Advances in medical sciences最新文献

Targeting treatment resistance in cervical cancer: A new avenue for senolytic therapies. 针对宫颈癌的耐药性：老年溶解疗法的新途径

IF 2.5 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Advances in medical sciences

Pub Date : 2024-11-14 DOI: 10.1016/j.advms.2024.11.001

Madré Meyer, Carla Fourie, Haynes van der Merwe, Hennie Botha, Anna-Mart Engelbrecht

Cervical cancer poses a significant global health challenge, particularly impacting women in economically developing nations. This disparity stems from a combination of factors, including inadequate screening infrastructure and resource limitations. However, the foremost contributor is the widespread lack of awareness and limited accessibility to Human Papillomavirus (HPV) vaccination, which is a key preventative measure against cervical cancer development. Despite advancements in cervical cancer prevention, treatment resistance remains a major hurdle in achieving improved patient outcomes. Cellular senescence, specifically the senescence-associated secretory phenotype (SASP) and its bidirectional relationship with the immune system, has been implicated in resistance to conventional cervical cancer chemotherapy treatments. The exact mechanisms by which this state of growth arrest and the associated changes in immune regulation contribute to cervical cancer progression and the associated drug resistance are not entirely understood. This underscores the necessity for innovative strategies to address the prevalence of treatment-resistant cervical cancer, with one promising avenue being the utilisation of senolytics. Senolytics are agents that have promising efficacy in clearing senescent cells from tumour tissues, however neither the utilisation of senolytics for addressing senescence-induced treatment resistance nor the potential integration of immunotherapy as senolytic agents in cervical cancer treatment has been explored to date. This review provides a concise overview of the mechanisms underlying senescence induction and the pivotal role of the immune system in this process. Additionally, it explores various senolytic approaches that hold significant potential for advancing cervical cancer research.

宫颈癌对全球健康构成了重大挑战，尤其影响到经济发展中国家的妇女。造成这种差异的因素很多，包括筛查基础设施不足和资源限制。然而，最主要的原因是人们普遍缺乏对人类乳头瘤病毒（HPV）疫苗接种的认识，而且接种机会有限，而接种HPV疫苗是预防宫颈癌发展的关键措施。尽管在宫颈癌预防方面取得了进展，但治疗耐药性仍是改善患者预后的一大障碍。细胞衰老，特别是衰老相关分泌表型（SASP）及其与免疫系统的双向关系，已被认为与传统宫颈癌化疗的耐药性有关。这种生长停滞状态和相关的免疫调节变化导致宫颈癌进展和相关耐药性的确切机制尚不完全清楚。这凸显了采用创新策略来解决宫颈癌耐药问题的必要性，其中一个很有前景的方法就是使用抗衰老剂。衰老剂是一种在清除肿瘤组织中衰老细胞方面具有良好疗效的药物，但迄今为止，还没有人探索过利用衰老剂来解决衰老引起的耐药性问题，也没有人探索过将免疫疗法作为衰老剂整合到宫颈癌治疗中的可能性。本综述简要概述了衰老诱导的基本机制以及免疫系统在这一过程中的关键作用。此外，它还探讨了在推进宫颈癌研究方面具有巨大潜力的各种衰老溶解方法。

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引用次数: 0

Recurrent hepatocellular carcinoma is associated with the enrichment of MYC targets gene sets, elevated high confidence deleterious mutations and alternative splicing of DDB2 and BRCA1 transcripts 复发性肝细胞癌与 MYC 目标基因组的富集、高置信度的有害突变以及 DDB2 和 BRCA1 转录本的替代剪接有关。

IF 2.5 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Advances in medical sciences

Pub Date : 2024-10-30 DOI: 10.1016/j.advms.2024.10.004

Oğuzhan Karaosmanoğlu

Purpose

Recurrence is the main cause of hepatocellular carcinoma (HCC) related deaths. Underlying recurrence biology can be better understood by comparative analysis of the complete set of transcripts between recurrent and non-recurrent HCC. In this study, transcriptomic data (GSE56545) from 21 male patients diagnosed with either recurrent or non-recurrent HCC were reanalyzed to identify deregulated pathways, somatic mutations, fusion transcripts, alternative splicing events, and the immune context in recurrent HCC.

Materials and methods

DESeq2 was used for differential expression analysis, Mutect2 for somatic mutation analysis, Arriba and STAR-Fusion for fusion transcript analysis, and rMATs for alternative splicing analysis.

