Novel insights into D-Pinitol based therapies:a link between tau hyperphosphorylation and insulin resistance

Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.

Brain-derived neurotrophic factor signaling in the neuromuscular junction during developmental axonal competition and synapse elimination

During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.

Regulation of TMEM100 expression by epigenetic modification,effects on proliferation and invasion of esophageal squamous carcinoma

BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a prevalent malignancy with a high morbidity and mortality rate.TMEM100 has been shown to be suppressor gene in a variety of tumors,but there are no reports on the role of TMEM100 in esophageal cancer(EC).AIM To investigate epigenetic regulation of TMEM100 expression in ESCC and the effect of TMEM100 on ESCC proliferation and invasion.METHODS Firstly,we found the expression of TMEM100 in EC through The Cancer Genome Atlas database.The correlation between TMEM100 gene expression and the survival of patients with EC was further confirmed through Kaplan-Meier analysis.We then added the demethylating agent 5-AZA to ESCC cell lines to explore the regulation of TMEM100 expression by epigenetic modification.To observe the effect of TMEM100 expression on tumor proliferation and invasion by overexpressing TMEM100.Finally,we performed gene set enrichment analysis using the Kyoto Encyclopaedia of Genes and Genomes Orthology-Based Annotation System database to look for pathways that might be affected by TMEM100 and verified the effect of TMEM100 expression on the mitogen-activated protein kinases(MAPK)pathway.RESULTS In the present study,by bioinformatic analysis we found that TMEM100 was lowly expressed in EC patients compared to normal subjects.Kaplan-meier survival analysis showed that low expression of TMEM100 was associated with poor prognosis in patients with EC.Then,we found that the demethylating agent 5-AZA resulted in increased expression of TMEM100 in ESCC cells[quantitative real-time PCR(qRT-PCR)and western blotting].Subsequently,we confirmed that overexpression of TMEM100 leads to its increased expression in ESCC cells(qRT-PCR and western blotting).Overexpression of TMEM100 also inhibited proliferation,invasion and migration of ESCC cells(cell counting kit-8 and clone formation assays).Next,by enrichment analysis,we found that the gene set was significantly enriched in the MAPK signaling pathway.The involvement of TMEM100 in the regulation of MAPK signaling pathway in ESCC cell was subsequently verified by western blotting.CONCLUSION TMEM100 is a suppressor gene in ESCC,and its low expression may lead to aberrant activation of the MAPK pathway.Promoter methylation may play a key role in regulating TMEM100 expression.

Genome-wide characterization of mapk gene family in black rockfish Sebastes schlegelii and their expression patterns against Edwardsiella piscicida infection

Mitogen-activated protein kinases(MAPKs)play pivotal roles in response to environmental stresses and bacterial infections.Compared with those in the higher vertebrates,studies of mapk gene family are still limited in teleost.Identification,characterization,classification,and expression profiling of totally 15 mapk genes in black rockfish(Sebastes schlegelii)were conducted.Phylogenetic relationships show that these mapk genes could be divided into extracellular signal-regulated kinase(ERK),c-Jun N-terminal kinase(JNK),and p38 sub-families.In addition,gene structures,syntenic analysis,and selective pressure analysis are performed to confirm their annotations.Results of selective pressure analysis indicate that mapk1,mapk3,mapk7,mapk10,mapk11,and mapk12 underwent significantly-positive selections,while the others genes such as mapk4,mapk6,mapk15,mapk8a,mapk8b,mapk9,mapk13,mapk14a,and mapk14b were under purifying selections.Moreover,results of qRT-PCR indicate that mapk genes in 8 healthy tissues displayed different expression patterns.The expression patterns of several mapk genes including mapk12,mapk13,mapk14a,mapk14b,and mapk15 were significantly changed in mucosal tissues after Edwardsiella piscicida infection.This study demonstrates that mapk genes in black rockfish play vital prevention roles against bacterial infection,which not only helps us understand the structure and function of mapk genes in black rockfish,but also provides a reference to understand the role of mapk genes in teleost immune responses.

