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Label-based comparative proteomics of oral mucosal tissue to understand progression of precancerous lesions to oral squamous cell carcinoma 基于标签的口腔黏膜组织比较蛋白质组学,了解癌前病变到口腔鳞状细胞癌的发展过程
IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-13 DOI: 10.1016/j.bbrep.2024.101842
<div><h3>Introduction</h3><div>Oral squamous cell carcinomas typically arise from precancerous lesions such as leukoplakia and erythroplakia. These lesions exhibit a range of histological changes from hyperplasia to dysplasia and carcinoma in situ, during their transformation to malignancy. The molecular mechanisms driving this multistage transition remain incompletely understood. To bridge this knowledge gap, our current study utilizes label based comparative proteomics to compare protein expression profiles across different histopathological grades of leukoplakia, erythroplakia, and oral squamous cell carcinoma samples, aiming to elucidate the molecular changes underlying lesion evolution.</div></div><div><h3>Methodology</h3><div>An 8-plex iTRAQ proteomics of 4 biological replicates from 8 clinical phenotypes of leukoplakia and erythroplakia, with hyperplasia, mild dysplasia, moderate dysplasia; along with phenotypes of well differentiated squamous cell carcinoma and moderately differentiated squamous cell carcinoma was carried out using the Orbitrap Fusion Lumos mass spectrometer. Raw files were processed with Maxquant, and statistical analysis across groups was conducted using MetaboAnalyst. Statistical tools such as ANOVA, PLS-DA VIP scoring, and correlation analysis were employed to identify differentially expressed proteins that had a linear expression variation across phenotypes of hyperplasia to cancer. Validation was done using Bioinformatic tools such as ClueGO + Cluepedia plugin in Cytoscape to extract functional annotations from gene ontology and pathway databases.</div></div><div><h3>Results and discussion</h3><div>A total of 2685 protein groups and 12,397 unique peptides were identified, and 61 proteins consistently exhibited valid reporter ion corrected intensities across all samples. Of these, 6 proteins showed linear varying expression across the analysed sample phenotypes. Collagen type VI alpha 2 chain (COL6A2), Fibrinogen β chain (FGB), and Vimentin (VIM) were found to have increased linear expression across pre-cancer phenotypes of leukoplakia to cancer, while Annexin A7 (ANXA7) was seen to be having a linear decreasing expression. Collagen type VI alpha 2 chain (COL6A2) and Annexin A2 (ANXA2) had increased linear expression across precancer phenotypes of erythroplakia to cancer. The mass spectrometry proteomics data have been deposited to the ProteomeXchanger Consortium via the PRIDE partner repository with the data set identifier PXD054190. These differentially expressed proteins mediate cancer progression mainly through extracellular exosome; collagen-containing extracellular matrix, hemostasis, platelet aggregation, and cell adhesion molecule binding.</div></div><div><h3>Conclusion</h3><div>Label-based proteomics is an ideal platform to study oral cancer progression. The differentially expressed proteins provide insights into the molecular mechanisms underlying the progression of oral premalignant lesions to malignant ph
导言:口腔鳞状细胞癌通常源于癌前病变,如白斑病和红斑病。这些病变在向恶性肿瘤转化的过程中会出现一系列组织学变化,从增生到发育不良和原位癌。驱动这种多阶段转变的分子机制仍不完全清楚。为了弥补这一知识空白,我们目前的研究利用基于标记的比较蛋白质组学比较了不同组织病理学等级的白斑病、红斑病和口腔鳞状细胞癌样本的蛋白质表达谱,旨在阐明病变演变的分子变化。方法 使用 Orbitrap Fusion Lumos 质谱仪对白斑病和红斑病的 8 种临床表型(增生、轻度发育不良、中度发育不良)以及分化良好的鳞状细胞癌和中度分化的鳞状细胞癌表型的 4 个生物重复样本进行了 8 重 iTRAQ 蛋白组学分析。使用 Maxquant 处理原始文件,并使用 MetaboAnalyst 进行跨组统计分析。采用方差分析、PLS-DA VIP 评分和相关性分析等统计工具来识别从增生到癌症的不同表型中具有线性表达变化的差异表达蛋白。利用Cytoscape中的ClueGO + Cluepedia插件等生物信息学工具从基因本体论和通路数据库中提取功能注释进行验证。其中,6 种蛋白质在分析样本表型中的表达呈线性变化。在从白斑病到癌症的癌前表型中,六型胶原蛋白α2链(COL6A2)、纤维蛋白原β链(FGB)和波形蛋白(VIM)的线性表达量增加,而Annexin A7(ANXA7)的线性表达量下降。六型胶原α2链(COL6A2)和Annexin A2(ANXA2)在红斑狼疮到癌症的癌前表型中的线性表达增加。质谱蛋白质组学数据已通过 PRIDE 合作伙伴存储库存入 ProteomeXchanger Consortium,数据集标识符为 PXD054190。这些差异表达的蛋白质主要通过细胞外基质、含胶原的细胞外基质、止血、血小板聚集和细胞粘附分子结合介导癌症进展。差异表达的蛋白质有助于深入了解口腔癌前病变向恶性表型发展的分子机制。这项研究对于口腔癌前病变的早期检测、风险分层、潜在治疗目标以及预防恶性病变具有转化价值。
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引用次数: 0
LINC01322 may serve as a potential diagnostic marker for advanced stage tumors in renal cell carcinoma patients eligible for total nephrectomy LINC01322 可作为符合全肾切除术条件的肾细胞癌患者晚期肿瘤的潜在诊断标志物
IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-13 DOI: 10.1016/j.bbrep.2024.101843

