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Therapeutic potential of Parkin and its regulation in Parkinson's disease. 帕金森病中 Parkin 及其调控的治疗潜力。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-03 DOI: 10.1016/j.bcp.2024.116600
N Safreena, Indu C Nair, Goutam Chandra

Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the midbrain substantia nigra, resulting in motor and non-motor symptoms. While the exact etiology of PD remains elusive, a growing body of evidence suggests that dysfunction in the parkin protein plays a pivotal role in the pathogenesis of the disease. Parkin is an E3 ubiquitin ligase that ubiquitinates substrate proteins to control a number of crucial cellular processes including protein catabolism, immune response, and cellular apoptosis.While autosomal recessive mutations in the PARK2 gene, which codes for parkin, are linked to an inherited form of early-onset PD, heterozygous mutations in PARK2 have also been reported in the more commonly occurring sporadic PD cases. Impairment of parkin's E3 ligase activity is believed to play a pathogenic role in both familial and sporadic forms of PD.This article provides an overview of the current understanding of the mechanistic basis of parkin's E3 ligase activity, its major physiological role in controlling cellular functions, and how these are disrupted in familial and sporadic PD. The second half of the manuscript explores the currently available and potential therapeutic strategies targeting parkin structure and/or function in order to slow down or mitigate the progressive neurodegeneration in PD.

帕金森病(Parkinson's disease,PD)是一种令人衰弱的神经退行性疾病,其特征是中脑黑质多巴胺能神经元的逐渐丧失,从而导致运动和非运动症状。虽然帕金森病的确切病因仍难以确定,但越来越多的证据表明,帕金蛋白的功能障碍在该病的发病机制中起着关键作用。Parkin是一种E3泛素连接酶,可泛素化底物蛋白,以控制一系列关键的细胞过程,包括蛋白质分解、免疫反应和细胞凋亡。Parkin编码的PARK2基因的常染色体隐性突变与早发型帕金森氏症的遗传形式有关,而在更常见的散发性帕金森氏症病例中也有PARK2基因杂合突变的报道。本文概述了目前对 Parkin 的 E3 连接酶活性的机理基础、它在控制细胞功能方面的主要生理作用以及这些作用在家族性和散发性帕金森病中是如何被破坏的认识。手稿的后半部分探讨了针对帕金蛋白结构和/或功能的现有和潜在治疗策略,以减缓或减轻帕金森病的进行性神经变性。
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引用次数: 0
Interleukin-6 in non-infectious uveitis: Biology, experimental evidence and treatment strategies 非感染性葡萄膜炎中的白细胞介素-6:生物学、实验证据和治疗策略。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-02 DOI: 10.1016/j.bcp.2024.116605
Uveitis is the leading cause of visual impairment worldwide. Interleukin-6 (IL-6), which is upregulated in response to inflammation, is one of the most important inflammatory cytokines associated with uveitis. Two major IL-6 receptors (IL-6R) mediate the pro-inflammatory and anti-inflammatory biological effects of IL-6. This review summarized multiple perspectives on the mechanism of IL-6-mediated uveitis, based on experimental evidence from clinical and animal models. It includes discussions on the roles of the downstream IL-6 signaling pathway, immunocytes, and the blood-retinal barrier. Therapeutic strategies aimed at blocking the action of IL-6 have progressed in clinical practice. However, due to the adverse events associated with existing biologics including infections, drugs that selectively inhibit intraocular IL-6 still require further development. The novel concept of converting the pro-inflammatory effects of IL-6 into protective effects also requires further research. In addition, the relationship between the trans-presentation of IL-6R and T-helper17 cells in uveitis remains unexplored. This review aims to consolidate our current understanding of the biology, signaling pathways, experimental models, and immune pathogenesis related to IL-6 and uveitis. We also discuss clinical strategies focused on blocking IL-6 as a treatment for uveitis. Targeting IL-6 provides unlimited potential for improving the diagnosis, treatment, and prognosis of uveitis.