Results

The results revealed that MYC targets gene sets (Hallmark_MYC_targets_V1 and Hallmark_MYC_targets_V2) were significantly enriched in recurrent HCC. Among the MYC targets, CBX3, NOP56, CDK4, NPM1, MCM5, MCM4 and PA2G4 upregulation was significantly associated with poor survival. Somatic mutation analysis demonstrated that the numbers of high confidence deleterious mutations were significantly increased in recurrent HCC. Alternative splicing-mediated production of non-functional DDB2 and oncogenic BRCA1 D11q were discovered in recurrent HCC. Finally, CD8⁺ T-cells were significantly decreased in recurrent HCC.

Conclusions

These results indicated that the enrichment of MYC targets gene sets is one of the most critical factors that leads to the development of recurrent HCC. In addition, elevated deleterious mutation numbers and alternative spliced DDB2 and BRCA1 isoforms have been identified as prominent contributors to increasing genomic instability in male patients with recurrent HCC.

目的：复发是肝细胞癌（HCC）相关死亡的主要原因。通过比较分析复发和非复发 HCC 的全套转录本，可以更好地了解复发的生物学基础。本研究重新分析了21例诊断为复发性或非复发性HCC男性患者的转录组数据（GSE56545），以确定复发性HCC中的失调通路、体细胞突变、融合转录本、替代剪接事件和免疫环境：DESeq2用于差异表达分析，Mutect2用于体细胞突变分析，Arriba和STAR-Fusion用于融合转录本分析，rMATs用于替代剪接分析：结果发现，MYC靶基因集（Hallmark_MYC_targets_V1和Hallmark_MYC_targets_V2）在复发性HCC中明显富集。在MYC靶点中，CBX3、NOP56、CDK4、NPM1、MCM5、MCM4和PA2G4的上调与生存率低明显相关。体细胞突变分析表明，高置信度的有害突变数量在复发性 HCC 中明显增加。在复发性 HCC 中发现了替代剪接介导的无功能 DDB2 和致癌 BRCA1 D11q 的产生。最后，CD8+ T细胞在复发性HCC中明显减少：这些结果表明，MYC 靶基因组的富集是导致复发性 HCC 发生的最关键因素之一。结论：这些结果表明，MYC靶基因集的富集是导致复发性HCC发生的最关键因素之一，此外，有害突变数量的增加以及DDB2和BRCA1同工酶的替代剪接也是导致男性复发性HCC患者基因组不稳定性增加的主要原因。

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引用次数: 0

Knockout of histone deacetylase 8 gene in breast cancer cells may alter the expression pattern of the signaling molecules 在乳腺癌细胞中敲除组蛋白去乙酰化酶 8 基因可能会改变信号分子的表达模式。

IF 2.5 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Advances in medical sciences

Pub Date : 2024-10-20 DOI: 10.1016/j.advms.2024.10.003

Nahid Bahrami , Mohammad Abdi

Purpose

Breast cancer (BC) is the most common cancer diagnosed in the world and it is also the main leading cause of cancer deaths in women. Change in epigenetic mechanisms promotes BC initiation and progression. Histone deacetylase 8 (HDAC8) was found to act as a potential oncogene in different malignancies. For better understanding of the HDAC8 function in BC development, we investigated the effect of HDAC8 deletion on the expression of genes involved in signaling pathways.

Materials and methods

In this study, CRISPR technology was used to knockout the HDAC8 gene in MDA-MB-468, MDA-MB-231 and MCF-7 cell lines. For this purpose, two gRNAs were designed and cloned into the PX459 vector. The gRNA-containing vectors were transfected into the BC cell lines and then the effect of this deletion on the expression of genes involved in signaling pathway was determined using quantitative real-time PCR (qRT-PCR).

Results

Analysis of qRT-PCR results showed a reduction in the expression of studied genes in BC cell lines after deletion of the HDAC8 gene compared to untreated controls. Although this decline was not significant for FGF2 and FGFR1 genes, however the mTOR, IGF1R, INSR, VEGFA and VEGFR2 genes showed statistically significant reduction in the studied BC cell lines. In addition, the down-regulation of PDGFC and PDGFRA genes were only significant in the TNBC cell lines.

Conclusion

Overall, our study showed that HDAC8 can exert its oncogenic effects by altering the expression level of molecules involved in some signaling pathways, and inhibiting HDAC8 can revert these effects.

