Pub Date : 2020-04-01DOI: 10.1096/fasebj.2020.34.s1.09298
Dong-Hun Choi, Ki-chun Kwon, Dong-Ju Hwang, Hyun-Seob Um, Jung‐hoon Koo, Eung-Jun Kim, D. Yeom, Joon-Yong Cho
Brain iron increases with age and brain iron dyshomeostasis is proving increasingly likely to be involved in the pathology of Alzheimer’s disease (AD) and Parkinson’s disease (PD), possibly via promoting oxidative damage. There is therefore an urgent need to research into improving role iron play in AD. Sustained exercise may be ways to slow the rate of overload of iron, by perhaps alleviating oxidative stress due to the Fenton reaction. Yet, the exact mechanisms of the effects of exercise on iron toxicity are not well understood. Here, we explored whether treadmill exercise impacts the AD‐related mechanism(s) of brain iron status in vivo, using APP‐C105 AD‐model mice. We observed iron‐induced disruptions of amyloid precursor protein (APP) processing, neuronal apoptotic signaling, oxidative stress, and cognitive impairment in APP‐C105 AD‐model mice. Further, brain iron dyshomeostasis associated with Aβ‐induced neuronal cell death possibly via APP misprocessing, and oxidative stress and cognitive decline was blocked by treadmill exercise, suggesting effect led to mitigated Aβ‐induced neuronal cell death and cognitive decline by promoting non‐amyloidogenic pathway possibly via enhanced furin, concomitant with inhibiting oxidative stress possibly via down‐regulating brain iron dyshomeostasis. Together, we show evidences to suggest that treadmill exercise may be ways to inhibit Aβ‐induced neuronal cell death by up‐regulating non‐amyloidogenic pathway through enhanced furin, concomitant with down‐regulating iron‐mediated oxidative stress.
脑铁会随着年龄的增长而增加，事实证明，脑铁失衡越来越有可能与阿尔茨海默病（AD）和帕金森病（PD）的病理有关，可能是通过促进氧化损伤造成的。因此，迫切需要研究改善铁在阿尔茨海默病中的作用。持续运动或许是减缓铁超载速度的一种方法，因为它可以减轻芬顿反应引起的氧化应激。然而，运动对铁毒性影响的确切机制尚不十分清楚。在此，我们利用 APP-C105 AD 模型小鼠，探讨了跑步机运动是否会影响体内脑铁状态的 AD 相关机制。在 APP-C105 AD 模型小鼠中，我们观察到铁诱导的淀粉样前体蛋白（APP）加工、神经元凋亡信号传导、氧化应激和认知障碍的破坏。此外，跑步机运动阻断了与Aβ诱导的神经元细胞死亡（可能是通过APP错误处理）、氧化应激和认知功能下降相关的脑铁失衡，这表明跑步机运动通过促进非淀粉样蛋白生成途径（可能是通过增强嘌呤）缓解了Aβ诱导的神经元细胞死亡和认知功能下降，同时抑制了氧化应激（可能是通过下调脑铁失衡）。综上所述，我们有证据表明，跑步机运动可通过增强嘌呤上调非淀粉样蛋白生成途径，同时下调铁介导的氧化应激，从而抑制Aβ诱导的神经元细胞死亡。
{"title":"Treadmill exercise alleviates brain iron dyshomeostasis accelerating neuronal amyloid‐β production, neuronal cell death and cognitive impairment in transgenic mice model of Alzheimer’s disease","authors":"Dong-Hun Choi, Ki-chun Kwon, Dong-Ju Hwang, Hyun-Seob Um, Jung‐hoon Koo, Eung-Jun Kim, D. Yeom, Joon-Yong Cho","doi":"10.1096/fasebj.2020.34.s1.09298","DOIUrl":"https://doi.org/10.1096/fasebj.2020.34.s1.09298","url":null,"abstract":"Brain iron increases with age and brain iron dyshomeostasis is proving increasingly likely to be involved in the pathology of Alzheimer’s disease (AD) and Parkinson’s disease (PD), possibly via promoting oxidative damage. There is therefore an urgent need to research into improving role iron play in AD. Sustained exercise may be ways to slow the rate of overload of iron, by perhaps alleviating oxidative stress due to the Fenton reaction. Yet, the exact mechanisms of the effects of exercise on iron toxicity are not well understood. Here, we explored whether treadmill exercise impacts the AD‐related mechanism(s) of brain iron status in vivo, using APP‐C105 AD‐model mice. We observed iron‐induced disruptions of amyloid precursor protein (APP) processing, neuronal apoptotic signaling, oxidative stress, and cognitive impairment in APP‐C105 AD‐model mice. Further, brain iron dyshomeostasis associated with Aβ‐induced