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Investigation of the Effects of Saxagliptin in In Vitro and In Vivo Models of Diabetic Neuropathy 沙格列汀对糖尿病神经病变模型的体内外作用研究。
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-17 DOI: 10.1002/jbt.70653
Samet Oz, Seval Ulku Orhan, Asli Taslidere, Mete Ozcan, Suat Tekin

Diabetic neuropathy (DN), one of the most common microvascular complications of diabetes, is a condition involving complex pathophysiological mechanisms such as oxidative stress, inflammation, apoptosis, primarily resulting from chronic hyperglycemia. This study aimed to evaluate potential effects of Saxagliptin (Sax), a DPP-4 enzyme inhibitor, on in vitro and in vivo models of DN. Dorsal root ganglion neurons isolated from 1 to 2-day-old Wistar Albino rats were exposed to a high-glucose environment for 24 h to induce in vitro DN model. In this model, effects of Sax on cell viability and associated intracellular signaling pathways were investigated. In the in vivo model, streptozotocin-induced diabetic mice were divided into four groups: control, DN, DN+Sax-2, DN+Sax-10 (n = 10). For 15 days, DN group received 0.9% isotonic sodium chloride, while DN+Sax-2 and DN+Sax-10 groups were administered Sax orally via gavage at doses of 2 and 10 mg/kg, respectively, with concurrent nociceptive behavioral testing. At end of experiment, animals were decapitated, biochemical and histological analyses were performed on collected blood and pancreatic tissues. Sax, significantly increased cell viability via phosphoinositide 3-kinase pathway (p < 0.05). Compared to DN group, Sax-treated groups showed improvements in mechanical allodynia and thermal hyperalgesia; increased levels of superoxide dismutase, catalase, glutathione, total antioxidant status, interleukin-10; decreased levels of malondialdehyde, interleukin-1β, interleukin-6 (p < 0.05). Additionally, caspase-3 expression in pancreatic tissue was suppressed, and histopathological damage was markedly reduced (p < 0.0001). These findings suggest that Sax suppresses inflammation, inhibits oxidative damage and apoptosis, thereby reducing hyperalgesia, and may have therapeutic effects against DN.

糖尿病性神经病变(DN)是糖尿病最常见的微血管并发症之一,主要由慢性高血糖引起,涉及氧化应激、炎症、细胞凋亡等复杂的病理生理机制。本研究旨在评价DPP-4酶抑制剂沙格列汀(Saxagliptin, Sax)对DN体外和体内模型的潜在影响。将1 ~ 2日龄Wistar Albino大鼠背根神经节神经元置于高糖环境24h诱导体外DN模型。在这个模型中,我们研究了Sax对细胞活力和相关细胞内信号通路的影响。在体内模型中,将链脲佐菌素诱导的糖尿病小鼠分为对照组、DN组、DN+Sax-2组、DN+Sax-10组(n = 10)。DN组给予0.9%等渗氯化钠治疗15 d, DN+Sax-2组和DN+Sax-10组分别以2和10 mg/kg的剂量灌胃给予Sax,同时进行伤害行为测试。实验结束时,将动物斩首,采集血液和胰腺组织进行生化和组织学分析。phosphoinositide 3-kinase pathway显著提高细胞活力(p
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引用次数: 0
Theoretical, In Vitro Antiproliferative, and In Silico Molecular Docking and Pharmacokinetics Studies of Dehydrozingerone Mannich Base Heterocyclic Derivatives 脱氢姜酮曼尼希碱杂环衍生物的理论、体外抗增殖和硅分子对接及药代动力学研究。
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-17 DOI: 10.1002/jbt.70650
Senthil Kumar Raju, Praveen Sekar, Naveena Sundhararajan, Badriyah Shadid Alotaibi, Murugesan Sankarganesh, Ajmal R. Bhat, Sumeer Ahmed

