Radiation is an important modality in cancer treatment, and eighty percent of cancer patients need radiotherapy at some point during their clinical management. However, radiation-induced damage to normal tissues restr...Radiation is an important modality in cancer treatment, and eighty percent of cancer patients need radiotherapy at some point during their clinical management. However, radiation-induced damage to normal tissues restricts the therapeutic doses of radiation that can be delivered to tumours and thereby limits the effectiveness of the treatment. The use of radioprotectors represents an obvious strategy to obtain better tumour control using a higher dose in radiotherapy. However, most of the synthetic radioprotective compounds studied have shown inadequate clinical efficacy owing to their inherent toxicity and high cost. Hence, the development of radioprotective agents with lower toxicity and an extended window of protection has attracted a great deal of attention, and the identification of alternative agents that are less toxic and highly effective is an absolute necessity. Recent studies have shown that alpha-2-macroglobulin（α2M） possesses radioprotective effects. α2M is a tetrameric, disulfide-rich plasma glycoprotein that functions as a nonselective inhibitor of different types of non-specific proteases and as a carrier of cytokines, growth factors, and hormones. α2M induces protein factors whose interplay underlies radioprotection, which supports the idea that α2M is the central effector of natural radioprotection in the rat. Pretreatment with α2M has also induced a significant reduction of irradiation-induced DNA damage and the complete restoration of liver and body weight. Mihailovi？ et al. concluded that the radioprotection provided by α2M was in part mediated through cytoprotection of new blood cells produced in the bone marrow; these authors also indicated that an important aspect of the radioprotective effect of amifostine was the result of the induction of the endogenous cytoprotective capability of α2M. The radioprotective effects of α2M are possibly due to antioxidant, antifibrosis, and anti-inflammatory functions, as well as the maintenance of homeostasis, and enhancement of the DNA repair and cell recovery processes. This review is the first to summarise the observations and elucidate the possible mechanisms responsible for the beneficial effects of α2M. The lacunae in the existing knowledge and directions for future research are also addressed.展开更多
α 2-macroglobulin (α2M) could stimulate the regeneration of thymic and bone marrow cells in rats received γ-irradiation, but there was very few reports concerning its mechanism. Wistar rats were irradiated by 16Co ...α 2-macroglobulin (α2M) could stimulate the regeneration of thymic and bone marrow cells in rats received γ-irradiation, but there was very few reports concerning its mechanism. Wistar rats were irradiated by 16Co at 7 Gy, 8.5 Gy, 15 Gy total body doses. Blood plasma and some tissue’s extracts were collected α 2M level. a M activity and cathepsin D activity, malonaldehyde level were determined by radioimmunoassay, modified Schidlow’s method, Barrett’s method and Ohkawa’s method respectively.展开更多
Administered in vivo, covalent receptor-recognized α2-macroglobulin (α2M*)-antigen complexes enhance humoral and cell-mediated immunity. We hypothesized that in vivo α2M*-encapsulation could be promoted in the sett...Administered in vivo, covalent receptor-recognized α2-macroglobulin (α2M*)-antigen complexes enhance humoral and cell-mediated immunity. We hypothesized that in vivo α2M*-encapsulation could be promoted in the setting of vaccines that co-deliver α2M* with unbound antigen, thereby eliminating the need to prepare complexes in vitro. Mice immunized intradermally with co-delivered α2M* and OVA demonstrated antigen-specific immune responses, including anti-tumor responses, similar to those elicited by conjugated α2M*-OVA complexes. Enhanced immunity appears to result from in vivo α2M*-encapsulation of antigen. This finding represents a significant advancement in the development of α2M* as an antigen delivery vehicle capable of enhancing the presentation of subunit vaccines.展开更多