neuronal cell death possibly via APP misprocessing, and oxidative stress and cognitive decline was blocked by treadmill exercise, suggesting effect led to mitigated Aβ‐induced neuronal cell death and cognitive decline by promoting non‐amyloidogenic pathway possibly via enhanced furin, concomitant with inhibiting oxidative stress possibly via down‐regulating brain iron dyshomeostasis. Together, we show evidences to suggest that treadmill exercise may be ways to inhibit Aβ‐induced neuronal cell death by up‐regulating non‐amyloidogenic pathway through enhanced furin, concomitant with down‐regulating iron‐mediated oxidative stress.","PeriodicalId":22447,"journal":{"name":"The FASEB Journal","volume":" 31","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141219117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-04-01DOI: 10.1096/fasebj.2020.34.s1.09899
Nicholas C. Bauer, Anli Yang, Xin Wang, Yunli Zhou, A. Klibanski, R. Soberman
The ability of the long noncoding RNA MEG3 to suppress cell proliferation led to its recognition as a tumor suppressor. MEG3 has previously been shown to bind to p53 in vitro, which led us to hypothesize that MEG3 functions by disrupting the interaction of p53 and its E3 ubiquitin ligase Mdm2. To test this hypothesis in vivo, we built a cross‐nearest neighbor/Monte Carlo analytical method based on two color direct stochastic optical reconstruction microscopy (dSTORM), a single‐molecule localization microscopy (SMLM) technique. Our data support the interaction of MEG3 and p53. Surprisingly, this association had no effect on the binding of p53 and Mdm2, distinct from the most commonly proposed model for the mechanism of MEG3 action. Additionally, our mathematical approach to analyzing SMLM data has general applicability to assessing molecular interactions in a native cellular context.
{"title":"The interaction between p53 and Mdm2 is independent of MEG3–p53 association","authors":"Nicholas C. Bauer, Anli Yang, Xin Wang, Yunli Zhou, A. Klibanski, R. Soberman","doi":"10.1096/fasebj.2020.34.s1.09899","DOIUrl":"https://doi.org/10.1096/fasebj.2020.34.s1.09899","url":null,"abstract":"The ability of the long noncoding RNA MEG3 to suppress cell proliferation led to its recognition as a tumor suppressor. MEG3 has previously been shown to bind to p53 in vitro, which led us to hypothesize that MEG3 functions by disrupting the interaction of p53 and its E3 ubiquitin ligase Mdm2. To test this hypothesis in vivo, we built a cross‐nearest neighbor/Monte Carlo analytical method based on two color direct stochastic optical reconstruction microscopy (dSTORM), a single‐molecule localization microscopy (SMLM) technique. Our data support the interaction of MEG3 and p53. Surprisingly, this association had no effect on the binding of p53 and Mdm2, distinct from the most commonly proposed model for the mechanism of MEG3 action. Additionally, our mathematical approach to analyzing SMLM data has general applicability to assessing molecular interactions in a native cellular context.","PeriodicalId":22447,"journal":{"name":"The FASEB Journal","volume":" 25","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141219236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-04-01DOI: 10.1096/fasebj.2020.34.s1.02011
Arash Y. Tehrani, N. Fameli, Zoe White, Mitra Esfandiarei, Casey van Breemen, Pascal Bernatchez
Endothelial function is strongly associated with vascular health and homeostasis. However, therapeutically relevant approaches capable of stimulating the protective properties of the endothelium remain elusive.
