BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against...BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.展开更多
To investigate the effect of calcitonin gene related peptide (CGRP) on bone resorption mediated by interleukin 1β(IL 1β) in vitro , the osteoclasts isolated from the long bones of newborn SD rats were co cultured wi...To investigate the effect of calcitonin gene related peptide (CGRP) on bone resorption mediated by interleukin 1β(IL 1β) in vitro , the osteoclasts isolated from the long bones of newborn SD rats were co cultured with osteoblasts on ivory slices placed in 24 well plates . 24 h later, conditioned media containing CGRP and/or IL 1β were added to the wells respectively, and continued culturing for 48 h. After the cells were stripped off by ultrasonication, the ivory slices were stained in toludine blue. The number and the total area of resorption lacunae on each slice were measured by computer imaging analysis system. Our results showed that IL 1β significantly stimulated bone resorption, but CGRP inhibited the effect mediated by IL 1β in a dose dependent manner. It is suggested that CGRP may inhibit osteoclastic bone resorption through two ways: One is that CGRP functions directly on osteoclasts to block their activation; the other is that CGRP regulates the release of cytokines by osteoblasts and indirectly affects the function of osteoclasts.展开更多
AIM To investigate the effects of active vitamin D3 on autophagy and interleukin(IL)-1β expression in Salmonella-infected intestinal epithelial cells(IECs).METHODS Caco-2 cells, NOD2 siR NA-, Atg16L1 siR NA- or vitam...AIM To investigate the effects of active vitamin D3 on autophagy and interleukin(IL)-1β expression in Salmonella-infected intestinal epithelial cells(IECs).METHODS Caco-2 cells, NOD2 siR NA-, Atg16L1 siR NA- or vitamin D receptor(VDR) siR NA-transfected Caco-2 cells were pretreated with 1,25-dihydroxyvitamin D3(1,25D3), and then infected by wild-type S. typhimurium strain SL1344. The conversion of LC3-I to LC3-II was detected by Western blot analysis and LC3+ autophagosome was analyzed by immunofluorescence. Caco-2 cells or VDR si RNA-transfected cells were pretreated with 1,25D3, and then infected by SL1344. Membrane protein and total RNA were analyzed by Western blot and RT-PCR for VDR and Atg16L1 protein and m RNA expression, respectively. Atg16L1 si RNA-transfected Caco-2 cells were pretreated by 1,25D3 and then infected with SL1344. Total RNA was analyzed by RT-PCR for IL-1β mR NA expression.RESULTS The active form of vitamin D, 1,25D3, showed enhanced VDR-mediated Atg16L1 mR NA expression, membranous Atg16L1 protein expression leading to autophagic LC3 II proteins expression and LC3 punctae in Salmonella-infected Caco-2 cells which was counteracted by Atg16L1 and VDR si RNA, but Atg16L1 mediated suppression of IL-1β expression. Thus, active vitamin D may enhance autophagy but suppress inflammatory IL-1β expression in Salmonella-infected IECs.CONCLUSION Active vitamin D might enhance autophagic clearance of Salmonella infection, while modulation of inflammatory responses prevents the host from detrimental effects of overwhelming inflammation.展开更多
Background:Amyotrophic lateral sclerosis(ALS)is irreversible and fatal within 3-5 years,with limited options for treatment.It is imperative to develop a symptom-based treatment that may increase the survival of ALS pa...Background:Amyotrophic lateral sclerosis(ALS)is irreversible and fatal within 3-5 years,with limited options for treatment.It is imperative to develop a symptom-based treatment that may increase the survival of ALS patients and improve their quality of life.Inflammation status,especially elevated interleukin 1β(IL1β),has been reported to play a critical role in ALS progression.Our study determined that neutralizing circulating IL1βslows down the progression of ALS in an ALS mouse model.Methods:The ALS mouse model was developed by microinjection of lentivirus-carrying OPTN^(E478G)(optineurin,a mutation from ALS patients)into the intra-motor cortex of mice.Peripheral circulating IL1βwas neutralized by injecting anti-IL1βan-tibody into the tail vein.Enzyme-linked immunosorbent assay(ELISA)and real-time polymerase chain reaction(RT-PCR)were carried out to determine the protein and