Emerging roles for β-arrestin-1 in the control of the pancreatic β-cell function and mass: New therapeutic strategies and consequences for drug screening

Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase in β-cell mass, decreased β-cell survival and impaired glucose-dependent insulin release. Pancreatic β-cell proliferation, survival and secretion are thought to be regulated by signalling pathways linked to G-protein coupled receptors (GPCRs), such as the glucagon-like peptide-1 (GLP-1) and the pituitary adenylate cyclase-activating polypeptide (PACAP) receptors. β-arrestin-1 serves as a multifunctional adaptor protein that mediates receptor desensitization, receptor internalization, and links GPCRs to downstream pathways such as tyrosine kinase Src, ERK1/2 or Akt/PKB. Importantly, recent studies found that β-arrestin-1 mediates GLP-1 signalling to insulin secretion, GLP-1 antiapoptotic effect by phosphorylating the proapoptotic protein Bad through ERK1/2 activation, and PACAP potentiation of glucose-induced long-lasting ERK1/2 activation controlling IRS-2 expression. Together, these novel findings reveal an important functional role for β-arrestin-1 in the regulation of insulin secretion and β-cell survival by GPCRs.     

丝状真菌细胞凋亡研究进展

细胞凋亡是真核生物中保守而重要的细胞死亡机制,与癌症、艾滋病等多种疾病密切相关.与酵母菌这一细胞凋亡模式生物相比,丝状真菌凋亡研究起步较晚但具有其独特的优势.近年来丝状真菌细胞凋亡的内外源诱因、细胞凋亡的特征以及信号传导通路等方面的研究进展迅速.丝状真菌,尤其是构巢曲霉和烟曲霉有望成为细胞凋亡研究新的模式物种.此外,研究丝状真菌细胞凋亡现象在农业和医疗领域也具有重要的应用价值,可为生物防治和人类真菌病的治疗提供新的思路.工业丝状真菌细胞凋亡研究有助于构建性状更加优良的工程菌株.     

Licorice-derived dehydroglyasperin C increases MKP-1 expression and suppresses inflammation-mediated neurodegeneration

Recent studies have demonstrated that microglial hyperactivation-mediated neuroinflammation is involved in the pathogenesis of several neurodegenerative diseases. Thus, inhibiting microglial production of the neurotoxic mediator tumor necrosis factor-α (TNF-α) is considered a promising strategy to protect against neurodegeneration. Here, we investigated the inhibitory effect of licorice-derived dehydroglyasperin C (DGC) on lipopolysaccharide (LPS)-induced TNF-α production and inflammation-mediated neurodegeneration. We found that DGC pre-treatment attenuated TNF-α production in response to LPS stimulation of BV-2 microglia. DGC pre-treatment attenuated LPS-induced inhibitor of κB-α (IκB-α) and p65 phosphorylation and decreased the DNA binding activity of nuclear factor-κB (NF-κB). DGC pre-treatment also inhibited LPS-mediated phosphorylation of p38 mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinase (ERK). Interestingly, DGC treatment of BV-2 microglia significantly increased MAPK phosphatase 1 (MKP-1) mRNA and protein expression, which is a phosphatase of p38 MAPK and ERK, suggesting that the DGC-mediated increase in MKP-1 expression might inhibit LPS-induced MAPKs and NF-κB activation and further TNF-α production. We also found that LPS-mediated microglial neurotoxicity can be attenuated by DGC. The addition of conditioned media (CM) from DGC- and LPS-treated microglia to neurons helped maintain healthy cell body and neurite morphology and increased the number of microtubule-associated protein 2-positive cells and the level of synaptophysin compared to treatment with CM from LPS-treated microglia. Taken together, these data suggest that DGC isolated from licorice may inhibit microglia hyperactivation by increasing MKP-1 expression and acting as a potent anti-neurodegenerative agent.     