Background

Renal cell carcinoma (RCC) is a common urological cancer globally and shows a favorable prognosis in early stages of the tumor progression. Due to the poor prognosis for metastatic RCC patients, it is crucial to explore the molecular biology of RCC progression to establish efficient diagnostic and therapeutic markers for these patients. Long non-coding RNAs (lncRNAs) have critical roles in regulation of tumor cell proliferation, migration, and apoptosis during RCC progression. For the first time in the present study, we assessed the LINC01322 RNA expression levels in RCC patients to introduce that as a potential tumor marker among these patients.

Methods

we visualized LINC01322 expression data using the online tool Gene Expression Profiling Interactive Analysis (GEPIA2) across different cancers and normal tissues. Fifty fresh samples of RCC tumor tissues and their adjacent normal margins were collected to analyze the RNA expression of LINC01322 and its association with the clinicopathological features of RCC patients. The SYBR green method was used in real-time PCR to measure the LINC01322 RNA expression levels in RCC patients.

Results

Based on in-silico analysis, we hypothesized that LINC01322 could be involved in RCC progression by interacting with VHL, thereby influencing the tumor microenvironment. There were significant increased levels of LINC01322 RNA expressions in advanced stage compared with primary stage tumors that were located in left kidney (p = 0.048). Left kidney that were undergone the total nephrectomy had significant higher levels of LINC01322 RNA expressions compared with tumors in right kidney (p = 0.045). There was a direct correlation between the levels of LINC01322 RNA expression and RCC tumor size.