gene expression levels of IL1β.TUNEL assay was used to assess the neural cell death.Immunofluorescent staining of MAP2 and CASP3 was accomplished to evaluate neuronal cell apoptosis.Glial fibrillary acidic protein staining was performed to ana-lyze the number of astrocytes.Rotarod test,grip strength test,balance beam test,and footprint test were conducted to assess the locomotive function after anti-IL1βtreatment.Results:The model revealed that neuroinflammation contributes to ALS progression.ALS mice exhibited elevated neuroinflammation and IL1βsecretion.After anti-IL1βtreatment,ALS mice revealed decreased neural cell death and astrogliosis and gained improved muscle strength and motor ability.Conclusions:Blocking IL1βis a promising strategy to slow down the progression of ALS.展开更多
目的 :探讨肠缺血再灌注 ( I/R)损伤时肺损伤的机制和白介素 1β及其受体拮抗蛋白 ( IL 1ra)的作用。方法 :用大鼠肠系膜上动脉夹闭造成 I/R损伤模型 ,利用放射免疫分析法测定损伤前后和各处理组血液、肺组织灌洗液中 IL 1β和 IL 1ra...目的 :探讨肠缺血再灌注 ( I/R)损伤时肺损伤的机制和白介素 1β及其受体拮抗蛋白 ( IL 1ra)的作用。方法 :用大鼠肠系膜上动脉夹闭造成 I/R损伤模型 ,利用放射免疫分析法测定损伤前后和各处理组血液、肺组织灌洗液中 IL 1β和 IL 1ra水平。同时采用逆转录聚合酶链反应 ( RT PCR)法测定肺组织中 IL 1β和IL 1ra m RNA的表达含量。经光镜和电镜观察肺局部白细胞浸润及组织损伤情况。结果 :I/R损伤后 6小时血液中 IL 1β和 IL 1ra有所增加 ,损伤组 IL 1β比对照组明显增加 ,而 IL 1ra不明显 ;但损伤组和对照组IL 1ra伤后 6小时比伤前自身对照组均明显增加。损伤组肺灌洗液中 IL 1β明显增多 ,而 IL 1ra不明显。肺组织中 IL 1β的 m RNA在损伤后表达明显增加 ,而 IL 1ra表达没有明显变化。经非特异性磷脂酶 A2( PLA2 )阻断剂 (氯喹和三氟拉嗪 )、血小板活化因子受体阻断剂 SR2 7417A、环氧化酶抑制剂消炎痛以及抗氧化剂愈创木酸等处理后 ,血清、肺灌洗液和肺组织中上述指标有不同程度的改变。肺内白细胞的聚集和浸润明显减少。结论 :IL 1β和 IL 1ra可能参与肠 I/R介导的急性肺损伤 ,并且和局部 PLA2展开更多
AIM: To evaluate the effects of positive regulation of recombinant human interleukin 1 receptor antagonist (rhIL-1Ra) on hepatic tissue recovery in acute liver injury in mice induced by carbon tetrachloride (CCl 4 ). ...AIM: To evaluate the effects of positive regulation of recombinant human interleukin 1 receptor antagonist (rhIL-1Ra) on hepatic tissue recovery in acute liver injury in mice induced by carbon tetrachloride (CCl 4 ). METHODS: Acute liver damage was induced by injecting 8-wk-old mice with CCl 4 1 mL/kg (1:3 dilution in corn oil) intraperitoneally (ip). Survival after liver failure was assessed by injecting 8-wk-old mice with a lethal dose of CCl 4 2.6 mL/kg (1:1 dilution in corn oil) ip. Mice were subcutaneously injected with 1 mg/kg recombinant human IL-1Ra twice a day after CCl 4 treatment for 5 d. Serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) levels were determined with a commercial assay kit. Serum IL-1β, IL-1Ra levels were measured by enzyme-linked immunosorbent assay kit. Quantitative real-time polymerase chain reaction was used to determine liver IL-1β, IL-1Ra and IL-6 expression during CCl 4-induced acute liver injury. Liver sections were stained with hematoxylin-eosin. A histology-injury grading system was used to evaluate the degree of necrosis after acute liver injury. Proliferating cell nuclear antigen (PCNA) staining was used to evaluate the role of rhIL-1Ra in promoting hepatocyte proliferation. RESULTS: Quantitative analysis showed a higher level of IL-6 mRNA expression and reduced serum AST and ALT levels in the livers of the rhIL-1Ra-treated group at the early phase of CCl 4-induced acute liver injury. Histological examination indicated a decrease in centrilobular necrotic areas in mice treated with rhIL-1Ra, and a novel role of rhIL-1Ra in promoting hepatocyte proliferation was also supported by an increase of PCNA staining. All these results, accompanied by a strong survival benefit in rhIL-1Ra-treated vs PBS-treated groups, demonstrated that rhIL-1Ra administration ameliorated the histological damage and accelerated the regeneration and recovery process of the liver. CONCLUSION: rhIL-1Ra could be further developed as a novel therapeutic agent for the treatment of acute liver injury because of its ability to reduce hepatocellular damage and facilitate liver regeneration.展开更多
Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not complet...Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not completely understood.Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role.Here,we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain,highlighting the role of interleukins and,in particular,interleukin 1βas a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.展开更多
文摘BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.