This study explores the design, synthesis, characterization, and pharmacological evaluation of chalcone-derived C-Mannich base compounds, which exhibit significant pharmacological potential in medicinal chemistry. A series of compounds 6(aj) was designed and investigated for the physicochemical properties, drug-likeness, toxicity profile, and molecular interactions through in silico methods. Computational tools, including SwissADME online server and ProTox II web tool were utilized to assess their pharmacokinetics, druggability, and toxicity, while molecular docking investigations were performed with the ADT tools, AutoDock 4.2 software to ascertain the binding interactions of query molecules with critical protein targets, such as ESR1, ERBB2, PIK3CA, PIK3R1, EGFR, SRC, STAT3 and IGF1R. The selected compounds 6(a, c, e, i, and j) were synthesized via a modified Mannich reaction utilizing dehydrozingerone (DHZ) along with 3-hydroxy benzaldehyde and various secondary amines. The synthesized derivatives were characterized using the spectral and CHN elemental analysis. The in vitro antiproliferative potential of selected derivatives 6(a, c, e, i, and j) was evaluated against the MCF-7 (breast adenocarcinoma), A549 (Small cell lung carcinoma), HeLa (Cervical cancer), HeP2 (Colon cancer), HepG2 (Liver carcinoma) and NHDF (Normal Human Dermal Fibroplasts) the MTT assay using doxorubicin as standard. The study demonstrates that DHZ-derived C-Mannich base compounds possess significant anticancer efficacy, positioning them as promising candidates for subsequent therapeutic development.

本研究探讨了查尔酮衍生的c -曼尼希碱类化合物的设计、合成、表征和药理评价,这些化合物在药物化学中具有重要的药理潜力。通过计算机方法设计和研究了一系列化合物6(A -j)的物理化学性质、药物相似性、毒性特征和分子相互作用。使用SwissADME在线服务器和ProTox II web工具等计算工具评估其药代动力学、药物耐受性和毒性,使用ADT工具、AutoDock 4.2软件进行分子对接研究,确定查询分子与关键蛋白靶点(如ESR1、ERBB2、PIK3CA、PIK3R1、EGFR、SRC、STAT3和IGF1R)的结合相互作用。以脱氢姜酮(DHZ)、3-羟基苯甲醛和多种仲胺为原料,经改性Mannich反应合成了化合物6(a、c、e、i和j)。利用光谱和CHN元素分析对合成的衍生物进行了表征。选择的衍生物6(a, c, e, i和j)对MCF-7(乳腺腺癌),A549(小细胞肺癌),HeLa(宫颈癌),HeP2(结肠癌),HepG2(肝癌)和NHDF(正常人真皮纤维细胞)的体外抗增殖潜力进行了MTT试验,以阿霉素为标准。该研究表明,dhz衍生的C-Mannich碱化合物具有显著的抗癌功效,将其定位为后续治疗开发的有希望的候选者。
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引用次数: 0
Synthesis and Biological Evaluation of Thiazolyl–Pyrimidine Hybrids as Potential Antiproliferative Agents With Molecular Docking Insights 噻唑嘧啶杂合体作为潜在抗增殖剂的合成及生物学评价。
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-14 DOI: 10.1002/jbt.70638
Sobhi M. Gomha, Sami A. Al-Hussain, Basant Farag, Tariq Z. Abolibda, AbdElAziz A. Nayl, Aamer Saeed, Abdelwahed R. Sayed, Magdi E. A. Zaki

A new series of thiazolyl–pyrimidine hybrids (5a–g, 7, and 10a–e) was synthesized via the condensation of bromoacetyl dihydropyrimidinone with various thiosemicarbazones. The identity of the synthesized compounds was established using elemental analysis along with IR, ¹H NMR, ¹³C NMR, and mass spectrometry. Their antiproliferative potential was subsequently assessed against MCF-7 (breast) and HepG-2 (liver) cancer cell lines, with doxorubicin employed as the standard reference. Several derivatives showed potent cytotoxicity; notably, 5g, 5b, 5f, and 10e exhibited IC₅₀ values of 3–5 μM, comparable to doxorubicin. Structure–activity relationship (SAR) studies indicated that electron-donating para-substituents and heteroaryl/coumarinyl moieties enhanced activity, while bulky fused rings and halogen groups reduced it. Given the persistent burden of breast and liver cancers, and the critical role of epidermal growth factor receptor (EGFR) in tumor progression, selected hybrids (5a, 5b, 5f, 5g, 10d, and 10e) were further investigated in silico. Molecular docking revealed strong binding to the cancer receptor, supporting their potential as anticancer leads. ADMET predictions suggested favorable pharmacokinetic and safety profiles. Collectively, these findings identify thiazolyl–pyrimidine hybrids as promising scaffolds and apoptosis inducers for future breast and liver cancer therapy.

