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991.
Weijun Li Zhenhong Zhu Kai He Xiaoyu Ma Robert J. Pignolo Gary C. Sieck Jinghua Hu Haitao Wang 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(24)
Skeletal muscle atrophy is commonly associated with aging, immobilization, muscle unloading, and congenital myopathies. Generation of mature muscle cells from skeletal muscle satellite cells (SCs) is pivotal in repairing muscle tissue. Exercise therapy promotes muscle hypertrophy and strength. Primary cilium is implicated as the mechanical sensor in some mammalian cells, but its role in skeletal muscle cells remains vague. To determine mechanical sensors for exercise-induced muscle hypertrophy, we established three SC-specific cilium dysfunctional mouse models—Myogenic factor 5 (Myf5)-Arf-like Protein 3 (Arl3)−/−, Paired box protein Pax-7 (Pax7)-Intraflagellar transport protein 88 homolog (Ift88)−/−, and Pax7-Arl3−/−—by specifically deleting a ciliary protein ARL3 in MYF5-expressing SCs, or IFT88 in PAX7-expressing SCs, or ARL3 in PAX7-expressing SCs, respectively. We show that the Myf5-Arl3−/− mice develop grossly the same as WT mice. Intriguingly, mechanical stimulation-induced muscle hypertrophy or myoblast differentiation is abrogated in Myf5-Arl3−/− and Pax7-Arl3−/− mice or primary isolated Myf5-Arl3−/− and Pax7-Ift88−/− myoblasts, likely due to defective cilia-mediated Hedgehog (Hh) signaling. Collectively, we demonstrate SC cilia serve as mechanical sensors and promote exercise-induced muscle hypertrophy via Hh signaling pathway.Exercise is considered as the primary intervention to improve muscle strength and to counteract muscle atrophy. While physical exercise training is considered a suitable intervention to improve muscle strength and endurance in healthy individuals, some people are resistant to the beneficial effects of exercise (1–3). It has been debated whether exercise is beneficial or harmful for patients with myopathic disorders (4) and type 2 diabetes (5). This so-called “exercise resistance” is considered congenital, and one recently identified causative factor involved in exercise resistance is hepatokine selenoprotein P (2, 6).Primary cilia have a mechanosensory function in bone cells (7), renal cells (8), and airway smooth muscle cells exert a role in sensing oscillatory fluid flow and transducing extracellular mechano-chemical signals into intracellular biochemical responses (9). Intriguingly, low muscle tone is a clinical feature often present in congenital ciliopathies with unclear underlying mechanisms (10). Arf-like Protein 3 (ARL3) is a highly conserved ciliary protein across ciliated organisms. ARL3, a regulator of intraflagellar transport in primary cilia, has been reported involving with various ciliary signaling functions (11, 12) and maintaining cell division polarity (13). Arl3 mutations cause Joubert syndrome (14, 15). Arl3−/− knockout does not affect cilia structure but compromises ciliary function (16).Cells utilize primary cilia to convert environmental cues, mechanical or chemical, into various cellular signaling essential for development (17–21). During skeletal muscle development, Hedgehog (Hh) signaling helps to initiate the myogenic program (22). In myoblast cells, Fu et al. (23) showed that primary cilia are assembled during the initial stages of myogenic differentiation but disappear as cells progress through myogenesis. The ablation of primary cilia suppresses Hh signaling and myogenic differentiation while enhancing proliferation. However, there are still significant gaps in our understanding of how exercise and mechanical signals activate the Hh signaling pathway. In the present study, we hypothesize that