目的：乳腺癌（BC）是世界上最常见的癌症，也是女性癌症死亡的主要原因。表观遗传机制的变化会促进乳腺癌的发生和发展。组蛋白去乙酰化酶 8（HDAC8）被发现在不同的恶性肿瘤中充当潜在的致癌基因。为了更好地了解HDAC8在BC发病中的功能，我们研究了HDAC8缺失对信号通路相关基因表达的影响：本研究采用CRISPR技术在MDA-MB-468、MDA-MB-231和MCF-7细胞系中敲除HDAC8基因。为此，研究人员设计了两个 gRNA，并将其克隆到 PX459 载体中。将含 gRNA 的载体转染到 BC 细胞系中，然后使用实时定量 PCR（qRT-PCR）测定这种缺失对信号通路相关基因表达的影响：qRT-PCR结果分析表明，与未处理的对照组相比，HDAC8基因缺失后，BC细胞系中研究基因的表达量有所下降。虽然FGF2和FGFR1基因的表达量下降不明显，但在所研究的BC细胞系中，mTOR、IGF1R、INSR、VEGFA和VEGFR2基因的表达量出现了统计学意义上的显著下降。此外，PDGFC 和 PDGFRA 基因的下调仅在 TNBC 细胞系中明显：总之，我们的研究表明，HDAC8可以通过改变参与某些信号通路的分子的表达水平来发挥其致癌作用，而抑制HDAC8可以逆转这些作用。

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引用次数: 0

Combination therapy of placenta-derived mesenchymal stem cells and artificial dermal scaffold promotes full-thickness skin defects vascularization in rat animal model 胎盘间充质干细胞与人工真皮支架的联合疗法促进了大鼠动物模型全厚皮肤缺损血管的形成。

IF 2.5 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Advances in medical sciences

Pub Date : 2024-10-17 DOI: 10.1016/j.advms.2024.10.002

Kun Zhang , Dongjie Xiao , Fang Li , Guodong Song , Guobao Huang , Yunshan Wang , Hua Liu

Purpose

Recently, placenta-derived mesenchymal stem cells (PMSCs) have garnered considerable attention in tissue repair and regeneration. The present study was conducted to evaluate the effect of PMSCs on artificial dermal scaffold (ADS) angiogenesis and their combination therapy on wound closure.

Material and methods

Herein, the growth and survival of PMSCs in ADS were explored. CCK8, scratch wound, and tubule formation assays were employed to investigate the effects of ADS conditioned medium (CM) and ADS-PMSCs CM on human umbilical vein endothelial cells (HUVECs). The effect of ADS-PMSCs on full-thickness skin defects healing was evaluated based on a rat model. Wound healing progresses was meticulously investigated through hematoxylin and eosin (HE), Masson's trichrome, and immunohistochemical staining analyses.

Results

In vitro cell culture results demonstrated the proliferation of PMSCs in ADS. The ADS-PMSCs CM notably stimulated the proliferation, migration, and tube formation of HUVECs compared to the ADS CM group. In the rat full-thickness skin defect model, the ADS-PMSCs treatment significantly accelerated the vascularization area of ADS after 2 weeks. Besides, HE and Masson's trichrome staining results indicated that ADS-PMSCs treatment significantly enhanced fibroblast proliferation and collagen fiber 2 weeks after surgical procedure. Compared to the ADS group, collagen fiber arrangement was thicker in the ADS-PMSCs group. Immunohistochemical staining reinforced this finding, illustrating a substantial increase in CD31 expression within the ADS-PMSCs group.

Conclusions

The results suggest that the combination of ADS with PMSCs accelerates ADS vascularization by fostering granulation tissue development and boosting the formation of new blood vessels.

目的：最近，胎盘间充质干细胞（PMSCs）在组织修复和再生方面受到广泛关注。本研究旨在评估胎盘间充质干细胞对人工真皮支架（ADS）血管生成的影响及其对伤口闭合的联合治疗作用。采用 CCK8、划痕伤口和小管形成试验研究 ADS 条件培养基（CM）和 ADS-PMSCs CM 对人脐静脉内皮细胞（HUVECs）的影响。以大鼠模型为基础，评估了 ADS-PMSCs 对全厚皮肤缺损愈合的影响。通过苏木精和伊红（HE）、马森三色染色和免疫组化染色分析，对伤口愈合进展进行了细致的研究：体外细胞培养结果表明，PMSCs 在 ADS 中增殖。与 ADS CM 组相比，ADS-PMSCs CM 组明显刺激了 HUVECs 的增殖、迁移和管形成。在大鼠全厚皮肤缺损模型中，ADS-PMSCs 治疗 2 周后明显加快了 ADS 的血管化面积。此外，HE 和 Masson's trichrome 染色结果表明，ADS-PMSCs 治疗能明显促进成纤维细胞的增殖和胶原纤维的形成。与 ADS 组相比，ADS-PMSCs 组的胶原纤维排列更粗。免疫组化染色证实了这一发现，表明 ADS-PMSCs 组 CD31 表达量大幅增加：结论：研究结果表明，ADS 与 PMSCs 的结合可促进肉芽组织的发育和新血管的形成，从而加速 ADS 的血管化。

