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Effects of protein glycation and protective mechanisms against glycative stress 蛋白质糖化的影响和糖化应激的保护机制
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-25 DOI: 10.1016/j.coph.2024.102464
Jade A. Najjar, John W. Calvert

Glycation is a posttranslational modification of proteins that contributes to the vast array of biological information that can be conveyed via a singular proteome. Understanding the role of advanced glycation end-products (AGEs) in human health and pathophysiology can be difficult, as the physiological effects of AGEs have been associated with multiple biological processes and disease state development, including acute myocardial ischemia-reperfusion injury, heart failure, and atherosclerosis, as well as tumor cell migration. The critical role of the glyoxalase system in the detoxification of methylglyoxal and other AGEs has been well established. Recently, evidence has emerged that DJ-1 displays antiglycative activity and may contribute to another mechanism of protection against protein glycation outside of the glyoxalase system. Identification of potential substrates of DJ-1 and determination of the pathways in which DJ-1 operates, is needed to fully understand the role of this protein in modulating biological homeostasis and the development of disease.

糖化是蛋白质的一种翻译后修饰,可通过单个蛋白质组传递大量生物信息。了解高级糖化终产物(AGEs)在人类健康和病理生理学中的作用可能很困难,因为 AGEs 的生理效应与多种生物过程和疾病状态的发展有关,包括急性心肌缺血再灌注损伤、心力衰竭、动脉粥样硬化以及肿瘤细胞迁移。乙二醛酶系统在甲基乙二醛和其他 AGEs 的解毒过程中的关键作用已得到公认。最近有证据表明,DJ-1 具有抗糖化活性,可能是乙二醛酶系统之外另一种防止蛋白质糖化的机制。要全面了解 DJ-1 蛋白在调节生物稳态和疾病发展中的作用,就需要鉴定 DJ-1 的潜在底物并确定 DJ-1 的作用途径。
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引用次数: 0
Pharmaceutical therapies targeting autophagy for the treatment of age-related macular degeneration 治疗老年性黄斑变性的自噬药物疗法
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-23 DOI: 10.1016/j.coph.2024.102463
Kirstan A. Vessey , Andrew I. Jobling , Ursula Greferath , Erica L. Fletcher

Age-related macular degeneration (AMD) is a major cause of irreversible vision loss in the elderly. Although new therapies have recently emerged, there are currently no ways of preventing the development of the disease. Changes in intracellular recycling processes. Changes in intracellular recycling processes, called autophagy, lead to debris accumulation and cellular dysfunction in AMD models and AMD patients. Drugs that enhance autophagy hold promise as therapies for slowing AMD progression in preclinical models; however, more studies in humans are required. While a definitive cure for AMD will likely hinge on a personalized medicine approach, treatments that enhance autophagy hold promise for slowing vision loss.

老年黄斑变性(AMD)是导致老年人视力不可逆转丧失的主要原因。虽然最近出现了一些新疗法,但目前还没有预防该病发展的方法。细胞内循环过程的变化。细胞内循环过程(自噬)的变化会导致AMD模型和AMD患者体内碎片堆积和细胞功能障碍。在临床前模型中,增强自噬功能的药物有望成为减缓老年性黄斑变性进展的疗法;然而,还需要在人体中进行更多的研究。虽然彻底治愈老年性黄斑变性可能取决于个性化医疗方法,但增强自噬功能的疗法有望减缓视力丧失。
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引用次数: 0
Shaping DNA damage responses: Therapeutic potential of targeting telomeric proteins and DNA repair factors in cancer 塑造 DNA 损伤反应:针对癌症端粒蛋白和 DNA 修复因子的治疗潜力
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-21 DOI: 10.1016/j.coph.2024.102460
Yu Bin Ng, Semih Can Akincilar

