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CAR设计 1

基因编辑 1

嵌合抗原受体（CAR） 1

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Toll-like receptors in innate immunity and infectious diseases

Min-Hao WU, Ping ZHANG, Xi HUANG,

《医学前沿（英文）》 2010年第4卷第4期页码 385-393 doi: 10.1007/s11684-010-0600-x

摘要： The protective ability of host defense system is largely dependent on germ-line encoded pattern-recognition receptors (PRRs). These PRRs respond to a variety of exogenous pathogens or endogenous danger signals, by recognizing some highly conserved structures such as pathogen-associated molecular patterns (PAMPs) and danger/damage associated molecular patterns (DAMPs). The most studied PRRs are Toll-like receptors (TLRs). Activation of TLRs triggers production of inflammatory cytokines and type I interferons (IFNs) via myeloid differentiation primary response gene 88 (MyD88)-dependent or-independent signaling respectively, thereby modulating innate and adaptive immunity, as well as inflammatory responses. This review introduces the classification, structure, and specific ligands of TLRs, and focuses on their signal pathways and biological activities, as well as clinical relevance. These studies of TLRs in the innate immune system have implications for the prevention and treatment of a variety of infectious diseases, including tuberculosis (TB), microbial keratitis, and hepatitis B and C.

关键词： Toll-like receptors innate immunity infectious disease inflammation

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Group III metabotropic glutamate receptors and drug addiction

null

《医学前沿（英文）》 2013年第7卷第4期页码 445-451 doi: 10.1007/s11684-013-0291-1

摘要：

Neuroadaptations of glutamatergic transmission in the limbic reward circuitry are linked to persistent drug addiction. Accumulating data have demonstrated roles of ionotropic glutamate receptors and group I and II metabotropic glutamate receptors (mGluRs) in this event. Emerging evidence also identifies Gαi/o-coupled group III mGluRs (mGluR4/7/8 subtypes enriched in the limbic system) as direct substrates of drugs of abuse and active regulators of drug action. Auto- and heteroreceptors of mGluR4/7/8 reside predominantly on nerve terminals of glutamatergic corticostriatal and GABAergic striatopallidal pathways, respectively. These presynaptic receptors regulate basal and/or phasic release of respective transmitters to maintain basal ganglia homeostasis. In response to operant administration of common addictive drugs, such as psychostimulants (cocaine and amphetamine), alcohol and opiates, limbic group III mGluRs undergo drastic adaptations to contribute to the enduring remodeling of excitatory synapses and to usually suppress drug seeking behavior. As a result, a loss-of-function mutation (knockout) of individual group III receptor subtypes often promotes drug seeking. This review summarizes the data from recent studies on three group III receptor subtypes (mGluR4/7/8) expressed in the basal ganglia and analyzes their roles in the regulation of dopamine and glutamate signaling in the striatum and their participation in the addictive properties of three major classes of drugs (psychostimulants, alcohol, and opiates).

关键词： group III metabotropic glutamate receptors cocaine amphetamine alcohol opiate

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Expression of protease-activated receptors on platelets in healthy individuals

Rui ZHU, Lin SHEN

《医学前沿（英文）》 2009年第3卷第2期页码 236-239 doi: 10.1007/s11684-009-0040-7

摘要： This study aimed to investigate the expression of protease-activated receptors (PARs) on platelets in healthy individuals and preliminarily elucidate physiological functions of PARs. Thirty healthy volunteers, who did not take any anticoagulants and antiplatelet agents within 10 days before the examination, were recruited. Fasting venous blood (5 mL) was taken from the medial cubital vein in each individual and platelet-rich plasma (PRP) was prepared. The expression of PAR1 mRNA and PAR4 mRNA in PRP was determined by RT-PCR analysis. The results showed that the average levels of PAR1 mRNA and PAR4 mRNA on platelets in healthy individuals were 0.1601 ± 0.0269 and 0.1073 ± 0.0194 respectively. In combination with literature analysis, it was concluded that the thrombin signaling pathway plays a vital role in the development of hemostasis and thrombosis, and the selective PARs antagonist has the potential for extensive application in clinical practice.