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引用次数: 0

Enhancing the accuracy and effectiveness of diagnosis of spontaneous bacterial peritonitis in cirrhotic patients: A machine learning approach utilizing clinical and laboratory data 提高肝硬化患者自发性细菌性腹膜炎诊断的准确性和有效性：一种利用临床和实验室数据的机器学习方法。

IF 2.5 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Advances in medical sciences

Pub Date : 2024-10-16 DOI: 10.1016/j.advms.2024.10.001

Babak Khorsand , Mohsen Rajabnia , Ali Jahanian , Mobin Fathy , Somayye Taghvaei , Hamidreza Houri

Purpose

Spontaneous bacterial peritonitis (SBP) is a bacterial infection of ascitic fluid that develops naturally, without being triggered by any surgical conditions or procedures, and is a common complication of cirrhosis. With a potential mortality rate of 40 %, accurate diagnosis and prompt initiation of appropriate antibiotic therapy are crucial for optimizing patient outcomes and preventing life-threatening complications. This study aimed to expand the use of computational models to improve the diagnostic accuracy of SBP in cirrhotic patients by incorporating a broader range of data, including clinical variables and laboratory values.

Patients and methods

We employed 5 machine learning classification methods - Decision Tree, Support Vector Machine, Naive Bayes, K-Nearest Neighbor, and Random Forest, utilizing a variety of demographic, clinical, and laboratory features and biomarkers.

Results

Ascitic fluid markers, including white blood cell (WBC) count, lactate dehydrogenase (LDH), total protein, and polymorphonuclear cells (PMN), significantly differentiated between SBP and non-SBP patients. The Random Forest model demonstrated the highest overall accuracy at 86 %, while the Naive Bayes model achieved the highest sensitivity at 72 %. Utilizing 10 key features instead of the full feature set improved model performance, notably enhancing specificity and accuracy.

Conclusion

Our analysis highlights the potential of machine learning to enhance the accuracy of SBP diagnosis in cirrhotic patients. Integrating these models into clinical workflows could substantially improve patient outcomes. To achieve this, ongoing multidisciplinary research is crucial. Ensuring model interpretability, continuous monitoring, and rigorous validation will be essential for the successful implementation of real-time clinical decision support systems.

目的：自发性细菌性腹膜炎（SBP）是一种腹腔积液的细菌感染，是肝硬化的常见并发症。腹腔积液的潜在死亡率高达 40%，因此准确诊断和及时启动适当的抗生素治疗对于优化患者预后和预防危及生命的并发症至关重要。本研究旨在扩大计算模型的使用范围，通过纳入更广泛的数据（包括临床变量和实验室值）来提高肝硬化患者SBP的诊断准确性：我们采用了 5 种机器学习分类方法--决策树、支持向量机、Naive Bayes、K-近邻和随机森林，并利用了各种人口统计学、临床和实验室特征及生物标志物：结果：腹水标志物，包括白细胞（WBC）计数、乳酸脱氢酶（LDH）、总蛋白和多形核细胞（PMN），能显著区分SBP和非SBP患者。随机森林模型的总体准确率最高，达 86%，而 Naive Bayes 模型的灵敏度最高，达 72%。利用 10 个关键特征而不是全部特征集提高了模型的性能，尤其是提高了特异性和准确性：我们的分析凸显了机器学习在提高肝硬化患者 SBP 诊断准确性方面的潜力。将这些模型整合到临床工作流程中可以大大改善患者的预后。为此，持续的多学科研究至关重要。确保模型的可解释性、持续监测和严格验证对于实时临床决策支持系统的成功实施至关重要。

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引用次数: 0

Metabolic dysfunction-associated steatotic liver disease - A new indication for sodium-glucose Co-transporter-2 inhibitors 代谢功能障碍相关性脂肪肝--钠-葡萄糖共转运体-2 抑制剂的新适应症。

IF 2.5 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Advances in medical sciences

Pub Date : 2024-09-01 DOI: 10.1016/j.advms.2024.09.001

Grzegorz Procyk , Jakub Jaworski , Aleksandra Gąsecka , Krzysztof J. Filipiak , Josip A. Borovac

Metabolic dysfunction–associated steatotic liver disease (MASLD) has been proposed as a new name for the previous non-alcoholic fatty liver disease (NAFLD). There are some differences between MASLD and NAFLD, e.g., diagnostic criteria. MASLD is a hepatic steatosis without harmful alcohol consumption and is caused by metabolic factors. The prevalence of MASLD varies amongst different populations. The change in lifestyle plays a fundamental role in MASLD management, while there is no registered pharmacotherapy in this indication. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been suggested to have a beneficial effect on hepatic steatosis, hence, they have been widely investigated as potential therapeutics in MASLD. In this review, we aimed to thoroughly summarize current evidence from original research about the effects of SGLT2i use on MASLD. Almost all discussed studies advocate using SGLT2i in MASLD because of their beneficial effects. It includes the loss of body weight, which is beneficial per se, and the improvement in hepatic parameters. Most importantly, steatosis reduction has been observed in patients using SGLT2i. We highly recommend further research in this field, which we believe will eventually lead to a new indication for SGLT2i, i.e., MASLD.