Shelterin proteins regulate genomic stability by preventing inappropriate DNA damage responses (DDRs) at telomeres. Unprotected telomeres lead to persistent DDR causing cell cycle inhibition, growth arrest, and apoptosis. Cancer cells rely on DDR to protect themselves from DNA lesions and exogenous DNA-damaging agents such as chemotherapy and radiotherapy. Therefore, targeting DDR machinery is a promising strategy to increase the sensitivity of cancer cells to existing cancer therapies. However, the success of these DDR inhibitors depends on other mutations, and over time, patients develop resistance to these therapies. This suggests the need for alternative approaches. One promising strategy is co-inhibiting shelterin proteins with DDR molecules, which would offset cellular fitness in DNA repair in a mutation-independent manner. This review highlights the associations and dependencies of the shelterin complex with the DDR proteins and discusses potential co-inhibition strategies that might improve the therapeutic potential of current inhibitors.

Shelterin 蛋白通过防止端粒上不适当的 DNA 损伤反应(DDR)来调节基因组的稳定性。不受保护的端粒会导致持续的DDR,引起细胞周期抑制、生长停滞和细胞凋亡。癌细胞依赖 DDR 来保护自己免受 DNA 病变和化疗、放疗等外源性 DNA 损伤药物的伤害。因此,靶向 DDR 机制是提高癌细胞对现有癌症疗法敏感性的一种有前途的策略。然而,这些 DDR 抑制剂的成功取决于其他突变,随着时间的推移,患者会对这些疗法产生抗药性。这表明需要采用替代方法。一种很有前景的策略是将保护蛋白与 DDR 分子共同抑制,这将以一种与突变无关的方式抵消 DNA 修复中的细胞适应性。本综述强调了保护蛋白复合物与 DDR 蛋白的关联性和依赖性,并讨论了潜在的联合抑制策略,这些策略可能会提高当前抑制剂的治疗潜力。
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引用次数: 0
Editorial overview: Special issue on “Rheumatology: Therapeutic advances for autoimmune and musculoskeletal diseases” 编辑综述:风湿病学》特刊:自身免疫性疾病和肌肉骨骼疾病的治疗进展 "特刊。
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-18 DOI: 10.1016/j.coph.2024.102462
Larry W. Moreland, Kristine Kuhn
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引用次数: 0
In the heart and beyond: Mitochondrial dysfunction in heart failure with preserved ejection fraction (HFpEF) 心脏内外:射血分数保留型心力衰竭(HFpEF)的线粒体功能障碍
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-16 DOI: 10.1016/j.coph.2024.102461
Nisha Bhattarai , Iain Scott

Heart failure with preserved ejection fraction (HFpEF) is a major cardiovascular disorder with increasing prevalence and a limited range of targeted treatment options. While HFpEF can be derived from several different etiologies, much of the current growth in the disease is being driven by metabolic dysfunction (e.g. obesity, diabetes, hypertension). Deleterious changes in mitochondrial energy metabolism are a common feature of HFpEF, and may help to drive the progression of the disease. In this brief article we aim to review various aspects of cardiac mitochondrial dysfunction in HFpEF, discuss the emerging topic of HFpEF-driven mitochondrial dysfunction in tissues beyond the heart, and examine whether supporting mitochondrial function may be a therapeutic approach to arrest or reverse disease development.

射血分数保留型心力衰竭(HFpEF)是一种主要的心血管疾病,发病率越来越高,但有针对性的治疗方案却很有限。虽然射血分数保留型心力衰竭可由几种不同的病因引起,但目前这种疾病的增长主要是由代谢功能障碍(如肥胖、糖尿病、高血压)驱动的。线粒体能量代谢的畸形变化是高频低氧血症的常见特征,可能有助于推动疾病的进展。在这篇短文中,我们旨在回顾高频低氧血症(HFpEF)中心脏线粒体功能障碍的各个方面,讨论高频低氧血症(HFpEF)驱动的心脏以外组织线粒体功能障碍这一新兴话题,并探讨支持线粒体功能是否可能成为阻止或逆转疾病发展的一种治疗方法。
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引用次数: 0
Advanced therapeutic approaches in sarcoglycanopathies 肌糖蛋白病的先进治疗方法
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-06 DOI: 10.1016/j.coph.2024.102459
Martina Scano, Alberto Benetollo, Francesco Dalla Barba, Dorianna Sandonà

