeless”avulsed teeth.展开更多
Severe muscle injury is hard to heal and always results in a poor prognosis.Recent studies found that extracellular vesicle-based therapy has promising prospects for regeneration medicine,however,whether extracellular...Severe muscle injury is hard to heal and always results in a poor prognosis.Recent studies found that extracellular vesicle-based therapy has promising prospects for regeneration medicine,however,whether extracellular vesicles have therapeutic effects on severe muscle injury is still unknown.Herein,we extracted apoptotic extracellular vesicles derived from mesenchymal stem cells(MSCs-Apo EVs)to treat cardiotoxin induced tibialis anterior(TA)injury and found that MSCs-Apo EVs promoted muscles regeneration and increased the proportion of multinucleated cells.Besides that,we also found that apoptosis was synchronized during myoblasts fusion and MSCs-Apo EVs promoted the apoptosis ratio as well as the fusion index of myoblasts.Furthermore,we revealed that MSCs-Apo EVs increased the relative level of creatine during myoblasts fusion,which was released via activated Pannexin 1 channel.Moreover,we also found that activated Pannexin 1 channel was highly expressed on the membrane of myoblasts-derived Apo EVs(Myo-Apo EVs)instead of apoptotic myoblasts,and creatine was the pivotal metabolite involved in myoblasts fusion.Collectively,our findings firstly revealed that MSCs-Apo EVs can promote muscle regeneration and elucidated that the new function of Apo EVs as passing inter-cell messages through releasing metabolites from activated Pannexin 1 channel,which will provide new evidence for extracellular vesicles-based therapy as well as improving the understanding of new functions of extracellular vesicles.展开更多
The loss-of-function mutations in the ALPL result in hypophosphatasia(HPP), an inborn metabolic disorder that causes skeletal mineralization defects. In adults, the main clinical features are early loss of primary or ...The loss-of-function mutations in the ALPL result in hypophosphatasia(HPP), an inborn metabolic disorder that causes skeletal mineralization defects. In adults, the main clinical features are early loss of primary or secondary teeth, osteoporosis, bone pain,chondrocalcinosis, and fractures. However, guidelines for the treatment of adults with HPP are not available. Here, we show that ALPL deficiency caused a reduction in intracellular Ca2+ influx, resulting in an osteoporotic phenotype due to downregulated osteogenic differentiation and upregulated adipogenic differentiation in both human and mouse bone marrow mesenchymal stem cells(BMSCs). Increasing the intracellular level of calcium in BMSCs by ionomycin treatment rescued the osteoporotic phenotype in alpl+/- mice and BMSC-specific(Prrx1-alpl-/-) conditional alpl knockout mice. Mechanistically, ALPL was found to be required for the maintenance of intracellular Ca2+ influx, which it achieves by regulating L-type Ca2+ channel trafficking via binding to the α2δsubunits to regulate the internalization of the L-type Ca2+ channel. Decreased Ca2+ flux inactivates the Akt/GSK3β/β-catenin signaling pathway, which regulates lineage differentiation of BMSCs. This study identifies a previously unknown role of the ectoenzyme ALPL in the maintenance of calcium channel trafficking to regulate stem cell lineage differentiation and bone homeostasis. Accelerating Ca2+ flux through L-type Ca2+ channels by ionomycin treatment may be a promising therapeutic approach for adult patients with HPP.展开更多
Inflammatory response plays a critical role in myocardial infarction(MI)repair.The neutrophil apoptosis and subsequent macrophage ingestion can result in inflammation resolution and initiate regeneration,while the the...Inflammatory response plays a critical role in myocardial infarction(MI)repair.The neutrophil apoptosis and subsequent macrophage ingestion can result in inflammation resolution and initiate regeneration,while the therapeutic strategy that simulates and enhances this natural process has not been established.Here,we constructed engineered neutrophil apoptotic bodies(eNABs)to simulate natural neutrophil apoptosis,which regulated inflammation response and enhanced MI repair.The eNABs were fabricated by combining