代谢功能障碍相关性脂肪性肝病（MASLD）已被提出作为之前的非酒精性脂肪肝（NAFLD）的新名称。MASLD 与 NAFLD 在诊断标准等方面存在一些差异。非酒精性脂肪肝是一种肝脏脂肪变性，没有饮酒的危害，是由代谢因素引起的。MASLD在不同人群中的发病率各不相同。改变生活方式在 MASLD 的治疗中起着根本性的作用，但目前还没有针对这一适应症的注册药物疗法。钠-葡萄糖共转运体 2 抑制剂（SGLT2i）被认为对肝脏脂肪变性有好处，因此作为 MASLD 的潜在治疗药物被广泛研究。在这篇综述中，我们旨在全面总结目前有关使用 SGLT2i 对 MASLD 的影响的原创性研究证据。几乎所有讨论过的研究都主张在 MASLD 中使用 SGLT2i，因为它们具有有益的作用。其中包括减轻体重（这本身就是有益的）和改善肝脏参数。最重要的是，在使用 SGLT2i 的患者中观察到脂肪变性减轻。我们强烈建议在这一领域开展进一步研究，相信最终会为 SGLT2i 带来新的适应症，即 MASLD。

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引用次数: 0

An evaluation of the effect of the use of platelet-rich fibrin on tonsillectomy results 评估使用富血小板纤维蛋白对扁桃体切除术效果的影响。

IF 2.5 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Advances in medical sciences

Pub Date : 2024-09-01 DOI: 10.1016/j.advms.2024.09.004

Aslıhan Oflaz Çapar, Emre Solguntekin, Kerem Kökoğlu, Mehmet Ilhan Şahin

Purpose

The aim of this study was to investigate the effect of liquid platelet-rich fibrin (PRF) during tonsillectomy on postoperative results.

Patients and methods

This study included 41 patients who underwent tonsillectomy between April 2022 and January 2023. Liquid-PRF at a dose of 1 cc was injected to three different points of one of the tonsil fossae, selected at random intraoperatively. The same amount of physiological saline was injected to the symmetrical points on the opposite tonsil fossa using the same size injector. Pain, wound healing, and bleeding were evaluated on postoperative days 1, 7, and 14. The data of both sides were compared statistically as the study and control sides.

Results

The pain scores were the highest for both sides on postoperative day 1, and gradually decreased in the following days, with no significant difference determined between the sides (p > 0.05). Wound healing rates in the 1st week and 2 nd week were similar for both sides. Although there were more patients who have 100 % epithelization in the PRF group on the postoperative day 14, the difference between the groups was not statistically significant (p > 0.05).

Conclusions

The injection of PRF following tonsillectomy had no significant effect on postoperative pain, wound healing, or bleeding.

目的：本研究旨在探讨扁桃体切除术中液态富血小板纤维蛋白（PRF）对术后效果的影响：本研究纳入了在 2022 年 4 月至 2023 年 1 月期间接受扁桃体切除术的 41 名患者。在术中随机选择扁桃体窝的三个不同点注射 1cc 剂量的液体-PRF。使用相同大小的注射器，在对侧扁桃体窝的对称点注射相同剂量的生理盐水。术后第 1、7 和 14 天对疼痛、伤口愈合和出血情况进行评估。将两侧的数据作为研究侧和对照侧进行统计比较：结果：术后第 1 天两侧疼痛评分最高，随后几天逐渐降低，两侧疼痛评分无明显差异（P>0.05）。第 1 周和第 2 周的伤口愈合率两侧相似。虽然术后第 14 天 PRF 组上皮化生率达 100% 的患者较多，但组间差异无统计学意义（P>0.05）：扁桃体切除术后注射 PRF 对术后疼痛、伤口愈合和出血无明显影响。

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引用次数: 0

Angiopoietin-like 4 facilitates human aortic smooth muscle cell phenotype switch and dysfunctions through the PI3K/Akt signaling in aortic dissection 血管生成素样 4 在主动脉夹层中通过 PI3K/Akt 信号转导促进人类主动脉平滑肌细胞表型转换和功能障碍。

IF 2.5 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Advances in medical sciences

Pub Date : 2024-09-01 DOI: 10.1016/j.advms.2024.09.006

Wei He , Quan Zheng , Tingfang Zou , Wei Yan , Xue Gao , Chunle Wang , Yaoyao Xiong

Purpose

Vascular smooth muscle cell (VSMC) phenotype switch and dysfunctions have been reported to participate in aortic dissection (AD) progression. This study was aimed to investigate the role of angiopoietin-like 4 (ANGPTL4) in regulating VSMCs phenotype switch.

