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Mutations in Rv0678, Rv2535c, and Rv1979c Confer Resistance to Bedaquiline in Clinical Isolates of Mycobacterium Tuberculosis. Rv0678、Rv2535c 和 Rv1979c 基因突变导致临床结核分枝杆菌对贝达喹啉产生耐药性。
Pub Date : 2024-09-23 DOI: 10.2174/0118761429314641240815080447
Khaoula Balgouthi, Manaf AlMatar, Hamza Saghrouchni, Osman Albarri, Işıl Var

Introduction: Reduced bedaquiline (BDQ) sensitivity to antimycobacterial drugs has been linked to mutations in the Rv0678, pepQ, and Rv1979c genes of Mycobacterium tuberculosis (MTB). Resistance-causing mutations in MTB strains under treatment may have an impact on novel BDQ-based medication regimens intended to reduce treatment time. Due to this, we investigated the genetic basis of BDQ resistance in Turkish TB patients with MTB clinical isolates. Furthermore, mutations in the genes linked to efflux pumps were examined as a backup resistance mechanism.

Methods: We scrutinized 100 MTB clinical isolates from TB patients using convenience sampling. Eighty MDR and twenty pan-drug susceptible MTB strains were among these isolates. Sequencing was performed on all strains, and genomic analyses were performed to find mutations in BDQ resistance-associated genes, including Rv0678 and pepQ(Rv2535c), which correspond to a putative Xaa-Pro aminopeptidase, and Rv1979c. Of the 74 isolates with PepQ (Rv2535c) mutations, four isolates (2.96%) exhibited MGIT-BDQ susceptibility.

Results: Twenty-one (19.11%) of the ninety-one isolates carrying mutations, including Rv1979c, were MGIT-BDQ-sensitive. Nonetheless, out of the 39 isolates with Rv0678 mutations, four (2.96%) were sensitive to MGIT-BDQ. It was found that resistance-associated variants (RAVs) in Rv0678, pepQ, and Rv1979c are often linked to BDQ resistance.

Conclusion: In order to include variations in efflux pump genes in genome-based diagnostics for drug-resistant MTB, further evidence about their involvement in resistance is needed.

导言:结核分枝杆菌(MTB)的 Rv0678、epQ 和 Rv1979c 基因突变与贝达喹啉(BDQ)对抗结核药物的敏感性降低有关。正在接受治疗的 MTB 菌株中的致耐药性突变可能会对旨在缩短治疗时间的基于 BDQ 的新型药物治疗方案产生影响。因此,我们研究了土耳其肺结核患者临床分离的 MTB 菌株对 BDQ 产生耐药性的基因基础。此外,我们还将与外排泵相关的基因突变作为一种后备耐药机制进行了研究:方法:我们采用便利抽样法仔细检查了来自结核病患者的 100 例 MTB 临床分离株。这些分离株中有 80 株 MDR MTB 和 20 株泛药敏 MTB。我们对所有菌株进行了测序,并通过基因组分析发现了 BDQ 耐药性相关基因的突变,包括 Rv0678 和 pepQ(Rv2535c)(对应于一种假定的 Xaa-Pro 氨基肽酶)以及 Rv1979c。在 PepQ(Rv2535c)突变的 74 个分离株中,有 4 个分离株(2.96%)表现出对 MGIT-BDQ 的敏感性:结果:在包括 Rv1979c 在内的 91 个携带突变的分离株中,有 21 个(19.11%)对 MGIT-BDQ 敏感。然而,在 39 个携带 Rv0678 突变的分离株中,有 4 个(2.96%)对 MGIT-BDQ 敏感。研究发现,Rv0678、pepQ 和 Rv1979c 中的抗性相关变异(RAVs)往往与 BDQ 抗性有关:结论:为了将外排泵基因变异纳入耐药 MTB 的基因组诊断中,需要进一步证明它们与耐药性的关系。
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引用次数: 0
Mechanism, Potential, and Concerns of Immunotherapy for Hepatocellular Carcinoma and Liver Transplantation. 肝细胞癌和肝移植免疫疗法的机理、潜力和担忧。
Pub Date : 2024-09-02 DOI: 10.2174/0118761429310703240823045808
Bruno Sensi, Roberta Angelico, Luca Toti, Luigi Conte, Alessandro Coppola, Giuseppe Tisone, Tommaso Maria Manzia

In the last decade, immunotherapy (IT) has revolutionized oncology and found indications in many cancers, including hepatocellular carcinoma (HCC). In HCC, IT has become the leading systemic therapy for advanced diseases. At the same time, it carries the promise of being a valuable therapy in other settings, including intermediate-stage and unresectable disease, as a downstaging or conversion modality. More controversial is the role of IT in relationship to liver transplantation (LT): on one side, it could be a helpful tool to control or downstage HCC before LT or to treat tumor recurrence after LT, while on the other, it carries the risk of graft rejection and graft loss. This review aims to cover these concerns in depth and unravel the current literature.