内皮功能与血管健康和平衡密切相关。然而，能够刺激内皮保护特性的相关治疗方法仍未出现。
{"title":"Pleiotropic Activation of Endothelial Function by Angiotensin II Receptor Blockers is Crucial to Their Protective Anti‐vascular Remodeling Effects","authors":"Arash Y. Tehrani, N. Fameli, Zoe White, Mitra Esfandiarei, Casey van Breemen, Pascal Bernatchez","doi":"10.1096/fasebj.2020.34.s1.02011","DOIUrl":"https://doi.org/10.1096/fasebj.2020.34.s1.02011","url":null,"abstract":"Endothelial function is strongly associated with vascular health and homeostasis. However, therapeutically relevant approaches capable of stimulating the protective properties of the endothelium remain elusive.","PeriodicalId":22447,"journal":{"name":"The FASEB Journal","volume":" 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141218520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-04-01DOI: 10.1096/fasebj.2020.34.s1.00112
Mary P. Nivison, Allegra VanderWilde, Pravita Balijepalli, Kathryn E. Meier
Dietary and nutritional factors are considered critical modulating factors in prostate cancer development. Epidemiological data have suggested to the idea that dietary consumption of lycopene, found in tomatoes, may prevent prostate cancer. This study examined the mechanism by which lycopene interacts with prostate cancer cells, with the goal of discovering less toxic treatment and prevention options. The hypothesis that was addressed was that lycopene interferes with growth factor‐mediated signal transduction in prostate cancer cells. The effects of lycopene on PC‐3, a human prostate cancer cell line, were analyzed using proliferation assays, immunoblot analysis, and confocal microscopy. The growth factors used were lysophosphatidic acid (LPA) and epidermal growth factor (EGF). Lycopene (10 μM) inhibited LPA and EGF‐induced proliferation of PC‐3 cells, confirming previous unpublished results. Lycopene also inhibited activation of Akt in response to LPA and EGF as assessed by immunoblotting. Confocal immunofluorescence microscopy showed that the decrease in activated Akt was most prominent in the cell nucleus. These results confirm the ability of lycopene to inhibit growth factor response in human prostate cancer cells, and suggest new directions for future studies.
{"title":"Effects of Lycopene on Growth Factor Response in Prostate Cancer Cells","authors":"Mary P. Nivison, Allegra VanderWilde, Pravita Balijepalli, Kathryn E. Meier","doi":"10.1096/fasebj.2020.34.s1.00112","DOIUrl":"https://doi.org/10.1096/fasebj.2020.34.s1.00112","url":null,"abstract":"Dietary and nutritional factors are considered critical modulating factors in prostate cancer development. Epidemiological data have suggested to the idea that dietary consumption of lycopene, found in tomatoes, may prevent prostate cancer. This study examined the mechanism by which lycopene interacts with prostate cancer cells, with the goal of discovering less toxic treatment and prevention options. The hypothesis that was addressed was that lycopene interferes with growth factor‐mediated signal transduction in prostate cancer cells. The effects of lycopene on PC‐3, a human prostate cancer cell line, were analyzed using proliferation assays, immunoblot analysis, and confocal microscopy. The growth factors used were lysophosphatidic acid (LPA) and epidermal growth factor (EGF). Lycopene (10 μM) inhibited LPA and EGF‐induced proliferation of PC‐3 cells, confirming previous unpublished results. Lycopene also inhibited activation of Akt in response to LPA and EGF as assessed by immunoblotting. Confocal immunofluorescence microscopy showed that the decrease in activated Akt was most prominent in the cell nucleus. These results confirm the ability of lycopene to inhibit growth factor response in human prostate cancer cells, and suggest new directions for future studies.","PeriodicalId":22447,"journal":{"name":"The FASEB Journal","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89112038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The entire FASEB community is saddened by the death of The FASEB Journal former Editor-in-Chief, on July 10, 2019. The FASEB Journal’s current Editor-in-Chief Thoru Pederson said: “In all ways of the mind, Gerry was a true renaissance individual. His sterling qualities as a physician, scientist, and mentor, and as a gifted author, were widely known. His leadership as the Editor-in-Chief of The FASEB Journal was an outstanding contribution in his later career, and his editorials on those pages were both eloquent and elegant. We shall not see the likes of him again anytime soon.” Amore comprehensive memoir of Dr. Weissmannwill appear in the October 2019 issue of the journal.
