Wound healing in diabetic ulcers remains a significant clinical challenge,primarily due to bacterial infection and impaired angiogenesis.Periplaneta americana extract(PAE)has been widely used to treat diabetic wounds,...Wound healing in diabetic ulcers remains a significant clinical challenge,primarily due to bacterial infection and impaired angiogenesis.Periplaneta americana extract(PAE)has been widely used to treat diabetic wounds,yet its underlying mechanisms are not fully understood.This study aimed to elucidate these mechanisms by analyzing long non-coding RNA(lncRNA)expressions in the wound tissues from diabetic anal fistula patients treated with or without PAE,using high-throughput sequencing.Peripheral blood monocytes from patients were differentiated into M0 macrophages with human macrophage colony-stimulating factor(hMCSF)and subsequently polarized into M1 macrophages with lipopolysaccharide.The results indicated that LINC01133 and SLAMF9 were downregulated in wound tissues of patients treated with PAE.Furthermore,PAE suppressed M1 macrophage polarization and enhanced human umbilical vein endothelial cell(HUVEC)proliferation,migration,and angiogenesis.These effects were diminished when LINC01133 or SLAMF9 were overexpressed.Mechanistically,LINC01133 was shown to upregulate SLAMF9 through interaction with ELAVL1.Overexpression of SLAMF9 reversed the effects of LINC01133 silencing on macrophage polarization and HUVEC functions.In conclusion,PAE facilitates the healing of infected diabetic ulcers by downregulating the LINC01133/SLAMF9 pathway.展开更多
Dynamic communication between hepatocytes and the environment is critical in hepatocellular carcinoma (HCC) development.Clinical immunotherapy against HCC is currently unsatisfactory and needs more systemic considerat...Dynamic communication between hepatocytes and the environment is critical in hepatocellular carcinoma (HCC) development.Clinical immunotherapy against HCC is currently unsatisfactory and needs more systemic considerations, including theidentification of new biomarkers and immune checkpoints. Transmembrane 4 L six family member 5 (TM4SF5) is known to promoteHCC, but it remains unclear how cancerous hepatocytes avoid immune surveillance and whether avoidance can be blocked. Weinvestigated how TM4SF5-mediated hepatic tumorigenesis avoids surveillance by natural killer (NK) cells, which are prevalent in theliver, and whether the avoidance can be blocked by anti-TM4SF5 agents. We used comprehensive structure activity relationshipanalysis to identify TM4SF5-specific isoxazole (TSI)-based small molecules that inhibit TM4SF5-mediated effects. TM4SF5 expressedby hepatocytes reduced NK cell cytotoxicity by downregulating stimulatory ligands/receptors, including signaling lymphocyticactivation molecule family member 7 (SLAMF7). TM4SF5 bound SLAMF7 depending on N-glycosylation and caused intracellulartrafficking of SLAMF7 from the plasma membrane to lysosomes for degradation. TSI treatments in cell lines and animal models ofHCC blocked this binding, intracellular trafficking, and downregulation, resulting in higher levels of stimulatory NK cell ligands. Inmouse xenograft models, TSI treatment abrogated HCC development by increasing the abundance and dispersion of Slamf7-positive cells in liver tissues, recapitulating the phenotype of Tm4sf5-knockout mice and indicating TSI-mediated restoration of NKcell surveillance. These findings suggest that TSIs can inhibit TM4SF5-mediated liver carcinogenesis by increasing NK cellsurveillance.展开更多