Acute exercise induces biphasic increase in respiratory mRNA in skeletal muscle

Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) promotes the expression of oxidative enzymes in skeletal muscle. We hypothesized that activation of the p38 MAPK (mitogen-activated protein kinase) in response to exercise was associated with exercise-induced PGC-1α and respiratory enzymes expression and aimed to demonstrate this under the physiological level. We subjected mice to a single bout of treadmill running and found that the exercise induced a biphasic increase in the expression of respiratory enzymes mRNA. The second phase of the increase was accompanied by an increase in PGC-1α protein, but the other was not. Administration of SB203580 (SB), an inhibitor of p38 MAPK, suppressed the increase in PGC-1α expression and respiratory enzymes mRNA in both phases. These data suggest that p38 MAPK is associated with the exercise-induced expression of PGC-1α and biphasic increase in respiratory enzyme mRNAs in mouse skeletal muscle under physiological conditions.     

纹状体神经通路与运动调控

纹状体(striatum)是机体运动中枢的关键组成部分,对机体随意运动、非意识性运动、肌张力、身体姿态、精细运动等调节均发挥重要作用。纹状体功能异常导致运动失调:一类为运动减少,肌张力亢进,如帕金森病;另一类为运动过多,肌张力不足,如舞蹈病。一般认为,纹状体接收大脑运动皮层传来的运动相关信号,经其加工处理后,经丘脑返传回运动皮层,最终由运动皮层发出运动执行信号,经锥体系完成运动。可见,纹状体的运动调控功能有赖于复杂的神经通路系统。本文综述近几年来有关纹状体神经通路与运动调控的研究进展,以期更深入理解纹状体运动调控神经机制及其与临床疾病的关系。     

PI3K和受体型酪氨酸激酶介导家蚕麻痹肽免疫诱导信号的传递

【目的】普遍存在于鳞翅目昆虫中的ENF肽具有非常相似的结构和生理功能, 对昆虫的发育、 免疫、 应激反应等方面都起着重要的调控作用。有研究报道, 作为ENF肽家族成员之一的家蚕Bombyx mori麻痹肽（paralytic peptide, PP）通过激活MAPK来调控家蚕的免疫应答, 但其完整的分子作用机制尚不明确。本研究旨在解析传递家蚕PP免疫诱导信号的分子通路。【方法】首先通过荧光定量PCR检测了多种昆虫细胞系在PP诱导下抗菌肽基因的转录水平, 并利用Western blot检测p38 MAPK的磷酸化水平, 然后利用不同信号传递分子的抑制剂处理BmE细胞筛选参与传递PP免疫诱导信号的分子。【结果】PI3K抑制剂LY294002和受体型酪酸激酶抑制剂Genistein抑制了PP对BmE细胞抗菌肽基因表达的诱导作用; 且BmE细胞和家蚕血细胞在PP的诱导下, Akt和大小约为70 kDa的细胞膜蛋白均出现磷酸化水平的动态变化。【结论】PI3K/Akt信号通路和Genistein敏感性的受体型酪氨酸激酶介导了PP免疫诱导信号的传递。     

生态-经济发展情景下内蒙古宏观生态系统模拟与分析

内蒙古自治区是我国北方面积最大、种类最全的生态功能区,是我国北方的重要生态屏障,其宏观生态系统状况不仅关系民众生存和生计,而且关系华北、东北、西北乃至全国的生态安全。构建了1990、2000及2015年3期宏观生态系统格局与影响因子数据集;融合区域生态系统发展规划,设置了基准、生态-经济协同发展和生态-经济权衡发展三种情景;应用土地利用均衡分析模型,模拟了3种情景下2025年及2035年内蒙古六大类生态系统结构与空间格局变化。结果表明：在延续历史发展趋势的基准情景和注重经济发展的生态-经济权衡发展情景下,草地和农田生态系统在2035年均无法恢复至2000年的水平,宏观生态系统结构难以达到规划目标;在注重生态保育的生态-经济协同发展情景下,草地、森林与湿地生态系统面积增长较大,符合内蒙古构建中国北方生态屏障的战略定位。从空间上看,农田生态系统面积的减少主要集中在农牧交错带地区,该区域的退耕还草构成了草地生态系统增加的主要来源;草地生态系统面积扩张还分布在近十年来发生草地退化的区域,这与近年来通过实施"京津风沙源治理"、"草原奖补政策"等生态工程建设后内蒙古自治区原有退化的草地生态系统在逐渐恢复的趋势相吻合;森林生态系统面积增加主要集中分布在大兴安岭等几个植被恢复地;城市生态系统主要以原有城镇居民点为中心,在其周边区域呈扩散式增长,特别是在采矿场、工业用地、交通沿线附近城镇面积增加较为显著;荒漠生态系统的缩减主要发生在与其它生态系统的交界处,这与开发利用的便利性、原有生态系统的可开发潜力等密切相关。研究表明,生态-经济发展情景下的宏观生态系统的空间显性模拟是区域国土空间规划和可持续发展的重要科学依据。     

p38α‐MAPK‐deficient myeloid cells ameliorate symptoms and pathology of APP‐transgenic Alzheimer's disease mice