近十年来,免疫疗法(IT)在肿瘤学领域掀起了一场革命,并在包括肝细胞癌(HCC)在内的多种癌症中找到了适应症。在肝细胞癌领域,免疫疗法已成为治疗晚期疾病的主要系统疗法。与此同时,在其他情况下,包括中晚期和无法切除的疾病,它也有望成为一种有价值的疗法,作为一种降期或转换模式。更具争议性的是 IT 在肝移植(LT)中的作用:一方面,它可能是在 LT 前控制或降低 HCC 分期或在 LT 后治疗肿瘤复发的有用工具,而另一方面,它又存在移植物排斥和移植物丢失的风险。本综述旨在深入探讨这些问题,并对现有文献进行解读。
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引用次数: 0
Paeoniflorin Alleviates Anxiety and Visceral Hypersensitivity via HPA Axis and BDNF/TrkB/PLCγ1 Pathway in Maternal Separation-induced IBS-like Rats. 芍药苷通过HPA轴和BDNF/TrkB/PLCγ1通路缓解母鼠分离诱发的肠易激综合征样大鼠的焦虑和内脏超敏反应
Pub Date : 2024-03-15 DOI: 10.2174/0118761429280572240311060851
Ruifeng Liang, Wenjing Ge, Xianmei Song, Huisen Wang, Weifeng Cui, Xuexia Zhang, Zheng Wei, Gengsheng Li

Background: Irritable Bowel Syndrome (IBS) is a prevalent gastrointestinal disorder that significantly diminishes the quality of life for affected individuals. The pathophysiology of IBS remains poorly understood, and available therapeutic options for IBS are limited. The crucial roles of brain-gut interaction, which is mediated by the Hypothalamic-Pituitary-Adrenocortical (HPA) axis and the autonomic nervous system in IBS, have attracted increasing attention.

Objective: The objective of this study was to examine the impact of paeoniflorin (PF) on anxiety and visceral hypersensitivity in maternal separation-induced IBS-like rats.

Methods: The IBS-like rat model was established through the implementation of Maternal Separation (MS) and subsequently subjected to various doses of PF administered via oral gavage for 14 days. Anxiety-like behavior was evaluated using the Open Field Test (OFT) and Elevated Plus Maze (EPM) test. The assessment of visceral sensitivity involved the utilization of the Abdominal Withdrawal Reflex (AWR) score and electromyographic (EMG) responses of the external oblique muscle in response to colorectal distention. The levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), and corticotrophin-releasing hormone (CRH) were examined by ELISA. Quantitative real-time PCR (qRT-PCR) and immunofluorescence were employed to detect the expressions of CRH receptors 1 (CRHR1) and 2 (CRHR2). Glucocorticoid receptors (GR), mineralocorticoid receptor (MR), brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), and phospholipase C γ1 (PLCγ1) were examined by Western blot.

Results and discussion: The results showed that MS induced anxiety-like behavior and visceral hypersensitivity, while PF treatment attenuated these changes. Furthermore, the HPA axis hyperactivity in MS rats was attenuated by PF treatment, indicated by reduced serum ACTH, CORT, and CRH levels and recovered hippocampal CRHR1 and GR expressions. In addition, PF inhibited BDNF/TrkB signaling by downregulating the protein levels of BDNF, TrkB, and phospho-PLCγ1 in the colon.

Conclusion: These findings suggest that PF alleviated anxiety and visceral hypersensitivity in MS-induced IBS-like rats, which may be the modulation of HPA axis activity and BDNF/TrkB/PLCγ1 signaling pathway.

背景:肠易激综合征(IBS肠易激综合征(IBS)是一种常见的胃肠道疾病,严重影响患者的生活质量。人们对肠易激综合征的病理生理学仍然知之甚少,现有的治疗方法也很有限。由下丘脑-垂体-肾上腺皮质轴(HPA)和自主神经系统介导的脑-肠相互作用在肠易激综合征中的关键作用已引起越来越多的关注:本研究的目的是探讨芍药苷(PF)对母体分离诱导的IBS样大鼠焦虑和内脏超敏性的影响:方法:通过实施母体分离(MS)建立肠易激综合征样大鼠模型,然后通过口服给药的方式给大鼠注射不同剂量的芍药苷(PF),持续14天。焦虑样行为的评估采用开阔地试验(OFT)和高架迷宫试验(EPM)。对内脏敏感性的评估包括腹部回缩反射(AWR)评分和腹外斜肌对大肠胀气的肌电图(EMG)反应。通过 ELISA 检测了促肾上腺皮质激素(ACTH)、皮质酮(CORT)和促肾上腺皮质激素释放激素(CRH)的水平。采用定量实时 PCR(qRT-PCR)和免疫荧光法检测 CRH 受体 1(CRHR1)和 2(CRHR2)的表达。糖皮质激素受体(GR)、矿皮质激素受体(MR)、脑源性神经营养因子(BDNF)、酪氨酸受体激酶B(TrkB)和磷脂酶Cγ1(PLCγ1)通过Western印迹进行检测:结果表明,MS可诱导焦虑样行为和内脏过敏,而PF治疗可减轻这些变化。此外,血清促肾上腺皮质激素(ACTH)、促肾上腺皮质激素(CORT)和促肾上腺皮质激素(CRH)水平的降低以及海马 CRHR1 和 GR 表达的恢复表明,PF 治疗可减轻 MS 大鼠 HPA 轴的过度活跃。此外,PF 通过下调结肠中 BDNF、TrkB 和 phospho-PLCγ1 的蛋白水平,抑制了 BDNF/TrkB 信号转导:这些研究结果表明,PF 可减轻 MS 诱导的肠易激综合征样大鼠的焦虑和内脏超敏反应,这可能是 HPA 轴活性和 BDNF/TrkB/PLCγ1 信号通路的调节作用。
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引用次数: 0
siRNA Targeting ECE-1 Partially Reverses Pulmonary Arterial Hypertensionassociated Damage in a Monocrotaline Model. 靶向 ECE-1 的 siRNA 部分逆转单克隆模型中与肺动脉高压相关的损伤
Pub Date : 2024-03-08 DOI: 10.2174/0118761429283384240226074921
Citlali Margarita Blancas-Napoles, Sandra Edith Cabrera-Becerra, Vivany Maydel Sierra-Sánchez, Sergio Adrian Ocampo-Ortega, Vanessa Giselle Garcia-Rubio, Rodrigo Romero-Nava, Fengyang Huang, Enrique Hong, Asdrúbal Aguilera-Méndez, Santiago Villafaña