natural neutrophil apoptotic body membrane which has excellent inflammation-tropism and immunoregulatory properties,and mesoporous silica nanoparticles loaded with hexyl 5-aminolevulinate hydrochloride(HAL).The eNABs actively targeted to macrophages and the encapsulated HAL simultaneously initiated the biosynthesis pathway of heme to produce anti-inflammatory bilirubin after intracellular release,thereby further enhancing the anti-inflammation effects.In in vivo studies,the eNABs efficiently modulated inflammation responses in the infarcted region to ameliorate cardiac function.This study demonstrates an effective biomimetic construction strategy to regulate macrophage functions for MI repair.展开更多
Estrogen deficiency is one of the most frequent causes of osteoporosis in postmenopausal women.Under chronic inflammatory conditions caused by estrogen deficiency,activated T cells contribute to elevated levels of pro...Estrogen deficiency is one of the most frequent causes of osteoporosis in postmenopausal women.Under chronic inflammatory conditions caused by estrogen deficiency,activated T cells contribute to elevated levels of proinflammatory cytokines,impaired osteogenic differentiation capabilities of bone marrow mesenchymal stem cells(BMMSCs),and disturbed regulatory T cell(Treg)/Th17 cell balance.However,therapeutic strategies that re-establish immune homeostasis in this disorder have not been well developed.Here,we produced T cell-depleting nanoparticles(TDNs)that ameliorated the osteopenia phenotype and rescued the osteogenic deficiency of BMMSCs in ovariectomized(OVX)mice.TDNs consist of monocyte chemotactic protein-1(MCP-1)-encapsulated mesoporous silica nanoparticles as the core and Fas-ligand(FasL)as the corona.We showed that the delicate design of the TDNs enables rapid release of MCP-1 to recruit activated T cells and then induces their apoptosis through the conjugated FasL both in vitro and in vivo.Apoptotic signals recognized by macrophages help skew the Treg/Th17 cell balance and create an immune tolerant state,further attenuating the osteogenic deficiency of BMMSCs and the osteopenia phenotype.Mechanistically,we found that the therapeutic effects of TDNs were partially mediated by apoptotic T cell-derived extracellular vesicles(ApoEVs),which promoted macrophage transformation towards the M2 phenotype.These findings demonstrate that TDNs may represent a promising strategy for treating osteoporosis and other immune disorders.展开更多
基金Supported by Natural Science Foundation of Beijing(No.7222025)Beijing Hospitals Authority’Ascent Plan(No.DFL20190201)Natural Science Foundation of Beijing Projects(No.81602408).
文摘AIM:To evaluate the relationship between gene polymorphism(BclI,ER22/23EK,N363S)and the occurrence,progression and sensitivity to glucocorticoid of lacrimal gland benign lymphoepithelial lesion(LGBLEL).METHODS:Clinical peripheral blood samples of 52 LGBLEL patients and 10 normal volunteers were collected for DNA extraction and polymerase chain reaction sequencing to analyze single nucleotide polymorphism(SNP)genotypes.The lacrimal tissues of LGBLEL were surgically removed and made into paraffin sections for subsequent hematoxylin-eosin(HE)and Masson staining analysis.The duration of disease and hormone use of LGBLEL patients from diagnosis to surgery were also analyzed.The Meta-analysis follows PRISMA guidelines to conducted a systematic review of human studies investigating the relationship between the NR3C1 BclI polymorphism and glucocorticoids(GCs)sensitivity.RESULTS:There was no association between ER22/23EK or N363S and the occurrence of LGBLEL or GCs sensitivity(P>0.05);BclI GC genotype was closely related to GCs resistance(P=0.03)as is the minor allele C(P=0.0017).The HE staining and Masson staining showed that the GC genotype of BclI remarkably slowed down the disease progression and reduced fibrosis(P<0.05),especially for GCs-dependent patients(P<0.0001).Meta-analysis showed that BclI was not significantly associated with GCs responsiveness.CONCLUSION:The LGBLEL patients who carry the NR3C1 BclI allele C may be more sensitive to GCs and associated with lower fibrosis and slower disease progression.The results may guide the clinical treatment strategy for the LGBLEL patients.