葡萄膜炎是全球视力受损的主要原因。白细胞介素-6(IL-6)在炎症反应中上调,是与葡萄膜炎相关的最重要的炎症细胞因子之一。两种主要的 IL-6 受体(IL-6R)介导了 IL-6 的促炎和抗炎生物效应。本综述基于临床和动物模型的实验证据,从多个角度总结了 IL-6 介导葡萄膜炎的机制。其中包括对下游 IL-6 信号通路、免疫细胞和血液-视网膜屏障作用的讨论。旨在阻断 IL-6 作用的治疗策略在临床实践中取得了进展。然而,由于现有生物制剂存在感染等不良反应,选择性抑制眼内 IL-6 的药物仍需进一步开发。将 IL-6 的促炎作用转化为保护作用的新概念也需要进一步研究。此外,葡萄膜炎中 IL-6R 的转呈与 T-helper17 细胞之间的关系仍有待探索。本综述旨在巩固我们目前对 IL-6 与葡萄膜炎相关的生物学、信号通路、实验模型和免疫发病机制的理解。我们还讨论了以阻断 IL-6 作为葡萄膜炎治疗方法的临床策略。以IL-6为靶点可为改善葡萄膜炎的诊断、治疗和预后提供无限潜力。
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引用次数: 0
Targeting fibroblast activation protein with chimeric antigen receptor macrophages. 用嵌合抗原受体巨噬细胞靶向成纤维细胞活化蛋白。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-01 DOI: 10.1016/j.bcp.2024.116604
Yizhi Mao, Chen Yao, Shimeng Zhang, Qi Zeng, Jing Wang, Chunjie Sheng, Shuai Chen

Under the rapid advancement of chimeric antigen receptor T cell (CAR-T) technology, CAR-macrophages (CAR-Ms) are also being developed currently in the pre-clinical stage and have been shown to inhibit tumor growth in several mouse tumor models. Fibroblast activation protein (FAP) is a type II transmembrane serine protease, which is expressed in stromal fibroblasts of over 90 % of common human epithelial cancers and is upregulated in fibrotic diseases of the liver, lung and colon, etc. In this study, we firstly constructed FAP-CAR macrophages to target FAP+ cells through in vitro phagocytosis assays. In subsequent in vivo assays, we discovered that FAP-CAR-ΔZETA bone marrow-derived macrophages (BMDMs) rather than FAP-CAR BMDMs, exhibited a pronounced anti-tumor effect in mouse subcutaneous MC38 colon cancer model. In addition, FAP-CAR and FAP-CAR-ΔZETA BMDMs therapy could effectively improve CCl4-induced liver fibrosis in mice. Collectively CAR-Ms targeting FAP demonstrated great therapeutic potential in cancer and liver fibrosis therapy.

随着嵌合抗原受体 T 细胞(CAR-T)技术的快速发展,CAR-巨噬细胞(CAR-Ms)目前也处于临床前开发阶段,并已在多个小鼠肿瘤模型中显示出抑制肿瘤生长的作用。成纤维细胞活化蛋白(FAP)是一种Ⅱ型跨膜丝氨酸蛋白酶,在90%以上的常见人类上皮癌的基质成纤维细胞中表达,并在肝脏、肺部和结肠等纤维化疾病中上调。在本研究中,我们首先构建了 FAP-CAR 巨噬细胞,通过体外吞噬实验靶向 FAP+ 细胞。在随后的体内试验中,我们发现在小鼠皮下 MC38 结肠癌模型中,FAP-CAR-ΔZETA 骨髓衍生巨噬细胞(BMDMs)而非 FAP-CAR BMDMs 具有明显的抗肿瘤作用。此外,FAP-CAR 和 FAP-CAR-ΔZETA BMDMs 还能有效改善 CCl4 诱导的小鼠肝纤维化。总之,靶向FAP的CAR-Ms在癌症和肝纤维化治疗中展现出了巨大的治疗潜力。
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引用次数: 0
Epoxytiglianes induce keratinocyte wound healing responses via classical protein kinase C activation to promote skin re-epithelialization 环氧替格连内酯通过经典的蛋白激酶 C 激活诱导角质形成细胞的伤口愈合反应,从而促进皮肤再上皮化。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-01 DOI: 10.1016/j.bcp.2024.116607
Epoxytiglianes are a novel class of diterpene esters. The prototype epoxytigliane, EBC-46 (tigilanol tiglate), is a potent anti-cancer agent in clinical development for local treatment of a range of human and animal tumors. EBC-46 also consistently promotes wound re-epithelialization at the treatment sites, mediated via activation of classical protein kinase C (PKC) isoforms. We have previously shown that epoxytiglianes stimulate proliferative and wound repopulation responses in immortalized human skin keratinocytes (HaCaTs) in vitro, abrogated by pan-PKC