Aims: The aim of this study was to develop a possible treatment for pulmonary arterial hypertension.

Background: Pulmonary arterial hypertension (PAH) is a rare disease characterised by a pulmonary arterial pressure greater than 20 mmHg. One of the factors that contribute to PAH is an increase in the production of endothelin-1, a polypeptide that increases vascular resistance in the pulmonary arteries, leading to increased pulmonary arterial pressure and right ventricular hypertrophy.

Objective: The objective of this study was to design, synthesize, and evaluate two siRNAs directed against endothelin-1 in a rat model of PAH induced with monocrotaline.

Methods: Wistar rats were administered monocrotaline (60 mg/kg) to induce a PAH model. Following two weeks of PAH evolution, the siRNAs were administered, and after two weeks, right ventricular hypertrophy was evaluated using the RV/LV+S ratio, blood pressure, weight, and relative expression of ECE-1 (Endothelin-converting enzyme-1) mRNA (messenger RNA) by RT-PCR (real-time PCR).

Results: The monocrotaline group showed an increase in the hypertrophy index and in ECE-1 mRNA, as well as a significant decrease in weight compared to the control group, while in the monocrotaline + siRNA group, a significant decrease was observed in the relative expression of ECE-1 mRNA, as well as in right ventricular hypertrophy.

Conclusions: Based on the above information, we conclude that the administration of siRNAs directed to ECE-1 decreases the damage associated with PAH.

目的:本研究旨在开发一种治疗肺动脉高压的可行方法:肺动脉高压(PAH)是一种罕见的疾病,其特征是肺动脉压力超过 20 mmHg。导致 PAH 的因素之一是内皮素-1(一种增加肺动脉血管阻力的多肽)的分泌增加,从而导致肺动脉压升高和右心室肥大:本研究的目的是设计、合成和评估两种针对内皮素-1 的 siRNA,并将其应用于用单克 罗林诱导的 PAH 大鼠模型中:方法:给 Wistar 大鼠注射单氯他林(60 毫克/千克)诱导 PAH 模型。方法:给 Wistar 大鼠注射单氯肾上腺素(60 毫克/千克)诱导 PAH 模型,在 PAH 演变两周后注射 siRNAs,两周后用 RV/LV+S 比值、血压、体重和 RT-PCR(实时 PCR)检测 ECE-1(内皮素转换酶-1)mRNA(信使 RNA)的相对表达来评估右心室肥大:结果:与对照组相比,单克洛他林组的肥厚指数和ECE-1 mRNA均有所增加,体重也显著下降;而在单克洛他林+siRNA组,ECE-1 mRNA的相对表达量和右心室肥厚均显著下降:根据上述信息,我们得出结论:服用针对 ECE-1 的 siRNA 可减少 PAH 引起的损伤。
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引用次数: 0
A Promising Breakthrough: The Potential of VORASIDENIB in the Treatment of Low-grade Glioma. 有望取得突破:VORASIDENIB治疗低级别胶质瘤的潜力。
Pub Date : 2024-02-29 DOI: 10.2174/0118761429290327240222061812
Alice Bombino, Marcello Magnani, Alfredo Conti

Introduction: Gliomas are common malignant brain tumors characterized by diffuse brain infiltration. World Health Organization grade II and grade III diffuse gliomas are considered lower-grade gliomas (LGGs) and have isocitrate dehydrogenase (IDH) mutations. LGGs are challenging due to their infiltrative nature, making them capable of progressing into higher-grade malignancies. Vorasidenib is a novel therapeutic agent targeting mutant IDH1/2, sparking interest in the field.

Mechanism of action: Vorasidenib inhibits mutant IDH1/2 through a unique mechanism, reducing the production of the oncometabolite 2-hydroxyglutarate (2-HG). This alteration affects key enzymes and DNA methylation, impacting tumor growth and invasion. Preclinical Evidence: Preclinical studies show vorasidenib's efficacy in inhibiting mutant IDH1/2 and 2-HG production in glioma models. It suppresses tumor growth, making it a potential treatment option.