Seronegative spondyloarthropathy-associated inflammatory bowel disease

Seronegative spondyloarthropathy(SpA)usually starts in the third decade of life with negative rheumatoid factor,human leukocyte antigen-B27 genetic marker and clinical features of spinal and peripheral arthritis,dactylitis,enthesitis and extra-articular manifestations(EAMs).Cases can be classified as ankylosing spondylitis,psoriatic arthritis,reactive arthritis,enteropathic arthritis,or juvenileonset spondyloarthritis.Joint and gut inflammation is intricately linked in SpA and inflammatory bowel disease(IBD),with shared genetic and immunopathogenic mechanisms.IBD is a common EAM in SpA patients,while extraintestinal manifestations in IBD patients mostly affect the joints.Although individual protocols are available for the management of each disease,the standard therapeutic guidelines of SpA-associated IBD patients remain to be established.Nonsteroidal anti-inflammatory drugs are recommended as initial therapy of peripheral and axial SpA,whereas their use is controversial in IBD due to associated disease flares.Conventional disease-modifying anti-rheumatic drugs are beneficial for peripheral arthritis but ineffective for axial SpA or IBD therapy.Anti-tumor necrosis factor monoclonal antibodies are effective medications with indicated use in SpA and IBD,and a drug of choice for treating SpA-associated IBD.Janus kinase inhibitors,approved for treating SpA and ulcerative colitis,are promising therapeutics in SpA coexistent with ulcerative colitis.A tight collaboration between gastroenterologists and rheumatologists with mutual referral from early accurate diagnosis to appropriately prompt therapy is required in this complex clinical scenario.

N-乙酰半胱氨酸对PM2.5致大鼠肺损伤时MAPK主要通路蛋白活化及氧化炎症反应的影响（英文）

Objective To evaluate the antagonistic effects of N-acetylcysteine(NAC)on mitogen-activated protein kinases(MAPK)pathway activation,oxidative stress and inflammatory responses in rats with lung injury induced by fine particulate matter(PM2.5).Methods Forty eight male Wistar rats were randomly divided into six groups:blank control group(C1),water drip control group(C2),PM2.5 exposed group(P),low-dose NAC treated and PM2.5 exposed group(L),middle-dose NAC treated and PM2.5 exposed group(M),and high-dose NAC treated and PM2.5 exposed group(H).PM2.5 suspension(7.5 mg/kg)was administered tracheally once a week for four times.NAC of 125 mg/kg,250 mg/kg and 500 mg/kg was delivered intragastrically to L,M and H group respectively by gavage(10 ml/kg)for six days before PM2.5 exposure.The histopathological changes and human mucin 5 subtype AC(MUC5AC)content in lung tissue of rats were evaluated.We investigated IL-6 in serum and bronchoalveolar lavage fluid(BALF)by Enzyme-linked immunosorbent assay(ELISA),MUC5AC in lung tissue homogenate by ELISA,glutathione peroxidase(GSH-PX)in serum and BALF by spectrophotometry,and the expression of p-ERK1/2,p-JNK1/2 and p-p38 proteins by Western blot.All the measurements were analyzed and compared statistically.Results Lung tissue of rats exposed to PM2.5 showed histological destruction and increased mucus secretion of bronchial epithelial cells.Rats receiving NAC treatment showed less histological destruction and mucus secretion.Of P,L,M and H group,MUC5AC in lung tissue,IL-6 in serum and BALF were higher than controls(C1 and C2)(all P<0.05),with the highest levels found in the P group and a decreasing trend with increase of NAC dose.The activity of GSH-PX in serum and BALF of PM2.5 exposed rats(P,L,M and H)was lower than that of controls(all P<0.05),with higher activities found in NAC treated rats(L,M,and H),and an increasing trend with increase of NAC dose.The expressions of p-ERK1/2,p-JNK1/2 and p-p38 proteins in PM2.5 exposed lung tissue(P,L,M and H)was higher than controls(all P<0.05),with decreased levels and dose dependent downregulation found in NAC treated rats.Conclusion NAC can antagonize major MAPK pathway activation,lung oxidative stress and inflammatory injury induced by PM2.5 in rats.

p21活性蛋白激酶在喉癌和喉咽癌中的表达及临床意义

p21活性蛋白激酶（p21-activated kinase 1,PAK1）是一种保守的丝氨酸/苏氨酸蛋白激酶,是Rho家族小鸟苷三磷酸酶（Rho-GTPase）Cdc42和Rac1下游的重要靶蛋白,参与调节细胞骨架的重组,提高细胞的运动性和侵袭力,有助于肿瘤的恶性进展.本研究采用免疫组化Envision二步法检测喉癌和喉咽癌组织中PAK1蛋白的表达情况,并探讨其临床病理学意义.