Materials and methods

Key genes were analyzed in AD using public datasets, and it was found that the central differential gene ANGPTL4 was up-regulated in AD. The KEGG signaling pathway annotation was performed to validate the associated pathways, and the expression of ANGPTL4 was verified using multiple datasets and clinical samples. Furthermore, the specific functions of ANGPTL4 on platelet-derived growth factor-BB (PDGF-BB)-treated human aortic smooth muscle cell (HASMC) phenotypes were investigated. The dynamic effects of ANGPTL4 and core signaling antagonists on HASMC phenotypes were examined.

Results

Hub gene ANGPTL4 was significantly up-regulated in AD. ANGPTL4 was linked to the PI3K/Akt signaling, angiogenesis, and neovascularization and remodeling. ANGPTL4 overexpression further enhanced PDGF-BB effects on HASMC phenotypes, including promoted cell viability and migration, decreased contractile VSMC markers α-SMA and SM22α, elevated ECM degradation markers MMP-2 and MMP-9, and promoted phosphorylation of PI3K and Akt. ANGPTL4 knockdown partially abolished PDGF-BB-induced contractile/synthetic VSMCs imbalance and HASMC dysfunctions. Furthermore, in ANGPTL4-overexpressing HASMCs pre-treated with PDGF-BB, the PI3K/Akt signaling inhibitor LY294002 also partially eliminated the effects caused by the PDGF-BB treatment and ANGPTL4 overexpression.

Conclusions

ANGPTL4 is significantly up-regulated in AD. ANGPTL4 overexpression further enhanced PDGF-BB effects on HASMC phenotype switch and dysfunctions, which might be involved in the PI3K/Akt signaling.

目的：据报道，血管平滑肌细胞（VSMC）表型转换和功能障碍参与了主动脉夹层（AD）的进展。本研究旨在探讨血管生成素样4（ANGPTL4）在调控血管平滑肌细胞表型转换中的作用：利用公开数据集分析了AD中的关键基因，发现中心差异基因ANGPTL4在AD中上调。通过KEGG信号通路注释验证了相关通路，并利用多个数据集和临床样本验证了ANGPTL4的表达。此外，还研究了ANGPTL4对血小板衍生生长因子-BB（PDGF-BB）处理的人主动脉平滑肌细胞（HASMC）表型的特定功能。研究了 ANGPTL4 和核心信号拮抗剂对 HASMC 表型的动态影响：结果：AD的枢纽基因ANGPTL4明显上调。ANGPTL4与PI3K/Akt信号传导、血管生成、新生血管形成和重塑有关。ANGPTL4 的过表达进一步增强了 PDGF-BB 对 HASMC 表型的影响，包括促进细胞活力和迁移、降低收缩性 VSMC 标志物 α-SMA 和 SM22α、提高 ECM 降解标志物 MMP-2 和 MMP-9，以及促进 PI3K 和 Akt 的磷酸化。敲除 ANGPTL4 可部分消除 PDGF-BB 诱导的收缩/合成 VSMC 失衡和 HASMC 功能障碍。此外，在用PDGF-BB预处理的ANGPTL4过表达的HASMC中，PI3K/Akt信号抑制剂LY294002也部分消除了PDGF-BB处理和ANGPTL4过表达造成的影响：结论：ANGPTL4在AD中明显上调。结论：ANGPTL4在AD中明显上调，ANGPTL4过表达进一步增强了PDGF-BB对HASMC表型转换和功能障碍的影响，这可能与PI3K/Akt信号转导有关。

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引用次数: 0

Reducing metastasis ability of gastric cancer cell line by targeting MMP16 using miR-193a-5p and 5-FU 利用 miR-193a-5p 和 5-FU 靶向 MMP16 降低胃癌细胞株的转移能力

IF 2.5 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Advances in medical sciences

Pub Date : 2024-09-01 DOI: 10.1016/j.advms.2024.09.008

Tahani Ahmad Almatrafi , Natrayan Lakshmaiya , Hailah M. Almohaimeed , Srikumar Chakravarthi , Ali H. Amin , Ayman Jafer , Amany I. Almars , Ammar A. Basabrain , Youssef S. Alghamdi , Mohamed J. Saadh , Reza Akhavan-Sigari

Purpose

Co-administration of microRNAs and chemotherapy drugs effectively treats several cancers. The current study sought to investigate the function of matrix metalloproteinase 16 (MMP16) and miR-193a-5p in the pathogenesis of gastric cancer (GC).

