Pub Date : 2024-09-23DOI: 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.
{"title":"Mutations in Rv0678, Rv2535c, and Rv1979c Confer Resistance to Bedaquiline in Clinical Isolates of Mycobacterium Tuberculosis.","authors":"Khaoula Balgouthi, Manaf AlMatar, Hamza Saghrouchni, Osman Albarri, Işıl Var","doi":"10.2174/0118761429314641240815080447","DOIUrl":"https://doi.org/10.2174/0118761429314641240815080447","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335058","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}
Pub Date : 2024-09-02DOI: 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。
{"title":"Mechanism, Potential, and Concerns of Immunotherapy for Hepatocellular Carcinoma and Liver Transplantation.","authors":"Bruno Sensi, Roberta Angelico, Luca Toti, Luigi Conte, Alessandro Coppola, Giuseppe Tisone, Tommaso Maria Manzia","doi":"10.2174/0118761429310703240823045808","DOIUrl":"https://doi.org/10.2174/0118761429310703240823045808","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121403","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}
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.
{"title":"Paeoniflorin Alleviates Anxiety and Visceral Hypersensitivity via HPA Axis and BDNF/TrkB/PLCγ1 Pathway in Maternal Separation-induced IBS-like Rats.","authors":"Ruifeng Liang, Wenjing Ge, Xianmei Song, Huisen Wang, Weifeng Cui, Xuexia Zhang, Zheng Wei, Gengsheng Li","doi":"10.2174/0118761429280572240311060851","DOIUrl":"https://doi.org/10.2174/0118761429280572240311060851","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results and discussion: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140144931","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}
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.
{"title":"siRNA Targeting ECE-1 Partially Reverses Pulmonary Arterial Hypertensionassociated Damage in a Monocrotaline Model.","authors":"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","doi":"10.2174/0118761429283384240226074921","DOIUrl":"https://doi.org/10.2174/0118761429283384240226074921","url":null,"abstract":"<p><strong>Aims: </strong>The aim of this study was to develop a possible treatment for pulmonary arterial hypertension.</p><p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Based on the above information, we conclude that the administration of siRNAs directed to ECE-1 decreases the damage associated with PAH.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140095392","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}
Pub Date : 2024-02-29DOI: 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}
Pub Date : 2024-02-27DOI: 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}
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.
{"title":"Ginsenoside Compound K Reduces Psoriasis-related Inflammation by Activation of the Glucocorticoid Receptor in Keratinocytes.","authors":"Wu Wang, Xiujin Xu, Mei Yang, Mengya Jiang, Dandan Wang, Caihong Tang, Wei Wei, Jingyu Chen","doi":"10.2174/0118761429254358231120135400","DOIUrl":"10.2174/0118761429254358231120135400","url":null,"abstract":"<p><strong>Aim: </strong>To investigate the effects and mechanism of Ginsenoside Compound K (GCK) on psoriasis, focusing on the glucocorticoid receptor (GR) in keratinocytes.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139934751","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}
Pub Date : 2024-01-26DOI: 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.
{"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}
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.
{"title":"Depression-like Behavior Induced by Repeated Administration of Dexamethasone to Lipopolysaccharide-inflamed Mice.","authors":"Fumiya Shibagaki, Naoko Kojima, Akane Furukawa, Noritaka Nakamichi","doi":"10.2174/0118761429275495231215054024","DOIUrl":"https://doi.org/10.2174/0118761429275495231215054024","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>This study was aimed at investigating depression-like symptoms and their pathogenesis in lipopolysaccharide (LPS)-inflamed mice treated with dexamethasone (DEX).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</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":"139572454","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}