In this study, we reported the effect of the ATP binding site competitive inhibitor Torin1 on activated α2-macroglobulin (α2M*)-induced cell proliferation and activation of mTORC1 and mTORC2 signaling in prostate ca...In this study, we reported the effect of the ATP binding site competitive inhibitor Torin1 on activated α2-macroglobulin (α2M*)-induced cell proliferation and activation of mTORC1 and mTORC2 signaling in prostate cancer cells. Torin1 significantly inhibited α2M*-induced cellproliferation as measured by protein and DNA synthesis. Translational activity, a major cellular response in malignant cells,is coordinately regulated by the mTORC1-S6-kinaseand mTORC1-4EBP1 axes. Torin1 significantly inhibited α2M*- and insulin-induced activation of mTORC1 as determined by phosphorylation of S6-kinaseat Thr389 and 4EBP1 at Thr37/46 compared to untreated cells employing Raptor immunoprecipitates. Torin1 also significantly inhibited α2M*- and insulin-induced upregulation of p-AktT308 and p-AktS473 in prostate cancer cells. The effect was comparable to that of insulin employed as a positive control. Finally, Torin1 inhibited α2M*- and insulin-induced activation of mTORC2 kinase assayas measured by phosphorylation of Akt at Ser473 inRictor immunoprecipitates of prostate cancer cells.展开更多
Introduction:Dexamethasone(Dex)caused impaired osteoblast differentiation and oxidative stress(OS)in bone marrow mesenchymal stem cells(BMSCs).This work sought to elucidate the precise molecular pathway through which ...Introduction:Dexamethasone(Dex)caused impaired osteoblast differentiation and oxidative stress(OS)in bone marrow mesenchymal stem cells(BMSCs).This work sought to elucidate the precise molecular pathway through which Dex influences osteogenic differentiation(OD)and OS in BMSCs.Methods:The expression of Runt-related transcription factor 1(RUNX1)and alpha-2 macroglobulin(A2M)was assessed in Dex-treated BMSCs using qRTPCR and Western Blot.Following the functional rescue experiments,cell proliferation was determined by MTT assay,reactive oxygen species(ROS)expression by DCFH-DA fluorescent probe,lactate dehydrogenase(LDH),superoxide dismutase(SOD),catalase(CAT),and glutathione peroxidase(Gpx)expression by kits,OD by alkaline phosphatase(ALP)staining and activity quantification,and the expression of OD-related proteins RUNX2,collagen type 1 alpha 1(COL1A1),and osteocalcin(OCN)by qRT-PCR and Western Blot.The binding of RUNX1 to A2M was initially analyzed through Jaspar website and subsequently verified by dual-luciferase reporter and ChIP assays.Results:Dextreated BMSCs had low RUNX1 and A2M expression.Dex treatment apparently elevated ROS and LDH levels,diminished cell proliferation rate and SOD,CAT,and Gpx expression,lightened intensity of ALP staining,and declined calcified nodules,ALP activity,and RUNX2,COL1A1,and OCN expression in BMSCs,which was counterweighed by RUNX1 or A2M overexpression.RUNX1 positively targeted A2M.A2M knockdown effectively nullified the ameliorative effects of RUNX1 overexpression on impaired OD and OS injury in Dex-induced BMSCs.Conclusions:Overexpression of RUNX1 attenuated Dex-induced impaired OD and OS injury in BMSCs by promoting A2M transcription.展开更多