以溴乙酰基二氢嘧啶酮与多种硫代氨基脲缩合为原料,合成了一系列新的噻唑基嘧啶杂化物(5a-g、7和10a-e)。通过元素分析、IR、¹H NMR、¹³C NMR和质谱分析确定了合成化合物的性质。随后,以阿霉素作为标准参比,评估了它们对MCF-7(乳腺癌)和HepG-2(肝癌)癌细胞系的抗增殖潜力。几种衍生物显示出强大的细胞毒性;值得注意的是,5g, 5b, 5f和10e的IC₅0值为3-5 μM,与阿霉素相当。构效关系(SAR)研究表明,给予电子的对取代基和杂芳基/香豆素基基团增强了活性,而大体积的融合环和卤素基则降低了活性。鉴于乳腺癌和肝癌的持续负担,以及表皮生长因子受体(EGFR)在肿瘤进展中的关键作用,我们选择了杂交基因(5a、5b、5f、5g、10d和10e)进行了进一步的硅片研究。分子对接显示与癌症受体的强结合,支持它们作为抗癌先导的潜力。ADMET预测显示良好的药代动力学和安全性。总的来说,这些发现确定了噻唑嘧啶杂合体是未来乳腺癌和肝癌治疗中有前途的支架和细胞凋亡诱导剂。
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引用次数: 0
DLX6 Drives Lung Adenocarcinoma Progression via the p27Kip1/CDK2-CCNE1 Signaling Pathway DLX6通过p27Kip1/CDK2-CCNE1信号通路驱动肺腺癌进展
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-14 DOI: 10.1002/jbt.70640
Zedong Sun, Feifan Ji, Jiayu Chen, Ningdan Song, Mingrui Liu, Minmin Zhou, Can Wang, Simian He, Ming Li, Quanli Zhang, Binhui Ren

Distal-less homeobox genes (DLX) comprise a family of cell-type-specific transcription factors crucial for the differentiation of various cell types. Despite reports of their dysregulated expression in cancer, the functional roles of DLX6 in carcinogenesis remain poorly understood. This study investigated the role and underlying mechanisms of DLX6 in Lung adenocarcinoma (LUAD). Analysis of data from The Cancer Genome Atlas (TCGA) and Tissue Microarray (TMA) demonstrated that elevated DLX6 expression was associated with poor prognosis in LUAD patients. Both in vitro and in vivo experiments confirmed that DLX6 promoted LUAD growth. Mechanistically, DLX6 transcriptionally inhibited cyclin-dependent kinase inhibitor 1B (CDKN1B), leading to activation of the p27Kip1/CDK2-CyclinE signaling axis and promoting the G1-to-S phase transition in the cell cycle. Functional rescue experiments confirmed that CDKN1B knockdown attenuated DLX6-mediated tumor growth. Furthermore, DLX6 was identified as a novel downstream target of miR-145, a tumor-suppressive microRNA. MiR-145 directly bound to DLX6, reducing its mRNA and protein levels and effectively counteracting DLX6's oncogenic effects. Collectively, these findings uncovered a previously uncharacterized role of DLX6 in LUAD development and proposed the miR-145/DLX6/p27Kip1/CDK2-CyclinE signal axis as a potential therapeutic target for LUAD management.

远端无同源盒基因(DLX)包括一个细胞类型特异性转录因子家族,对各种细胞类型的分化至关重要。尽管有报道称它们在癌症中的表达失调,但DLX6在癌变中的功能作用仍然知之甚少。本研究探讨DLX6在肺腺癌(LUAD)中的作用及其机制。来自癌症基因组图谱(TCGA)和组织微阵列(TMA)的数据分析表明,DLX6表达升高与LUAD患者预后不良相关。体外和体内实验均证实DLX6促进LUAD生长。从机制上讲,DLX6转录抑制细胞周期蛋白依赖性激酶抑制剂1B (CDKN1B),导致p27Kip1/CDK2-CyclinE信号轴的激活,促进细胞周期从g1到s的转变。功能修复实验证实,CDKN1B敲低可减弱dlx6介导的肿瘤生长。此外,DLX6被鉴定为肿瘤抑制microRNA miR-145的一个新的下游靶点。MiR-145直接与DLX6结合,降低其mRNA和蛋白水平,有效抵消DLX6的致癌作用。总的来说,这些发现揭示了DLX6在LUAD发展中以前未被描述的作用,并提出miR-145/DLX6/p27Kip1/CDK2-CyclinE信号轴作为LUAD管理的潜在治疗靶点。
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引用次数: 0
NENF, as a Biomarker for the Development of NAFLD to Liver Cancer by Enhancing the Tumor-Like Stem Cell Properties of L02 Cells to Promote the Progression of NAFLD to Liver Cancer NENF通过增强L02细胞的肿瘤样干细胞特性,促进NAFLD向肝癌发展,作为NAFLD向肝癌发展的生物标志物。
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-14 DOI: 10.1002/jbt.70617
Yuan Luo, Qi Yao

