Journal of cellular signaling最新文献

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Novel Drug Development for Treatment of COVID-19 by In Silico Analysis: Identification of SARS-Cov-2 Inhibiting Streptomyces Compounds 利用计算机分析开发治疗COVID-19的新药物:鉴定抑制SARS-Cov-2链霉菌的化合物

Journal of cellular signaling

Pub Date : 2023-05-18 DOI: 10.33696/signaling.4.092

J. Kumar, Prachi Gholap, T. Pillai

In accordance with the present epidemiological paradigm, viral mutations of the virus are on the rise, and their natural effects are being selected for at a higher rate than normal. According to the World Health Organization (WHO), the global COVID-19 pandemic induced by the Delta and Omicron strain of the SARS-CoV-2 virus could propagate and disseminate more rapidly than other viruses thanks to its many mutations, and these also caused some very significant health problems. The established medications would eventually start to lose their efficacy since the variation mutated more quickly than the original stain. As protein spikes are the point of origin or epitome for the mutations to take place, it would be most effective to target the remaining vital enzymes by binding the proteins with the largest pocket sizes. The objective of the current work is to employ in-silico analysis to discover the streptomyces chemicals that suppress the SARS-CoV-2 virus as well as its mutated strains thus promoting a healthy body. Based on the drug likeness property of compounds when subjected to molecular docking, a total of 14 compounds were identified and selected from the PUBCHEM database that showed highest binding energy with the targeted Receptor Binding Domain. The compounds namely - Streptomyces tanashiensis; Thaxtomin A; Bafilomycin A1 from Streptomyces griseus and few others as mentioned further on more research would support and confirm the utilizing of these to create new medications to treat the novel SARS-CoV-2 infectious strains.

根据目前的流行病学范式，病毒的病毒突变正在增加，它们的自然影响正在以比正常情况更高的速度被选择。根据世界卫生组织(WHO)的说法，由SARS-CoV-2病毒的Delta和Omicron株引起的全球COVID-19大流行由于其许多突变可能比其他病毒更快地繁殖和传播，这也造成了一些非常严重的健康问题。现有的药物最终会开始失去效力，因为变异比原始染色更快地发生突变。由于蛋白质尖刺是突变发生的起点或缩影，因此通过结合最大口袋大小的蛋白质来靶向剩余的重要酶将是最有效的。目前的工作目标是利用计算机分析来发现抑制SARS-CoV-2病毒及其突变株的链霉菌化学物质，从而促进健康的身体。根据化合物在分子对接时的药物相似性，从PUBCHEM数据库中筛选出14个与靶受体结合域结合能最高的化合物。化合物为- tanashiensis链霉菌;Thaxtomin;来自灰色链霉菌的巴菲霉素A1和其他一些被进一步提到的研究将支持和证实利用这些来创造新的药物来治疗新型SARS-CoV-2感染菌株。

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引用次数: 0

Potential Mechanism of CDC42 Promoting HCC Metastasis CDC42促进肝癌转移的潜在机制

Journal of cellular signaling

Pub Date : 2023-05-01 DOI: 10.33696/signaling.4.091

Miaoling Tang, Rongni Feng, Jun Yu Li

Hepatocellular carcinoma (HCC) is an aggressive malignancy with increasing morbidity and mortality worldwide. The migration and motility of HCC tumor cells are enhanced by the formation of invadopodia, which comprise membrane protrusions at the leading edge. Previous studies have showed that cell division cycle 42 (CDC42) plays an essential role in remodeling the cytoskeleton, which is associated with invadopodia formation and thus mediates cellular movement. Therefore, aberrant expression of CDC42 is hypothesized to promote tumor cell migration. In this review, we discuss the important role of CDC42 activation induced by guanine nucleotide-exchange factors (GEFs), which function as upstream regulators to activate CDC42, thereby mediating HCC invasion and metastasis by facilitating invadopodia formation. Furthermore, inhibitors targeting the CDC42-GEF interaction might be developed as an intervention against HCC metastasis.