目的:探讨痰液α2-巨球蛋白(A2M)动态表达对胸部肿瘤放射性肺损伤(RILI)的早期预测作用。方法:采用两阶段混合研究设计:横断面研究纳入145例胸部恶性肿瘤患者(对照组40例、轻度RILI组40例、重度RILI组36例、肺纤维化组29例),通过ELISA...目的:探讨痰液α2-巨球蛋白(A2M)动态表达对胸部肿瘤放射性肺损伤(RILI)的早期预测作用。方法:采用两阶段混合研究设计:横断面研究纳入145例胸部恶性肿瘤患者(对照组40例、轻度RILI组40例、重度RILI组36例、肺纤维化组29例),通过ELISA检测痰液及血浆A2M表达水平;前瞻性队列研究入组51例接受胸部放疗的恶性肿瘤患者,于放疗前、放疗期间(1~6周)及放疗后(1月、3月)动态采集痰液标本,根据放射性肺损伤程度分为轻度RILI组(1~2级,n=40)与重度RILI组(3~4级,n=11),构建COX风险比例模型分析A2M动态变化与RILI进展的关联。结果:横断面研究中,重度RILI组痰液A2M浓度显著高于对照组(8.113±0.746 vs 4.449±0.587μg/mL,P<0.001),且痰液A2M水平显著高于血浆(6.263±1.424 vs 2.959±0.931μg/mL,r=0.555,P<0.001);前瞻性队列显示,放疗5周时重度组痰A2M显著升高(9.074±2.201 vs 7.190±1.710μg/mL,P=0.003),其浓度变化量(ΔA2M)与RILI严重程度呈剂量依赖性(4.486±1.532 vs 2.622±1.127,P<0.001);COX回归提示放疗5周时痰A2M浓度是重度RILI的独立预测因子(HR=2.317,95%CI:0.568-9.449),ROC曲线显示其预测敏感性72.7%、特异性77.5%(AUC=0.804)。结论:痰液A2M动态监测能有效预警放射性肺损伤进程,其中放疗第5周可作为关键监测窗口期。展开更多
目的探讨CD109在基底细胞样乳腺癌(basal-like breast cancer,BLBC)中的表达及意义。方法采用免疫组织化学(S-P法)检测86例基底细胞样乳腺癌和90例浸润性乳腺癌中CD109的表达情况。结果 CD109在基底细胞样乳腺癌和浸润性乳腺癌中的阳性...目的探讨CD109在基底细胞样乳腺癌(basal-like breast cancer,BLBC)中的表达及意义。方法采用免疫组织化学(S-P法)检测86例基底细胞样乳腺癌和90例浸润性乳腺癌中CD109的表达情况。结果 CD109在基底细胞样乳腺癌和浸润性乳腺癌中的阳性表达率分别为61.6%、8.9%,两组差异具有统计学意义(P<0.01);CD109在基底细胞样乳腺癌中的高表达与患者年龄、肿瘤大小、肿瘤的组织学分级和淋巴结累及情况均无关。CD109表达阳性乳腺癌中组织学Ⅲ级比例明显高于阴性组,Spearman等级相关分析显示CD109表达与肿瘤组织学分级呈正相关(r=0.365,P<0.01)。结论 CD109是基底细胞样乳腺癌新的特异性标志物,CD109的表达可能与肿瘤的侵袭性有关;鉴于CD109是一种细胞表面蛋白,其有可能成为治疗乳腺癌的一个潜在分子靶点。展开更多
基金supported by grant of the Science and Technology Planning Project of Guangdong Province (2010B060900052 and 2009B030801186)the Fundamental Research Funds for the Central Universities (the Young Teacher Training Project of Sun Yat-sen University 09ykpy12)the Medical Scientific Research Project of Zhuhai City (2012003)
文摘Radiation is an important modality in cancer treatment, and eighty percent of cancer patients need radiotherapy at some point during their clinical management. However, radiation-induced damage to normal tissues restricts the therapeutic doses of radiation that can be delivered to tumours and thereby limits the effectiveness of the treatment. The use of radioprotectors represents an obvious strategy to obtain better tumour control using a higher dose in radiotherapy. However, most of the synthetic radioprotective compounds studied have shown inadequate clinical efficacy owing to their inherent toxicity and high cost. Hence, the development of radioprotective agents with lower toxicity and an extended window of protection has attracted a great deal of attention, and the identification of alternative agents that are less toxic and highly effective is an absolute necessity. Recent studies have shown that alpha-2-macroglobulin（α2M） possesses radioprotective effects. α2M is a tetrameric, disulfide-rich plasma glycoprotein that functions as a nonselective inhibitor of different types of non-specific proteases and as a carrier of cytokines, growth factors, and hormones. α2M induces protein factors whose interplay underlies radioprotection, which supports the idea that α2M is the central effector of natural radioprotection in the rat. Pretreatment with α2M has also induced a significant reduction of irradiation-induced DNA damage and the complete restoration of liver and body weight. Mihailovi？ et al. concluded that the radioprotection provided by α2M was in part mediated through cytoprotection of new blood cells produced in the bone marrow; these authors also indicated that an important aspect of the radioprotective effect of amifostine was the result of the induction of the endogenous cytoprotective capability of α2M. The radioprotective effects of α2M are possibly due to antioxidant, antifibrosis, and anti-inflammatory functions, as well as the maintenance of homeostasis, and enhancement of the DNA repair and cell recovery processes. This review is the first to summarise the observations and elucidate the possible mechanisms responsible for the beneficial effects of α2M. The lacunae in the existing knowledge and directions for future research are also addressed.