Conclusions

considering the substantial increase in LINC01322 RNA expression in advanced stage RCC tumors that are candidates for total nephrectomy; it could be suggested as a potential diagnostic indicator for high-risk patients. In-silico analysis also revealed that LINC01322 could be involved in regulation of tumor microenvironment during RCC progression by interacting with VHL. However, further investigations are needed to validate the potential link between LINC01322 and VHL during RCC progression. Evaluating the serum LINC01322 RNA levels in RCC patients is also necessary to use that as a diagnostic marker in clinical settings.
背景肾细胞癌(RCC)是全球常见的泌尿系统癌症,在肿瘤进展的早期预后良好。由于转移性 RCC 患者预后较差,因此探索 RCC 进展的分子生物学至关重要,以便为这些患者建立有效的诊断和治疗标记。长非编码 RNA(lncRNA)在 RCC 进展过程中对肿瘤细胞的增殖、迁移和凋亡起着关键的调控作用。在本研究中,我们首次评估了LINC01322 RNA在RCC患者中的表达水平,并将其作为一种潜在的肿瘤标志物引入这些患者中。我们收集了 50 份新鲜的 RCC 肿瘤组织及其邻近的正常边缘组织样本,以分析 LINC01322 的 RNA 表达及其与 RCC 患者临床病理特征的关联。结果基于体内分析,我们推测LINC01322可能通过与VHL相互作用参与RCC进展,从而影响肿瘤微环境。与原发期肿瘤相比,位于左肾的晚期肿瘤的 LINC01322 RNA 表达水平明显升高(p = 0.048)。与右肾肿瘤相比,接受全肾切除术的左肾肿瘤的 LINC01322 RNA 表达水平明显更高(p = 0.045)。LINC01322的RNA表达水平与RCC肿瘤的大小直接相关。体内分析还显示,LINC01322 可能通过与 VHL 相互作用,在 RCC 进展过程中参与肿瘤微环境的调控。然而,要验证LINC01322与VHL在RCC进展过程中的潜在联系还需要进一步的研究。评估RCC患者血清中的LINC01322 RNA水平对于将其作为临床诊断标志物也很有必要。
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引用次数: 0
A comprehensive review of arginine kinase proteins: What we need to know? 精氨酸激酶蛋白综述:我们需要知道什么?
IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-08 DOI: 10.1016/j.bbrep.2024.101837
The enzyme arginine kinase (AK), EC 2.7.3.3, catalyzes the reversible phosphorylation of arginine with adenosine triphosphate, forming phosphoarginine, which acts as an energy reservoir due to its high-energy phosphate content that can be rapidly transferred to ADP for ATP renewal. It has been proposed that AK should be associated with some ATP biosynthesis mechanisms, such as glycolysis and oxidative phosphorylation. Arginine kinase is an analogue of creatine kinase found in vertebrates. A literature survey has recovered the physicochemical and structural characteristics of AK. This enzyme is widely distributed in invertebrates such as protozoa, bacteria, porifera, cnidaria, mollusca, and arthropods. Arginine kinase may be involved in the response to abiotic and biotic stresses, being up regulated in several organisms and controlling energy homeostasis during environmental changes. Additionally, phosphoarginine plays a role in providing energy for the transport of protozoa, the beating of cilia, and flagellar movement, processes that demand continuous energy. Arginine kinase is also associated with allergies to shellfish and arthropods, such as shrimp, oysters, and cockroaches. Phenolic compounds such as resveratrol, which decrease AK activity by 50 % in Trypanosoma cruzi, inhibit the growth of the epimastigote and trypomastigote forms, making them a significant target for the development of medications for Chagas Disease treatment.
精氨酸激酶(AK)(EC 2.7.3.3)催化精氨酸与三磷酸腺苷发生可逆磷酸化反应,形成磷精氨酸,由于磷精氨酸含有高能磷酸,可迅速转化为 ADP 用于 ATP 的更新,因此可作为能量储备。有人提出,精氨酸激酶与某些 ATP 生物合成机制有关,如糖酵解和氧化磷酸化。精氨酸激酶是脊椎动物体内肌酸激酶的类似物。一项文献调查发现了精氨酸激酶的理化和结构特征。这种酶广泛分布于无脊椎动物,如原生动物、细菌、多孔动物、刺丝胞动物、软体动物和节肢动物。精氨酸激酶可能参与了对非生物和生物压力的反应,在一些生物体内被上调,并在环境变化时控制能量平衡。此外,磷精氨酸还在为原生动物的运输、纤毛跳动和鞭毛运动等需要持续能量的过程提供能量方面发挥作用。精氨酸激酶还与对贝类和节肢动物(如虾、牡蛎和蟑螂)过敏有关。酚类化合物(如白藜芦醇)能使克氏锥虫的精氨酸激酶活性降低 50%,从而抑制表表型和试表型锥虫的生长,使其成为开发治疗南美锥虫病药物的重要目标。
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引用次数: 0
Physical exercise improved the hematological effect of vitamin D in type 2 diabetes mellitus-induced nephrotoxicity in rats 体育锻炼可改善维生素 D 对 2 型糖尿病诱导的大鼠肾毒性的血液学影响
IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-04 DOI: 10.1016/j.bbrep.2024.101839

Introduction

Globally, one of the major causes of renal dysfunction is diabetes mellitus (DM), and diabetic-induced nephrotoxicity has been linked with anemia. Presently, numerous antidiabetic drugs have been designed for the management of this disorder but they possess their undesirable effects such as anemia and acute kidney injury. Hence, we explore the use of vitamin D with or without exercise for the management of DM-induced renal dysfunction.