Clinical evidence: Early clinical trials demonstrate vorasidenib's clinical activity in non-enhancing gliomas. It reduces 2-hydroxyglutarate levels and tumor cell proliferation, with an objective response rate and prolonged progression-free survival. The drug's safety profile is favorable. Challenges and Future Directions: Challenges include identifying predictive biomarkers and optimizing sequencing or combinations with existing therapies. Further research is needed to establish long-term effectiveness, evaluate side effects, and explore combinations with immunotherapy.

Conclusion: orasidenib significantly advances LGG treatment, targeting a prevalent mutation and slowing tumor growth. Promising preclinical and clinical evidence and manageable side effects suggest its potential impact on LGG management. However, more research, including large trials, is needed to confirm its efficacy and role in treatment.

简介胶质瘤是常见的恶性脑肿瘤,其特点是弥漫性脑浸润。世界卫生组织II级和III级弥漫性胶质瘤被认为是低级别胶质瘤(LGG),具有异柠檬酸脱氢酶(IDH)突变。低级别胶质瘤具有浸润性,可发展为高级别恶性肿瘤,因此具有挑战性。Vorasidenib是一种靶向突变IDH1/2的新型治疗药物,引发了该领域的兴趣:Vorasidenib通过独特的机制抑制突变体IDH1/2,减少副代谢产物2-羟基戊二酸(2-HG)的产生。这种改变会影响关键酶和 DNA 甲基化,从而影响肿瘤的生长和侵袭。临床前证据:临床前研究显示,vorasidenib 能有效抑制胶质瘤模型中突变的 IDH1/2 和 2-HG 的产生。临床证据:早期临床试验证明了vorasidenib在非增强型胶质瘤中的临床活性。它能降低2-羟基戊二酸水平和肿瘤细胞增殖,客观反应率高,无进展生存期延长。该药物的安全性良好。挑战与未来方向:挑战包括确定预测性生物标志物,优化排序或与现有疗法的组合。结论:orasidenib能显著推进LGG的治疗,靶向一种流行突变并减缓肿瘤生长。有前景的临床前和临床证据以及可控的副作用表明,它对LGG的治疗具有潜在影响。然而,还需要更多的研究(包括大型试验)来证实其疗效和在治疗中的作用。
{"title":"A Promising Breakthrough: The Potential of VORASIDENIB in the Treatment of Low-grade Glioma.","authors":"Alice Bombino, Marcello Magnani, Alfredo Conti","doi":"10.2174/0118761429290327240222061812","DOIUrl":"https://doi.org/10.2174/0118761429290327240222061812","url":null,"abstract":"<p><strong>Introduction: </strong>Gliomas are common malignant brain tumors characterized by diffuse brain infiltration. World Health Organization grade II and grade III diffuse gliomas are considered lower-grade gliomas (LGGs) and have isocitrate dehydrogenase (IDH) mutations. LGGs are challenging due to their infiltrative nature, making them capable of progressing into higher-grade malignancies. Vorasidenib is a novel therapeutic agent targeting mutant IDH1/2, sparking interest in the field.</p><p><strong>Mechanism of action: </strong>Vorasidenib inhibits mutant IDH1/2 through a unique mechanism, reducing the production of the oncometabolite 2-hydroxyglutarate (2-HG). This alteration affects key enzymes and DNA methylation, impacting tumor growth and invasion. Preclinical Evidence: Preclinical studies show vorasidenib's efficacy in inhibiting mutant IDH1/2 and 2-HG production in glioma models. It suppresses tumor growth, making it a potential treatment option.</p><p><strong>Clinical evidence: </strong>Early clinical trials demonstrate vorasidenib's clinical activity in non-enhancing gliomas. It reduces 2-hydroxyglutarate levels and tumor cell proliferation, with an objective response rate and prolonged progression-free survival. The drug's safety profile is favorable. Challenges and Future Directions: Challenges include identifying predictive biomarkers and optimizing sequencing or combinations with existing therapies. Further research is needed to establish long-term effectiveness, evaluate side effects, and explore combinations with immunotherapy.</p><p><strong>Conclusion: </strong>orasidenib significantly advances LGG treatment, targeting a prevalent mutation and slowing tumor growth. Promising preclinical and clinical evidence and manageable side effects suggest its potential impact on LGG management. However, more research, including large trials, is needed to confirm its efficacy and role in treatment.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139998680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Quercetin Enhances 5-fluorouracil Sensitivity by Regulating the Autophagic Flux and Inducing Drp-1 Mediated Mitochondrial Fragmentation in Colorectal Cancer Cells. 槲皮素通过调节自噬通量和诱导 Drp-1 介导的线粒体破碎增强结直肠癌细胞对 5-氟尿嘧啶的敏感性
Pub Date : 2024-02-27 DOI: 10.2174/0118761429283717231222104730
Mei Li, Jiaoxiu Fan, Min Hu, Junyu Xu, Ziyue He, Jun Zeng

Background: While chemotherapy treatment demonstrates its initial effectiveness in eliminating the majority of the tumor cell population, nevertheless, most patients relapse and eventually succumb to the disease upon its recurrence. One promising approach is to explore novel, effective chemotherapeutic adjuvants to enhance the sensitivity of cancer cells to conventional chemotherapeutic agents. In the present study, we explored the effect of quercetin on the sensitivity of colorectal cancer (CRC) cells to conventional chemotherapeutic agent 5-fluorouracil (5-FU) and the molecular mechanisms.