肝细胞癌(HCC)是一种侵袭性恶性肿瘤，在世界范围内发病率和死亡率都在不断上升。肝细胞癌肿瘤细胞的移动性和移动性通过侵足的形成而增强，侵足包括前缘的膜突起。先前的研究表明，细胞分裂周期42 (CDC42)在细胞骨架的重塑中起着重要作用，而细胞骨架与侵足形成有关，从而介导细胞运动。因此，CDC42的异常表达可能促进肿瘤细胞的迁移。在这篇综述中，我们讨论了鸟嘌呤核苷酸交换因子(GEFs)诱导CDC42激活的重要作用，该因子作为上游调节因子激活CDC42，从而通过促进侵过体形成介导HCC的侵袭和转移。此外，靶向CDC42-GEF相互作用的抑制剂可能被开发成一种干预HCC转移的方法。

引用次数: 0

A Computational Investigation on Rho-related GTP-binding Protein RhoB through Molecular Modeling and Molecular Dynamics Simulation Study rho相关gtp结合蛋白RhoB的分子建模和分子动力学模拟研究

Journal of cellular signaling

Pub Date : 2023-04-24 DOI: 10.33696/signaling.4.089

Shamrat Kumar Paul, Chowdhury Lutfun Nahar Metu, Sunita Kumari Sutihar, Md. Saddam, Bristi Paul, Md. Lutful Kabir, Md. Mostofa Uddin Helal

Background: An indispensable member of the Rho family, RhoB is an isoprenylated small GTPases that modulate the cellular cytoskeletal organization. While DNA gets damaged, it takes part in the neoplastic apoptotic mechanism. In this study, we evaluated the structure of Rho-related GTP-binding protein RhoB due to the unavailability of 3D structure in the protein data bank database. Results: The expected pI value of RhoB was 5.10 (acidic). The target–template alignment was computed using the GMQE value meanwhile 6hxu.1.A from Homo sapiens was selected as the template structure. The Swiss model was exploited to complete the model construction task. The structural compatibility and stability were revealed after a 100ns molecular dynamics simulation using GROMACA employing the OPLS-AA force field. Based on their fluctuating activity and their location between 100 and 110 and 140 and 150, PCA analysis discovered relevant residues. Conclusion: By providing an insight into the biophysical phenomenon of Rho-related GTP-binding protein RhoB inhibitors, this study will assist future investigations addressing the relationship between gene mutation and abnormalities produced by protein Rho-related GTP-binding protein RhoB in apoptotic events.

背景:RhoB是Rho家族不可或缺的成员，是一种调节细胞骨架组织的异戊二烯化小gtpase。当DNA受到损伤时，它参与了肿瘤细胞凋亡的机制。在本研究中，由于蛋白质数据库中没有三维结构，我们评估了RhoB相关gtp结合蛋白RhoB的结构。结果:RhoB的预期pI值为5.10(酸性)。同时使用GMQE值计算目标模板对齐。选择智人的A作为模板结构。利用瑞士模型完成模型构建任务。利用GROMACA在OPLS-AA力场下进行了100ns分子动力学模拟，揭示了结构的相容性和稳定性。根据它们的活性波动以及它们在100 - 110和140 - 150之间的位置，PCA分析发现了相关残基。结论:通过深入了解rho相关gtp结合蛋白RhoB抑制剂的生物物理现象，本研究将有助于进一步研究基因突变与rho相关gtp结合蛋白RhoB在凋亡事件中产生的异常之间的关系。

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引用次数: 0

Purinergic P2X7 Receptor as a Potential Targeted Therapy for COVID-19-associated Lung Cancer Progression 嘌呤能P2X7受体作为covid -19相关肺癌进展的潜在靶向治疗

Journal of cellular signaling

Pub Date : 2023-03-07 DOI: 10.33696/signaling.4.087

Hamidreza Zalpoor, A. Akbari, M. Nabi-Afjadi, Ali Norouzi, F. Seif, M. Pornour

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection is a serious threat to lung cancer patients. Hereby, we hypothesize that Coronavirus disease 2019 (COVID-19) may contribute to lung cancer progression by increasing extracellular adenosine triphosphate (ATP) levels and hyperactivating the purinergic P2X purinoceptor 7 receptor (P2X7R). Hyperactivation of P2X7R by increased extracellular ATP may stimulate multiple signaling pathways and factors such as NLRP3 inflammasome; as a result, interleukin (IL)-1β, and IL-18 pro-inflammatory cytokines are released, JNK, Rho kinase, HMGB1-RAGE, PI3K/AKT, hypoxia-inducible factor-1 alpha (HIF-1α), and ERK. NLRP3 activation may play a pivotal role in fatal cytokine storm in critically ill patients with COVID-19 and tumor progression in patients with lung cancer. Consequently, inhibiting these signaling pathways may deviate immune responses toward anti-tumoral responses, and suppress lung cancer progression and cytokine storms. Therefore, targeting P2X7R by means of oxidized ATP and anti-P2X7 monoclonal antibodies may provide promising therapeutic approaches to prevent lung cancer progression in COVID-19 patients; however, no clinical trials have yet been conducted, and their clinical efficacy remains to be elucidated.