文摘To investigate the effect of calcitonin gene related peptide (CGRP) on bone resorption mediated by interleukin 1β(IL 1β) in vitro , the osteoclasts isolated from the long bones of newborn SD rats were co cultured with osteoblasts on ivory slices placed in 24 well plates . 24 h later, conditioned media containing CGRP and/or IL 1β were added to the wells respectively, and continued culturing for 48 h. After the cells were stripped off by ultrasonication, the ivory slices were stained in toludine blue. The number and the total area of resorption lacunae on each slice were measured by computer imaging analysis system. Our results showed that IL 1β significantly stimulated bone resorption, but CGRP inhibited the effect mediated by IL 1β in a dose dependent manner. It is suggested that CGRP may inhibit osteoclastic bone resorption through two ways: One is that CGRP functions directly on osteoclasts to block their activation; the other is that CGRP regulates the release of cytokines by osteoblasts and indirectly affects the function of osteoclasts.
基金Supported by the Ministry of Science and Technology[MOST 103-2314-B-182-032(in part)]the Chang Gung Memorial Hospital,No.CMRPG8B1431,No.CMRPG8B1481 and No.CMRPG880443the Stem Cell Research Core Laboratory (grant CLRPG8B0052) for technical support
文摘AIM To investigate the effects of active vitamin D3 on autophagy and interleukin(IL)-1β expression in Salmonella-infected intestinal epithelial cells(IECs).METHODS Caco-2 cells, NOD2 siR NA-, Atg16L1 siR NA- or vitamin D receptor(VDR) siR NA-transfected Caco-2 cells were pretreated with 1,25-dihydroxyvitamin D3(1,25D3), and then infected by wild-type S. typhimurium strain SL1344. The conversion of LC3-I to LC3-II was detected by Western blot analysis and LC3+ autophagosome was analyzed by immunofluorescence. Caco-2 cells or VDR si RNA-transfected cells were pretreated with 1,25D3, and then infected by SL1344. Membrane protein and total RNA were analyzed by Western blot and RT-PCR for VDR and Atg16L1 protein and m RNA expression, respectively. Atg16L1 si RNA-transfected Caco-2 cells were pretreated by 1,25D3 and then infected with SL1344. Total RNA was analyzed by RT-PCR for IL-1β mR NA expression.RESULTS The active form of vitamin D, 1,25D3, showed enhanced VDR-mediated Atg16L1 mR NA expression, membranous Atg16L1 protein expression leading to autophagic LC3 II proteins expression and LC3 punctae in Salmonella-infected Caco-2 cells which was counteracted by Atg16L1 and VDR si RNA, but Atg16L1 mediated suppression of IL-1β expression. Thus, active vitamin D may enhance autophagy but suppress inflammatory IL-1β expression in Salmonella-infected IECs.CONCLUSION Active vitamin D might enhance autophagic clearance of Salmonella infection, while modulation of inflammatory responses prevents the host from detrimental effects of overwhelming inflammation.
基金National Natural Science Foundation of China(grant numbers:82172502 and 81974127).
文摘Background:Amyotrophic lateral sclerosis(ALS)is irreversible and fatal within 3-5 years,with limited options for treatment.It is imperative to develop a symptom-based treatment that may increase the survival of ALS patients and improve their quality of life.Inflammation status,especially elevated interleukin 1β(IL1β),has been reported to play a critical role in ALS progression.Our study determined that neutralizing circulating IL1βslows down the progression of ALS in an ALS mouse model.Methods:The ALS mouse model was developed by microinjection of lentivirus-carrying OPTN^(E478G)(optineurin,a mutation from ALS patients)into the intra-motor cortex of mice.Peripheral circulating IL1βwas neutralized by injecting anti-IL1βan-tibody into the tail vein.Enzyme-linked immunosorbent assay(ELISA)and real-time polymerase chain reaction(RT-PCR)were carried out to determine the protein and gene expression levels of IL1β.TUNEL assay was used to assess the neural cell death.Immunofluorescent staining of MAP2 and CASP3 was accomplished to evaluate neuronal cell apoptosis.Glial fibrillary acidic protein staining was performed to ana-lyze the number of astrocytes.Rotarod test,grip strength test,balance beam test,and footprint test were conducted to assess the locomotive function after anti-IL1βtreatment.Results:The model revealed that neuroinflammation contributes to ALS progression.ALS mice exhibited elevated neuroinflammation and IL1βsecretion.After anti-IL1βtreatment,ALS mice revealed decreased neural cell death and astrogliosis and gained improved muscle strength and motor ability.Conclusions:Blocking IL1βis a promising strategy to slow down the progression of ALS.