To explore the key risk genes involved in developing NAFLD into HCC. Four datasets-related NAFLD progression (NAFLD, NASH, Hepatofibrosis, Cirrhotic, and Tumor) were obtained from the GEO database. GO and KEGG analyses were performed to identify the biological functions, pathways, and cellular processes associated with the genes. GSVA analyses were performed to assess the variation in pathway activity across different samples based on gene expression profiles. We performed ordinal logistic regression analysis, collinearity analysis, importance analysis of influence factors (LASSO, XGBoost, and RandomForest), and Venn analysis to identify the hub genes within disease progression. The SHAP model and K-M survival analysis screened out risk genes-related development of NAFLD into HCC. The mRNAsi_score analysis evaluates the correlation of NENF expression and tumor stemness. A vector expressing NENF transfection was used to increase its expression. CCK8, cell spheroid formation assay, colony formation, transwell, western blot, and RT-PCR assays were used to detect cell viability, tumor stemness, and gene and protein expression. NENF high expression was associated with NAFLD progression NENF was identified as the risk gene and positively associated with mRNAsi_score. Its expressions gradually increased with the progress of NAFLD to HCC. NENF promoted cells' lipid accumulation. NENF enhanced the induction of L02 cells into stem cells and augmented the tumor-like stem cell properties of L02 cells. NENF, as an important biomarker, promoted the development of NAFLD devolved to HCC by enhancing the tumor-like stem cell properties of normal cells.

探讨NAFLD发展为HCC的关键危险基因。从GEO数据库中获得与NAFLD进展相关的4个数据集(NAFLD、NASH、肝纤维化、肝硬化和肿瘤)。进行GO和KEGG分析以确定与基因相关的生物学功能、途径和细胞过程。GSVA分析是基于基因表达谱来评估不同样本中通路活性的变化。我们进行了有序逻辑回归分析、共线性分析、影响因素的重要性分析(LASSO、XGBoost和RandomForest)和Venn分析,以确定疾病进展中的中心基因。SHAP模型和K-M生存分析筛选出NAFLD发展为HCC的相关风险基因。mRNAsi_score分析评估NENF表达与肿瘤干性的相关性。用转染NENF的载体提高其表达。CCK8、细胞球体形成实验、菌落形成、transwell、western blot和RT-PCR检测细胞活力、肿瘤干性、基因和蛋白表达。NENF高表达与NAFLD进展相关NENF被确定为危险基因,与mRNAsi_score呈正相关。随着NAFLD向HCC的发展,其表达逐渐增加。NENF促进细胞脂质积累。NENF增强了L02细胞向干细胞的诱导,增强了L02细胞的肿瘤样干细胞特性。NENF作为一个重要的生物标志物,通过增强正常细胞的肿瘤样干细胞特性,促进NAFLD向HCC转移的发展。
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引用次数: 0
Neurotoxicological Effects of 4-Bromodiphenyl Ether in Adult Zebrafish: DNA Damage, Oxidative Stress, Histology and Biomolecular Alterations 4-溴联苯醚对成年斑马鱼的神经毒理学影响:DNA损伤、氧化应激、组织学和生物分子改变。
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-14 DOI: 10.1002/jbt.70644
Shiv Kumar, Pooja Chadha

Polybrominated diphenyl ethers (PBDEs) have emerged as a major environmental pollutant and are widely employed in different industrial and consumer products. The 4-bromodipehnyl ether (BDE-3) is the most common and fundamental mono-BDE which is being used as a flame retardant in different products. The present investigation was conducted to evaluate the neurotoxicological effects of BDE-3 via. DNA damage, oxidative stress biomarkers, apoptotic, histopathological and ATR-FTIR analysis in brain of adult zebrafish. The 96 h LC50 was determined for zebrafish adult and further zebrafish were exposed to sublethal concentrations that is 0.48 mg/L (¼ LC50) and 0.97 mg/L (½ LC50) of BDE-3 for 96 h. The DNA damage in terms of tail length (TL), tail intensity (TI), tail moment (TM) and olive tail moment (OTM) was found to be significantly elevated in a concentration and duration dependant manner. A significantly increased MDA content, GST and AChE activity was reported in the brain tissue after BDE-3 exposure whereas a depleted SOD activity was observed. The histological analysis revealed the different types of alterations in brain tissue. The viable cell frequency was found to be decreased whereas apoptotic and necrotic cell frequency were found to be significantly increased in BDE-3 exposed groups. The structural alterations in different biomolecules were assessed via ATR-FTIR in brain tissue. The results of the present study inflict the accelerated lipid peroxidation, altered enzymatic activity, enhanced DNA damage, disrupted histology, cell viability and biomolecular alterations in brain of zebrafish even at sub-lethal concentrations, indicating the neurotoxic nature of BDE-3.