严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)感染是肺癌患者的严重威胁。因此，我们假设2019冠状病毒病(COVID-19)可能通过增加细胞外三磷酸腺苷(ATP)水平和过度激活嘌呤能P2X嘌呤受体7受体(P2X7R)来促进肺癌的进展。细胞外ATP增加导致P2X7R的过度激活可能刺激多种信号通路和因子，如NLRP3炎性体;因此，白细胞介素(IL)-1β和IL-18促炎细胞因子、JNK、Rho激酶、HMGB1-RAGE、PI3K/AKT、缺氧诱导因子-1α (HIF-1α)和ERK被释放。NLRP3激活可能在COVID-19危重患者致死性细胞因子风暴和肺癌患者肿瘤进展中发挥关键作用。因此，抑制这些信号通路可能使免疫反应偏离抗肿瘤反应，并抑制肺癌的进展和细胞因子风暴。因此，通过氧化ATP和抗p2x7单克隆抗体靶向P2X7R可能为预防COVID-19患者肺癌进展提供有希望的治疗方法;但尚未进行临床试验，其临床疗效有待阐明。

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引用次数: 1

Targeting SCUBE3 in Hepatocellular Carcinoma 靶向SCUBE3治疗肝细胞癌

Journal of cellular signaling

Pub Date : 2023-03-07 DOI: 10.33696/signaling.4.088

Teng Liu, Xia Yang, Ke Wang, Q. Luo

HCC is one of the most common malignant tumors. The life and health of humans are gravely threatened by HCC because of its hidden onset, high recurrence rate, poor therapeutic effect, and high mortality. It is essential to explore the particular pathological mechanisms of HCC in order to increase the rate of early diagnosis and enhance patient therapy outcomes. Recent research has demonstrated that SCUBE3 can influence HCC cell proliferation by regulating the TGFβ/PI3K/AKT/GSK3β pathway. The molecular regulatory network of HCC proliferation is improved by this research, which also offers a solid theoretical and experimental foundation for SCUBE3 as a potential new therapeutic target for HCC.

HCC是最常见的恶性肿瘤之一。HCC发病隐匿、复发率高、治疗效果差、死亡率高，严重威胁着人类的生命健康。为了提高HCC的早期诊断率和提高患者的治疗效果，有必要探讨HCC的特殊病理机制。最近的研究表明，SCUBE3可以通过调节TGFβ/PI3K/AKT/GSK3β通路影响HCC细胞增殖。本研究完善了HCC增殖的分子调控网络，也为SCUBE3作为HCC潜在的新治疗靶点提供了坚实的理论和实验基础。

引用次数: 0

Radiation-induced Bystander Effect and Its Possible Countermeasures 辐射诱发的旁观者效应及其可能的对策

Journal of cellular signaling

Pub Date : 2023-03-07 DOI: 10.33696/signaling.4.086

G. Ghosh

Ionizing radiation has been indispensable to medical diagnosis. In cancer, radiation therapy or radiotherapy (RT) offers patients a better chance of survival. It destroys cancer by depositing high-energy radiation on the cancer tissues, though it may directly damage a few normal cells. Therefore, the total radiation dose is administered in fractionated modalities over weeks or months. However, experimental evidence indicates that the irradiated cancer cells subsequently release cytokines in the blood that enter into nearby unirradiated nuclei/cells through several signaling pathways and cause radiation-induced bystander effects (RIBEs) such as DNA damage, chromosomal instability, mutation, and apoptosis in them as side effects of RT. Recently, many combined therapeutic protocols consisting of a few natural and synthetic products have been proposed to minimize RIBEs. This article reviews the present understanding of RIBEs and their possible countermeasures. Besides, a new protocol of combined therapy of nanoparticle-based ion treatment (NIT) and RT to minimize RIBEs has been proposed.