{"title":"In Memoriam: Gerald Weissmann","authors":"T. Pederson","doi":"10.1096/fj.190901ufm","DOIUrl":"https://doi.org/10.1096/fj.190901ufm","url":null,"abstract":"The entire FASEB community is saddened by the death of The FASEB Journal former Editor-in-Chief, on July 10, 2019. The FASEB Journal’s current Editor-in-Chief Thoru Pederson said: “In all ways of the mind, Gerry was a true renaissance individual. His sterling qualities as a physician, scientist, and mentor, and as a gifted author, were widely known. His leadership as the Editor-in-Chief of The FASEB Journal was an outstanding contribution in his later career, and his editorials on those pages were both eloquent and elegant. We shall not see the likes of him again anytime soon.” Amore comprehensive memoir of Dr. Weissmannwill appear in the October 2019 issue of the journal.","PeriodicalId":22447,"journal":{"name":"The FASEB Journal","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77659272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thomas C. F. Bodewes, Joel M. Johnson, M. Auster, C. Huynh, Sriya Muralidharan, M. Contreras, F. Logerfo, Leena Pradhan-Nabzdyk
In an effort to inhibit the response to vascular injury that leads to intimal hyperplasia, this study investigated the in vivo efficacy of intraluminal delivery of thrombospondin‐2 (TSP‐2) small interfering RNA (siRNA). Common carotid artery (CCA) balloon angioplasty injury was performed in rats. Immediately after denudation, CCA was transfected intraluminally (15 min) with one of the following: polyethylenimine (PEI)+TSP‐2 siRNA, saline, PEI only, or PEI+control siRNA. CCA was analyzed at 24 h or 21 d by using quantitative real‐time PCR and immunohistochemistry. TSP‐2 gene and protein expression were significantly up‐regulated after endothelial denudation at 24 h and 21 d compared with contralateral untreated, nondenuded CCA. Treatment with PEI+TSP‐2 siRNA significantly suppressed TSP‐2 gene expression (3.1‐fold) at 24 h and TSP‐2 protein expression, cell proliferation, and collagen deposition up to 21 d. These changes could be attributed to changes in TGF‐β and matrix metalloproteinase‐9, the downstream effectors of TSP‐2. TSP‐2 knockdown induced anti‐inflammatory M2 macrophage polarization at 21 d; however, it did not significantly affect intima/media ratios. In summary, these data demonstrate effective siRNA transfection of the injured arterial wall and provide a clinically effective and translationally applicable therapeutic strategy that involves nonviral siRNA delivery to ameliorate the response to vascular injury.—Bodewes, T.C.F., Johnson, J.M., Auster, M., Huynh, C., Muralidharan, S., Contreras, M., LoGerfo, F. W., Intraluminal delivery of thrombospondin‐2 small interfering RNA inhibits the vascular response to injury in a rat carotid balloon angioplasty model. FASEB J. 31, 109–119 (2017) www.fasebj.org
{"title":"Intraluminal delivery of thrombospondin‐2 small interfering RNA inhibits the vascular response to injury in a rat carotid balloon angioplasty model","authors":"Thomas C. F. Bodewes, Joel M. Johnson, M. Auster, C. Huynh, Sriya Muralidharan, M. Contreras, F. Logerfo, Leena Pradhan-Nabzdyk","doi":"10.1096/fj.201600501r","DOIUrl":"https://doi.org/10.1096/fj.201600501r","url":null,"abstract":"In an effort to inhibit the response to vascular injury that leads to intimal hyperplasia, this study investigated the in vivo efficacy of intraluminal delivery of thrombospondin‐2 (TSP‐2) small interfering RNA (siRNA). Common carotid artery (CCA) balloon angioplasty injury was performed in rats. Immediately after denudation, CCA was transfected intraluminally (15 min) with one of the following: polyethylenimine (PEI)+TSP‐2 siRNA, saline, PEI only, or PEI+control siRNA. CCA was analyzed at 24 h or 21 d by using quantitative real‐time PCR and immunohistochemistry. TSP‐2 gene and protein expression were significantly up‐regulated after endothelial denudation at 24 h and 21 d compared with contralateral untreated, nondenuded CCA. Treatment with PEI+TSP‐2 siRNA significantly suppressed TSP‐2 gene expression (3.1‐fold) at 24 h and TSP‐2 protein expression, cell proliferation, and collagen deposition up to 21 d. These changes could be attributed to changes in TGF‐β and matrix metalloproteinase‐9, the downstream effectors of TSP‐2. TSP‐2 knockdown induced anti‐inflammatory M2 macrophage polarization at 21 d; however, it did not significantly affect intima/media ratios. In summary, these data demonstrate effective siRNA transfection of the injured arterial wall and provide a clinically effective and translationally applicable therapeutic strategy that involves nonviral siRNA delivery to ameliorate the response to vascular injury.