Materials/methods

Sixty-five surgical patients, 15 receiving 5-fluorouracil (5-FU), provided GC and adjacent non-cancerous tissue. Following that, qPCR was used to assess the expression levels of MMP16 and miR-193a-5p in GC cells. The impact of miR-193a-5p and 5-FU administration on MMP16 mRNA expression was evaluated using qRT-PCR and Western blotting. MTT and Scratch tests were also conducted to assess their effects on cell viability and migration. Moreover, a rescue experiment using an MTT assay was performed. Using flow cytometry, the apoptotic rate was calculated. Finally, it was evaluated how MMP16 and miR-193a-5p related to the clinicopathological characteristics of the patients.

Results

The current study found that while MMP16 expression increased in GC patients (P < 0.0001), miR-193a-5p expression significantly decreased (P < 0.001). MMP16 down-regulation was another effect of miR-193a-5p replacement, particularly when 5-FU was added (P < 0.01). In addition, this study found that miR-193a-5p, by concentrating on MMP16, decreased the migration of GC cells brought on by MMP16. In GC cell lines, miR-193 and 5-FU induce apoptosis, with the 5-FU being more pronounced when combined with mir-193, according to flow cytometry results. A strong correlation was also found between clinicopathological traits associated with MMP16 and miR-193a-5p.

Conclusions

These findings suggest that miR-193a-5p, in conjunction with 5-FU, down-regulates MMP16 in GC, where it suppresses tumor growth.

目的：microRNAs与化疗药物联合应用可有效治疗多种癌症。本研究试图探讨基质金属蛋白酶16（MMP16）和miR-193a-5p在胃癌（GC）发病机制中的功能：65例手术患者（其中15例接受了5-氟尿嘧啶（5-FU）治疗）提供了GC和邻近的非癌组织。然后，使用 qPCR 评估 GC 细胞中 MMP16 和 miR-193a-5p 的表达水平。使用 qRT-PCR 和 Western 印迹法评估了 miR-193a-5p 和 5-FU 给药对 MMP16 mRNA 表达的影响。还进行了 MTT 和划痕试验，以评估它们对细胞活力和迁移的影响。此外，还利用 MTT 试验进行了挽救实验。使用流式细胞术计算了细胞凋亡率。最后，还评估了 MMP16 和 miR-193a-5p 与患者临床病理特征的关系：结果：目前的研究发现，虽然 MMP16 在 GC 患者（PConclusions.）中的表达增加，但 miR-193a-5p 在 GC 患者中的表达却没有增加：这些研究结果表明，miR-193a-5p 与 5-FU 联用可下调 MMP16 在 GC 中的表达，从而抑制肿瘤生长。

{"title":"Reducing metastasis ability of gastric cancer cell line by targeting MMP16 using miR-193a-5p and 5-FU","authors":"Tahani Ahmad Almatrafi , Natrayan Lakshmaiya , Hailah M. Almohaimeed , Srikumar Chakravarthi , Ali H. Amin , Ayman Jafer , Amany I. Almars , Ammar A. Basabrain , Youssef S. Alghamdi , Mohamed J. Saadh , Reza Akhavan-Sigari","doi":"10.1016/j.advms.2024.09.008","DOIUrl":"10.1016/j.advms.2024.09.008","url":null,"abstract":"<div><h3>Purpose</h3><div>Co-administration of microRNAs and chemotherapy drugs effectively treats several cancers. The current study sought to investigate the function of matrix metalloproteinase 16 (MMP16) and miR-193a-5p in the pathogenesis of gastric cancer (GC).</div></div><div><h3>Materials/methods</h3><div>Sixty-five surgical patients, 15 receiving 5-fluorouracil (5-FU), provided GC and adjacent non-cancerous tissue. Following that, qPCR was used to assess the expression levels of MMP16 and miR-193a-5p in GC cells. The impact of miR-193a-5p and 5-FU administration on MMP16 mRNA expression was evaluated using qRT-PCR and Western blotting. MTT and Scratch tests were also conducted to assess their effects on cell viability and migration. Moreover, a rescue experiment using an MTT assay was performed. Using flow cytometry, the apoptotic rate was calculated. Finally, it was evaluated how MMP16 and miR-193a-5p related to the clinicopathological characteristics of the patients.</div></div><div><h3>Results</h3><div>The current study found that while MMP16 expression increased in GC patients (P < 0.0001), miR-193a-5p expression significantly decreased (P < 0.001). MMP16 down-regulation was another effect of miR-193a-5p replacement, particularly when 5-FU was added (P < 0.01). In addition, this study found that miR-193a-5p, by concentrating on MMP16, decreased the migration of GC cells brought on by MMP16. In GC cell lines, miR-193 and 5-FU induce apoptosis, with the 5-FU being more pronounced when combined with mir-193, according to flow cytometry results. A strong correlation was also found between clinicopathological traits associated with MMP16 and miR-193a-5p.</div></div><div><h3>Conclusions</h3><div>These findings suggest that miR-193a-5p, in conjunction with 5-FU, down-regulates MMP16 in GC, where it suppresses tumor growth.</div></div>","PeriodicalId":7347,"journal":{"name":"Advances in medical sciences","volume":"69 2","pages":"Pages 463-473"},"PeriodicalIF":2.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LRRC45 promotes lung cancer proliferation and progression by enhancing c-MYC, slug, MMP2, and MMP9 expression LRRC45 通过增强 c-MYC、Slug、MMP2 和 MMP9 的表达，促进肺癌的增殖和进展。