Methods: MTT assay, colony formation assay and Hoechst staining were performed to investigate the growth inhibition effect of quercetin alone or combined with 5-FU. The expression levels of apoptosis- and autophagy-related proteins were assessed by western blotting. Intracellular ROS was detected using DCFH-DA. The change in the mitochondrial membrane potential was measured by a JC-1 probe. The effect of quercetin on mitochondrial morphology was examined using a mitochondrial-specific fluorescence probe, Mito-Tracker red.

Results: The results demonstrated quercetin-induced apoptosis and autophagy, as well as imbalanced ROS, decreased mitochondrial membrane potential, and Drp-1-mediated mitochondrial fission in CRC cells. Autophagy blockage with autophagy inhibitor chloroquine (CQ) enhanced quercetininduced cytotoxicity, indicating that quercetin-induced cytoprotective autophagy. Meanwhile, quercetin enhanced the sensitivity of CRC cells to 5- FU via the induction of mitochondrial fragmentation, which could be further enhanced when the quercetin-induced protective autophagy was blocked by CQ.

Conclusion: Our findings suggested that quercetin could induce protective autophagy and Drp-1-mediated mitochondrial fragmentation and enhance the sensitivity of CRC cells to conventional agent 5-FU, which not only suggests that quercetin may act as a chemotherapeutic adjuvant but also implies that the regulation of autophagic flux may be a potential therapeutic strategy for colorectal cancer.

背景:尽管化疗在消除大部分肿瘤细胞群方面显示出初步疗效,但大多数患者仍会复发,并最终因疾病复发而死亡。探索新型、有效的化疗辅助剂以提高癌细胞对传统化疗药物的敏感性是一种很有前景的方法。在本研究中,我们探讨了槲皮素对结直肠癌(CRC)细胞对常规化疗药物 5-氟尿嘧啶(5-FU)敏感性的影响及其分子机制:方法:采用MTT试验、菌落形成试验和Hoechst染色法研究槲皮素单独或与5-FU联用对CRC细胞生长的抑制作用。凋亡和自噬相关蛋白的表达水平由 Western 印迹法进行评估。使用 DCFH-DA 检测细胞内 ROS。线粒体膜电位的变化通过 JC-1 探针进行测量。使用线粒体特异性荧光探针 Mito-Tracker red 检测槲皮素对线粒体形态的影响:结果:槲皮素诱导了 CRC 细胞的凋亡和自噬,以及 ROS 失衡、线粒体膜电位降低和 Drp-1 介导的线粒体分裂。用自噬抑制剂氯喹(CQ)阻断自噬可增强槲皮素诱导的细胞毒性,表明槲皮素可诱导细胞保护性自噬。同时,槲皮素通过诱导线粒体破碎增强了CRC细胞对5-FU的敏感性,而当槲皮素诱导的保护性自噬被CQ阻断时,这种敏感性会进一步增强:我们的研究结果表明,槲皮素可诱导保护性自噬和Drp-1介导的线粒体破碎,并增强CRC细胞对传统药物5-FU的敏感性,这不仅表明槲皮素可作为一种化疗辅助药物,还意味着自噬通量的调节可能是结直肠癌的一种潜在治疗策略。
{"title":"Quercetin Enhances 5-fluorouracil Sensitivity by Regulating the Autophagic Flux and Inducing Drp-1 Mediated Mitochondrial Fragmentation in Colorectal Cancer Cells.","authors":"Mei Li, Jiaoxiu Fan, Min Hu, Junyu Xu, Ziyue He, Jun Zeng","doi":"10.2174/0118761429283717231222104730","DOIUrl":"https://doi.org/10.2174/0118761429283717231222104730","url":null,"abstract":"<p><strong>Background: </strong>While chemotherapy treatment demonstrates its initial effectiveness in eliminating the majority of the tumor cell population, nevertheless, most patients relapse and eventually succumb to the disease upon its recurrence. One promising approach is to explore novel, effective chemotherapeutic adjuvants to enhance the sensitivity of cancer cells to conventional chemotherapeutic agents. In the present study, we explored the effect of quercetin on the sensitivity of colorectal cancer (CRC) cells to conventional chemotherapeutic agent 5-fluorouracil (5-FU) and the molecular mechanisms.</p><p><strong>Methods: </strong>MTT assay, colony formation assay and Hoechst staining were performed to investigate the growth inhibition effect of quercetin alone or combined with 5-FU. The expression levels of apoptosis- and autophagy-related proteins were assessed by western blotting. Intracellular ROS was detected using DCFH-DA. The change in the mitochondrial membrane potential was measured by a JC-1 probe. The effect of quercetin on mitochondrial morphology was examined using a mitochondrial-specific fluorescence probe, Mito-Tracker red.</p><p><strong>Results: </strong>The results demonstrated quercetin-induced apoptosis and autophagy, as well as imbalanced ROS, decreased mitochondrial membrane potential, and Drp-1-mediated mitochondrial fission in CRC cells. Autophagy blockage with autophagy inhibitor chloroquine (CQ) enhanced quercetininduced cytotoxicity, indicating that quercetin-induced cytoprotective autophagy. Meanwhile, quercetin enhanced the sensitivity of CRC cells to 5- FU via the induction of mitochondrial fragmentation, which could be further enhanced when the quercetin-induced protective autophagy was blocked by CQ.</p><p><strong>Conclusion: </strong>Our findings suggested that quercetin could induce protective autophagy and Drp-1-mediated mitochondrial fragmentation and enhance the sensitivity of CRC cells to conventional agent 5-FU, which not only suggests that quercetin may act as a chemotherapeutic adjuvant but also implies that the regulation of autophagic flux may be a potential therapeutic strategy for colorectal cancer.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140133635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ginsenoside Compound K Reduces Psoriasis-related Inflammation by Activation of the Glucocorticoid Receptor in Keratinocytes. 人参皂苷化合物 K 通过激活角朊细胞中的糖皮质激素受体减轻与牛皮癣相关的炎症反应
Pub Date : 2024-02-21 DOI: 10.2174/0118761429254358231120135400
Wu Wang, Xiujin Xu, Mei Yang, Mengya Jiang, Dandan Wang, Caihong Tang, Wei Wei, Jingyu Chen

