Osteoarthritis(OA)is one of the most common degenerative and age-related diseases in joints,which affects 654 million people worldwide.Current therapies could not fundamentally reverse the pathologic process of OA due...Osteoarthritis(OA)is one of the most common degenerative and age-related diseases in joints,which affects 654 million people worldwide.Current therapies could not fundamentally reverse the pathologic process of OA due to the complex pathogenesis.Although OA mechanisms have been investigated on a large scale over the past decade,the OA pathology correlated with aging-associated changes is still largely unrevealed.Therefore,in-depth analysis of the aging microenvironment and aging-related molecular mechanisms in OA may offer additional strategies for clinical prevention and treatment.In this review,we discuss the potential pathogenesis of OA in light of aging-associated changes and summarize three main components of the aging microenvironment of the OA joint:immune homeostatic imbalance,cellular senescence,and stem cell exhaustion,which could be induced by aging and further exacerbate OA progression.Additionally,it is emphasized that immune homeostatic imbalance appears before established OA,which occurs in the early stage and is the therapeutic window of opportunity for better clinical outcomes.Importantly,we evaluate recent therapeutic targets and promising interventions against these components,as well as the challenges and prospects for precise and individualized therapies of OA patients,which we believe would guide the construction of novel combined strategies targeting aging-related factors against OA for better treatments in the future.展开更多
AIM: To elucidate the molecular and cellular features responsible for the increase of regulatory T cells (Tregs) in gastric cancer. METHODS: The frequencies of CD4 + Foxp3 + Tregs and the level of transforming growth ...AIM: To elucidate the molecular and cellular features responsible for the increase of regulatory T cells (Tregs) in gastric cancer. METHODS: The frequencies of CD4 + Foxp3 + Tregs and the level of transforming growth factor-β1 (TGF-β1) were analyzed from 56 patients with gastric cancer byflow cytometry and enzyme-linked immunosorbent assay respectively. Foxp3 gene expression was analyzed by real-time polymerase chain reaction. The gastric cancer microenvironment was modeled by establishing the coculture of gastric cancer cell line, MGC-803, with sorting CD4 + T cells. The normal gastric mucosa cell line, GES-1, was used as the control. The production of TGF-β1 was detected in supernatant of MGC and GES-1. The carboxyfluorescein diacetatesuccinimidyl ester (CFSE) dilution assay was performed to evaluate the proliferation characteristics of induced Tregs. Neutralizing anti-TGF-β1 antibody was added to the co-culture system for neutralization experiments. RESULTS: The level of serum TGF-β1 in gastric cancer patients (15.1 ± 5.5 ng/mL) was significantly higher than that of the genderand age-matched healthy controls (10.3 ± 3.4 ng/mL) (P < 0.05). Furthermore, the higher TGF-β1 level correlated with the increased population of CD4 + Foxp3 + Tregs in advanced gastric cancer (r = 0.576, P < 0.05). A significant higher frequency of CD4 + Foxp3 + Tregs was observed in PBMCs cultured with the supernatant of MGC than GES-1 (10.6% ± 0.6% vs 8.7% ± 0.7%, P < 0.05). Moreover, using the purified CD4 + CD25 T cells, we confirmed that the increased Tregs were mainly induced from the conversation of CD4 + CD25 naive T cells, and induced Tregs were functional and able to suppress the proliferation of effector T cells. Finally, we demonstrated that gastric cancer cells induced the increased CD4 + Foxp3 + Tregs via producing TGF-β1. Gastric cancer cells upregulated the production of TGF-β1 and blockade of TGF-β1 partly abrogated Tregs phenotype. CONCLUSION: Gastric cancer cell can induce Tregs development via producing TGF-β1, by which the existence of cross-talk between the tumor and immune cells might regulate anti-tumor immune responses.展开更多
Osteoarthritis(OA)is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA.These attem...Osteoarthritis(OA)is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA.These attempts involve repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype in synovium.In this study,we found that phosphoglycerate mutase 5(PGAM5)significantly increased in macrophages in OA synovium compared to controls based on histology of human samples and single-cell RNA sequencing results of mice models.To address the role of PGAM5 in macrophages in OA,we found conditional knockout of PGAM5 in macrophages greatly alleviated OA symptoms and promoted anabolic metabolism of chondrocytes in vitro and in vivo.Mechanistically,we found that PGAM5 enhanced M1 polarization via AKT-mTOR/p38/ERK pathways,whereas inhibited M2 polarization via STAT6-PPARγpathway in murine bone marrow-derived macrophages.Furthermore,we found that PGAM5 directly dephosphorylated Dishevelled Segment Polarity Protein 2(DVL2)which resulted in the inhibition ofβ-catenin and repolarization of M2 macrophages into M1 macrophages.Conditional knockout of both PGAM5 andβ-catenin in macrophages significantly exacerbated osteoarthritis compared to PGAM5-deficient mice.Motivated by these findings,we successfully designed mannose modified fluoropolymers combined with siPGAM5 to inhibit PGAM5 specifically in synovial macrophages via intra-articular injection,which possessed desired targeting abilities of synovial macrophages and greatly attenuated murine osteoarthritis.Collectively,these findings defined a key role for PGAM5 in orchestrating macrophage polarization and provides insights into novel macrophage-targeted strategy for treating OA.展开更多