电离辐射对医学诊断是不可或缺的。在癌症中，放射治疗或放疗(RT)为患者提供了更好的生存机会。它通过在癌组织上沉积高能辐射来摧毁癌症，尽管它可能直接损害一些正常细胞。因此，总辐射剂量在数周或数月内以分段方式给予。然而，实验证据表明，受辐照的癌细胞随后在血液中释放细胞因子，这些细胞因子通过几种信号通路进入附近未受辐照的细胞核/细胞，并引起辐射诱导的旁观者效应(RIBEs)，如DNA损伤、染色体不稳定、突变和细胞凋亡，作为辐射的副作用。最近，已经提出了许多由几种天然和合成产物组成的联合治疗方案，以尽量减少RIBEs。本文回顾了目前对RIBEs的认识和可能的对策。此外，还提出了一种纳米颗粒离子治疗(NIT)和RT联合治疗以减少RIBEs的新方案。

引用次数: 0

Augmenting Venetoclax Activity Through Signal Transduction in AML. 在AML中通过信号转导增强Venetoclax活性。

Journal of cellular signaling

Pub Date : 2023-01-01 DOI: 10.33696/signaling.4.085

Ian Michael Bouligny, Keri Renee Maher, Steven Grant

Venetoclax, a small-molecule B-cell lymphoma 2 (BCL-2) inhibitor, selectively eradicates leukemic stem cells (LSCs). While venetoclax has revolutionized the treatment of acute myeloid leukemia (AML), treatment failure and disease relapse are common. Mechanisms underlying venetoclax resistance are surprisingly heterogeneous. Venetoclax resistance encompasses a spectrum of genetic and epigenetic changes, with numerous pathways contributing to the upregulation of additional anti-apoptotic proteins. In this review, we address the mechanisms of venetoclax resistance in the context of signal transduction. We emphasize how aberrant cell signaling impairs apoptosis and predisposes to venetoclax failure. Commonly activated pathways, such as FLT3, PI3K/AKT/mTOR, and RAS, contribute to upregulated anti-apoptotic mediators and are frequently responsible for refractory disease or disease relapse. We highlight novel combination strategies aimed at disabling constitutively active signal transduction to augment response and overcome venetoclax resistance.

Venetoclax是一种小分子b细胞淋巴瘤2 (BCL-2)抑制剂，可选择性根除白血病干细胞(LSCs)。虽然venetoclax已经彻底改变了急性髓性白血病(AML)的治疗，但治疗失败和疾病复发是常见的。令人惊讶的是，venetoclax耐药机制存在异质性。Venetoclax耐药包括一系列遗传和表观遗传变化，有许多途径有助于上调额外的抗凋亡蛋白。在这篇综述中，我们在信号转导的背景下讨论了venetoclax耐药的机制。我们强调异常的细胞信号是如何损害细胞凋亡和导致血管衰竭的。FLT3、PI3K/AKT/mTOR和RAS等通常激活的通路有助于上调抗凋亡介质，并经常导致难治性疾病或疾病复发。我们强调了新的联合策略，旨在使本构主动信号转导失能，以增强反应和克服venetoclax耐药性。

引用次数: 2

Optogenetics Sheds Light on Brown and Beige Adipocytes. 光遗传学揭示棕色和米色脂肪细胞。

Journal of cellular signaling

Pub Date : 2023-01-01 DOI: 10.33696/signaling.4.105

Aaron Clifford Brown

Excessive food intake leads to lipid accumulation in white adipose tissue, triggering inflammation, cellular stress, insulin resistance, and metabolic syndrome. In contrast, the dynamic energy expenditure and heat generation of brown and beige adipose tissue, driven by specialized mitochondria, render it an appealing candidate for therapeutic strategies aimed at addressing metabolic disorders. This review examines the therapeutic potential of brown and beige adipocytes for obesity and metabolic disorders, focusing on recent studies that employ optogenetics for thermogenesis control in these cells. The findings delve into the mechanisms underlying UCP1-dependent and UCP1-independent thermogenesis and how optogenetic approaches can be used to precisely modulate energy expenditure and induce thermogenesis. The convergence of adipocyte biology and optogenetics presents an exciting frontier in combating metabolic disorders and advancing our understanding of cellular regulation and energy balance.