Methods

Thirty-six (36) Wistar rats were randomly separated into six (6) groups: control (vehicle treated), diabetes untreated (HFD + STZ), diabetes + vitamin D (HFD + STZ + vitamin D), diabetes + exercise (HFD + STZ + exercise), diabetes + vitamin D + exercise (HFD + STZ + vitamin D+ exercise), diabetes + metformin (HFD + STZ + metformin).

Results

Vitamin D with or without exercise significantly reduced T2DM-induced hyperglycemia. Also, a decrease in T2DM-induced increase in urea, creatinine, lactate dehydrogenase, lactate, cholesterol, and triglyceride and a rise in DM-associated reduction in high-density lipoprotein. These events were associated with a significant increase in red blood cells, hematocrit value, hemoglobin, erythropoietin, and a decrease in white blood cell count. Furthermore, vitamin D with or without exercise reversed T2DM-induced increase in pro-oxidant and pro-inflammatory markers. This observed oxido-inflammatory response was associated with a significant increase in xanthine oxidase activities and uric acid concentration. Interestingly, better recovery rates from DM-associated hematological imbalance were discovered in rats co-treated with vitamin D and exercise.

Conclusion

Our findings revealed that exercise enhanced the hematological effect of vitamin D in HFD + STZ-induced T2DM animals.
导言在全球范围内,导致肾功能障碍的主要原因之一是糖尿病(DM),而糖尿病引起的肾毒性与贫血有关。目前,许多抗糖尿病药物已被设计用于治疗这种疾病,但这些药物也有其不良反应,如贫血和急性肾损伤。因此,我们探讨了在运动或不运动的情况下使用维生素 D 来治疗 DM 引起的肾功能障碍。方法将 36 只 Wistar 大鼠随机分为六组:对照组(药物治疗)、未治疗糖尿病组(HFD + STZ)、糖尿病 + 维生素 D 组(HFD + STZ + 维生素 D)、糖尿病 + 运动组(HFD + STZ + 运动)、糖尿病 + 维生素 D + 运动组(HFD + STZ + 维生素 D + 运动)、糖尿病 + 二甲双胍组(HFD + STZ + 二甲双胍)。结果无论是否运动,维生素 D 都能显著降低 T2DM 引起的高血糖。此外,由 T2DM 引起的尿素、肌酐、乳酸脱氢酶、乳酸、胆固醇和甘油三酯的增加也有所减少,而由 DM 引起的高密度脂蛋白的减少则有所上升。这些事件与红细胞、血细胞比容值、血红蛋白、促红细胞生成素的显著增加和白细胞计数的减少有关。此外,无论是否运动,维生素 D 都能逆转 T2DM 诱导的促氧化和促炎症标志物的增加。观察到的这种氧化-炎症反应与黄嘌呤氧化酶活性和尿酸浓度的显著增加有关。结论我们的研究结果表明,运动增强了维生素 D 对 HFD + STZ 诱导的 T2DM 动物的血液学效应。
{"title":"Physical exercise improved the hematological effect of vitamin D in type 2 diabetes mellitus-induced nephrotoxicity in rats","authors":"","doi":"10.1016/j.bbrep.2024.101839","DOIUrl":"10.1016/j.bbrep.2024.101839","url":null,"abstract":"<div><h3>Introduction</h3><div>Globally, one of the major causes of renal dysfunction is diabetes mellitus (DM), and diabetic-induced nephrotoxicity has been linked with anemia. Presently, numerous antidiabetic drugs have been designed for the management of this disorder but they possess their undesirable effects such as anemia and acute kidney injury. Hence, we explore the use of vitamin D with or without exercise for the management of DM-induced renal dysfunction.</div></div><div><h3>Methods</h3><div>Thirty-six (36) Wistar rats were randomly separated into six (6) groups: control (vehicle treated), diabetes untreated (HFD + STZ), diabetes + vitamin D (HFD + STZ + vitamin D), diabetes + exercise (HFD + STZ + exercise), diabetes + vitamin D + exercise (HFD + STZ + vitamin D+ exercise), diabetes + metformin (HFD + STZ + metformin).