AIM To compare therapeutic responses of a vascular-disrupting-agent, combretastatin-A4-phosphate(CA4 P), among hepatocellular carcinomas(HCCs) and implanted rhabdomyosarcoma(R1) in the same rats by magneticresonance-i...AIM To compare therapeutic responses of a vascular-disrupting-agent, combretastatin-A4-phosphate(CA4 P), among hepatocellular carcinomas(HCCs) and implanted rhabdomyosarcoma(R1) in the same rats by magneticresonance-imaging(MRI), microangiography and histopathology.METHODS Thirty-six HCCs were created by diethylnitrosamine gavage in 14 rats that were also intrahepatically implanted with one R1 per rat as monitored by T2-/T1-weighted images(T2wI/T1wI) on a 3.0 T clinical MRIscanner. Vascular response and tumoral necrosis were detected by dynamic contrast-enhanced(DCE-) and CE-MRI before, 1 h after and 12 h after CA4P iv at 10 mg/kg(treatment group n = 7) or phosphate-buffered saline at 1.0 mL/kg(control group n = 7). Tumor blood supply was calculated by a semiquantitative DCE parameter of area under the time signal intensity curve(AUC30). In vivo MRI findings were verified by postmortem techniques.RESULTS On CE-T1wIs, unlike the negative response in all tumors of control animals, in treatment group CA4P caused rapid extensive vascular shutdown in all R1-tumors, but mildly or spottily in HCCs at 1 h. Consequently, tumor necrosis occurred massively in R1-tumors but patchily in HCCs at 12 h. AUC30 revealed vascular closure(66%) in R1-tumors at 1 h(P < 0.05), followed by further perfusion decrease at 12 h(P < 0.01), while less significant vascular clogging occurred in HCCs. Histomorphologically, CA4P induced more extensive necrosis in R1-tumors(92.6%) than in HCCs(50.2%)(P < 0.01); tumor vascularity heterogeneously scored +^+++ in HCCs but homogeneously scored ++ in R1-tumors.CONCLUSION This study suggests superior performance of CA4P in metastatic over primary liver cancers, which could guide future clinical applications of vascular-disruptingagents.展开更多
Background:Alzheimer’s disease(AD)is an age-related and progressive neurodegenerative disease that causes substantial public health care burdens.Intensive efforts have been made to find effective and safe treatment a...Background:Alzheimer’s disease(AD)is an age-related and progressive neurodegenerative disease that causes substantial public health care burdens.Intensive efforts have been made to find effective and safe treatment against AD.Salidroside(Sal)is the main effective component of Rhodiola rosea L.,which has several pharmacological activities.The objective of this study was to investigate the efficacy of Sal in the treatment of AD transgenic Drosophila and the associated mechanisms.Methods:We used tau transgenic Drosophila line(TAU)in which tau protein is expressed in the central nervous system and eyes by the Gal4/UAS system.After feeding flies with Sal,the lifespan and locomotor activity were recorded.We further examined the appearance of vacuoles in the mushroom body using immunohistochemistry,and detected the levels of total glycogen synthase kinase 3β(t-GSK-3β),phosphorylated GSK-3β(p-GSK-3β),t-tau and p-tau in the brain by western blot analysis.Results:Our results showed that the longevity was improved in salidroside-fed Drosophila groups as well as the locomotor activity.We also observed less vacuoles in the mushroom body,upregulated level of p-GSK-3βand downregulated p-tau following Sal treatment.Conclusion:Our data presented the evidence that Sal was capable of reducing the neurodegeneration in tau transgenic Drosophila and inhibiting neuronal loss.The neuroprotective effects of Sal were associated with its up-regulation of the p-GSK-3βand down-regulation of the p-tau.展开更多
OX40L is one of the co-stimulatory molecules that can be expressed by splenic lymphoid tissue inducer(Lti)cells,a subset of group 3 innate lymphoid cells(ILC3s).OX40L expression in subsets of intestinal ILC3s and the ...OX40L is one of the co-stimulatory molecules that can be expressed by splenic lymphoid tissue inducer(Lti)cells,a subset of group 3 innate lymphoid cells(ILC3s).OX40L expression in subsets of intestinal ILC3s and the molecular regulation of OX40L expression in ILC3s are unknown.Here,we showed intestinal ILC3s marked as an OX40L high population among all the intestinal leukocytes and were the dominant source of OX40L in Rag1–/–mice.All ILC3 subsets expressed OX40L,and NCR–ILC3s were the most abundant source of OX40L.The expression of OX40L in ILC3s could be upregulated during inflammation.In addition to tumor necrosis factor(TNF)-like cytokine 1A(TL1A),which has been known as a trigger for OX40L,we found that Poly(I:C)representing viral stimulus promoted OX40L expression in ILC3s via a cell-autonomous manner.Furthermore,we demonstrated that IL-7-STAT5 signaling sustained OX40L expression by ILC3s.Intestinal regulatory T cells(Tregs),most of which expressed OX40,had defective expansion in chimeric mice,in which ILC3s were specifically deficient for OX40L expression.Consistently,co-localization of Tregs and ILC3s was found in the cryptopatches of the intestine,which suggests the close interaction between ILC3s and Tregs.Our study has unveiled the crosstalk between Tregs and ILC3s in mucosal tissues through OX40–OX40L signaling,which is crucial for the homeostasis of intestinal Tregs.展开更多