关键词： protease-activated receptors platelet

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High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells

Synat Kang, Yanyan Li, Yifeng Bao, Yi Li

《医学前沿（英文）》 2019年第13卷第1期页码 69-82 doi: 10.1007/s11684-018-0677-1

摘要：

Cytokine-activated T cells (CATs) can be easily expanded and are widely applied to cancer immunotherapy. However, the good efficacy of CATs is rarely reported in clinical applications because CATs have no or very low antigen specificity. The low-efficacy problem can be resolved using T cell antigen receptor-engineered CAT (TCR-CAT). Herein, we demonstrate that NY-ESO-1_157–165 HLA-A*02:01-specific high-affinity TCR (HAT)-transduced CATs can specifically kill cancer cells with good efficacy. With low micromolar range dissociation equilibrium constants, HAT-transduced CATs showed good specificity with no off-target killing. Furthermore, the high-affinity TCR-CATs delivered significantly better activation and cytotoxicity than the equivalent TCR-engineered T cells (TCR-Ts) in terms of interferon-g and granzyme B production and in vitro cancer cell killing ability. TCR-CAT may be a very good alternative to the expensive TCR-T, which is considered an effective personalized cyto-immunotherapy.

关键词： cytokine-activated T cells high-affinity T cell receptor cancer immunotherapy TCR-CAT

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Distinct roles of ASIC3 and TRPV1 receptors in electroacupuncture-induced segmental and systemic analgesia

null

《医学前沿（英文）》 2016年第10卷第4期页码 465-472 doi: 10.1007/s11684-016-0482-7

摘要：

Previous studies have demonstrated the effects of different afferent fibers on electroacupuncture (EA)-induced analgesia. However, contributions of functional receptors expressed on afferent fibers to the EA analgesia remain unclear. This study investigates the roles of acid-sensing ion channel 3 (ASIC3) and transient receptor potential vanilloid 1 (TRPV1) receptors in EA-induced segmental and systemic analgesia. Effects of EA at acupoint ST36 with different intensities on the C-fiber reflex and mechanical and thermal pain thresholds were measured among the ASIC3⁻^/⁻, TRPV1⁻^/⁻, and C57BL/6 mice. Compared with C57BL/6 mice, the ipsilateral inhibition of EA with 0.8 C-fiber threshold (0.8Tc) intensity on C-fiber reflex was markedly reduced in ASIC3⁻^/⁻ mice, whereas the bilateral inhibition of 1.0 and 2.0Tc EA was significantly decreased in TRPV1⁻^/⁻ mice. The segmental increase in pain thresholds induced by 0.3 mA EA was significantly reduced in ASIC3⁻^/⁻ mice, whereas the systemic enhancement of 1.0 mA EA was markedly decreased in TRPV1⁻^/⁻ mice. Thus, segmental analgesia of EA with lower intensity is partially mediated by ASIC3 receptor on Aβ-fiber, whereas systemic analgesia induced by EA with higher intensity is more likely induced by TRPV1 receptor on Ad- and C-fibers.

关键词： electroacupuncture analgesia ASIC3 TRPV1 C-fiber reflex

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嵌合抗原受体和调节性T细胞——移植中人类白细胞抗原特异性免疫抑制的潜力 Review

Sabrina Wright, Conor Hennessy, Joanna Hester, Fadi Issa

《工程（英文）》 2022年第10卷第3期页码 30-43 doi: 10.1016/j.eng.2021.10.018

摘要：

嵌合抗原受体（CAR）是基因工程领域的一项突破，它彻底改变了过继细胞疗法（ACT）领域。表达这些受体的细胞通过在合成的CAR构建体中包含抗原特异性结合区域而被重新定向到预定的靶点。程序化特异性细胞在肿瘤学领域的优势已被临床证明，与同类未修饰的细胞相比，这种细胞具有更高的准确性、效力与更少的脱靶效应。与常规T细胞（Tconvs）不同，调节性T细胞（Treg）在抑制免疫激活和调节宿主免疫反应方面发挥着重要作用。Treg 中CAR的表达被认为是治疗自身免疫和炎症性疾病、移植物抗宿主病（GVHD）和器官移植排斥反应的一种方法。在后者中，它们作为同种异体移植受者免疫耐受的介质具有巨大的潜力。然而，目前对CAR-Treg 工程的研究非常有限，并且关于治疗用途的最佳设计存在不确定性。本文综述了CAR-Treg 发展的理论基础、其对人类移植的意义、潜在的设计、安全性考虑因素，以及迄今为止CAR-Treg在移植模型中的对比。