Background::Rheumatoid arthritis(RA)is a chronic autoimmune inflammatory disease.Its pathogenesis is not fully understood,and early diagnosis is challenging owing to the lack of effective biomarkers.This study aimed t...Background::Rheumatoid arthritis(RA)is a chronic autoimmune inflammatory disease.Its pathogenesis is not fully understood,and early diagnosis is challenging owing to the lack of effective biomarkers.This study aimed to analyze different samples to identify potential biomarkers and therapeutic targets.Methods::Microarray datasets of RA,osteoarthritis(OA),and healthy control(HC)were downloaded from the Gene Expression Omnibus database.R software was used to identify differentially expressed genes(DEGs),which were visualized using volcano and heat maps.Venn diagrams,principal component analysis,gene set enrichment analysis,gene ontology,and Kyoto Encyclopedia of genes and genomes were used to analyze the data.A protein–protein interaction network was constructed,and synovial tissues from patients with RA and OA were collected for verification using the collagen-induced arthritis mouse model.Results::More DEGs were found in synovial tissues than in peripheral blood mononuclear cells or fibroblast-like synoviocytes.Principal component analysis revealed significant differences between the RA and OA samples,highlighting the unique advantages of synovial tissue.Enrichment analysis revealed that metabolic and cytokine signaling pathways play crucial roles in the development of RA.Further analysis of the four synovial datasets identified 54 DEGs,of which signaling lymphocytic activation molecule family(SLAMF)8 was identified as the key molecule.SLAMF8 levels were increased in the synovial tissue of patients with RA compared to those of patients with OA(0.38±0.19 vs.12.40±1.66),and SLAMF8 levels were similarly elevated in collagen-induced arthritis model mice compared with those in the healthy mice(1.13±0.47 vs.9.05±2.52).Conclusions::This study established the unique advantages of synovial tissue for RA research and identified metabolic and cytokine signaling pathways as important for RA development.Thus,SLAMF8 may be a potential therapeutic target for RA.展开更多
AIM: To examine the genetic profile of primary uveal melanoma (UM) as compared to UM in immune escape.METHODS: Dendritic cells (DC) loaded with lysates of UM cells of high metastatic potential were used to stimulate C...AIM: To examine the genetic profile of primary uveal melanoma (UM) as compared to UM in immune escape.METHODS: Dendritic cells (DC) loaded with lysates of UM cells of high metastatic potential were used to stimulate CTLs(CTLs). When CTLs co-cultured with the UM cells, most UM cells could be eliminated. Survival UM cells grew slowly and were considered to be survival variants and examined by a microarray analysis. These differential genes were analyzed further with Venn Diagrams and functions related to immune escape. We additionally examined transcriptional changes of manually selected survival variants of UM cells and of clinical UM samples by quantitative real-time polymerase chain reaction (qRT-PCR), and analyzed the correlation of these expressions and patients’ survival.RESULTS: Gene expression analyses revealed a marked up-regulation of SLAMF7 and CCL22 and a significant down-regulation of KRT10, FXYD3 and ABCC2. The expression of these genes in the relapsed UM was significantly greater than those in primary UM. UM patients with overexpression of these genes had a shorter survival period as compared with those of their underexpression.CONCLUSION: Gene expression, in particular of SLAMF7, CCL22, KRT10, FXYD3 and ABCC2, differed between primary UM cells and survival variants of UM cells.展开更多