Small nucleolar RNAs(snoRNAs)play critical roles in various biological processes.The aberrant expression or depletion of snoRNAs is related to various diseases.In previous research,most of the snoRNAs were categorized...Small nucleolar RNAs(snoRNAs)play critical roles in various biological processes.The aberrant expression or depletion of snoRNAs is related to various diseases.In previous research,most of the snoRNAs were categorized as C/D box snoRNAs and H/ACA box snoRNAs,whose typical functions were thought of as regulation of 2′-O-ribose methylation and pseudouridylation of ribosome RNAs,respectively.However,in the past two decades,studies have revealed an increasing number of snoRNAs without specific targets or determined cell functions.These findings indicated that some potential roles of snoRNAs are still unknown.Numerous studies have indicated the correlation of snoRNAs with human diseases.SnoRNAs play various roles in abundant biological processes,and they have great potential in controlling human diseases.This new and rising field could benefit from investigations of the disease pathogenesis,biomarker identification,and the determination of novel therapeutic targets.This review summarized the reports on snoRNAs and the regulation of different diseases in recent years.展开更多
Mesenchymal stem cells(MSCs),which are pluripotent cells with immunomodulatory properties,have been considered good candidates for the therapy of several immune disorders,such as inflammatory bowel diseases,concanaval...Mesenchymal stem cells(MSCs),which are pluripotent cells with immunomodulatory properties,have been considered good candidates for the therapy of several immune disorders,such as inflammatory bowel diseases,concanavalin A-induced liver injury,and graft-versus-host disease.The embryo is a natural allograft to the maternal immune system.A successful pregnancy depends on the timely extinction of the inflammatory response induced by embryo implantation,followed by the switch to a tolerant immune microenvironment in both the uterus and the system.Excessive infiltration of immune cells and serious inflammatory responses are triggers for embryo rejection,which results in miscarriage.Here,we demonstrated that adoptive transfer of MSCs could prevent fetal loss in a lipopolysaccharide(LPS)-induced abortion model and immune response-mediated spontaneous abortion model.The immunosuppressive MSCs alleviated excessive inflammation by inhibiting CD4+T cell proliferation and promoting the decidual macrophage switch to M2 in a tumor necrosis factor-stimulated gene-6(TSG-6)-dependent manner.Cell-tocell contact with proinflammatory macrophages increased the TSG-6 production by the MSCs,thereby enhancing the suppressive regulation of T cells and macrophages.Moreover,proinflammatory macrophages in contact with the MSCs upregulated the expression of CD200 on the stem cells and facilitated the reprogramming of macrophages towards an anti-inflammatory skew through the interaction of CD200 with CD200R on proinflammatory macrophages.Therefore,the results demonstrate that a TSG-6-mediated paracrine effect,reinforced by cell-to-cell contact between MSCs and proinflammatory macrophages,is involved in the mechanism of MSC-mediated abortion relief through the induction of immune tolerance.Our study also indicates the potential application of MSCs in clinical recurrent miscarriages.展开更多
Focal segmental glomerulosclerosis （FSGS） is a histologically identifiable gtomerular injury often leading to proteinuria and renal failure. To identify its causal genes, whole-exome sequencing and Sanger sequencing...Focal segmental glomerulosclerosis （FSGS） is a histologically identifiable gtomerular injury often leading to proteinuria and renal failure. To identify its causal genes, whole-exome sequencing and Sanger sequencing were performed on a large Chinese cohort that comprised 40 FSGS families, 50 sporadic FSGS patients, 9 independent autosomal recessive Atport＇s syndrome （ARAS） patients, and 190 ethnically matched healthy controls. Patients with extrarenal manifestations, indicating systemic diseases or other known hereditary renal diseases, were excluded. Heterozygous COL4A3 mutations were identified in five （12.5%） FSGS families and one （2%） sporadic FSGS patient. All identified mutations disrupted highly conserved protein sequences and none of them was found in either public databases or the 190 healthy controls. Of the FSGS patients with heterozygous COL4A3 mutations, segmental thinning of the glomerular base membrane （GBM） was only detected in the patient with electronic microscopy examination results available. Five ARAS patients （55.6%） had homozygous or compound-heterozygous mutations in COL4.43 or COL4A4. Serious changes in the G BM, hearing loss, and ocular abnormalities were found in 100%, 80%, and 40% of the ARAS patients, respectively. Overall, a new sub- group of FSGS patients resulting from heterozygous C01.4A3 mutations was identified. The mutations are relatively frequent in famiUes diagnosed with inherited forms of FSGS. Thus, we suggest screening for C01.4A3 mutations in familial FSGS patients.展开更多