Aim: To investigate the effects and mechanism of Ginsenoside Compound K (GCK) on psoriasis, focusing on the glucocorticoid receptor (GR) in keratinocytes.

Methods: An imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model was generated to evaluate the anti-inflammatory effect of GCK. Hematoxylin and eosin (H&E) staining was used to assess skin pathological changes. Protein expression of K17 and p-p65 in mice skin was assayed by immunohistochemical. Protein expression and phosphorylation of p65 IκB were assayed by Western blot. Protein expression of K1, K6, K10, K16, K17, and GR were assayed by Western blot and immunofluorescence. Enzyme-linked immunosorbent assay (ELISA) was used to determine cytokine levels of TNF-α, IL-6, CXCL-8, and ICAM-1. Real-time polymerase chain reaction (RT-PCR) was used to quantify TNF-α, IL-6, IL-8, and ICAM-1 mRNA expression. Cell viability was determined by Cell Counting Kit-8(CCK-8) assay. A high-content cell-imaging system was used to assay cell proliferation. Nuclear translocation of p65 and GR was assayed by imaging flow cytometry and immunofluorescence microscopy. Small interfering RNA was used to confirm the role of GR in the anti-inflammatory and immunoregulatory effect of GCK in normal human epidermal keratinecytes (NHEKs).

Results: GCK reduced the psoriasis area, severity index, and epidermal thickening in IMQ-induced mice. GCK significantly attenuated the mRNA levels of IL-6, IL-8, TNF-α, and ICAM-1 and reduced epidermal hyperproliferation in the skin of IMQ-induced mice. GCK inhibited in vitro activation of NF-κB, leading to attenuated release of inflammatory mediators (IL-6, IL-8, TNF-α, and ICAM-1) and suppression of NHEK hyperproliferation and abnormal differentiation. These inhibitory effects of GCK were diminished by GR silencing in NHEKs.

Conclusion: GCK suppressed psoriasis-related inflammation by suppressing keratinocyte activation, which may be related to promoting GR nuclear translocation and inhibiting NF-κB activation. In summary, GCK appears to be a GR activator and a promising therapeutic candidate for antipsoriatic agents.

目的:研究人参皂苷化合物K(GCK)对银屑病的作用和机制,重点是角质形成细胞中的糖皮质激素受体(GR):方法:为了评估人参皂苷化合物 K(GCK)的抗炎作用,我们制作了一种咪喹莫特(IMQ)诱导的银屑病样皮炎小鼠模型。血红素和伊红(H&E)染色用于评估皮肤病理变化。用免疫组化方法检测小鼠皮肤中 K17 和 p-p65 的蛋白表达。通过 Western 印迹检测 p65 IκB 的蛋白表达和磷酸化。通过 Western 印迹和免疫荧光检测 K1、K6、K10、K16、K17 和 GR 的蛋白表达。酶联免疫吸附试验(ELISA)用于检测 TNF-α、IL-6、CXCL-8 和 ICAM-1 的细胞因子水平。实时聚合酶链反应(RT-PCR)用于量化 TNF-α、IL-6、IL-8 和 ICAM-1 mRNA 的表达。细胞活力由细胞计数试剂盒-8(CCK-8)测定。高含量细胞成像系统用于检测细胞增殖。通过成像流式细胞仪和免疫荧光显微镜检测 p65 和 GR 的核转运。用小干扰 RNA 证实了 GR 在正常人表皮角质细胞(NHEKs)中 GCK 的抗炎和免疫调节作用:结果:GCK减少了IMQ诱导小鼠的银屑病面积、严重程度指数和表皮增厚。GCK 能明显降低 IL-6、IL-8、TNF-α 和 ICAM-1 的 mRNA 水平,并减少 IMQ 诱导的小鼠皮肤表皮的过度增殖。GCK 可抑制 NF-κB 的体外激活,从而减少炎症介质(IL-6、IL-8、TNF-α 和 ICAM-1)的释放,抑制 NHEK 的过度增殖和异常分化。GCK的这些抑制作用在NHEKs中被GR沉默后减弱:结论:GCK通过抑制角质形成细胞的活化来抑制银屑病相关炎症,这可能与促进GR核转位和抑制NF-κB活化有关。总之,GCK似乎是一种GR激活剂,是一种很有希望的候选抗银屑病治疗药物。
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引用次数: 0
Curcumin and Berberine Arrest Maturation and Activation of Dendritic Cells Derived from Lupus Erythematosus Patients. 姜黄素和小檗碱能阻止红斑狼疮患者树突状细胞的成熟和活化
Pub Date : 2024-01-26 DOI: 10.2174/0118761429249908231221080806
Amin Reza Nikpoor, Mahmoud Mahmoudi, Abbas Shapouri-Moghaddam, Zahra Rezaieyazdi, Samaneh Mollazadeh, Nafiseh Tabasi, Atena Mansouri, Reyhane Modarres Moghadam, Amir Abbas Momtazi, Soran K Najmaldin, Ramiar Kamal Kheder, Seyed-Alireza Esmaeili