inhibitor, bisindolylmaleimide-1. In this study, we further investigate the specific PKC isoforms responsible for inducing such wound healing responses, following HaCaT treatment with 1.51 nM-15.1 µM EBC-46 or analogue, EBC-211. Classical PKC inhibition by GӦ6976 (1 μM), significantly attenuated epoxytigliane induced, HaCaT proliferation and wound repopulation at all epoxytigliane concentrations. PKC-βI/-βII isoform inhibition by enzastaurin (1 μM), significantly inhibited HaCaT proliferation and wound repopulation responses induced by both epoxytiglianes, especially at 1.51–151 nM. PKC-α inhibitor, Ro 31–8220 mesylate (10 nM), exerted lesser inhibitory effects on HaCaT responses. Epoxytigliane changes in key keratin (KRT17) and cell cycle (cyclin B1, CDKN1A) protein levels were partly attenuated by GӦ6976 and enzastaurin. GӦ6976 also inhibited increases in matrix metalloproteinase (MMP-1, MMP-7, MMP-10) activities. Phospho-PKC (p-PKC) studies confirmed that epoxytiglianes transiently activated classical PKC isoforms (p-PKCα, p-PKC-βI/-βII, p-PKCγ) in a dose- and time-dependent manner. By identifying how epoxytiglianes stimulate classical PKCs to facilitate keratinocyte healing responses and re-epithelialization, these findings support further epoxytigliane development as topical therapeutics for clinical situations involving impaired re-epithelialization, such as non-healing wounds in skin.
环氧替格连酯是一类新型的二萜酯。环氧替格连酯的原型 EBC-46(替吉烷醇替吉烷酸酯)是一种强效抗癌剂,目前正处于临床开发阶段,可用于一系列人类和动物肿瘤的局部治疗。EBC-46 还通过激活经典的蛋白激酶 C(PKC)同工酶,持续促进治疗部位的伤口再上皮化。我们以前的研究表明,环氧替格连内酯可刺激体外永生化人类皮肤角质细胞(HaCaTs)的增殖和伤口再填充反应,而泛 PKC 抑制剂双吲哚马来酰亚胺-1 则可抑制这种反应。在本研究中,我们进一步研究了用 1.51 nM-15.1 µM EBC-46 或类似物 EBC-211 处理 HaCaT 后,负责诱导这种伤口愈合反应的特定 PKC 同工酶。用 GӦ6976 (1 μM)对 PKC 进行经典抑制,可显著减少所有环氧替吉利安浓度下环氧替吉利安诱导的 HaCaT 增殖和伤口再填充。用恩杂陶灵(1 μM)抑制 PKC-βI/-βII 同工酶,可明显抑制两种环氧替格连内酯诱导的 HaCaT 增殖和伤口再增殖反应,尤其是在 1.51-151 nM 的浓度下。PKC-α 抑制剂甲磺酸 Ro 31-8220(10 nM)对 HaCaT 反应的抑制作用较小。关键角蛋白(KRT17)和细胞周期(细胞周期蛋白 B1、CDKN1A)蛋白水平的环氧三烯酸变化在一定程度上受到 GӦ6976 和 enzastaurin 的抑制。GӦ6976还抑制了基质金属蛋白酶(MMP-1、MMP-7、MMP-10)活性的增加。磷酸化 PKC(p-PKC)研究证实,环氧替格连内酯能以剂量和时间依赖性的方式瞬时激活经典的 PKC 异构体(p-PKCα、p-PKC-βI/-βII、p-PKCγ)。通过确定环氧替格连内酯如何刺激经典 PKC 促进角朊细胞愈合反应和再上皮化,这些研究结果支持进一步将环氧替格连内酯开发成局部治疗药物,用于治疗皮肤伤口不愈合等再上皮化受损的临床情况。
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引用次数: 0
Acetyl tributyl citrate attenuates 5-fluorouracil-induced inflammation, oxidative stress, and apoptosis in human keratinocytes 柠檬酸乙酰三丁酯可减轻 5-氟尿嘧啶诱导的人类角朊细胞炎症、氧化应激和细胞凋亡。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-01 DOI: 10.1016/j.bcp.2024.116606
5-Fluorouracil (5-FU) is a commonly used chemotherapy drug that effectively destroys cancer cells. Despite its widespread use and efficacy, it also presents considerable challenges, particularly with adverse effects on rapidly dividing normal cells, such as keratinocytes. These detrimental effects are attributed to inflammatory, oxidative, and apoptotic potentials, leading to severe skin disorders. Due to the lack of specific remedies for 5-FU-induced dermatological side effects, conventional treatments are applied instead, which provide limited relief and have drawbacks. This