primary cilia in satellite cells (SCs) transduce mechanical stimulation through activation of Hh signaling and promote muscle hypertrophy induced by exercise.Hypertrophy of skeletal muscle is a complex biological process that involves multiple cell types, including SCs, fibro-adipogenic precursors, endothelial cells, fibroblasts, pericytes, and immune cells. Removing cilia from fibro-adipogenic precursors can reduce intramuscular adipogenesis and increase myofibril size during muscle healing (24). SCs play an essential role in muscle hypertrophy and exercise adaptation (25, 26), especially in young mice (27). Mechanical signals can interrupt SC suppression in a skeletal muscle loss model induced by ovariectomy. Diminished SC number and elevated adipogenic gene expression in muscle caused by ovariectomy are averted by mechanical stimulation (28). Experiments in vitro indicate that mechanical stimulation enhances the fusion of SCs (29). SCs are a heterogeneous population of stem cells and committed progenitors (30). Paired box protein Pax-7 (Pax7) is a traditional marker of SCs and acts at different levels in a nonhierarchical regulatory network controlling SC-mediated muscle hypertrophy (31). A major target gene of Pax7 is Myogenic factor 5 (Myf5), and loss of Pax7 significantly decreases Myf5 expression in myoblasts (32). However, Myf5 is present in Pax3/Pax7 double mutants, indicating Myf5 activation occurs independently of Pax3/Pax7 (33). Furthermore, 10% of Pax7-expressing satellite cells have never expressed Myf5 (30). Parise et al. (34) observed an approximately sixfold increase in the number of Myf5-expressing cells by 48 h following exercise, which remained elevated until at least 96 h after exercise. We established three mouse models of Myf5-Arl3−/−, Pax7-Intraflagellar transport protein 88 homolog (Ift88−/−), and Pax7-Arl3−/− to investigate the SC during mechanical stimulation and exercise. In the present study, we provide exciting evidence that SC cilia act as the key mechanical sensor for exercise-induced hypertrophy. 相似文献
992.
Miaomiao Han Jingyu Ma Suidong Ouyang Yanyan Wang Tingting Zheng Peishan Lu Zihan Zheng Weiheng Zhao Hongjin Li Yun Wu Baohua Zhang Ran Hu Kinya Otsu Xinguang Liu Ying Wan Huabin Li Gonghua Huang 《Cellular & molecular immunology》2022,19(7):805
Dendritic cells (DCs) play a critical role in controlling T helper 2 (Th2) cell-dependent diseases, but the signaling mechanism that triggers this function is not fully understood. We showed that p38α activity in DCs was decreased upon HDM stimulation and dynamically regulated by both extrinsic signals and Th2-instructive cytokines. p38α-specific deletion in cDC1s but not in cDC2s or macrophages promoted Th2 responses under HDM stimulation. Further study showed that p38α in cDC1s regulated Th2-cell differentiation by modulating the MK2−c-FOS−IL-12 axis. Importantly, crosstalk between p38α-dependent DCs and Th2 cells occurred during the sensitization phase, not the effector phase, and was conserved between mice and humans. Our results identify p38α signaling as a central pathway in DCs that integrates allergic and parasitic instructive signals with Th2-instructive cytokines from the microenvironment to regulate Th2-cell differentiation and function, and this finding may offer a novel strategy for the treatment of allergic diseases and parasitic infection. 相似文献
993.
目的构建抑制人聚ADP核糖聚合酶1(hPARP1)活性的短发夹RNA(shorthairpinRNA,shRNA)表达载体。方法化学合成2对编码短发夹RNA序列的、靶向hPARP1基因的寡核苷酸,各69对碱基,退火,然后利用BamHⅡ及EcoRⅠ与pSIRENRetroQ载体连接。用EcoRⅠ及BglⅡ切取其中U6启动子及下游的shRNA部分,与pEGFPC1载体重组构建pEGFPC1shRNA载体。结果重组构建的pEGFPC1P1、pEGFPC1P2、pEGFPC1N载体经双酶切电泳分析及插入基因片段序列分析,结果表明330个碱基成功插入到预计位点。结论载体的成功构建,为进一步研究聚ADP核糖聚合酶在DNA修复过程中的功能打下基础。 相似文献
994.