—Bodewes, T.C.F., Johnson, J.M., Auster, M., Huynh, C., Muralidharan, S., Contreras, M., LoGerfo, F. W., Intraluminal delivery of thrombospondin‐2 small interfering RNA inhibits the vascular response to injury in a rat carotid balloon angioplasty model. FASEB J. 31, 109–119 (2017) www.fasebj.org","PeriodicalId":22447,"journal":{"name":"The FASEB Journal","volume":"13 1","pages":"109 - 119"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84380181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nathalia M Pinheiro, F. R. Santana, R. R. Almeida, M. Guerreiro, M. Martins, L. Caperuto, N. Câmara, L. A. Wensing, V. Prado, I. Tiberio, Marco Antônio M. Prado, C. Prado
Nicotinic α‐7 acetylcholine receptor (nAChRα7) is a critical regulator of cholinergic anti‐inflammatory actions in several diseases, including acute respiratory distress syndrome(ARDS). Given the potential importance of α7nAChR as a therapeutic target, we evaluated whether PNU‐282987, an α7nAChR agonist, is effective in protecting the lung against inflammation. We performed intratracheal instillation of LPS to generate acute lung injury (ALI) in C57BL/6 mice. PNU‐282987 treatment, either before or after ALI induction, reduced neutrophil recruitment and IL‐ 1β, TNF‐α, IL‐6, keratinocyte chemoattractant (KC), and IL‐10 cytokine levels in the bronchoalveolar lavage fluid (P> 0.05). In addition, lung NF‐κB phosphorylation decreased, along with collagen fiber deposition and the number of matrix metalloproteinase‐9+ and −2+ cells, whereas the number of tissue inhibitor of metalloproteinase‐1+ cells increased (P < 0.05). PNU‐282987 treatment also reduced lung mRNA levels and the frequency of M1 macrophages, whereas cells expressing the M2‐related markers CD206 and IL‐10 increased, suggesting changes in the macrophage profile. Finally, PNU‐282987 improved lung function in LPS‐treated animals. The collective results suggest that PNU‐282987, anagonist of α7nAChR, reducesLPS‐induced experimental ALI, thus supporting the notion that drugs that act on α7nAChRs should be explored for ARDS treatment in humans.—Pinheiro, N. M., Santana, F. P. R., Almeida, R. R., Guerreiro, M., Martins, M.A., Caperuto, L.C., Câmara, N.O.S., Wensing, L.A., Prado, V. F., Tibério, I. F. L. C., Prado, M.A.M., Prado, C. M. Acute lung injury is reduced by the α7nAChR agonist PNU‐282987 through changes in the macrophage profile. FASEB J. 31, 320–332 (2017) www.fasebj.org
烟碱α‐7乙酰胆碱受体(nAChRα7)是多种疾病(包括急性呼吸窘迫综合征(ARDS))中胆碱能抗炎作用的关键调节因子。考虑到α7nAChR作为治疗靶点的潜在重要性，我们评估了α7nAChR激动剂PNU‐282987是否能有效保护肺部免受炎症的影响。我们对C57BL/6小鼠进行气管内灌注LPS诱导急性肺损伤(ALI)。PNU - 282987治疗，无论是在ALI诱导之前还是之后，都能降低支气管肺泡灌洗液中中性粒细胞募集和IL - 1β、TNF - α、IL - 6、角化细胞趋化剂(KC)和IL - 10细胞因子的水平(P < 0.05)。肺NF - κB磷酸化水平降低，胶原纤维沉积减少，基质金属蛋白酶- 9+和- 2+细胞数量减少，组织金属蛋白酶- 1+细胞数量增加(P < 0.05)。PNU - 282987治疗还降低了肺mRNA水平和M1巨噬细胞的频率，而表达M2相关标志物CD206和IL - 10的细胞增加，表明巨噬细胞谱发生了变化。最后，PNU - 282987改善了LPS处理动物的肺功能。综上所述，α7nAChR拮抗剂PNU - 282987可降低lps诱导的实验性ALI，从而支持应探索作用于α7nAChR的药物用于人类ARDS治疗的观点。-Pinheiro, N. M, Santana, F. P. R, Almeida, R. R, Guerreiro, M.， Martins, M.， Caperuto, l.c.， c玛拉，N.O.S, Wensing, l.a.， Prado, V. F.， tibrio, i.f.l.c, Prado, M. a.m.， Prado, C. . α7nAChR受体拮抗剂PNU‐282987通过巨噬细胞的改变减少急性肺损伤。[j] .农业工程学报，2016,32 (5):359 - 359 (2017)www.fasebj.org