基金The Project Supported by National Natural Science Foundation of China
文摘α 2-macroglobulin (α2M) could stimulate the regeneration of thymic and bone marrow cells in rats received γ-irradiation, but there was very few reports concerning its mechanism. Wistar rats were irradiated by 16Co at 7 Gy, 8.5 Gy, 15 Gy total body doses. Blood plasma and some tissue’s extracts were collected α 2M level. a M activity and cathepsin D activity, malonaldehyde level were determined by radioimmunoassay, modified Schidlow’s method, Barrett’s method and Ohkawa’s method respectively.
文摘Administered in vivo, covalent receptor-recognized α2-macroglobulin (α2M*)-antigen complexes enhance humoral and cell-mediated immunity. We hypothesized that in vivo α2M*-encapsulation could be promoted in the setting of vaccines that co-deliver α2M* with unbound antigen, thereby eliminating the need to prepare complexes in vitro. Mice immunized intradermally with co-delivered α2M* and OVA demonstrated antigen-specific immune responses, including anti-tumor responses, similar to those elicited by conjugated α2M*-OVA complexes. Enhanced immunity appears to result from in vivo α2M*-encapsulation of antigen. This finding represents a significant advancement in the development of α2M* as an antigen delivery vehicle capable of enhancing the presentation of subunit vaccines.
文摘In this study, we reported the effect of the ATP binding site competitive inhibitor Torin1 on activated α2-macroglobulin (α2M*)-induced cell proliferation and activation of mTORC1 and mTORC2 signaling in prostate cancer cells. Torin1 significantly inhibited α2M*-induced cellproliferation as measured by protein and DNA synthesis. Translational activity, a major cellular response in malignant cells,is coordinately regulated by the mTORC1-S6-kinaseand mTORC1-4EBP1 axes. Torin1 significantly inhibited α2M*- and insulin-induced activation of mTORC1 as determined by phosphorylation of S6-kinaseat Thr389 and 4EBP1 at Thr37/46 compared to untreated cells employing Raptor immunoprecipitates. Torin1 also significantly inhibited α2M*- and insulin-induced upregulation of p-AktT308 and p-AktS473 in prostate cancer cells. The effect was comparable to that of insulin employed as a positive control. Finally, Torin1 inhibited α2M*- and insulin-induced activation of mTORC2 kinase assayas measured by phosphorylation of Akt at Ser473 inRictor immunoprecipitates of prostate cancer cells.
基金the Natural Science Foundation of Fujian Province(No.2023J011558)the Innovation of Science and Technology of Fujian Province(No.2021Y9098)Fujian Provincial Finance Project(No.BPB-2022FSH).