文摘目的 :探讨肠缺血再灌注 ( I/R)损伤时肺损伤的机制和白介素 1β及其受体拮抗蛋白 ( IL 1ra)的作用。方法 :用大鼠肠系膜上动脉夹闭造成 I/R损伤模型 ,利用放射免疫分析法测定损伤前后和各处理组血液、肺组织灌洗液中 IL 1β和 IL 1ra水平。同时采用逆转录聚合酶链反应 ( RT PCR)法测定肺组织中 IL 1β和IL 1ra m RNA的表达含量。经光镜和电镜观察肺局部白细胞浸润及组织损伤情况。结果 :I/R损伤后 6小时血液中 IL 1β和 IL 1ra有所增加 ,损伤组 IL 1β比对照组明显增加 ,而 IL 1ra不明显 ;但损伤组和对照组IL 1ra伤后 6小时比伤前自身对照组均明显增加。损伤组肺灌洗液中 IL 1β明显增多 ,而 IL 1ra不明显。肺组织中 IL 1β的 m RNA在损伤后表达明显增加 ,而 IL 1ra表达没有明显变化。经非特异性磷脂酶 A2( PLA2 )阻断剂 (氯喹和三氟拉嗪 )、血小板活化因子受体阻断剂 SR2 7417A、环氧化酶抑制剂消炎痛以及抗氧化剂愈创木酸等处理后 ,血清、肺灌洗液和肺组织中上述指标有不同程度的改变。肺内白细胞的聚集和浸润明显减少。结论 :IL 1β和 IL 1ra可能参与肠 I/R介导的急性肺损伤 ,并且和局部 PLA2
基金Supported by The Chinese Human Liver Proteome Project, No. 2004BA711A19-08National 863 Project, No.2007AA02Z100
文摘AIM: To evaluate the effects of positive regulation of recombinant human interleukin 1 receptor antagonist (rhIL-1Ra) on hepatic tissue recovery in acute liver injury in mice induced by carbon tetrachloride (CCl 4 ). METHODS: Acute liver damage was induced by injecting 8-wk-old mice with CCl 4 1 mL/kg (1:3 dilution in corn oil) intraperitoneally (ip). Survival after liver failure was assessed by injecting 8-wk-old mice with a lethal dose of CCl 4 2.6 mL/kg (1:1 dilution in corn oil) ip. Mice were subcutaneously injected with 1 mg/kg recombinant human IL-1Ra twice a day after CCl 4 treatment for 5 d. Serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) levels were determined with a commercial assay kit. Serum IL-1β, IL-1Ra levels were measured by enzyme-linked immunosorbent assay kit. Quantitative real-time polymerase chain reaction was used to determine liver IL-1β, IL-1Ra and IL-6 expression during CCl 4-induced acute liver injury. Liver sections were stained with hematoxylin-eosin. A histology-injury grading system was used to evaluate the degree of necrosis after acute liver injury. Proliferating cell nuclear antigen (PCNA) staining was used to evaluate the role of rhIL-1Ra in promoting hepatocyte proliferation. RESULTS: Quantitative analysis showed a higher level of IL-6 mRNA expression and reduced serum AST and ALT levels in the livers of the rhIL-1Ra-treated group at the early phase of CCl 4-induced acute liver injury. Histological examination indicated a decrease in centrilobular necrotic areas in mice treated with rhIL-1Ra, and a novel role of rhIL-1Ra in promoting hepatocyte proliferation was also supported by an increase of PCNA staining. All these results, accompanied by a strong survival benefit in rhIL-1Ra-treated vs PBS-treated groups, demonstrated that rhIL-1Ra administration ameliorated the histological damage and accelerated the regeneration and recovery process of the liver. CONCLUSION: rhIL-1Ra could be further developed as a novel therapeutic agent for the treatment of acute liver injury because of its ability to reduce hepatocellular damage and facilitate liver regeneration.
基金supported by UniversitàCattolica(D1 intramural funds to RP)Italian Ministry of University and Research(PRIN 2022ZYLB7B,P2022YW7BP funds to CG).
文摘Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not completely understood.Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role.Here,we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain,highlighting the role of interleukins and,in particular,interleukin 1βas a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.