</div></div><div><h3>Results</h3><div>Vitamin D with or without exercise significantly reduced T2DM-induced hyperglycemia. Also, a decrease in T2DM-induced increase in urea, creatinine, lactate dehydrogenase, lactate, cholesterol, and triglyceride and a rise in DM-associated reduction in high-density lipoprotein. These events were associated with a significant increase in red blood cells, hematocrit value, hemoglobin, erythropoietin, and a decrease in white blood cell count. Furthermore, vitamin D with or without exercise reversed T2DM-induced increase in pro-oxidant and pro-inflammatory markers. This observed oxido-inflammatory response was associated with a significant increase in xanthine oxidase activities and uric acid concentration. Interestingly, better recovery rates from DM-associated hematological imbalance were discovered in rats co-treated with vitamin D and exercise.</div></div><div><h3>Conclusion</h3><div>Our findings revealed that exercise enhanced the hematological effect of vitamin D in HFD + STZ-induced T2DM animals.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142422979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Molecular dynamics of three different α-helices in ribosomal protein L25 from Escherichia coli 大肠杆菌核糖体蛋白 L25 中三种不同 α-螺旋的分子动力学特征
IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-29 DOI: 10.1016/j.bbrep.2024.101836
A true native protein state is realized in a water solution where proteins exhibit their dynamic properties important for the functioning. This is way we have analyzed the dynamics of α-helices inside ribosomal protein L25 from Escherichia coli in a water solution. The dynamics of only main chain Cα-atoms have been simulated along the five independent trajectories at a total time 200ns. Superposed average dynamics picture of L25 structure coincides very well with the NMR protein structure in a water solution. Dynamic shifts of Cα-atoms of the α-helices are related with a restraint status of the residue side chain. In contrast, Cα-atoms of the β-sheet, which form a hydrophobic core, show very low dynamic motion and higher stability. Dynamic specificity of the main chain of protein L25 could explain its particular features in the complex with 5S rRNA and in the structure of the ribosome.
真正的原生蛋白质状态是在水溶液中实现的,在水溶液中,蛋白质表现出对其功能非常重要的动态特性。因此,我们分析了水溶液中大肠杆菌核糖体蛋白 L25 内部 α-螺旋的动态。我们在总时间为 200ns 的条件下,沿着五个独立轨迹模拟了主链 Cα 原子的动态。L25 结构的叠加平均动力学图像与水溶液中的核磁共振蛋白质结构非常吻合。α-螺旋的 Cα 原子的动态移动与残基侧链的限制状态有关。相比之下,构成疏水核心的 β 片状结构的 Cα 原子的动态运动非常小,稳定性更高。蛋白质 L25 主链的动态特异性可以解释其与 5S rRNA 复合物和核糖体结构的特殊性。
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引用次数: 0
Lutein and zeaxanthin reduce neuronal cell damage caused by lipid peroxidation 叶黄素和玉米黄质可减少脂质过氧化对神经细胞造成的损伤
IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-27 DOI: 10.1016/j.bbrep.2024.101835
Oxidative stress and lipid peroxide levels in the brain increase with aging. The carotenoids lutein and zeaxanthin have potent antioxidant properties and the ability to improve cognitive function. However, their effects on neuronal damage via lipid peroxidation remain unknown. Therefore, we aimed to elucidate the effects of these carotenoids on neuronal damage induced by accumulated peroxidized lipids. We developed an oxidative stress model of lipid peroxidation-induced neuronal damage using differentiated neuronal cells derived from human neuroblastoma SH-SY5Y cells in vitro. Combining rotenone and RSL3 increased mitochondrial oxidative stress and lipid reactive oxygen species (ROS), which resulted in enhanced neuronal damage. Lutein and zeaxanthin were added to the cells for 1 week, and these carotenoids suppressed mitochondrial oxidative stress and lipid peroxidation in differentiated neuronal cells and mitigated neuronal damage. Further investigation is required to clarify the underlying pathways in detail.