Sarcoglycanopathies are rare autosomal recessive diseases belonging to the family of limb-girdle muscular dystrophies. They are caused by mutations in the genes coding for α-, β-, γ-, and δ-sarcoglycan. The mutations impair the assembly of a key structural complex, which normally protects the sarcolemma of striated muscle from contraction-derived stress. Although heterogeneous, sarcoglycanopathies are characterized by progressive muscle degeneration, increased serum creatine kinase levels, loss of ambulation often during adolescence, and variable cardio-respiratory impairment. Genetic defects can impair sarcoglycan synthesis or produce a protein that is defective in folding. There is currently no effective treatment available; however, both gene replacement strategy and small molecule-based approaches show great promise and have entered or are starting to enter clinical trials.

肌糖蛋白病是一种罕见的常染色体隐性遗传病,属于肢腰肌营养不良症家族。它们是由α-、β-、γ-和δ-肌糖蛋白的编码基因突变引起的。突变会影响一个关键结构复合物的组装,而该复合物通常能保护横纹肌的肌浆膜免受来自收缩的压力。尽管存在差异,但肌球蛋白病的特征是肌肉进行性退化、血清肌酸激酶水平升高、通常在青春期丧失行动能力以及不同程度的心肺功能损害。基因缺陷会影响肌球蛋白的合成或产生折叠缺陷的蛋白质。目前还没有有效的治疗方法;不过,基因替代策略和基于小分子的方法都显示出巨大的前景,并已进入或开始进入临床试验阶段。
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引用次数: 0
From “contraindicated” to “first line” – Current mechanistic insights beyond canonical β-receptor signaling 从 "禁忌症 "到 "一线治疗"--当前超越典型β受体信号转导的机理认识
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-17 DOI: 10.1016/j.coph.2024.102458
Theresa Brand , Ann-Kathrin Lukannek , Valérie Jahns , Roland Jahns , Kristina Lorenz

β-blockers are a solid pillar in the treatment of cardiovascular diseases. However, they are highly discussed regarding effectiveness for certain indications and side-effects. Even though there are up to 20 licensed compounds, only four are used for heart failure (HF) therapy. On the receptor level several key characteristics seem to influence the clinical outcome: subtype selectivity, antagonistic vs (inverse/biased) agonistic properties and -in particular- ancillary capacities. On a molecular level, divergent and novel signaling patterns are being identified and extra-cardiac effects on e.g. inflammation, metabolism and oxidative stress are highlighted. This review discusses different well-known and newly discovered characteristics that need to be considered for HF therapy and in the context of co-morbidities.

β 受体阻滞剂是治疗心血管疾病的坚实支柱。然而,它们在某些适应症的疗效和副作用方面却备受争议。尽管有多达 20 种获得许可的化合物,但只有 4 种用于心力衰竭(HF)治疗。在受体层面,有几个关键特征似乎会影响临床结果:亚型选择性、拮抗与(反向/偏向)激动特性,尤其是辅助能力。在分子水平上,不同的新型信号传导模式正在被确定,对炎症、新陈代谢和氧化应激等心脏外影响也得到了强调。本综述讨论了在高血压治疗和并发症方面需要考虑的各种众所周知的和新发现的特性。
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引用次数: 0
The complement pathway as a therapeutic target for neovascular age-related macular degeneration-mediated subretinal fibrosis 补体途径是新生血管性老年黄斑变性介导的视网膜下纤维化的治疗靶点
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-03-30 DOI: 10.1016/j.coph.2024.102448
Heping Xu , Caijiao Yi , Mei Chen

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in the elderly in developed countries. Intravitreal injection of VEGF inhibitors is the mainstream therapy for nAMD, although nearly 50% of the patients do not respond or respond poorly to the therapy. One of the main reasons for the poor outcome of the therapy is the development of subretinal macular fibrosis, a process of excessive deposition of extracellular matrix proteins around the diseased blood vessels. Currently, there is no medication to prevent or treat the condition. Here, we discussed recent advances in the pathogenesis of nAMD-mediated macular fibrosis, with a focus on the role of the complement system. We further proposed approaches to target the complement system for the management of macular fibrosis and highlighted the area of further research for future clinical applications of complement-based therapy.