Background Ectonucleotide pyrophosphatase/phosphodiesterase （ENPP）-I is a membrane-bound protein that catalyzes the hydrolysis of extracellular nucleoside triphosphates to monophosphate and extracellular inorganic p...Background Ectonucleotide pyrophosphatase/phosphodiesterase （ENPP）-I is a membrane-bound protein that catalyzes the hydrolysis of extracellular nucleoside triphosphates to monophosphate and extracellular inorganic pyrophosphate （ePPi）. Mechanical stimulation regulates ENPP-1 expression. This study sought to investigate the changes in ENPP-1 expression after stimulation using cyclic mechanical tension （CMT）.展开更多
Mural cells(MCs)wrap around the endothelium,and participate in the development and homeostasis of vasculature.MCs have been reported as heterogeneous population morphologically and functionally.However,the transcripti...Mural cells(MCs)wrap around the endothelium,and participate in the development and homeostasis of vasculature.MCs have been reported as heterogeneous population morphologically and functionally.However,the transcriptional heterogeneity of MCs was rarely studied.In this study,we illustrated the transcriptional heterogeneity of MCs with different perspectives by using publicly available single-cell dataset GSE109774.Specifically,MCs are transcriptionally different from other cell types,and ligand-receptor interactions of different cells with MCs vary.Re-clustering of MCs identified five distinct subclusters.The heterogeneity of MCs in tissues was reflected by MC coverage,various distribution of MC subclusters,and ligand-receptor interactions of MCs and parenchymal cells.The transcriptomic diversity of MCs revealed in this article will help facilitate further research into MCs.展开更多
Background:Scleroderma is characterized by inflammation and fibrosis,predominantly occurring in the skin and extending to various parts of the body.The pathophysiology of scleroderma is multifaceted,with the current u...Background:Scleroderma is characterized by inflammation and fibrosis,predominantly occurring in the skin and extending to various parts of the body.The pathophysiology of scleroderma is multifaceted,with the current understanding including endothelial damage,inflammatory cell infiltration,and fibroblast activation in its progression.Nonetheless,the mechanism of cellular interactions and the precise spatial distribution of these cellular events within the fibrotic tissues remain elusive,highlighting a critical gap in our comprehensive understanding of scleroderma’s pathogenesis.Methods:In this study,we administered bleomycin intradermally to the dorsal skin of four individual murine models.Subsequently,skin tissues were harvested at predetermined intervals for comprehensive spatial transcriptomic analysis to determine the spatial dynamics influencing scleroderma pathogenesis.To validate the possible results from bioinformatic analysis,further in vitro and in vivo experiments were conducted.Results:Analysis of the spatial transcriptome revealed significant alterations in cell clusters during the progression of scleroderma.Gene Ontology analysis identified disruptions in lipid metabolism as the disease advanced.Pseudotime analysis provided evidence for a phenotypic transition from adipocytes to fibroblasts.In vitro studies demonstrated increased expression of Col1a1 andα-SMA as the disease progressed.These fibroblasts have been identified as key contributors to the increasing inflammation.Co-culturing TGF-βinduced adipocytes with RAW264.7 cells resulted in overexpression of pro-inflammatory cytokines in the RAW264.7 cells.Both in vitro and in vivo experiments confirmed adipocyte loss and fibroblast formation,with transformed fibroblasts showing pronounced pro-inflammatory characteristics,highlighting their crucial role in the disease mechanism.Conclusions:Our study showed the spatial distribution and dynamic alterations of various cell types during scleroderma progression.Crucially,we identified the transformation of adipocytes into fibroblasts as a key factor promoting disease advancement.These emergent fibroblasts intensify inflammation,indicating that research on these cell clusters could reveal key scleroderma mechanisms and guide future therapies.展开更多
In this article,there were two annotation mistakes about the precise deletion position in COL4A3 and COL4A4 mutations in ARAS patients(summarized in Figure 2E).This was caused by a bug in the old version(v3.4)of Varia...In this article,there were two annotation mistakes about the precise deletion position in COL4A3 and COL4A4 mutations in ARAS patients(summarized in Figure 2E).This was caused by a bug in the old version(v3.4)of Variant Caller for Ion Torrent.The variant in family AP5 should be described as‘chr2:227942771delG’,instead of‘chr:227942770delG’,in the COL4A4 gene.The variant identified in family AP1 should be described as‘chr2:228172490delA’,instead of‘chr:228172489delA’,in the COL4A3 gene.The corrected Figure 2E is shown as below.The results and conclusions of the article are not affected,and the authors apologize for these errors.展开更多
基金supported by grants from National Natural Science Foundation of China(32370892)Science and Technology Commission of Shanghai Municipality(23141901200)+3 种基金Shanghai Natural Science Foundation(24ZR1450100)Health Commission of Shanghai Municipality(2022JC029)Biomaterials and Regenerative Medicine Institute Cooperative Research Project,Shanghai Jiaotong University School of Medicine(2022LHA11)Talent-Introduction Program of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine(2022YJRC05).