基金Supported by Natural Science Foundation of China,No.31971248National Clinical Research Center for Oral Diseases Project of Military Stomatology,No.LCA202007。
文摘BACKGROUND Tooth avulsion is one of the most severe types of dental trauma.Most avulsed teeth undergo long-term ankylosis and replacement resorption after delayed reimplantation and exhibit a poor prognosis.The aim of this work was to improve the success rate of avulsed teeth after delayed reimplantation using autologous platelet-rich fibrin(PRF).CASE SUMMARY Case 1 was a 14-year-old boy who fell and knocked out his left upper central incisor 18 h prior to his arrival at the department.The diagnoses were avulsion of tooth 21,lateral luxation of tooth 11 and alveolar fracture of teeth 11 and 21.In case 2,a 17-year-old boy fell 2 h prior to his presentation to the hospital,and his left upper lateral incisor was completely knocked out of the alveolar socket.The diagnoses included avulsion of tooth 22,complicated crown fracture of tooth 11and complicated crown-root fracture of tooth 21.The avulsed teeth were reimplanted along with autologous PRF granules and splinted using a semiflexible titanium preshaped labial arch.The root canals of the avulsed teeth were filled with calcium hydroxide paste,and root canal filling was performed 4 wk after reimplantation.The reimplanted teeth showed no symptoms of inflammatory root resorption or ankylosis at the 3-,6-,and 12-mo follow-up examinations after reimplantation with autologous PRF.In addition to the avulsed teeth,the other injured teeth were treated using corresponding conventional treatment methods.CONCLUSION These cases provide examples of the successful use of PRF to reduce pathological root resorption of the avulsed teeth,and the application of PRF may provide new healing opportunities for traditionally“hopeless”avulsed teeth.
基金supported by the National Key Research and Development Program of China(2021YFA1100600)National Natural Science Foundation of China(82170955,32101096,and 32100953)+1 种基金Shaanxi Provincial Key Research and Development Plan Project(2022SF-095)the Youth Talent Training Project for School of Stomatology in Fourth Military Medical University(2020QNYC01)。
文摘Severe muscle injury is hard to heal and always results in a poor prognosis.Recent studies found that extracellular vesicle-based therapy has promising prospects for regeneration medicine,however,whether extracellular vesicles have therapeutic effects on severe muscle injury is still unknown.Herein,we extracted apoptotic extracellular vesicles derived from mesenchymal stem cells(MSCs-Apo EVs)to treat cardiotoxin induced tibialis anterior(TA)injury and found that MSCs-Apo EVs promoted muscles regeneration and increased the proportion of multinucleated cells.Besides that,we also found that apoptosis was synchronized during myoblasts fusion and MSCs-Apo EVs promoted the apoptosis ratio as well as the fusion index of myoblasts.Furthermore,we revealed that MSCs-Apo EVs increased the relative level of creatine during myoblasts fusion,which was released via activated Pannexin 1 channel.Moreover,we also found that activated Pannexin 1 channel was highly expressed on the membrane of myoblasts-derived Apo EVs(Myo-Apo EVs)instead of apoptotic myoblasts,and creatine was the pivotal metabolite involved in myoblasts fusion.Collectively,our findings firstly revealed that MSCs-Apo EVs can promote muscle regeneration and elucidated that the new function of Apo EVs as passing inter-cell messages through releasing metabolites from activated Pannexin 1 channel,which will provide new evidence for extracellular vesicles-based therapy as well as improving the understanding of new functions of extracellular vesicles.