study investigated the impact of acetyl tributyl citrate (ATBC) in 5-FU-treated human keratinocytes. The findings indicated that ATBC substantially reduced inflammation caused by 5-FU, as demonstrated by nuclear translocation of nuclear factor kappa B and expression of its downstream genes, including tumor necrosis factor, interleukin 1 beta (IL1B), and IL6. ATBC also markedly decreased oxidative stress, indicated by reactive oxygen species levels and the antioxidant gene expression such as superoxide dismutase 1 (SOD1), SOD2, and heme oxygenase 1 in 5-FU-treated cells. Furthermore, ATBC attenuated 5-FU-induced apoptosis, as determined by lactate dehydrogenase release and Annexin V/propidium iodide flow cytometry, with the potential involvement of interferon-related genes. Following this, protein kinase C delta was predicted as a possible molecular target of ATBC. These findings propose ATBC as a therapeutic agent for managing the cutaneous side effects associated with 5-FU treatment.
5-氟尿嘧啶(5-FU)是一种常用的化疗药物,能有效摧毁癌细胞。尽管这种药物被广泛使用且疗效显著,但它也带来了相当大的挑战,尤其是对快速分裂的正常细胞(如角质形成细胞)的不利影响。这些不利影响可归因于炎症、氧化和凋亡潜能,从而导致严重的皮肤疾病。由于缺乏针对 5-FU 引起的皮肤病副作用的特效疗法,人们只能采用传统疗法,但这些疗法的缓解效果有限,而且存在缺陷。本研究调查了柠檬酸乙酰三丁酯(ATBC)对 5-FU 处理的人类角质细胞的影响。研究结果表明,ATBC 大大减少了 5-FU 引起的炎症,核因子卡巴 B 的核转位及其下游基因(包括肿瘤坏死因子、白细胞介素 1 beta(IL1B)和 IL6)的表达均证明了这一点。ATBC 还能显著降低氧化应激,这体现在 5-FU 处理细胞中的活性氧水平和超氧化物歧化酶 1 (SOD1)、SOD2 和血红素加氧酶 1 等抗氧化基因的表达上。此外,通过乳酸脱氢酶释放和附件素 V/碘化丙啶流式细胞术测定,ATBC 可减轻 5-FU 诱导的细胞凋亡,这可能与干扰素相关基因的参与有关。随后,蛋白激酶 C delta 被预测为 ATBC 可能的分子靶点。这些发现建议将 ATBC 作为一种治疗药物,用于控制与 5-FU 治疗相关的皮肤副作用。
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引用次数: 0
Targeting IL-17 and its receptors: A feasible way for natural herbal medicines to modulate fibroblast-like synoviocytes in rheumatoid arthritis 靶向 IL-17 及其受体:天然草药调节类风湿性关节炎成纤维细胞样滑膜细胞的可行方法。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-30 DOI: 10.1016/j.bcp.2024.116598
Rheumatoid arthritis (RA) is characterized by processive synovial hyperplasia and abnormal proliferation of fibroblast-like synoviocytes (FLSs), and can eventually lead to progressive joint destruction. Increasing evidence has demonstrated that cytokines play pivotal roles in the pathogenesis of RA. In particular, the production of interleukin (IL)-17 by T helper 17 (Th17) cells is closely associated with the development of RA, and inhibition of IL-17/IL-17R could regulate the production of inflammatory factors by FLSs, which may be a feasible way to reduce inflammation and bone destruction in RA. Currently, accumulating evidence suggests that the utilization of natural herbal medicines is advantageous in the management of RA. In our present paper, a comprehensive reference search was conducted of the classic Materia Medica books, literature, online databases, academic search engines, and MS. or Ph. D theses. In conclusion, natural herbal medicines with antirheumatic activities that modulate FLSs by targeting IL-17/IL-17R were summarized. Furthermore, we also discuss the limitations and potential research directions for the future development of natural herbal medicines as candidate drugs for RA management in the clinic.