文摘Osteoarthritis(OA)is one of the most common degenerative and age-related diseases in joints,which affects 654 million people worldwide.Current therapies could not fundamentally reverse the pathologic process of OA due to the complex pathogenesis.Although OA mechanisms have been investigated on a large scale over the past decade,the OA pathology correlated with aging-associated changes is still largely unrevealed.Therefore,in-depth analysis of the aging microenvironment and aging-related molecular mechanisms in OA may offer additional strategies for clinical prevention and treatment.In this review,we discuss the potential pathogenesis of OA in light of aging-associated changes and summarize three main components of the aging microenvironment of the OA joint:immune homeostatic imbalance,cellular senescence,and stem cell exhaustion,which could be induced by aging and further exacerbate OA progression.Additionally,it is emphasized that immune homeostatic imbalance appears before established OA,which occurs in the early stage and is the therapeutic window of opportunity for better clinical outcomes.Importantly,we evaluate recent therapeutic targets and promising interventions against these components,as well as the challenges and prospects for precise and individualized therapies of OA patients,which we believe would guide the construction of novel combined strategies targeting aging-related factors against OA for better treatments in the future.
基金Supported by Shanghai Municipal Natural Science Foundation, No. 10ZR1420000National Natural Science Foundation of China, No. 81072009
文摘AIM: To elucidate the molecular and cellular features responsible for the increase of regulatory T cells (Tregs) in gastric cancer. METHODS: The frequencies of CD4 + Foxp3 + Tregs and the level of transforming growth factor-β1 (TGF-β1) were analyzed from 56 patients with gastric cancer byflow cytometry and enzyme-linked immunosorbent assay respectively. Foxp3 gene expression was analyzed by real-time polymerase chain reaction. The gastric cancer microenvironment was modeled by establishing the coculture of gastric cancer cell line, MGC-803, with sorting CD4 + T cells. The normal gastric mucosa cell line, GES-1, was used as the control. The production of TGF-β1 was detected in supernatant of MGC and GES-1. The carboxyfluorescein diacetatesuccinimidyl ester (CFSE) dilution assay was performed to evaluate the proliferation characteristics of induced Tregs. Neutralizing anti-TGF-β1 antibody was added to the co-culture system for neutralization experiments. RESULTS: The level of serum TGF-β1 in gastric cancer patients (15.1 ± 5.5 ng/mL) was significantly higher than that of the genderand age-matched healthy controls (10.3 ± 3.4 ng/mL) (P < 0.05). Furthermore, the higher TGF-β1 level correlated with the increased population of CD4 + Foxp3 + Tregs in advanced gastric cancer (r = 0.576, P < 0.05). A significant higher frequency of CD4 + Foxp3 + Tregs was observed in PBMCs cultured with the supernatant of MGC than GES-1 (10.6% ± 0.6% vs 8.7% ± 0.7%, P < 0.05). Moreover, using the purified CD4 + CD25 T cells, we confirmed that the increased Tregs were mainly induced from the conversation of CD4 + CD25 naive T cells, and induced Tregs were functional and able to suppress the proliferation of effector T cells. Finally, we demonstrated that gastric cancer cells induced the increased CD4 + Foxp3 + Tregs via producing TGF-β1. Gastric cancer cells upregulated the production of TGF-β1 and blockade of TGF-β1 partly abrogated Tregs phenotype. CONCLUSION: Gastric cancer cell can induce Tregs development via producing TGF-β1, by which the existence of cross-talk between the tumor and immune cells might regulate anti-tumor immune responses.
基金This work was supported by grants from National Natural Science Foundation of China(81830078,82071868,32370892)Science and Technology Commission of Shanghai Municipality(23141901200)+2 种基金Health Commission of Shanghai Municipality(2022JC029)Biomaterials and Regenerative Medicine Institute Cooperative Research Project,Shanghai Jiaotong University School of Medicine(2022LHA11)Shanghai Key Laboratory of Orthopedic Implant(No.KFKT202206).
文摘Osteoarthritis(OA)is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA.These attempts involve repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype in synovium.In this study,we found that phosphoglycerate mutase 5(PGAM5)significantly increased in macrophages in OA synovium compared to controls based on histology of human samples and single-cell RNA sequencing results of mice models.To address the role of PGAM5 in macrophages in OA,we found conditional knockout of PGAM5 in macrophages greatly alleviated OA symptoms and promoted anabolic metabolism of chondrocytes in vitro and in vivo.Mechanistically,we found that PGAM5 enhanced M1 polarization via AKT-mTOR/p38/ERK pathways,whereas inhibited M2 polarization via STAT6-PPARγpathway in murine bone marrow-derived macrophages.Furthermore,we found that PGAM5 directly dephosphorylated Dishevelled Segment Polarity Protein 2(DVL2)which resulted in the inhibition ofβ-catenin and repolarization of M2 macrophages into M1 macrophages.Conditional knockout of both PGAM5 andβ-catenin in macrophages significantly exacerbated osteoarthritis compared to PGAM5-deficient mice.Motivated by these findings,we successfully designed mannose modified fluoropolymers combined with siPGAM5 to inhibit PGAM5 specifically in synovial macrophages via intra-articular injection,which possessed desired targeting abilities of synovial macrophages and greatly attenuated murine osteoarthritis.Collectively,these findings defined a key role for PGAM5 in orchestrating macrophage polarization and provides insights into novel macrophage-targeted strategy for treating OA.