Phagocytosis,a vital defense mechanism,involves the recognition and elimination of foreign substances by cells.Phagocytes,such as neutrophils and macrophages,rapidly respond to invaders;macrophages are especially impo...Phagocytosis,a vital defense mechanism,involves the recognition and elimination of foreign substances by cells.Phagocytes,such as neutrophils and macrophages,rapidly respond to invaders;macrophages are especially important in later stages of the immune response.They detect“find me”signals to locate apoptotic cells and migrate toward them.Apoptotic cells then send“eat me”signals that are recognized by phagocytes via specific receptors.“Find me”and“eat me”signals can be strategically harnessed to modulate antitumor immunity in support of cancer therapy.These signals,such as calreticulin and phosphatidylserine,mediate potent pro-phagocytic effects,thereby promoting the engulfment of dying cells or their remnants by macrophages,neutrophils,and dendritic cells and inducing tumor cell death.This review summarizes the phagocytic“find me”and“eat me”signals,including their concepts,signaling mechanisms,involved ligands,and functions.Furthermore,we delineate the relationships between“find me”and“eat me”signaling molecules and tumors,especially the roles of these molecules in tumor initiation,progression,diagnosis,and patient prognosis.The interplay of these signals with tumor biology is elucidated,and specific approaches to modulate“find me”and“eat me”signals and enhance antitumor immunity are explored.Additionally,novel therapeutic strategies that combine“find me”and“eat me”signals to better bridge innate and adaptive immunity in the treatment of cancer patients are discussed.展开更多
目的探讨2型糖尿病(T2DM)患者免疫细胞及其淋巴细胞激活分子家族成员(SLAMF)的表达情况。方法选取2018年1月至2019年12月该院收治的82例T2DM患者作为研究组,选取同期接受健康体检的82例健康人作为对照组。比较两组生化指标水平及免疫细...目的探讨2型糖尿病(T2DM)患者免疫细胞及其淋巴细胞激活分子家族成员(SLAMF)的表达情况。方法选取2018年1月至2019年12月该院收治的82例T2DM患者作为研究组,选取同期接受健康体检的82例健康人作为对照组。比较两组生化指标水平及免疫细胞表达情况及各免疫细胞SLAMF分子表达情况。结果研究组总胆固醇、LDL-C及HDL-C水平低于对照组,甘油三酯、空腹血糖水平高于对照组(P<0.05)。研究组CD4^(+)T细胞比例高于对照组,CD56^(+)总NK细胞表达低于对照组,且主要表现为CD56 dim NK细胞亚群比例降低(P<0.05),研究组外周血总T细胞比例高于对照组,CD4^(+)细胞低于对照组(P<0.05),CD4^(-)T细胞、NK细胞均较对照组明显降低(P<0.05);研究组总T细胞、CD4^(+)T细胞、CD4^(-)T细胞、NK细胞的SLAMF4、SLAMF5、SLAMF6分子平均荧光强度(MFI)表达水平无明显差异(P>0.05),研究组T细胞、CD4^(+)T细胞、CD4^(-)T细胞、NK细胞的SLAMF3分子MFI高于对照组(P>0.05),研究组NK细胞SLAMF7分子MFI低于对照组(P<0.05)。结论T2MD患者外周血单个核细胞免疫细胞比例异常,且外周血单个核细胞中的总T细胞、CD4^(+)T细胞、CD4^(-)T细胞及NK细胞的SLAMF3、SLAMF7分子表达升高。展开更多
基金supported by the Natural Science Foundation of Hunan Province(No.2021JJ30516).
文摘Wound healing in diabetic ulcers remains a significant clinical challenge,primarily due to bacterial infection and impaired angiogenesis.Periplaneta americana extract(PAE)has been widely used to treat diabetic wounds,yet its underlying mechanisms are not fully understood.This study aimed to elucidate these mechanisms by analyzing long non-coding RNA(lncRNA)expressions in the wound tissues from diabetic anal fistula patients treated with or without PAE,using high-throughput sequencing.Peripheral blood monocytes from patients were differentiated into M0 macrophages with human macrophage colony-stimulating factor(hMCSF)and subsequently polarized into M1 macrophages with lipopolysaccharide.The results indicated that LINC01133 and SLAMF9 were downregulated in wound tissues of patients treated with PAE.Furthermore,PAE suppressed M1 macrophage polarization and enhanced human umbilical vein endothelial cell(HUVEC)proliferation,migration,and angiogenesis.These effects were diminished when LINC01133 or SLAMF9 were overexpressed.Mechanistically,LINC01133 was shown to upregulate SLAMF9 through interaction with ELAVL1.Overexpression of SLAMF9 reversed the effects of LINC01133 silencing on macrophage polarization and HUVEC functions.In conclusion,PAE facilitates the healing of infected diabetic ulcers by downregulating the LINC01133/SLAMF9 pathway.
基金supported by the National Research Foundation of Korea(NRF)funded by the Korea government(MSIT)(NRF-2022R1C1C2003502)to HSKby Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT&Future Planning(NRF-2020R1A2C3008993 and NRF-2021M3A9D3024752)to J.W.L.Graphical elements used in the figures of this manuscript were created with BioRender.com.