IF 2.5 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Advances in medical sciences

Pub Date : 2024-09-01 DOI: 10.1016/j.advms.2024.09.007

Qian Wang , Xin-Yan Liu , Xiao-Qi Zhang , Zheng-Xing Huo , Cheng-Yu Chen , Shi Chen , Cheng-Yong Liu , Jia Zhu , Shan-Shan Liu , Bing Lu

Background

The leucine-rich repeat-containing (LRRC) superfamily members are known for their significant roles in tumorigenesis and cellular proliferation. However, the specific regulatory role of LRRC45 in lung cancer remains unexplored. This study investigated the impact and underlying mechanisms of LRRC45 on the proliferative, migratory, and invasive capacities of lung adenocarcinoma (LUAD) cells, potentially identifying new targets for therapeutic intervention.

Material and methods

The importance of LRRC45 in lung cancer was analyzed using the online databases of UCSC Xena, TCGA, TISIDB, and UALCAN, whereas to detect target gene expression, we used the qRT-PCR, Western blot, and immunofluorescence confocal. The cell growth was monitored by colony formation assay and migration was examined by cell migration assay. Finally, a xenograft mouse tumor model using A549 cells was used to explore the in vivo effect of LRRC45 in lung cancer.

Results

Inhibition of LRRC45 expression led to a notable decrease in proliferation, migration, and invasion of A549 and H1299 cells. LRRC45 silencing significantly reduced the tumor volume and improved the mice's survival. Additionally, inhibition of LRRC45 expression dramatically suppressed c-MYC, Slug, MMP2, and MMP9 expression. Overexpression of c-MYC and/or Slug in the LRRC45-deficient cells can partially or totally restore the LRRC45 deficiency-suppressed growth. Moreover, the overexpression of MMP2 and/or MMP9 could partially or totally restore LRRC45 deficiency-reduced cell metastasis.

Conclusions

LRRC45 could promote the proliferative, migrative, and invasive capacities of lung cancer cells by increasing c-MYC, Slug, MMP2, and MMP9 expression, indicating the therapeutic implications and potential significance of these pathways in lung cancer.

背景：众所周知，含亮氨酸丰富重复序列（LRRC）超家族成员在肿瘤发生和细胞增殖中发挥着重要作用。然而，LRRC45在肺癌中的具体调控作用仍未得到探索。本研究探讨了 LRRC45 对肺腺癌（LUAD）细胞增殖、迁移和侵袭能力的影响及其内在机制，从而为治疗干预寻找新的靶点：利用UCSC Xena、TCGA、TISIDB和UALCAN在线数据库分析了LRRC45在肺癌中的重要性，并利用qRT-PCR、Western印迹和免疫荧光共聚焦技术检测了靶基因的表达。通过集落形成试验监测细胞生长，通过细胞迁移试验检测细胞迁移。最后，利用 A549 细胞异种移植小鼠肿瘤模型来探讨 LRRC45 在肺癌中的体内效应：结果：抑制 LRRC45 的表达可显著减少 A549 和 H1299 细胞的增殖、迁移和侵袭。沉默 LRRC45 能显著减少肿瘤体积，提高小鼠存活率。此外，抑制 LRRC45 的表达还能显著抑制 c-MYC、Slug、MMP2 和 MMP9 的表达。在LRRC45缺陷细胞中过表达c-MYC和/或Slug可以部分或完全恢复LRRC45缺陷抑制的生长。此外，MMP2和/或MMP9的过表达可部分或完全恢复LRRC45缺陷抑制的细胞转移：结论：LRRC45可通过增加c-MYC、Slug、MMP2和MMP9的表达来促进肺癌细胞的增殖、迁移和侵袭能力，表明了这些通路在肺癌中的治疗意义和潜在重要性。

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引用次数: 0