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disease recognized by elevated activity of autoimmune cells, loss of tolerance, and decreased regulatory T cells producing inhibitory cytokines. Despite many efforts, the definitive treatment for lupus has not been fully understood. Curcumin (CUR) and berberine (BBR) have significant immunomodulatory roles and anti-inflammatory properties that have been demonstrated in various studies. This study aimed to investigate the anti-inflammatory properties of CUR and BBR on human monocyte-derived dendritic cells (DCs) with an special focus on the maturation and activation of DCs.

Methods: Human monocytes were isolated from the heparinized blood of SLE patients and healthy individuals, which were then exposed to cytokines (IL-4 and GM-CSF) for five days to produce immature DCs. Then, the obtained DCs were characterized by FITC-uptake assay and then cultured in the presence of CUR, BBR, or lipopolysaccharide (LPS) for 48 h. Finally, the maturation of DCs was analyzed by the level of maturation using flow cytometry or real-time PCR methods.

Results: The results showed promising anti-inflammatory effects of CUR and BBR in comparison with LPS, supported by a significant reduction of not only co-stimulatory and antigen-presenting factors such as CD80, CD86, CD83, CD1a, CD14, and HLA-DR but also inflammatory cytokines such as IL-12.

Conclusion: CUR and BBR could arrest DC maturation and develop a tolerogenic DC phenotype that subsequently promoted the expression of inhibitory cytokines and reduced the secretion of proinflammatory markers.

背景:系统性红斑狼疮(SLE)是一种复杂的自身免疫性疾病,表现为自身免疫细胞活性增强、耐受性丧失以及产生抑制性细胞因子的调节性 T 细胞减少。尽管做了很多努力,但狼疮的最终治疗方法仍未完全明了。姜黄素(CUR)和小檗碱(BBR)具有显著的免疫调节作用和抗炎特性,这已在多项研究中得到证实。方法:从系统性红斑狼疮患者和健康人肝素化血液中分离人单核细胞,然后将其暴露于细胞因子(IL-4 和 GM-CSF)中 5 天,以产生未成熟的 DCs。然后,用 FITC 摄取测定法对获得的 DCs 进行表征,再在 CUR、BBR 或脂多糖(LPS)存在下培养 48 小时:结果:结果表明,与 LPS 相比,CUR 和 BBR 具有很好的抗炎效果,不仅共刺激因子和抗原递呈因子(如 CD80、CD86、CD83、CD1a、CD14 和 HLA-DR)显著减少,而且炎性细胞因子(如 IL-12)也显著减少:结论:CUR 和 BBR 可阻止 DC 成熟并形成一种可耐受的 DC 表型,从而促进抑制性细胞因子的表达并减少促炎标志物的分泌。
{"title":"Curcumin and Berberine Arrest Maturation and Activation of Dendritic Cells Derived from Lupus Erythematosus Patients.","authors":"Amin Reza Nikpoor, Mahmoud Mahmoudi, Abbas Shapouri-Moghaddam, Zahra Rezaieyazdi, Samaneh Mollazadeh, Nafiseh Tabasi, Atena Mansouri, Reyhane Modarres Moghadam, Amir Abbas Momtazi, Soran K Najmaldin, Ramiar Kamal Kheder, Seyed-Alireza Esmaeili","doi":"10.2174/0118761429249908231221080806","DOIUrl":"https://doi.org/10.2174/0118761429249908231221080806","url":null,"abstract":"<p><strong>Background: </strong>Systemic lupus erythematosus (SLE) is a complex autoimmune disease recognized by elevated activity of autoimmune cells, loss of tolerance, and decreased regulatory T cells producing inhibitory cytokines. Despite many efforts, the definitive treatment for lupus has not been fully understood. Curcumin (CUR) and berberine (BBR) have significant immunomodulatory roles and anti-inflammatory properties that have been demonstrated in various studies. This study aimed to investigate the anti-inflammatory properties of CUR and BBR on human monocyte-derived dendritic cells (DCs) with an special focus on the maturation and activation of DCs.</p><p><strong>Methods: </strong>Human monocytes were isolated from the heparinized blood of SLE patients and healthy individuals, which were then exposed to cytokines (IL-4 and GM-CSF) for five days to produce immature DCs. Then, the obtained DCs were characterized by FITC-uptake assay and then cultured in the presence of CUR, BBR, or lipopolysaccharide (LPS) for 48 h. Finally, the maturation of DCs was analyzed by the level of maturation using flow cytometry or real-time PCR methods.</p><p><strong>Results: </strong>The results showed promising anti-inflammatory effects of CUR and BBR in comparison with LPS, supported by a significant reduction of not only co-stimulatory and antigen-presenting factors such as CD80, CD86, CD83, CD1a, CD14, and HLA-DR but also inflammatory cytokines such as IL-12.</p><p><strong>Conclusion: </strong>CUR and BBR could arrest DC maturation and develop a tolerogenic DC phenotype that subsequently promoted the expression of inhibitory cytokines and reduced the secretion of proinflammatory markers.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139572452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Depression-like Behavior Induced by Repeated Administration of Dexamethasone to Lipopolysaccharide-inflamed Mice. 反复给发炎的脂多糖小鼠注射地塞米松诱发抑郁样行为
Pub Date : 2024-01-26 DOI: 10.2174/0118761429275495231215054024
Fumiya Shibagaki, Naoko Kojima, Akane Furukawa, Noritaka Nakamichi