目的:验证Binl—b蛋白及其mRNA在少弱精子症模型大鼠附睾中的表达,探讨Binl—b在病理状态下附睾中表达的改变。方法:取雄性大鼠30只,随机分为两组,模型组给予雷公藤(10mg/ kg/d)灌胃,连用8W成少弱精子症模型;对照组给予1%羧甲基纤维钠混悬液灌胃。采用免疫组化S—P法和原位杂交方法检测Binl—b蛋白和Binl—bmRNA在两组大鼠附睾组织中的表达情况。结果:Binl—b蛋白表达于对照组、模型组大鼠的附睾管腔上皮、主细胞、基细胞,但在模型组中表达明显增强(P<0.01)。Binl—bmRNA表达于模型组、对照组附睾管腔上皮、主细胞、基细胞,但其在模型组中的表达明显增强(P<0.01)。结论:Binl—b蛋白及其mRNA在少弱精子症大鼠附睾内表达较正常大鼠明显增强,提示Binl—b可能是病理状态下雄性大鼠生殖系统的内源性防御分子之一。 相似文献
995.
四川省一起伴中毒性休克综合征的人感染猪链球菌2型暴发 总被引:24,自引:2,他引:24
杨维中 余宏杰 景怀琦 徐建国 陈志海 祝小平 汪华 刘学成 王世文 刘伦光 祖荣强 罗隆泽 向妮娟 刘红露 钟文君 刘莉 孟玲 袁珩 高永军 杜化茂 欧阳宾 叶长芸 金冬 吕强 崔志刚 黄燕 张守印 安向东 黄婷 周兴余 冯燎 庞启迪 舒跃龙 王宇 《中华流行病学杂志》2006,27(3):185-191
目的 调查2005年7月中旬四川省资阳市一家医院报告5例以败血症休克为主要临床表现的聚集性病例的病因。方法 建立了病例主动发现、报告的加强监测系统,根据病例的流行病学暴露史和临床表现进行临床诊断;采集患者标本进行细菌分离培养和生化反应鉴定,应用PCR方法对猪链球菌2型的种属和毒力基因进行检测和序列测定;与当地往年报告的流行性脑脊髓膜炎发病数进行比较。结果 2005年6月10日至8月21日,四川省共报告了68例实验室确诊人感染猪链球菌病例,发病前都有屠宰、洗切、加工等病(死)猪的直接暴露史。其中26例(38%)表现为中毒性休克综合征,15例(58%)死亡。其他病例临床表现为轻型败血症或脑膜炎。分离菌株应用PCR方法检测猪链球菌2型的种属和毒力基因(tuf、16S rRNA、cps2J、mrp、sly、ef)均为阳性。同期还报告了136例有相似暴露史,但缺乏实验室确诊依据的临床诊断病例。结论 证实该起发生在四川省部分农村地区直接暴露于病(死)猪后的疾病为猪链球菌2型感染暴发。推测这种罕见的、表现为高病死率的中毒性休克综合征可能是由于感染某种高致病性菌株循环所致。 相似文献
996.
997.
急性期精神分裂症返回抑制时间进程的初步研究 总被引:1,自引:0,他引:1
目的探讨急性期精神分裂症返回抑制时间进程的基本属性。方法30例健康志愿者及41例符合ICD-10精神分裂症诊断标准的急性期患者分别接受线索-靶子实验。靶子位置的2个水平分别为线索化位置和非线索化位置。线索开始呈现到靶子开始呈现的时间间隔(stimulus onsetasynchrony,SOA)的9个水平分别为300ms,400ms,500ms,600ms,700ms,800ms,1200ms,1500ms和2500ms。记录被试的反应时和错误率。结果(1)经重复测量方差分析,发现分组因素的主效应显著(P=0.000),健康对照组的平均反应时(365ms)短于精神分裂症患者的平均反应时(521ms)。靶子位置的主效应显著(P=0.000),靶子在线索化位置的反应时(458ms)长于非线索化位置的反应时(428ms)。SOA主效应不显著(P=0.338)。分组和SOA之间、分组和靶子位置之间、SOA和靶子位置之间以及分组、SOA和靶子位置之间的交互作用均不显著(P均〉0.05)。(2)健康对照组在所有SOA水平上靶子在线索化位置的反应时均长于非线索化位置的反应时,差异均达非常显著性(P均〈0.01)。(3)精神分裂症患者在所有SOA水平上靶子在线索化位置的反应时均长于非线索化位置的反应时,其中SOA为400ms,700ms和2500ms时,差异有显著性(P〈0.05);SOA为600ms,800ms,1200ms和1500ms时,差异有非常显著性(P〈0.01);而SOA为300ms和500ms时,差异无显著性(P〉0.05)。结论正常人自SOA300ms以后就出现稳定的返回抑制,而急性期精神分裂症患者的返回抑制延迟出现,SOA600ms以后出现稳定的返回抑制。 相似文献
998.