Alzheimer''s disease (AD), the most common cause of dementia in the elderly, is pathologically characterized by extracellular deposition of amyloid‐β peptides (Aβ) and microglia‐dominated inflammatory activation in the brain. p38α‐MAPK is activated in both neurons and microglia. How p38α‐MAPK in microglia contributes to AD pathogenesis remains unclear. In this study, we conditionally knocked out p38α‐MAPK in all myeloid cells or specifically in microglia of APP‐transgenic mice, and examined animals for AD‐associated pathologies (i.e., cognitive deficits, Aβ pathology, and neuroinflammation) and individual microglia for their inflammatory activation and Aβ internalization at different disease stages (e.g., at 4 and 9 months of age). Our experiments showed that p38α‐MAPK‐deficient myeloid cells were more effective than p38α‐MAPK‐deficient microglia in reducing cerebral Aβ and neuronal impairment in APP‐transgenic mice. Deficiency of p38α‐MAPK in myeloid cells inhibited inflammatory activation of individual microglia at 4 months but enhanced it at 9 months. Inflammatory activation promoted microglial internalization of Aβ. Interestingly, p38α‐MAPK‐deficient myeloid cells reduced IL‐17a‐expressing CD4‐positive lymphocytes in 9 but not 4‐month‐old APP‐transgenic mice. By cross‐breeding APP‐transgenic mice with Il‐17a‐knockout mice, we observed that IL‐17a deficiency potentially activated microglia and reduced Aβ deposition in the brain as shown in 9‐month‐old myeloid p38α‐MAPK‐deficient AD mice. Thus, p38α‐MAPK deficiency in all myeloid cells, but not only in microglia, prevents AD progression. IL‐17a‐expressing lymphocytes may partially mediate the pathogenic role of p38α‐MAPK in peripheral myeloid cells. Our study supports p38α‐MAPK as a therapeutic target for AD patients.     

A comprehensive network map of IL-17A signaling pathway

Interleukin-17A (IL-17A) is one of the member of IL-17 family consisting of other five members (IL-17B to IL-17F). The Gamma delta (γδ) T cells and T helper 17 (Th17) cells are the major producers of IL-17A. Aberrant signaling by IL-17A has been implicated in the pathogenesis of several autoimmune diseases including idiopathic pulmonary fibrosis, acute lung injury, chronic airway diseases, and cancer. Activation of the IL-17A/IL-17 receptor A (IL-17RA) system regulates phosphoinositide 3-kinase/AKT serine/threonine kinase/mammalian target of rapamycin (PI3K/AKT/mTOR), mitogen-activated protein kinases (MAPKs) and activation of nuclear factor-κB (NF-κB) mediated signaling pathways. The IL-17RA activation orchestrates multiple downstream signaling cascades resulting in the release of pro-inflammatory cytokines such as interleukins (IL)-1β, IL-6, and IL-8, chemokines (C-X-C motif) and promotes neutrophil-mediated immune response. Considering the biomedical importance of IL-17A, we developed a pathway resource of signaling events mediated by IL-17A/IL-17RA in this study. The curation of literature data pertaining to the IL-17A system was performed manually by the NetPath criteria. Using data mined from the published literature, we describe an integrated pathway reaction map of IL-17A/IL-17RA consisting of 114 proteins and 68 reactions. That includes detailed information on IL-17A/IL-17RA mediated signaling events of 9 activation/inhibition events, 17 catalysis events, 3 molecular association events, 68 gene regulation events, 109 protein expression events, and 6 protein translocation events. The IL-17A signaling pathway map data is made freely accessible through the WikiPathways Database (https://www.wikipathways.org/index.php/Pathway: WP5242).Supplementary InformationThe online version contains supplementary material available at 10.1007/s12079-022-00686-y.