关键词：嵌合抗原受体（CAR）调节性T细胞异性免疫 CAR设计基因编辑

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Anti-β glycoprotein I antibodies in complex with β2 glycoprotein I induce platelet activation via two receptors

null

《医学前沿（英文）》 2016年第10卷第1期页码 76-84 doi: 10.1007/s11684-015-0426-7

摘要：

Anti-β₂ glycoprotein I (anti-β₂GP I ) antibodies are important contributors to thrombosis, especially in patients with antiphospholipid syndrome (APS). However, the mechanism by which anti-β₂GP I antibodies are involved in the pathogenesis of thrombosis is not fully understood. In this report, we investigated the role of anti-β₂GP I antibodies in complexes with β₂GP I as mediators of platelet activation, which can serve as a potential source contributing to thrombosis. We examined the involvement of the apolipoprotein E receptor 2' (apoER2') and glycoprotein I ba (GP I bα) in platelet activation induced by the anti-β₂GP I /β₂GP I complex. The interaction between the anti-β₂GP I /β₂GP I complex and platelets was examined using in vitro methods, in which the Fc portion of the antibody was immobilized using protein A coated onto a microtiter plate. Platelet activation was assessed by measuring GP II b/ III a activation and P-selectin expression and thromboxane B₂ production as well as p38 mitogen-activated protein kinase phosphorylation. Our results revealed that the anti-β₂GP I /β₂GP I complex was able to activate platelets, and this activation was inhibited by either the anti-GP I bα antibody or the apoER2' inhibitor. Results showed that the anti-β₂GP I /β₂GP I complex induced platelet activation via GP I bα and apoER2', which may then contribute to the prothrombotic tendency in APS patients.

关键词： anti-β2GP I /β2GP I complex platelet GP I bα apoER2' thrombosis

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A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal carcinoma

《医学前沿（英文）》 2023年第17卷第2期页码 275-289 doi: 10.1007/s11684-022-0945-y

摘要： The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC.

关键词： epidermal growth factor receptor ErbB receptors HM781-36B nasopharyngeal carcinoma molecular targeted therapy cisplatin

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Construction and identification of lentiviral RNA interference vector of rat leptin receptor gene

Zhengjuan LIU, Jie BIAN, Yuchuan WANG, Yongli ZHAO, Dong YAN, Xiaoxia WANG

《医学前沿（英文）》 2009年第3卷第1期页码 57-60 doi: 10.1007/s11684-009-0003-z

摘要： Leptin resistance is a main mechanism of acquired childhood obesity, and the suppression of long form of leptin receptor (OBRb) gene expression in diet-induced obese rats indicates that the down-regulation of OBRb gene expression plays a pivotal role in the mechanism of leptin resistance. The aim of the present study was to construct the lentiviral RNA interference (RNAi) vector of rat OBRb gene and evaluate the effects of siRNA on silencing OBRb gene expression. The target sequence of siRNA-OBRb was designed, and the complementary DNA containing both sense and antisense oligonucleotides was synthesized. After phosphorylation and annealing, these double-stranded DNA was cloned to pRNA-lentivector-VGFP to construct pRNA-Lenti-OBRb-VGFP recombinants with U6-containing promoter, target sequence and Poly III terminator. Then, the products were confirmed by electrophoresis and sequencing analysis, and the effects of RNAi on reducing gene expression were further confirmed by real-time polymerase chain reaction in transfected rat glioma cells expressing OBRb. The target sequence of siRNA-OBRb was successfully cloned to pRNA-lentivector-VGFP, and the RNAi protocol specifically reduced the expression of OBRb mRNA by approximately 80% compared with controls in transfected rat glioma cells. The successful construction of rat lentivirus vectors expressing OBRb-specific shRNA may be useful for further investigation .

关键词： receptors leptin RNA interference lentivirus vector