类风湿性关节炎(RA)的特点是滑膜增生和成纤维细胞样滑膜细胞(FLS)的异常增殖,最终可导致进行性关节破坏。越来越多的证据表明,细胞因子在 RA 的发病机制中起着关键作用。抑制IL-17/IL-17R可调节FLS产生炎症因子,这可能是减少RA炎症和骨破坏的可行方法。目前,越来越多的证据表明,利用天然草药治疗 RA 具有优势。本文对经典本草书籍、文献、在线数据库、学术搜索引擎以及硕士或博士论文进行了全面的参考检索。最后,我们总结了通过靶向 IL-17/IL-17R 来调节 FLSs 的具有抗风湿活性的天然草药。此外,我们还讨论了天然草药作为候选药物在临床上治疗RA的局限性和未来发展的潜在研究方向。
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引用次数: 0
Protective role of 2-aminothiazole derivative against ethanol-induced teratogenic effects in-vivo zebrafish 2-aminothiazole 衍生物对乙醇诱导的体内斑马鱼致畸效应的保护作用。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-30 DOI: 10.1016/j.bcp.2024.116601
Teratology investigates the origins of congenital disabilities, often linked to environmental factors such as ethanol (EtOH) exposure. Ethanol at 150 μM has been associated with teratogenic effects, oxidative stress, immunological responses, and endocrine disruptions. Fetal alcohol spectrum disorder (FASD) arises from maternal alcohol consumption during pregnancy, leading to developmental delays and cognitive impairment. Due to their diverse therapeutic applications, amino thiazole derivatives are crucial in drug development. This study aimed to determine whether the 2-amino thiazole derivative, notably the 1-(4-chlorophenyl)-N-(6-nitrobenzo[d]thiazol-2-yl)ethan-1-imine (N4) compound, reduces teratogenic effects induced by embryonic EtOH exposure in a zebrafish model. Teratogenic effects, mortality, locomotion behaviour, oxidative stress, gene expression, and tissue damage were evaluated in larvae over a 7-day experimental period using three treatment concentrations (50, 100, and 150 μM). Results showed that EtOH induced morphological defects in the head, eyes, and body length of exposed larvae, along with behavioural abnormalities and oxidative damage. N4 effectively mitigated these toxic effects in a concentration-dependent manner, reducing oxidative damage, preventing teratogenic effects, and averting tissue damage induced by EtOH exposure. This study highlights the potential of N4 to enhance antioxidant and anti-inflammatory effects against ethanol-induced oxidative stress, offering promising therapeutic strategies for FASD treatment.
畸胎学研究先天性残疾的起源,这通常与环境因素有关,如接触乙醇(EtOH)。150 μM 的乙醇与致畸作用、氧化应激、免疫反应和内分泌紊乱有关。胎儿酒精谱系障碍(FASD)源于母亲在怀孕期间饮酒,导致发育迟缓和认知障碍。由于氨基噻唑衍生物具有多种治疗用途,因此在药物开发中至关重要。本研究旨在确定 2-氨基噻唑衍生物,特别是 1-(4-氯苯基)-N-(6-硝基苯并[d]噻唑-2-基)乙烷-1-亚胺(N4)化合物,是否能在斑马鱼模型中减少胚胎暴露于乙醇引起的致畸效应。在为期 7 天的实验中,使用三种处理浓度(50、100 和 150 μM)对斑马鱼幼体的致畸效应、死亡率、运动行为、氧化应激、基因表达和组织损伤进行了评估。结果表明,EtOH 会导致暴露幼虫的头部、眼睛和体长出现形态缺陷,同时还会导致行为异常和氧化损伤。N4 以浓度依赖性的方式有效减轻了这些毒性效应,减少了氧化损伤,防止了致畸效应,并避免了暴露于乙醇引起的组织损伤。这项研究强调了 N4 在增强抗氧化和抗炎作用以对抗乙醇诱导的氧化应激方面的潜力,为治疗 FASD 提供了有前景的治疗策略。
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引用次数: 0
Fat mass and obesity-associated protein alleviates cerebral ischemia/reperfusion injury by inhibiting ferroptosis via miR-320-3p/SLC7A11 axis 脂肪量和肥胖相关蛋白通过 miR-320-3p/SLC7A11 轴抑制铁蛋白沉积减轻脑缺血再灌注损伤
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-30 DOI: 10.1016/j.bcp.2024.116603