MEKK3在信号转导途径中的表达机制及其与恶性肿瘤的关系

MEKK3 （MAP kinase kinase kinases 3）是丝裂原活化蛋白激酶（mitogenactivated protein kinases, MAPK ）信号转导通路中的重要节点，与恶性肿瘤密切相关，是近年来恶性肿瘤的研究热点。本文就MEKK3在信号转导通路中的表达机制及其与恶性肿瘤的关系、研究进展做了综述。

受体酪氨酸激酶Eph受体与肿瘤的研究进展

Eph （erythropoietin producing human hepatocellular carcinoma cell line） 是已知最大的受体酪氨酸激酶（receptor tyrosine kinases，RTKs）家族最大的一个亚群。Eph不仅在胚胎神经及脉管系统发育和分化中发挥作用，而且在不同组织和细胞之间参与多条信号通路转导和免疫功能的调节，与肿瘤的发生发展等过程密切相关。本文就目前对Eph受体的了解及其与肿瘤相关研究进展进行综述。

丝裂原活化蛋白激酶p38信号传导机制在高温致畸中的作用

高温是常见的致畸因素之一．对多种哺乳动物包括人类具有致畸作用，但高温致畸机制尚不明确。最近研究发现，高温作为外源性刺激会使胚胎发育的敏感期生物体细胞凋亡发生紊乱，引起胚胎发育异常，导致先天畸形的发生。其凋亡作用机制涉及丝裂原活化蛋白激酶（mitagen-activated protein kinases，MAPKs）凋亡信号通路中的丝裂原活化蛋白激酶p38（p38MAPK）．p38MAPK信号传导通路在高温致畸中发挥重要作用，成为高温致畸机制研究的新领域。

间接荧光染色-流式细胞术检测细胞内磷酸化Erk1/2

丝裂源活化的蛋白激酶（mitogen-activatedprotein kinases,MAPKs）家族参与细胞生长、增殖、分化和凋亡等重要过程。MAPK家族成员p42/44MAPK（Erk1/2）在生长因子、细胞因子、营养物质和能量刺激下活化,促进细胞增殖或抵抗凋亡;Erk1/2分子中Thr202和Tyr204位氨基酸残基的磷酸化是其活化的标志[1]。

Ephs/ephrins的结构功能与恶性脑胶质瘤

受体酪氨酸激酶（receptor tyrosine kinases，RTK）家族成员Ephs及其配体ephrins在胚胎发育尤其是中枢神经系统的发育中的作用是目前的研究热点之一。近年来，学者们对Ephs和ephfins诱导恶性肿瘤的发生发展过程产生了极大的兴趣。

蛋白激酶CK2及其抑制剂与头颈部鳞癌的关系

蛋白激酶CK2是真核细胞中普遍存在的第二信使非依赖性丝/苏氨酸蛋白激酶,目前蛋白激酶CK2已成为抗肿瘤的重要靶点之一,其抑制剂具有抗肿瘤作用。本文简介了蛋白激酶CK2的分子结构、主要功能及其作用机制,蛋白激酶CK2抑制剂的分类及其作用机制,蛋白激酶CK2及其抑制剂与头颈部鳞癌的关系。

水稻MAPK基因Os MPK4的克隆鉴定、蛋白表达和转基因载体构建

克隆鉴定了一个水稻促分裂原活化蛋白激酶（mitogen-activated protein kinases, MAPK）基因OsMPK4．OsMPK4基因cDNA全长1483bp，包含一个1131bp的开放阅读框，编码一个由376个氨基酸组成的蛋白，预测分子量为42．8kD．OsMPK4基因位于水稻第10号染色体上，由6个外显子和5个内含子组成．OsMPK4蛋白具有MAPK的11个保守结构域及磷酸化位点TEY模体．系统进化树分析表明，OsMPK4属于B组MAPK成员，与已知水稻MAPK蛋白有56％～74％的一致性．原核表达了OsMPK4基因，纯化获得重组OsMPK4融合蛋白，并构建OsMPK4的转基因双元载体，用于OsMPK4的生化功能及其生物学功能研究．

自噬凋亡通路与肺腺癌EGFR-TKIs治疗策略

表皮生长因子受体酪氨酸激酶抑制剂（epider-mal growth factor receptor tyrosine kinases inhibitor,EGFR-TKIs）是一类作用于细胞内EGFR酪氨酸激酶区的小分子药物,可抑制酪氨酸激酶磷酸化和下游信号传导,抑制肿瘤细胞的损伤修复、使细胞分裂阻滞在G1期、诱导和维持细胞凋亡、抗新生血管形成等[1-3]。