文摘Dynamic communication between hepatocytes and the environment is critical in hepatocellular carcinoma (HCC) development.Clinical immunotherapy against HCC is currently unsatisfactory and needs more systemic considerations, including theidentification of new biomarkers and immune checkpoints. Transmembrane 4 L six family member 5 (TM4SF5) is known to promoteHCC, but it remains unclear how cancerous hepatocytes avoid immune surveillance and whether avoidance can be blocked. Weinvestigated how TM4SF5-mediated hepatic tumorigenesis avoids surveillance by natural killer (NK) cells, which are prevalent in theliver, and whether the avoidance can be blocked by anti-TM4SF5 agents. We used comprehensive structure activity relationshipanalysis to identify TM4SF5-specific isoxazole (TSI)-based small molecules that inhibit TM4SF5-mediated effects. TM4SF5 expressedby hepatocytes reduced NK cell cytotoxicity by downregulating stimulatory ligands/receptors, including signaling lymphocyticactivation molecule family member 7 (SLAMF7). TM4SF5 bound SLAMF7 depending on N-glycosylation and caused intracellulartrafficking of SLAMF7 from the plasma membrane to lysosomes for degradation. TSI treatments in cell lines and animal models ofHCC blocked this binding, intracellular trafficking, and downregulation, resulting in higher levels of stimulatory NK cell ligands. Inmouse xenograft models, TSI treatment abrogated HCC development by increasing the abundance and dispersion of Slamf7-positive cells in liver tissues, recapitulating the phenotype of Tm4sf5-knockout mice and indicating TSI-mediated restoration of NKcell surveillance. These findings suggest that TSIs can inhibit TM4SF5-mediated liver carcinogenesis by increasing NK cellsurveillance.
基金National Natural Science Foundation of China,Grant/Award Numbers:82071834,82101896,82271839Dalian Medical University Interdisciplinary Research Cooperation Project Team Funding,Grant/Award Number:JCHZ2023010。
文摘Background::Rheumatoid arthritis(RA)is a chronic autoimmune inflammatory disease.Its pathogenesis is not fully understood,and early diagnosis is challenging owing to the lack of effective biomarkers.This study aimed to analyze different samples to identify potential biomarkers and therapeutic targets.Methods::Microarray datasets of RA,osteoarthritis(OA),and healthy control(HC)were downloaded from the Gene Expression Omnibus database.R software was used to identify differentially expressed genes(DEGs),which were visualized using volcano and heat maps.Venn diagrams,principal component analysis,gene set enrichment analysis,gene ontology,and Kyoto Encyclopedia of genes and genomes were used to analyze the data.A protein–protein interaction network was constructed,and synovial tissues from patients with RA and OA were collected for verification using the collagen-induced arthritis mouse model.Results::More DEGs were found in synovial tissues than in peripheral blood mononuclear cells or fibroblast-like synoviocytes.Principal component analysis revealed significant differences between the RA and OA samples,highlighting the unique advantages of synovial tissue.Enrichment analysis revealed that metabolic and cytokine signaling pathways play crucial roles in the development of RA.Further analysis of the four synovial datasets identified 54 DEGs,of which signaling lymphocytic activation molecule family(SLAMF)8 was identified as the key molecule.SLAMF8 levels were increased in the synovial tissue of patients with RA compared to those of patients with OA(0.38±0.19 vs.12.40±1.66),and SLAMF8 levels were similarly elevated in collagen-induced arthritis model mice compared with those in the healthy mice(1.13±0.47 vs.9.05±2.52).Conclusions::This study established the unique advantages of synovial tissue for RA research and identified metabolic and cytokine signaling pathways as important for RA development.Thus,SLAMF8 may be a potential therapeutic target for RA.
基金Supported by National Natural Science Foundation of China(No.81570891No.81272981)+4 种基金the Beijing Municipal Administration of Hospitals'Ascent Plan(No.DFL20150201)Science&Technology Project of Beijing Municipal Science&Technology Commission(No.Z151100001615052)Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support(No.ZYLX201307)Beijing Natural Science Foundation(No.7151003)Advanced Health Care Professionals Development Project of Beijing Municipal Health Bureau(No.2014-2-003)
文摘AIM: To examine the genetic profile of primary uveal melanoma (UM) as compared to UM in immune escape.METHODS: Dendritic cells (DC) loaded with lysates of UM cells of high metastatic potential were used to stimulate CTLs(CTLs). When CTLs co-cultured with the UM cells, most UM cells could be eliminated. Survival UM cells grew slowly and were considered to be survival variants and examined by a microarray analysis. These differential genes were analyzed further with Venn Diagrams and functions related to immune escape. We additionally examined transcriptional changes of manually selected survival variants of UM cells and of clinical UM samples by quantitative real-time polymerase chain reaction (qRT-PCR), and analyzed the correlation of these expressions and patients’ survival.RESULTS: Gene expression analyses revealed a marked up-regulation of SLAMF7 and CCL22 and a significant down-regulation of KRT10, FXYD3 and ABCC2. The expression of these genes in the relapsed UM was significantly greater than those in primary UM. UM patients with overexpression of these genes had a shorter survival period as compared with those of their underexpression.CONCLUSION: Gene expression, in particular of SLAMF7, CCL22, KRT10, FXYD3 and ABCC2, differed between primary UM cells and survival variants of UM cells.