新生血管性老年黄斑变性(nAMD)是发达国家老年人失明的主要原因。玻璃体内注射血管内皮生长因子抑制剂是治疗 nAMD 的主流疗法,但近 50% 的患者对该疗法无反应或反应不佳。治疗效果不佳的主要原因之一是视网膜下黄斑纤维化的发生,这是一种细胞外基质蛋白在病变血管周围过度沉积的过程。目前,还没有药物可以预防或治疗这种情况。在此,我们讨论了nAMD介导的黄斑纤维化发病机制的最新进展,重点是补体系统的作用。我们进一步提出了针对补体系统治疗黄斑纤维化的方法,并强调了基于补体疗法的未来临床应用的进一步研究领域。
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引用次数: 0
Targeting TRP channels for pain relief: A review of current evidence from bench to bedside 靶向 TRP 通道缓解疼痛:从临床到床边的现有证据综述
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-03-11 DOI: 10.1016/j.coph.2024.102447
Ari-Pekka Koivisto , Thomas Voets , Michael J. Iadarola , Arpad Szallasi

Several decades of research support the involvement of transient receptor potential (TRP) channels in nociception. Despite the disappointments of early TRPV1 antagonist programs, the TRP family remains a promising therapeutic target in pain disorders. High-dose capsaicin patches are already in clinical use to relieve neuropathic pain. At present, localized injections of the side-directed TRPV1 agonist capsaicin and resiniferatoxin are undergoing clinical trials in patients with osteoarthritis and bone cancer pain. TRPA1, TRPM3, and TRPC5 channels are also of significant interest. This review discusses the role of TRP channels in human pain conditions.

数十年的研究支持瞬时受体电位(TRP)通道参与痛觉。尽管早期的 TRPV1 拮抗剂项目令人失望,但 TRP 家族仍然是治疗疼痛疾病的一个很有前景的靶点。高剂量辣椒素贴片已在临床上用于缓解神经性疼痛。目前,局部注射侧向 TRPV1 激动剂辣椒素和树脂铁氧体正在骨关节炎和骨癌疼痛患者中进行临床试验。TRPA1、TRPM3 和 TRPC5 通道也很受关注。本综述将讨论 TRP 通道在人类疼痛状况中的作用。
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引用次数: 0
Estrogen related receptor alpha: Potential modulator of age-related macular degeneration 雌激素相关受体α:老年性黄斑变性的潜在调节剂
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-03-05 DOI: 10.1016/j.coph.2024.102439
Fatima Massare Somers , Goldis Malek

To develop effective therapies for complex blinding diseases such as age-related macular degeneration (AMD), identification of mechanisms involved in its initiation and progression is needed. The estrogen-related receptor alpha (ESRRA) is an orphan nuclear receptor that regulates several AMD-associated pathogenic pathways. However, it has not been investigated in detail in the ocular posterior pole during aging or in AMD. This review delves into the literature highlighting the significance of ESRRA as a molecular target that may be important in the pathobiology of AMD, and discusses data available supporting the targeting of this receptor signaling pathway as a therapeutic option for AMD.

要开发出治疗老年性黄斑变性(AMD)等复杂致盲疾病的有效疗法,就必须确定其发生和发展的机制。雌激素相关受体α(ESRRA)是一种孤儿核受体,可调节多种与老年性黄斑变性相关的致病途径。然而,目前尚未对其在眼球后极老化或 AMD 中的作用进行详细研究。这篇综述深入探讨了 ESRRA 作为一个分子靶点的重要性,它可能在老年性黄斑变性的病理生物学中具有重要作用,并讨论了支持将该受体信号通路作为老年性黄斑变性治疗靶点的现有数据。
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引用次数: 0
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Current Opinion in Pharmacology
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