Background: Over the years, animal models of depression have been developed by loading chronic stress, inducing neuroinflammation, or administering drugs that induce depression; however, these results have poor reproducibility. Therefore, it is necessary to develop animal models that exhibit definitive symptoms of depression for studies on potential therapeutics.

Objective: This study was aimed at investigating depression-like symptoms and their pathogenesis in lipopolysaccharide (LPS)-inflamed mice treated with dexamethasone (DEX).

Methods: Male ICR mice were injected with LPS, followed by injection with DEX a day later and each day for 6 consecutive days. Depression-like behavior, expression of the glial markers glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1), and the number of the immature neuronal marker doublecortin (DCX)-positive cells were assessed using tail-suspension test (TST), forced swim test (FST), western blot analysis, and immunohistochemical analysis.

Results: Mice in the LPS+DEX group had significantly longer immobility time in the TST and FST than did those in the LPS- or DEX-only and control groups on day 7 post-LPS administration. GFAP and Iba1 expression was significantly elevated in the hippocampus of mice in the LPS group than in those of mice in the control group. Moreover, a significantly lower number of DCX-positive cells was observed in the hippocampal dentate gyrus of mice in the LPS+DEX group compared with that in mice in the LPS- or DEX-only and control groups on day 7 after LPS administration.

Conclusion: Repeated DEX administration to LPS-inflamed mice may induce definitive depression-like symptoms by decreasing the number of immature neurons in the hippocampal dentate gyrus. This novel mouse model of depression was produced by repeated administration of steroids to inflamed mice.

背景:多年来,人们通过加载慢性应激、诱发神经炎症或服用诱发抑郁症的药物等方法建立了抑郁症动物模型;然而,这些结果的可重复性很差。因此,有必要开发能表现出抑郁症明确症状的动物模型,以研究潜在的治疗方法:本研究旨在探讨用地塞米松(DEX)治疗脂多糖(LPS)炎症小鼠的抑郁症状及其发病机制:方法:给雄性ICR小鼠注射LPS,一天后注射DEX,连续6天每天注射。采用尾悬吊试验(TST)、强迫游泳试验(FST)、Western印迹分析和免疫组化分析评估抑郁样行为、胶质标记物胶质纤维酸性蛋白(GFAP)和电离钙结合适配器分子1(Iba1)的表达以及未成熟神经元标记物双皮质素(DCX)阳性细胞的数量:结果:在注射 LPS 后第 7 天,LPS+DEX 组小鼠在 TST 和 FST 中的静止时间明显长于仅注射 LPS 或 DEX 组和对照组小鼠。LPS 组小鼠海马的 GFAP 和 Iba1 表达明显高于对照组。此外,在注射 LPS 后第 7 天,在 LPS+DEX 组小鼠的海马齿状回中观察到的 DCX 阳性细胞数量明显少于注射 LPS 或仅注射 DEX 组和对照组的小鼠:结论:对LPS炎症小鼠重复给予DEX可通过减少海马齿状回中未成熟神经元的数量诱发明确的抑郁症状。这种新型抑郁症小鼠模型是通过对发炎小鼠重复施用类固醇而产生的。
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引用次数: 0
Are Purinergic Receptors Overlooked Targets in HyperinflammatoryResponses? 嘌呤能受体是否是高炎症反应中被忽视的目标?
Pub Date : 2024-01-02 DOI: 10.2174/0118761429268892231116044537
Paulo A. F. Pacheco, Robson Xavier Faria
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引用次数: 0
期刊
Current molecular pharmacology
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