基金Shandong Provincial Laboratory Project,Grant/Award Number:SYS202202National Natural Science Foundation of China,Grant/Award Numbers:81972888,82272819+2 种基金Research Project of Jinan Microecological Biomedicine Shandong Laboratory,Grant/Award Numbers:JNL-202219B,JNL-202204A,JNL-2023017DJiangsu Provincial Key Research and Development Program,Grant/Award Number:BE2022840Nanjing University of Chinese Medicine,Grant/Award Number:2020YLXK007。
文摘Phagocytosis,a vital defense mechanism,involves the recognition and elimination of foreign substances by cells.Phagocytes,such as neutrophils and macrophages,rapidly respond to invaders;macrophages are especially important in later stages of the immune response.They detect“find me”signals to locate apoptotic cells and migrate toward them.Apoptotic cells then send“eat me”signals that are recognized by phagocytes via specific receptors.“Find me”and“eat me”signals can be strategically harnessed to modulate antitumor immunity in support of cancer therapy.These signals,such as calreticulin and phosphatidylserine,mediate potent pro-phagocytic effects,thereby promoting the engulfment of dying cells or their remnants by macrophages,neutrophils,and dendritic cells and inducing tumor cell death.This review summarizes the phagocytic“find me”and“eat me”signals,including their concepts,signaling mechanisms,involved ligands,and functions.Furthermore,we delineate the relationships between“find me”and“eat me”signaling molecules and tumors,especially the roles of these molecules in tumor initiation,progression,diagnosis,and patient prognosis.The interplay of these signals with tumor biology is elucidated,and specific approaches to modulate“find me”and“eat me”signals and enhance antitumor immunity are explored.Additionally,novel therapeutic strategies that combine“find me”and“eat me”signals to better bridge innate and adaptive immunity in the treatment of cancer patients are discussed.
文摘目的探讨2型糖尿病(T2DM)患者免疫细胞及其淋巴细胞激活分子家族成员(SLAMF)的表达情况。方法选取2018年1月至2019年12月该院收治的82例T2DM患者作为研究组,选取同期接受健康体检的82例健康人作为对照组。比较两组生化指标水平及免疫细胞表达情况及各免疫细胞SLAMF分子表达情况。结果研究组总胆固醇、LDL-C及HDL-C水平低于对照组,甘油三酯、空腹血糖水平高于对照组(P<0.05)。研究组CD4^(+)T细胞比例高于对照组,CD56^(+)总NK细胞表达低于对照组,且主要表现为CD56 dim NK细胞亚群比例降低(P<0.05),研究组外周血总T细胞比例高于对照组,CD4^(+)细胞低于对照组(P<0.05),CD4^(-)T细胞、NK细胞均较对照组明显降低(P<0.05);研究组总T细胞、CD4^(+)T细胞、CD4^(-)T细胞、NK细胞的SLAMF4、SLAMF5、SLAMF6分子平均荧光强度(MFI)表达水平无明显差异(P>0.05),研究组T细胞、CD4^(+)T细胞、CD4^(-)T细胞、NK细胞的SLAMF3分子MFI高于对照组(P>0.05),研究组NK细胞SLAMF7分子MFI低于对照组(P<0.05)。结论T2MD患者外周血单个核细胞免疫细胞比例异常,且外周血单个核细胞中的总T细胞、CD4^(+)T细胞、CD4^(-)T细胞及NK细胞的SLAMF3、SLAMF7分子表达升高。