基金funded by grants from the National Natural Science Foundation of China (Nos. 81620108007 and 81870768)the National Key Research and Development Program of China (Nos. 2016YFC1101400 and 2017YFA0104800)the Scientific Young Alma of Shaanxi province (2018KJXX-015)。
文摘The loss-of-function mutations in the ALPL result in hypophosphatasia(HPP), an inborn metabolic disorder that causes skeletal mineralization defects. In adults, the main clinical features are early loss of primary or secondary teeth, osteoporosis, bone pain,chondrocalcinosis, and fractures. However, guidelines for the treatment of adults with HPP are not available. Here, we show that ALPL deficiency caused a reduction in intracellular Ca2+ influx, resulting in an osteoporotic phenotype due to downregulated osteogenic differentiation and upregulated adipogenic differentiation in both human and mouse bone marrow mesenchymal stem cells(BMSCs). Increasing the intracellular level of calcium in BMSCs by ionomycin treatment rescued the osteoporotic phenotype in alpl+/- mice and BMSC-specific(Prrx1-alpl-/-) conditional alpl knockout mice. Mechanistically, ALPL was found to be required for the maintenance of intracellular Ca2+ influx, which it achieves by regulating L-type Ca2+ channel trafficking via binding to the α2δsubunits to regulate the internalization of the L-type Ca2+ channel. Decreased Ca2+ flux inactivates the Akt/GSK3β/β-catenin signaling pathway, which regulates lineage differentiation of BMSCs. This study identifies a previously unknown role of the ectoenzyme ALPL in the maintenance of calcium channel trafficking to regulate stem cell lineage differentiation and bone homeostasis. Accelerating Ca2+ flux through L-type Ca2+ channels by ionomycin treatment may be a promising therapeutic approach for adult patients with HPP.
基金This work was supported by National Key Research and Development Program of China(2016YFC1101400)National Natural Science Foundation of China(31800817)+4 种基金Innovative Talent Project of Shaanxi province(2020KJXX-057)National Natural Science Foundation of China(31870970)National Natural Science Foundation of China(81991504)Key Research and Development Program of Shaanxi Province(2019SF-073)Young Talent Support Program of Stomatology of FMMU(41741835-MZ2020D5).
文摘Inflammatory response plays a critical role in myocardial infarction(MI)repair.The neutrophil apoptosis and subsequent macrophage ingestion can result in inflammation resolution and initiate regeneration,while the therapeutic strategy that simulates and enhances this natural process has not been established.Here,we constructed engineered neutrophil apoptotic bodies(eNABs)to simulate natural neutrophil apoptosis,which regulated inflammation response and enhanced MI repair.The eNABs were fabricated by combining natural neutrophil apoptotic body membrane which has excellent inflammation-tropism and immunoregulatory properties,and mesoporous silica nanoparticles loaded with hexyl 5-aminolevulinate hydrochloride(HAL).The eNABs actively targeted to macrophages and the encapsulated HAL simultaneously initiated the biosynthesis pathway of heme to produce anti-inflammatory bilirubin after intracellular release,thereby further enhancing the anti-inflammation effects.In in vivo studies,the eNABs efficiently modulated inflammation responses in the infarcted region to ameliorate cardiac function.This study demonstrates an effective biomimetic construction strategy to regulate macrophage functions for MI repair.
基金This work was supported by the National Natural Science Foundation of China(81930025,31800817,81670915,and 31870970)Innovative Talent Project of Shaanxi province(2020KJXX-057)Key Research and Development Program of Shaanxi Province(2019SF-073).
文摘Estrogen deficiency is one of the most frequent causes of osteoporosis in postmenopausal women.Under chronic inflammatory conditions caused by estrogen deficiency,activated T cells contribute to elevated levels of proinflammatory cytokines,impaired osteogenic differentiation capabilities of bone marrow mesenchymal stem cells(BMMSCs),and disturbed regulatory T cell(Treg)/Th17 cell balance.However,therapeutic strategies that re-establish immune homeostasis in this disorder have not been well developed.Here,we produced T cell-depleting nanoparticles(TDNs)that ameliorated the osteopenia phenotype and rescued the osteogenic deficiency of BMMSCs in ovariectomized(OVX)mice.TDNs consist of monocyte chemotactic protein-1(MCP-1)-encapsulated mesoporous silica nanoparticles as the core and Fas-ligand(FasL)as the corona.We showed that the delicate design of the TDNs enables rapid release of MCP-1 to recruit activated T cells and then induces their apoptosis through the conjugated FasL both in vitro and in vivo.Apoptotic signals recognized by macrophages help skew the Treg/Th17 cell balance and create an immune tolerant state,further attenuating the osteogenic deficiency of BMMSCs and the osteopenia phenotype.Mechanistically,we found that the therapeutic effects of TDNs were partially mediated by apoptotic T cell-derived extracellular vesicles(ApoEVs),which promoted macrophage transformation towards the M2 phenotype.These findings demonstrate that TDNs may represent a promising strategy for treating osteoporosis and other immune disorders.