文摘Introduction:Dexamethasone(Dex)caused impaired osteoblast differentiation and oxidative stress(OS)in bone marrow mesenchymal stem cells(BMSCs).This work sought to elucidate the precise molecular pathway through which Dex influences osteogenic differentiation(OD)and OS in BMSCs.Methods:The expression of Runt-related transcription factor 1(RUNX1)and alpha-2 macroglobulin(A2M)was assessed in Dex-treated BMSCs using qRTPCR and Western Blot.Following the functional rescue experiments,cell proliferation was determined by MTT assay,reactive oxygen species(ROS)expression by DCFH-DA fluorescent probe,lactate dehydrogenase(LDH),superoxide dismutase(SOD),catalase(CAT),and glutathione peroxidase(Gpx)expression by kits,OD by alkaline phosphatase(ALP)staining and activity quantification,and the expression of OD-related proteins RUNX2,collagen type 1 alpha 1(COL1A1),and osteocalcin(OCN)by qRT-PCR and Western Blot.The binding of RUNX1 to A2M was initially analyzed through Jaspar website and subsequently verified by dual-luciferase reporter and ChIP assays.Results:Dextreated BMSCs had low RUNX1 and A2M expression.Dex treatment apparently elevated ROS and LDH levels,diminished cell proliferation rate and SOD,CAT,and Gpx expression,lightened intensity of ALP staining,and declined calcified nodules,ALP activity,and RUNX2,COL1A1,and OCN expression in BMSCs,which was counterweighed by RUNX1 or A2M overexpression.RUNX1 positively targeted A2M.A2M knockdown effectively nullified the ameliorative effects of RUNX1 overexpression on impaired OD and OS injury in Dex-induced BMSCs.Conclusions:Overexpression of RUNX1 attenuated Dex-induced impaired OD and OS injury in BMSCs by promoting A2M transcription.
文摘目的:探讨痰液α2-巨球蛋白(A2M)动态表达对胸部肿瘤放射性肺损伤(RILI)的早期预测作用。方法:采用两阶段混合研究设计:横断面研究纳入145例胸部恶性肿瘤患者(对照组40例、轻度RILI组40例、重度RILI组36例、肺纤维化组29例),通过ELISA检测痰液及血浆A2M表达水平;前瞻性队列研究入组51例接受胸部放疗的恶性肿瘤患者,于放疗前、放疗期间(1~6周)及放疗后(1月、3月)动态采集痰液标本,根据放射性肺损伤程度分为轻度RILI组(1~2级,n=40)与重度RILI组(3~4级,n=11),构建COX风险比例模型分析A2M动态变化与RILI进展的关联。结果:横断面研究中,重度RILI组痰液A2M浓度显著高于对照组(8.113±0.746 vs 4.449±0.587μg/mL,P<0.001),且痰液A2M水平显著高于血浆(6.263±1.424 vs 2.959±0.931μg/mL,r=0.555,P<0.001);前瞻性队列显示,放疗5周时重度组痰A2M显著升高(9.074±2.201 vs 7.190±1.710μg/mL,P=0.003),其浓度变化量(ΔA2M)与RILI严重程度呈剂量依赖性(4.486±1.532 vs 2.622±1.127,P<0.001);COX回归提示放疗5周时痰A2M浓度是重度RILI的独立预测因子(HR=2.317,95%CI:0.568-9.449),ROC曲线显示其预测敏感性72.7%、特异性77.5%(AUC=0.804)。结论:痰液A2M动态监测能有效预警放射性肺损伤进程,其中放疗第5周可作为关键监测窗口期。
文摘目的探讨CD109在基底细胞样乳腺癌(basal-like breast cancer,BLBC)中的表达及意义。方法采用免疫组织化学(S-P法)检测86例基底细胞样乳腺癌和90例浸润性乳腺癌中CD109的表达情况。结果 CD109在基底细胞样乳腺癌和浸润性乳腺癌中的阳性表达率分别为61.6%、8.9%,两组差异具有统计学意义(P<0.01);CD109在基底细胞样乳腺癌中的高表达与患者年龄、肿瘤大小、肿瘤的组织学分级和淋巴结累及情况均无关。CD109表达阳性乳腺癌中组织学Ⅲ级比例明显高于阴性组,Spearman等级相关分析显示CD109表达与肿瘤组织学分级呈正相关(r=0.365,P<0.01)。结论 CD109是基底细胞样乳腺癌新的特异性标志物,CD109的表达可能与肿瘤的侵袭性有关;鉴于CD109是一种细胞表面蛋白,其有可能成为治疗乳腺癌的一个潜在分子靶点。