{"title":"Acute lung injury is reduced by the α7nAChR agonist PNU‐282987 through changes in the macrophage profile","authors":"Nathalia M Pinheiro, F. R. Santana, R. R. Almeida, M. Guerreiro, M. Martins, L. Caperuto, N. Câmara, L. A. Wensing, V. Prado, I. Tiberio, Marco Antônio M. Prado, C. Prado","doi":"10.1096/fj.201600431r","DOIUrl":"https://doi.org/10.1096/fj.201600431r","url":null,"abstract":"Nicotinic α‐7 acetylcholine receptor (nAChRα7) is a critical regulator of cholinergic anti‐inflammatory actions in several diseases, including acute respiratory distress syndrome(ARDS). Given the potential importance of α7nAChR as a therapeutic target, we evaluated whether PNU‐282987, an α7nAChR agonist, is effective in protecting the lung against inflammation. We performed intratracheal instillation of LPS to generate acute lung injury (ALI) in C57BL/6 mice. PNU‐282987 treatment, either before or after ALI induction, reduced neutrophil recruitment and IL‐ 1β, TNF‐α, IL‐6, keratinocyte chemoattractant (KC), and IL‐10 cytokine levels in the bronchoalveolar lavage fluid (P> 0.05). In addition, lung NF‐κB phosphorylation decreased, along with collagen fiber deposition and the number of matrix metalloproteinase‐9+ and −2+ cells, whereas the number of tissue inhibitor of metalloproteinase‐1+ cells increased (P < 0.05). PNU‐282987 treatment also reduced lung mRNA levels and the frequency of M1 macrophages, whereas cells expressing the M2‐related markers CD206 and IL‐10 increased, suggesting changes in the macrophage profile. Finally, PNU‐282987 improved lung function in LPS‐treated animals. The collective results suggest that PNU‐282987, anagonist of α7nAChR, reducesLPS‐induced experimental ALI, thus supporting the notion that drugs that act on α7nAChRs should be explored for ARDS treatment in humans.—Pinheiro, N. M., Santana, F. P. R., Almeida, R. R., Guerreiro, M., Martins, M.A., Caperuto, L.C., Câmara, N.O.S., Wensing, L.A., Prado, V. F., Tibério, I. F. L. C., Prado, M.A.M., Prado, C. M. Acute lung injury is reduced by the α7nAChR agonist PNU‐282987 through changes in the macrophage profile. FASEB J. 31, 320–332 (2017) www.fasebj.org","PeriodicalId":22447,"journal":{"name":"The FASEB Journal","volume":"21 1","pages":"320 - 332"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78893339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Farnaghi, I. Prasadam, G. Cai, T. Friis, Zhibin Du, R. Crawford, Xinzhan Mao, Yin Xiao
The contribution of metabolic factors on the severity of osteoarthritis (OA) is not fully appreciated. This study aimed to define the effects of hyper cholesterolemia on the progression of OA. A polipoprotein E‐deficient (ApoE−/−) mice and rats with diet‐induced hypercholesterolemia (DIHC) rats were used to explore the effects of hyper cholesterolemia on the progression of OA. Both models exhibited OA‐like changes, characterized primarily by a loss of proteoglycans, collagen and aggrecan degradation, osteophyte formation, changes to subchondral bone architecture, and cartilage degradation. Surgical destabilization of the knees resulted in a dramatic increase of degradative OA symptoms in animals fed a high‐cholesterol diet compared with controls. Clinically relevant doses of free cholesterol resulted in mitochondrial dysfunction, overproduction of reactive oxygen species (ROS), and increased expression of degenerative and hypertrophic markers in chondrocytes and breakdown of the cartilage matrix. We showed that the severity of diet‐induced OA changes could be attenuated by treatment with both atorvastatin and a mitochondrial targeting antioxidant. The protective effects of the mitochondrial targeting antioxidant were associated with suppression of oxidative damage to chondrocytes and restoration of extracellular matrix homeostasis of the articular chondrocytes. In summary, our data show that hypercholesterolemia precipitates OA progression by mitochondrial dysfunction in chondrocytes, in part by increasing ROS production and apoptosis. By addressing the mitochondrial dysfunction using antioxidants, we were able attenuate the OA progression in our animal models. This approach may form the basis for novel treatment options for this OA risk group in humans.—Farnaghi, S., Prasadam, I., Cai, G., Friis, T., Du, Z., Crawford, R., Mao, X., Xiao, Y. Protective effects of mitochondria‐targeted antioxidants and statins on cholesterolinduced osteoarthritis. FASEB J. 31, 356–367 (2017) www.fasebj.org
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