随着年龄的增长,大脑中的氧化应激和过氧化脂质含量也会增加。类胡萝卜素叶黄素和玉米黄质具有强大的抗氧化特性,能够改善认知功能。然而,它们通过脂质过氧化对神经元损伤的影响仍然未知。因此,我们旨在阐明这些类胡萝卜素对累积过氧化脂质诱导的神经元损伤的影响。我们利用从人类神经母细胞瘤 SH-SY5Y 细胞中分化出来的神经元细胞,在体外建立了脂质过氧化诱导神经元损伤的氧化应激模型。将鱼藤酮和 RSL3 结合使用会增加线粒体氧化应激和脂质活性氧(ROS),从而导致神经元损伤加剧。在细胞中添加叶黄素和玉米黄质一周后,这些类胡萝卜素抑制了分化神经元细胞的线粒体氧化应激和脂质过氧化反应,减轻了神经元损伤。要详细阐明其潜在的途径,还需要进一步的研究。
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引用次数: 0
The dose-effect response of combined red and infrared photobiomodulation on insulin resistance in skeletal muscle cells 红外线和红外线联合光生物调节对骨骼肌细胞胰岛素抵抗的剂量效应响应
IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.bbrep.2024.101831
Obesity is a major public health problem and is a major contributor to the development of insulin resistance. In previous studies we observed that single-wavelength red or infrared photobiomodulation (PBM) improved insulin signaling in adipocytes and skeletal muscle of mice fed a high-fat diet, but information about the combination of different wavelengths, as well as the effect of different light doses (J/cm2) is lacking. Therefore, the aim of this study was to investigate the effects of different doses of dual-wavelength PBM on insulin signaling in muscle cell, and explore potential mechanisms involved. Mouse myoblasts (C2C12) were differentiated into myotubes and cultured in palmitic acid, sodium oleate and l-carnitine (PAL) to induce insulin resistance high or in glucose medium (CTRL). Then, they received SHAM treatment (lights off, 0 J/cm2) or PBM (660 + 850 nm; 2, 4 or 8 J/cm2). PAL induced insulin resistance (assessed by Akt phosphorylation at ser473), attenuated maximal citrate synthase activity, and increased the phosphorylation of c-Jun NH(2) terminal kinase (JNK) (T183/Y185). PBM at doses of 4 or 8 J/cm2 reversed these PAL-induced responses. Furthermore, at doses of 2, 4 or 8 J/cm2, PBM reversed the increase in mitofusin-2 content induced by PAL. In conclusion, the combination of dual-wavelength red and infrared PBM at doses of 4 and 8 J/cm2 improved intracellular insulin signaling in musculoskeletal cells, and this effect appears to involve the modulation of mitochondrial function and the attenuation of the activation of stress kinases.
肥胖是一个主要的公共健康问题,也是导致胰岛素抵抗的一个主要因素。在之前的研究中,我们观察到单波长红色或红外光生物调节(PBM)改善了高脂饮食小鼠脂肪细胞和骨骼肌中的胰岛素信号传导,但缺乏有关不同波长的组合以及不同光剂量(J/cm2)的影响的信息。因此,本研究旨在探讨不同剂量的双波长 PBM 对肌肉细胞中胰岛素信号转导的影响,并探索其中的潜在机制。将小鼠肌母细胞(C2C12)分化成肌管,并在棕榈酸、油酸钠和左旋肉碱(PAL)诱导高胰岛素抵抗或葡萄糖培养基(CTRL)中培养。然后,它们接受 SHAM 处理(关灯,0 J/cm2)或 PBM(660 + 850 nm;2、4 或 8 J/cm2)。PAL 可诱导胰岛素抵抗(通过 Akt 在 ser473 处的磷酸化进行评估),减弱柠檬酸合成酶的最大活性,并增加 c-Jun NH(2) 末端激酶(JNK)的磷酸化(T183/Y185)。剂量为 4 或 8 J/cm2 的 PBM 逆转了这些 PAL 诱导的反应。此外,在剂量为 2、4 或 8 J/cm2 时,PBM 逆转了 PAL 诱导的丝裂霉素-2 含量的增加。总之,4 J/cm2 和 8 J/cm2 剂量的红外线和红外线双波长 PBM 组合改善了肌肉骨骼细胞内的胰岛素信号传导,这种效应似乎涉及线粒体功能的调节和应激激酶激活的减弱。
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引用次数: 0
CEACAM1 increased the lymphangiogenesis through miR-423-5p and NF- kB in Non-Small Cell Lung Cancer CEACAM1 通过 miR-423-5p 和 NF- kB 增加非小细胞肺癌的淋巴管生成
IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.bbrep.2024.101833