文摘AIM To compare therapeutic responses of a vascular-disrupting-agent, combretastatin-A4-phosphate(CA4 P), among hepatocellular carcinomas(HCCs) and implanted rhabdomyosarcoma(R1) in the same rats by magneticresonance-imaging(MRI), microangiography and histopathology.METHODS Thirty-six HCCs were created by diethylnitrosamine gavage in 14 rats that were also intrahepatically implanted with one R1 per rat as monitored by T2-/T1-weighted images(T2wI/T1wI) on a 3.0 T clinical MRIscanner. Vascular response and tumoral necrosis were detected by dynamic contrast-enhanced(DCE-) and CE-MRI before, 1 h after and 12 h after CA4P iv at 10 mg/kg(treatment group n = 7) or phosphate-buffered saline at 1.0 mL/kg(control group n = 7). Tumor blood supply was calculated by a semiquantitative DCE parameter of area under the time signal intensity curve(AUC30). In vivo MRI findings were verified by postmortem techniques.RESULTS On CE-T1wIs, unlike the negative response in all tumors of control animals, in treatment group CA4P caused rapid extensive vascular shutdown in all R1-tumors, but mildly or spottily in HCCs at 1 h. Consequently, tumor necrosis occurred massively in R1-tumors but patchily in HCCs at 12 h. AUC30 revealed vascular closure(66%) in R1-tumors at 1 h(P < 0.05), followed by further perfusion decrease at 12 h(P < 0.01), while less significant vascular clogging occurred in HCCs. Histomorphologically, CA4P induced more extensive necrosis in R1-tumors(92.6%) than in HCCs(50.2%)(P < 0.01); tumor vascularity heterogeneously scored +^+++ in HCCs but homogeneously scored ++ in R1-tumors.CONCLUSION This study suggests superior performance of CA4P in metastatic over primary liver cancers, which could guide future clinical applications of vascular-disruptingagents.
基金This work was supported by grants from the National Natural Science Fund(91332107,81430022,81371407).
文摘Background:Alzheimer’s disease(AD)is an age-related and progressive neurodegenerative disease that causes substantial public health care burdens.Intensive efforts have been made to find effective and safe treatment against AD.Salidroside(Sal)is the main effective component of Rhodiola rosea L.,which has several pharmacological activities.The objective of this study was to investigate the efficacy of Sal in the treatment of AD transgenic Drosophila and the associated mechanisms.Methods:We used tau transgenic Drosophila line(TAU)in which tau protein is expressed in the central nervous system and eyes by the Gal4/UAS system.After feeding flies with Sal,the lifespan and locomotor activity were recorded.We further examined the appearance of vacuoles in the mushroom body using immunohistochemistry,and detected the levels of total glycogen synthase kinase 3β(t-GSK-3β),phosphorylated GSK-3β(p-GSK-3β),t-tau and p-tau in the brain by western blot analysis.Results:Our results showed that the longevity was improved in salidroside-fed Drosophila groups as well as the locomotor activity.We also observed less vacuoles in the mushroom body,upregulated level of p-GSK-3βand downregulated p-tau following Sal treatment.Conclusion:Our data presented the evidence that Sal was capable of reducing the neurodegeneration in tau transgenic Drosophila and inhibiting neuronal loss.The neuroprotective effects of Sal were associated with its up-regulation of the p-GSK-3βand down-regulation of the p-tau.
基金This study was supported by grants 2015CB943400 and 2014CB943300 from the Ministry of Science and Technology of Chinagrant XDB19000000 from the“Strategic priority research program of the Chinese Academy of Sciences”+1 种基金grants 91542102 and 31570887 from the National Natural Science Foundation of ChinaChina's Youth 1000 Talent Program to Q.J.
文摘OX40L is one of the co-stimulatory molecules that can be expressed by splenic lymphoid tissue inducer(Lti)cells,a subset of group 3 innate lymphoid cells(ILC3s).OX40L expression in subsets of intestinal ILC3s and the molecular regulation of OX40L expression in ILC3s are unknown.Here,we showed intestinal ILC3s marked as an OX40L high population among all the intestinal leukocytes and were the dominant source of OX40L in Rag1–/–mice.All ILC3 subsets expressed OX40L,and NCR–ILC3s were the most abundant source of OX40L.The expression of OX40L in ILC3s could be upregulated during inflammation.In addition to tumor necrosis factor(TNF)-like cytokine 1A(TL1A),which has been known as a trigger for OX40L,we found that Poly(I:C)representing viral stimulus promoted OX40L expression in ILC3s via a cell-autonomous manner.Furthermore,we demonstrated that IL-7-STAT5 signaling sustained OX40L expression by ILC3s.Intestinal regulatory T cells(Tregs),most of which expressed OX40,had defective expansion in chimeric mice,in which ILC3s were specifically deficient for OX40L expression.Consistently,co-localization of Tregs and ILC3s was found in the cryptopatches of the intestine,which suggests the close interaction between ILC3s and Tregs.Our study has unveiled the crosstalk between Tregs and ILC3s in mucosal tissues through OX40–OX40L signaling,which is crucial for the homeostasis of intestinal Tregs.