Fat mass and obesity-associated protein (FTO) is a demethylase and has recently been found to have a protective effect in acute ischemic stroke (AIS), but the underlying mechanism is unclear to a large extent. New studies have found that the expression of certain miRNAs may be affected by N6-methyladenosine (m6A) levels. Here, using high-throughput sequencing and quantitative polymerase chain reaction, we found miR-320-3p was significantly up-regulated in AIS patients. miR-320-3p aggravated the neurobehavioral manifestation, infarct volume and histopathology of middle cerebral artery occlusion/reperfusion model mice. Mechanically, miR-320-3p binds to the 3′ untranslated region of solute carrier family 7 member 11 (SLC7A11) mRNA, promoting oxidative stress and ferroptosis induced by oxygen-glucose deprivation/reoxygenation in neurons. FTO inhibited the m6A methylation of the primary transcript pri-miR-320 and the maturation of miR-320-3p, thus having a protective effect on cerebral ischemia/reperfusion injury after AIS. Clinically, we also confirmed the down-regulation of FTO and SLC7A11 mRNA in the peripheral blood of AIS patients and their correlation with the expression of miR-320-3p. Our study found that FTO inhibits ferroptosis through miR-320-3p/SLC7A11 axis in an m6A-dependent manner, and thus has a protective effect on cerebral ischemic reperfusion injury. Our results provided a promising therapeutic target of cerebral ischemia/reperfusion injury after AIS.
脂肪量与肥胖相关蛋白(FTO)是一种去甲基化酶,最近发现它对急性缺血性中风(AIS)有保护作用,但其潜在机制在很大程度上还不清楚。新的研究发现,某些 miRNA 的表达可能受 N6-甲基腺苷(m6A)水平的影响。在此,我们利用高通量测序和定量聚合酶链反应发现,miR-320-3p 在 AIS 患者中显著上调;miR-320-3p 会加重大脑中动脉闭塞/再灌注模型小鼠的神经行为表现、梗死体积和组织病理学。在机制上,miR-320-3p 与溶质运载家族 7 成员 11(SLC7A11)mRNA 的 3' 非翻译区结合,促进氧化应激和缺氧-葡萄糖/复氧诱导的神经元铁蛋白沉积。FTO 可抑制主转录本 pri-miR-320 的 m6A 甲基化和 miR-320-3p 的成熟,从而对 AIS 后的脑缺血再灌注损伤具有保护作用。在临床上,我们也证实了 AIS 患者外周血中 FTO 和 SLC7A11 mRNA 的下调及其与 miR-320-3p 表达的相关性。我们的研究发现,FTO通过miR-320-3p/SLC7A11轴以m6A依赖的方式抑制铁氧化,从而对脑缺血再灌注损伤具有保护作用。我们的研究结果为 AIS 后脑缺血再灌注损伤提供了一个很有前景的治疗靶点。
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引用次数: 0
Insights into the modulatory effects of host-gut microbial xanthine co-metabolism on high-fat diet-fed mice 洞察宿主-肠道微生物黄嘌呤协同代谢对高脂饮食喂养小鼠的调节作用。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-29 DOI: 10.1016/j.bcp.2024.116596
Gut microbiota-mediated endobiotic and xenobiotic metabolism play crucial roles in disease progression, and drug therapy/toxicity. Our recent study suggested that gut microbiota-mediated xanthine metabolism is correlated with resistance to high-fat diet (HFD)-induced obesity. Here, we explored the role of host-gut microbial xanthine co-metabolism in the prevention and treatment of HFD-induced obesity by orally administration of Bifidobacterium longum, xanthine, and a xanthine oxidase inhibitor (topiroxostat). The findings indicate that xanthine exhibits a significantly protective effect against HFD-induced obesity. While B. longum, xanthine, and topiroxostat did not alleviate the dysbiosis of the weight and glucose metabolism of HFD-induced obesity (DIO) and obesity resistance (DIR) mice. 16S rRNA sequencing analyses revealed that treatments with B. longum significantly altered gut microbiota composition in HFD-fed and DIO mice. Microbial interaction network analysis revealed several Bacteroidetes