Environmentally persistent free radicals (EPFRs) in biochars have the ability of catalytic formation of reactive oxygen species, which may pose potential oxidative stresses to eco-environment and human health. Therefore, comprehending the formation and characteristics of EPFRs in biochars is important for their further applications. In this study, the woody lignocellulosic biomass (wood chips, pine needle and barks), non-woody lignocellulosic biomass (rice husk, corn stover, and duckweed), and non-lignocellulosic biomass (anaerobically digested sludge) were selected as biomass feedstock to prepare biochars under different pyrolysis temperatures (200–700 °C). The impact of biomass feedstock on formation of biochar-bound EPFRs was systematically compared. Elemental compositions and atomic ratios of H/C and O/C varied greatly among different biomass feedstocks and the subsequently resulting biochars. EPFRs in biochars derived from the studied lignocellulosic biomass have similar levels of spin concentrations (1018–1019 spins per g) except for lower EPFRs in biochars under 200 and 700 °C; however, sludge-based biochars, a typical non-lignocellulosic-biomass-based biochar, have much lower EPFRs (1016 spins per g) than lignocellulosic-biomass-based biochars under all the studied pyrolysis temperatures. Values of g factors ranged from 2.0025 to 2.0042 and line width was in the range of 2.15–11.3 for EPFRs in the resulting biochars. Spin concentrations of biochar-bound EPFRs increased with the increasing pyrolysis temperatures from 200 to 500 °C, and then decreased rapidly from 500 to 700 °C and oxygen-centered radicals shifted to carbon-centered radicals with the increasing pyrolysis temperatures from 200 to 700 °C for all the studied biomass feedstock. 300–500 °C was the appropriate pyrolysis temperature range for higher levels of spin concentrations of biochar-bound EPFRs. Moreover, EPFRs'' concentrations had significantly positive correlation with C contents and weak or none correlation with contents of transition metals. Overall, different types of biomass feedstock have significant impact on the formation of EPFRs in the resulting biochars.Environmentally persistent free radicals (EPFRs) in biochars have the ability of catalytic formation of reactive oxygen species, which may pose potential oxidative stresses to eco-environment and human health. 相似文献
999.
1000.
Yang Dai Jingcao Huang Pu Kuang Yiguo Hu Qiang Zeng Wanhua Zhang He Li Fangfang Wang Tingting Guo Dan Zhang Dongni Yi Yuhuan Zheng Ting Liu 《American journal of cancer research》2022,12(6):2817
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is a high-risk disease subtype with a dismal prognosis. Inhibiting BCR-ABL kinase alone is insufficient to eradicate Ph+ALL clones, and alternative BCR-ABL-dependent and -independent pathways need to be targeted as an effective strategy. Our study revealed that the combination of dasatinib and interferon-α showed synergistic activity against Ph+ALL, inducing mitochondrial dysfunction and causing necrosis-like cell lysis. Mechanistic studies showed that the induced cell death was caspase-3-independent. Canonical necroptosis signals, such as RIP1 and MLKL, were not activated; instead, the pyroptosis executor Gasdermin D was upregulated expression and activated. The expression levels of extracellular ATP and IL-1β were also upregulated, both of which are markers of pyroptotic cell death. In a murine Ph+ALL model, the dual drug treatment prolonged the survival of tumor-bearing mice. More importantly, we incorporated the dual drugs to maintenance therapy in 39 patients who were unfit for allogeneic stem cell transplantation (allo-HSCT). The median follow-up was 28.5 months, the 4-year disease-free survival and overall survival rates were 52.2% and 65.2%, respectively. Our data suggest that the combination of dasatinib and interferon-α has potential synergistic activity against Ph+ALL and shows promise as a maintenance therapy for Ph+ALL patients who are unfit for allo-HSCT. 相似文献