Background

Lung cancer causes significant mortality, with invasion and metastasis being the main features that cause most cancer deaths. Lymph node metastasis is the primary metastatic route in non-small cell carcinoma (NSCLC) and influences the staging and prognosis of NSCLC. Cumulative studies have reported that Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is involved in the progression of various cancers. However, few studies have discussed the function of CEACAM1 in lymphangiogenesis in NSCLC. Here, we examined how CEACAM1 influences lymphangiogenesis in NSCLC.

Methods

A total of 30 primary squamous cell carcinoma (LUSC) patients diagnosed with LN metastasis were prospectively selected. LUSC tumor tissues, para-cancerous tissues, and positive lymph node tissues were harvested. The expression and subcellular location of CEACAM1, CD31, and LVYE1 in clinical samples were detected by immunohistochemistry. Next, the CEACAM1 and hsa-miR-423-5p expressions were detected by qPCR. The protein expression of lymphangiogenesis-associated proteins and critical cytokines of the NF–κB pathway in HDLECs was detected by Western blot. A tube formation assay was performed to detect the lymphangiogenesis in different groups. The interaction between CEACAM1 and hsa-miR-423-5p was verified using a dual luciferase assay.

Results

CEACAM1 was found to be a potential gene associated with lung cancer prognosis. It was positively correlated with angiogenesis and lymphangiogenesis. Then, we detected the function of CEACAM1 in lymphangiogenesis and found that CEACAM1 promoted lymphangiogenesis. hsa-miR-423-5p overexpression inhibited lymphangiogenesis via targeting CEACAM1. Finally, we observed that CEACAM1 can activate the NF–κB pathway and, therefore, promote lymphangiogenesis.