species, such as Amulumruptor caecigallinarius and Muribaculum intestinale, as keystone taxa that were notably enriched by B. longum. Untargeted metabolomics analysis implied that xanthine might serve as a crucial molecule in regulating body weight, exerting a preventive effect on HFD-induced obesity. This study offers new perspectives on the influence of host-gut microbial xanthine co-metabolism on HFD-fed mice and emphasizes the promising role of xanthine in promoting weight loss
肠道微生物群介导的内生物和外生物代谢在疾病进展和药物治疗/毒性方面发挥着至关重要的作用。我们最近的研究表明,肠道微生物群介导的黄嘌呤代谢与抵抗高脂饮食(HFD)诱导的肥胖相关。在此,我们通过口服长双歧杆菌、黄嘌呤和黄嘌呤氧化酶抑制剂(托吡罗司他),探讨了宿主-肠道微生物黄嘌呤协同代谢在预防和治疗高脂饮食诱发肥胖中的作用。研究结果表明,黄嘌呤对高氟酸诱导的肥胖具有明显的保护作用。长春花酵母菌、黄嘌呤和托吡咯司他并不能缓解高频分解诱导肥胖(DIO)和肥胖抵抗(DIR)小鼠体重和糖代谢紊乱。16S rRNA测序分析表明,使用长春花酵母菌治疗可显著改变HFD喂养小鼠和DIO小鼠的肠道微生物群组成。微生物相互作用网络分析揭示了几个类杆菌属物种,如Amulumruptor caecigallinarius和Muribaculum intestinale,它们是关键的类群,被龙胆球菌明显富集。非靶向代谢组学分析表明,黄嘌呤可能是调节体重的关键分子,对高氟酸诱导的肥胖具有预防作用。这项研究为研究宿主-肠道微生物黄嘌呤协同代谢对HFD喂养小鼠的影响提供了新的视角,并强调了黄嘌呤在促进体重减轻方面的作用。
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引用次数: 0
Defects of parvalbumin-positive interneurons are implicated in psychiatric disorders 副发光素阳性中间神经元的缺陷与精神疾病有关。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-29 DOI: 10.1016/j.bcp.2024.116599
Psychiatric disorders are a common cause of severe long-term disability and socioeconomic burden worldwide. Although our understanding of these disorders has advanced substantially over the last few years, little has changed the standards of care for these illnesses. Fast-spiking parvalbumin-positive interneurons (PVIs), a subpopulation of gamma-aminobutyric acid (GABA)ergic interneurons, are widely distributed in the hippocampus and have been reported to play an important role in various mental disorders. However, the mechanisms underlying the regulation of the molecular networks relevant to depression and schizophrenia (SCZ) are unknown. Here, we discuss the functions of PVIs in psychiatric disorders, including depression and SCZ. After reviewing several studies, we concluded that dysfunction in PVIs could cause depression-like behavior, as well as cognitive categories in SCZ, which might be mediated in large part by greater synaptic variability. In summary, this scientific review aims to discuss the current knowledge regarding the function of PVIs in depression and SCZ. Moreover, we highlight the importance of neurogenesis and synaptic plasticity in the pathogenesis of depression and SCZ, which seem to be mediated by PVIs activity. These findings provide a better understanding of the role of PVIs in psychiatric disorders.
精神障碍是造成全球严重长期残疾和社会经济负担的常见原因。尽管在过去几年中,我们对这些疾病的认识有了长足的进步,但对这些疾病的治疗标准却没有什么改变。快速尖峰副发光素阳性中间神经元(PVIs)是γ-氨基丁酸(GABA)能中间神经元的一个亚群,广泛分布于海马中,据报道在各种精神障碍中发挥着重要作用。然而,与抑郁症和精神分裂症(SCZ)相关的分子网络的调控机制尚不清楚。在此,我们讨论了 PVIs 在抑郁症和精神分裂症等精神疾病中的功能。在回顾了多项研究后,我们得出结论:PVIs 的功能障碍可能会导致类似抑郁症的行为以及 SCZ 的认知类别,而这在很大程度上可能是由突触的更大变异性介导的。总之,这篇科学综述旨在讨论当前有关 PVIs 在抑郁症和 SCZ 中的功能的知识。此外,我们还强调了神经发生和突触可塑性在抑郁症和 SCZ 发病机制中的重要性,而这似乎是由 PVIs 活性介导的。这些发现使我们对 PVIs 在精神疾病中的作用有了更好的理解。
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Biochemical pharmacology
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