过量的食物摄入会导致白色脂肪组织中的脂质堆积，引发炎症、细胞应激、胰岛素抵抗和代谢综合征。相比之下，由专门的线粒体驱动的棕色和米色脂肪组织的动态能量消耗和热量产生，使其成为治疗代谢紊乱的有吸引力的候选治疗策略。这篇综述考察了棕色和米色脂肪细胞对肥胖和代谢紊乱的治疗潜力，重点是最近利用光遗传学控制这些细胞产热的研究。研究结果深入探讨了UCP1依赖性和UCP1非依赖性产热的机制，以及光遗传学方法如何用于精确调节能量消耗和诱导产热。脂肪细胞生物学和光遗传学的融合为对抗代谢紊乱和推进我们对细胞调节和能量平衡的理解提供了一个令人兴奋的前沿。

引用次数: 0

Targeting the Complex Protein Network of MYCN-amplified Anaplastic Ependymoma: A Case Report 靶向mycn扩增间变性室管膜瘤复杂蛋白网络1例

Journal of cellular signaling

Pub Date : 2022-12-22 DOI: 10.33696/signaling.3.082

MD Michael P. Castro

The MYCN oncoprotein has been notoriously undruggable and is infamous for causing aggressive cancer with poor outcomes in children and adults. Following surgery, radiation, and chemotherapy, patients who develop progressive disease have few treatment options. An analysis of the dysregulated protein network caused by MYCN amplification suggested co-targeting PLK1, AURKA, CKS1, AKT, MTOR, and USP7 would be useful to take advantage of synthetic lethal vulnerabilities while overcoming redundancies and resistance mechanisms that stabilize N-Myc by preventing its proteasome degradation. Naturopathic compounds, (genistein, tanshinone, resveratrol, betulinic acid) and fluoxetine were re-purposed to target the complex protein network in a patient with MYCN -amplified and PTEN -deficient multifocal, relapsed anaplastic ependymoma following standard therapy. The patient achieved a clinically meaningful and durable response for 6 months prior to developing disease progression characterized by chromosome 11q ( YAP1, BIRC2/3 ) amplification. The experience suggests molecularly-informed integration of naturopathic compounds can have utility for disease control and survival. The success, although anecdotal, suggests that the previous failure of single agent strategies could be overcome with a network targeting approach that simultaneously precipitates cell cycle arrest, rescues FBXW7 ubiquitination, and enhances oxidative stress. As such, MYCN may no longer be strictly unactionable but appears amenable to co-targeting key nodes in its self-sustaining disease network.

众所周知，MYCN癌蛋白是不可药物治疗的，并且因在儿童和成人中导致预后不良的侵袭性癌症而臭名昭著。在手术、放疗和化疗之后，进展性疾病的患者几乎没有治疗选择。对MYCN扩增引起的失调蛋白网络的分析表明，共同靶向PLK1、AURKA、CKS1、AKT、MTOR和USP7将有助于利用合成的致命脆弱性，同时克服冗余和耐药机制，通过阻止其蛋白酶体降解来稳定N-Myc。自然疗法化合物(染料木黄酮、丹参酮、白藜芦醇、白桦酸)和氟西汀被重新用于MYCN扩增和PTEN缺乏的多灶性复发间变性室管膜瘤患者的复杂蛋白网络。在以染色体11q (YAP1, BIRC2/3)扩增为特征的疾病进展之前，患者在6个月内获得了具有临床意义的持久缓解。这一经验表明，从分子上了解自然疗法化合物的整合对疾病控制和生存有帮助。这一成功，虽然是传闻，但表明先前单药策略的失败可以通过网络靶向方法来克服，同时沉淀细胞周期阻滞，挽救FBXW7泛素化，并增强氧化应激。因此，MYCN可能不再是严格不可操作的，而似乎可以共同靶向其自我维持疾病网络中的关键节点。

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New Insights into the Proteolytic Regulation of the Structural Protein Junctophilin-2 by Calpain Calpain对结构蛋白Junctophilin-2蛋白水解调控的新认识

Journal of cellular signaling

Pub Date : 2022-12-22 DOI: 10.33696/signaling.3.081

G. Weninger, S. Lehnart

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