基金supported by the National Natural Science Foundation of China(No.82172473,82072462,81802191)the Natural Science Foundation of Shandong Province,China(No.ZR2019PH068)+1 种基金Public Welfare Basic Research Program of Zhejiang Province,China(No.LY20H060002)2018 Xinhua-uOttawa joint clinical research,China(No.18JX008).
文摘Small nucleolar RNAs(snoRNAs)play critical roles in various biological processes.The aberrant expression or depletion of snoRNAs is related to various diseases.In previous research,most of the snoRNAs were categorized as C/D box snoRNAs and H/ACA box snoRNAs,whose typical functions were thought of as regulation of 2′-O-ribose methylation and pseudouridylation of ribosome RNAs,respectively.However,in the past two decades,studies have revealed an increasing number of snoRNAs without specific targets or determined cell functions.These findings indicated that some potential roles of snoRNAs are still unknown.Numerous studies have indicated the correlation of snoRNAs with human diseases.SnoRNAs play various roles in abundant biological processes,and they have great potential in controlling human diseases.This new and rising field could benefit from investigations of the disease pathogenesis,biomarker identification,and the determination of novel therapeutic targets.This review summarized the reports on snoRNAs and the regulation of different diseases in recent years.
基金supported by the National Basic Research Program of China(2015CB943300 and 2017YFC1001403)the Nature Science Foundation from the National Nature Science Foundation of China(NSFC)(81630036,91542116,31570920,81490744,31171437,31270969,81571512,and 81501334)+3 种基金the Innovation-oriented Science and Technology Grant from the NHC Key Laboratory of Reproduction Regulation(CX2017-2)the Program of Shanghai Academic/Technology Research Leader(17XD1400900)the Key Project of Shanghai Municipal Education Commission(MECSM)(14ZZ013)the Key Project of Shanghai Basic Research from Shanghai Municipal Science and Technology Commission(STCSM)(12JC1401600).
文摘Mesenchymal stem cells(MSCs),which are pluripotent cells with immunomodulatory properties,have been considered good candidates for the therapy of several immune disorders,such as inflammatory bowel diseases,concanavalin A-induced liver injury,and graft-versus-host disease.The embryo is a natural allograft to the maternal immune system.A successful pregnancy depends on the timely extinction of the inflammatory response induced by embryo implantation,followed by the switch to a tolerant immune microenvironment in both the uterus and the system.Excessive infiltration of immune cells and serious inflammatory responses are triggers for embryo rejection,which results in miscarriage.Here,we demonstrated that adoptive transfer of MSCs could prevent fetal loss in a lipopolysaccharide(LPS)-induced abortion model and immune response-mediated spontaneous abortion model.The immunosuppressive MSCs alleviated excessive inflammation by inhibiting CD4+T cell proliferation and promoting the decidual macrophage switch to M2 in a tumor necrosis factor-stimulated gene-6(TSG-6)-dependent manner.Cell-tocell contact with proinflammatory macrophages increased the TSG-6 production by the MSCs,thereby enhancing the suppressive regulation of T cells and macrophages.Moreover,proinflammatory macrophages in contact with the MSCs upregulated the expression of CD200 on the stem cells and facilitated the reprogramming of macrophages towards an anti-inflammatory skew through the interaction of CD200 with CD200R on proinflammatory macrophages.Therefore,the results demonstrate that a TSG-6-mediated paracrine effect,reinforced by cell-to-cell contact between MSCs and proinflammatory macrophages,is involved in the mechanism of MSC-mediated abortion relief through the induction of immune tolerance.Our study also indicates the potential application of MSCs in clinical recurrent miscarriages.
基金This workwas supported by grants from the National Basic Research Program of China 973, grant no. 2012CB517600 （no. 2012CB517604）, the National Natural Science Foundation of China （no. 81030015, 81070568, 81370015, and 81000295）, the International Cooperation and Exchange Projects of Shanghai Science and Technology Committee （no. 14430721000）, and the Chinese Medical Association Clinical Research Special Fund （no. 13030280413）.