Conclusion

We found that CEACAM1 enhanced lymphangiogenesis in NSCLC via NF-kB activation and was repressed by miR-423-5p. This suggests the value of CEACAM1 as a new therapeutic marker in NSCLC.
背景肺癌会导致大量死亡,侵袭和转移是导致大多数癌症死亡的主要特征。淋巴结转移是非小细胞癌(NSCLC)的主要转移途径,影响着 NSCLC 的分期和预后。大量研究表明,癌胚抗原相关细胞粘附分子 1(CEACAM1)参与了多种癌症的进展。然而,很少有研究讨论 CEACAM1 在 NSCLC 淋巴管生成中的功能。本文研究了 CEACAM1 如何影响 NSCLC 的淋巴管生成。方法前瞻性地选择了 30 例确诊为 LN 转移的原发性鳞状细胞癌(LUSC)患者。方法前瞻性地选择了30例确诊为淋巴结转移的原发性鳞状细胞癌(LUSC)患者,采集了LUSC肿瘤组织、癌旁组织和阳性淋巴结组织。通过免疫组化检测临床样本中 CEACAM1、CD31 和 LVYE1 的表达和亚细胞位置。然后,通过 qPCR 检测 CEACAM1 和 hsa-miR-423-5p 的表达。通过 Western 印迹检测了 HDLECs 中淋巴管生成相关蛋白和 NF-κB 通路关键细胞因子的蛋白表达。用试管形成试验检测不同组淋巴管生成的情况。结果发现 CEACAM1 是与肺癌预后相关的潜在基因。它与血管生成和淋巴管生成呈正相关。然后,我们检测了 CEACAM1 在淋巴管生成中的功能,发现 CEACAM1 促进淋巴管生成。最后,我们观察到 CEACAM1 可激活 NF-κB 通路,从而促进淋巴管生成。这表明 CEACAM1 可作为一种新的 NSCLC 治疗标记物。
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引用次数: 0
Depletion of the Rho GTPases Cdc42, Rac1 or RhoA reduces PDGF-induced STAT1 and STAT3 signaling 消耗 Rho GTP 酶 Cdc42、Rac1 或 RhoA 可减少 PDGF 诱导的 STAT1 和 STAT3 信号传导
IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-25 DOI: 10.1016/j.bbrep.2024.101828
This study investigates the role of Rho GTPases, specifically Cdc42, Rac1, and RhoA, in platelet-derived growth factor receptors (PDGFRα and PDGFRβ) signaling. Signal transducer and activator of transcription (STAT) proteins, essential for cellular processes such as proliferation and immune response, are activated downstream of PDGFRs. Dysregulation of these pathways is linked to various diseases, including cancer. The current study examines the effects of Rho GTPase depletion on PDGFR phosphorylation, STAT protein stability, and downstream signaling. Results indicate that depletion of Cdc42, Rac1, or RhoA impairs PDGFR phosphorylation and reduces STAT1 and STAT3 signaling, without significantly affecting AKT and ERK1/2 pathways. The findings highlight the critical regulatory roles of Rho GTPases in PDGFR-mediated STAT signaling.
本研究探讨了 Rho GTPases(特别是 Cdc42、Rac1 和 RhoA)在血小板衍生生长因子受体(PDGFRα 和 PDGFRβ)信号传导中的作用。信号转导和激活转录(STAT)蛋白是细胞增殖和免疫反应等过程所必需的,它们在 PDGFR 的下游被激活。这些通路的失调与包括癌症在内的各种疾病有关。目前的研究探讨了 Rho GTPase 缺失对 PDGFR 磷酸化、STAT 蛋白稳定性和下游信号转导的影响。结果表明,消耗 Cdc42、Rac1 或 RhoA 会损害 PDGFR 磷酸化并减少 STAT1 和 STAT3 信号传导,但不会显著影响 AKT 和 ERK1/2 通路。这些发现突显了 Rho GTPases 在 PDGFR 介导的 STAT 信号转导中的关键调节作用。
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引用次数: 0
Anthricin-induced hyperactive proteasome and its molecular mechanism 炭疽素诱导的蛋白酶体亢进及其分子机制
IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 DOI: 10.1016/j.bbrep.2024.101830
Recently, targeted protein degradation has attracted increasing interest as a new drug discovery approach. This method aims to control the function of drug targets by inducing their degradation through protein degradation systems such as the proteasome. Concurrently, compounds that enhance proteasome activity have also garnered attention. In 2023, we reported that anthricin (also known as 4-deoxypodophyllotoxin), a natural product that belongs to the lignan family, enhances proteasome activity. However, whether this enhancement was because of increased proteasome expression or improved proteasome function remains unclear. In this study, we investigated the structure–activity relationship of anthricin and its analogs in enhancing proteasome activity, the effects of anthricin on proteasome-related gene expression, and the direct binding between anthricin and the proteasome using pull-down assay. Moreover, we assessed the interaction between anthricin and the proteasome using molecular dynamics (MD) simulations. The results showed that anthricin does not induce proteasome-related gene expression, but instead binds to the β-subunit of the proteasome, bringing the side chains of three amino acid residues (Thr1, Asp17, and Lys33) at the catalytic site closer together, thereby inducing a hyperactive state. To the best of our knowledge, this study is the first to suggest the mechanism of proteasome activity enhancement by anthricin at the molecular level. The findings could contribute to the development of new chemotypes to enhance the effects of targeted protein degraders by regulating proteasome activity.
最近,靶向蛋白质降解作为一种新的药物发现方法引起了越来越多的关注。这种方法旨在通过蛋白酶体等蛋白质降解系统诱导药物靶点降解,从而控制药物靶点的功能。与此同时,能增强蛋白酶体活性的化合物也备受关注。2023 年,我们报道了木质素家族的天然产物 anthricin(又称 4-deoxypodophyllotoxin)能增强蛋白酶体的活性。然而,这种增强是由于蛋白酶体表达的增加还是蛋白酶体功能的改善仍不清楚。在这项研究中,我们研究了花翠素及其类似物在增强蛋白酶体活性方面的结构-活性关系、花翠素对蛋白酶体相关基因表达的影响以及花翠素与蛋白酶体之间的直接结合。此外,我们还利用分子动力学(MD)模拟评估了蒽素与蛋白酶体之间的相互作用。结果表明,蒽素并不诱导蛋白酶体相关基因的表达,而是与蛋白酶体的β亚基结合,使催化位点的三个氨基酸残基(Thr1、Asp17和Lys33)的侧链靠拢,从而诱导蛋白酶体进入亢奋状态。据我们所知,这项研究首次在分子水平上提出了蒽素增强蛋白酶体活性的机制。这些发现有助于开发新的化学类型,通过调节蛋白酶体的活性来增强靶向蛋白降解剂的效果。
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