文摘Focal segmental glomerulosclerosis （FSGS） is a histologically identifiable gtomerular injury often leading to proteinuria and renal failure. To identify its causal genes, whole-exome sequencing and Sanger sequencing were performed on a large Chinese cohort that comprised 40 FSGS families, 50 sporadic FSGS patients, 9 independent autosomal recessive Atport＇s syndrome （ARAS） patients, and 190 ethnically matched healthy controls. Patients with extrarenal manifestations, indicating systemic diseases or other known hereditary renal diseases, were excluded. Heterozygous COL4A3 mutations were identified in five （12.5%） FSGS families and one （2%） sporadic FSGS patient. All identified mutations disrupted highly conserved protein sequences and none of them was found in either public databases or the 190 healthy controls. Of the FSGS patients with heterozygous COL4A3 mutations, segmental thinning of the glomerular base membrane （GBM） was only detected in the patient with electronic microscopy examination results available. Five ARAS patients （55.6%） had homozygous or compound-heterozygous mutations in COL4.43 or COL4A4. Serious changes in the G BM, hearing loss, and ocular abnormalities were found in 100%, 80%, and 40% of the ARAS patients, respectively. Overall, a new sub- group of FSGS patients resulting from heterozygous C01.4A3 mutations was identified. The mutations are relatively frequent in famiUes diagnosed with inherited forms of FSGS. Thus, we suggest screening for C01.4A3 mutations in familial FSGS patients.
文摘Background Ectonucleotide pyrophosphatase/phosphodiesterase （ENPP）-I is a membrane-bound protein that catalyzes the hydrolysis of extracellular nucleoside triphosphates to monophosphate and extracellular inorganic pyrophosphate （ePPi）. Mechanical stimulation regulates ENPP-1 expression. This study sought to investigate the changes in ENPP-1 expression after stimulation using cyclic mechanical tension （CMT）.
基金supported in part by the National Key Research and Development Program of China(2019YFA0802700,2017YFA0103700)the National Natural Science Foundation of China(91739301,91339205,81130005)。
文摘Mural cells(MCs)wrap around the endothelium,and participate in the development and homeostasis of vasculature.MCs have been reported as heterogeneous population morphologically and functionally.However,the transcriptional heterogeneity of MCs was rarely studied.In this study,we illustrated the transcriptional heterogeneity of MCs with different perspectives by using publicly available single-cell dataset GSE109774.Specifically,MCs are transcriptionally different from other cell types,and ligand-receptor interactions of different cells with MCs vary.Re-clustering of MCs identified five distinct subclusters.The heterogeneity of MCs in tissues was reflected by MC coverage,various distribution of MC subclusters,and ligand-receptor interactions of MCs and parenchymal cells.The transcriptomic diversity of MCs revealed in this article will help facilitate further research into MCs.
基金supported from grants from the National Natural Science Foundation of China(No.82102327)Clinical Research Program of 9th People’s Hospital,Shanghai JiaoTong University School of Medicine(No.JYLJ202103)。
文摘Background:Scleroderma is characterized by inflammation and fibrosis,predominantly occurring in the skin and extending to various parts of the body.The pathophysiology of scleroderma is multifaceted,with the current understanding including endothelial damage,inflammatory cell infiltration,and fibroblast activation in its progression.Nonetheless,the mechanism of cellular interactions and the precise spatial distribution of these cellular events within the fibrotic tissues remain elusive,highlighting a critical gap in our comprehensive understanding of scleroderma’s pathogenesis.Methods:In this study,we administered bleomycin intradermally to the dorsal skin of four individual murine models.Subsequently,skin tissues were harvested at predetermined intervals for comprehensive spatial transcriptomic analysis to determine the spatial dynamics influencing scleroderma pathogenesis.To validate the possible results from bioinformatic analysis,further in vitro and in vivo experiments were conducted.Results:Analysis of the spatial transcriptome revealed significant alterations in cell clusters during the progression of scleroderma.Gene Ontology analysis identified disruptions in lipid metabolism as the disease advanced.Pseudotime analysis provided evidence for a phenotypic transition from adipocytes to fibroblasts.In vitro studies demonstrated increased expression of Col1a1 andα-SMA as the disease progressed.These fibroblasts have been identified as key contributors to the increasing inflammation.Co-culturing TGF-βinduced adipocytes with RAW264.7 cells resulted in overexpression of pro-inflammatory cytokines in the RAW264.7 cells.Both in vitro and in vivo experiments confirmed adipocyte loss and fibroblast formation,with transformed fibroblasts showing pronounced pro-inflammatory characteristics,highlighting their crucial role in the disease mechanism.Conclusions:Our study showed the spatial distribution and dynamic alterations of various cell types during scleroderma progression.Crucially,we identified the transformation of adipocytes into fibroblasts as a key factor promoting disease advancement.These emergent fibroblasts intensify inflammation,indicating that research on these cell clusters could reveal key scleroderma mechanisms and guide future therapies.
文摘In this article,there were two annotation mistakes about the precise deletion position in COL4A3 and COL4A4 mutations in ARAS patients(summarized in Figure 2E).This was caused by a bug in the old version(v3.4)of Variant Caller for Ion Torrent.The variant in family AP5 should be described as‘chr2:227942771delG’,instead of‘chr:227942770delG’,in the COL4A4 gene.The variant identified in family AP1 should be described as‘chr2:228172490delA’,instead of‘chr:228172489delA’,in the COL4A3 gene.The corrected Figure 2E is shown as below.The results and conclusions of the article are not affected,and the authors apologize for these errors.