多溴联苯醚(PBDEs)已成为一种主要的环境污染物,广泛应用于各种工业和消费品中。4-溴二苯醚(BDE-3)是最常见和最基本的单溴二苯醚,在不同的产品中被用作阻燃剂。本研究旨在评价BDE-3的神经毒理学作用。成年斑马鱼脑DNA损伤、氧化应激生物标志物、细胞凋亡、组织病理学及ATR-FTIR分析。测定成年斑马鱼96小时的LC50,并进一步将斑马鱼暴露在亚致死浓度为0.48 mg/L(¼LC50)和0.97 mg/L(½LC50)的BDE-3中96小时。尾长(TL)、尾强(TI)、尾矩(TM)和橄榄尾矩(OTM)的DNA损伤呈浓度和持续时间依赖性显著升高。BDE-3暴露后脑组织中MDA含量、GST和AChE活性显著增加,而SOD活性降低。组织学分析揭示了脑组织中不同类型的改变。BDE-3暴露组活细胞频率明显降低,凋亡和坏死细胞频率明显升高。利用ATR-FTIR技术观察脑组织中不同生物分子的结构变化。本研究结果表明,即使在亚致死浓度下,BDE-3也会加速斑马鱼的脂质过氧化,改变酶活性,增强DNA损伤,破坏组织学,细胞活力和生物分子改变,表明BDE-3具有神经毒性。
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引用次数: 0
Celastrol Mitigates Colistin-Induced Renal Toxicity in Rats via Modulating Nrf-2/HO-1 and NF-κB Signaling Pathways 雷公藤红素通过调节Nrf-2/HO-1和NF-κB信号通路减轻粘菌素诱导的大鼠肾毒性
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-12 DOI: 10.1002/jbt.70641
Mohammed Z. Nasrullah, Usama A. Fahmy, Ashraf B. Abdel-Naim, Elmoiz Y. Babekir, Amro H. Alhothaly, Amar M. Elmesilhy, Rawan S. Albalawi, Amal Hofni

Colistin (CST) is an effective antibiotic that decreases the mortality rates accompanying nosocomial infection with multidrug-resistant resistant bacteria. However, its use is limited because of the high potential of inducing severe nephrotoxicity. Celastrol (CELA) is a medicinally promising triterpenoid and the most abundant bioactive constituent of the root pulps of the widely used Chinese herb, Tripterygium wilfordii. CELA confers cellular protection because of its antioxidant, anti-inflammatory, and antiapoptotic activities. The current study aimed to investigate the potential nephroprotective effects of CELA against CST-induced nephrotoxicity. Rats were divided into five groups, and treated as follows: Group One received vehicles only; Group Two received CELA only; Group Three received CST only and Groups Four and Five received CST and CELA (0.5 or 1 mg/kg). Microscopical examination of H&E-stained kidney sections indicated that CST-only-treated animals exhibited distortion in the renal histological features; Also, Masson's trichrome, Picrosirius Red, and Periodic acid–Schiff staining highlighted fibrotic changes. This was associated with increased kidney serum markers (urea, creatinine, and cystatin C), induced oxidative stress (increased levels of MDA, decreased activities of SOD and CAT, and reduced the protein levels of Nrf-2 and HO-1), increased the immunoreactivity of the inflammatory markers (COX-2, iNOS, TNF-α, and NF-κB), and stimulated apoptosis (increased the transcription of Bax and CASP3 and decreased that of Bcl-2). In contrast, pretreatment with CELA significantly reduced the histopathological changes, oxidative stress, inflammation, and apoptosis. Therefore, CELA showed significant renal protection against CST-induced kidney injury.

粘菌素(CST)是一种有效的抗生素,可降低多药耐药菌院内感染的死亡率。然而,它的使用受到限制,因为它极有可能诱发严重的肾毒性。雷公藤红素(CELA)是一种具有药用前景的三萜化合物,是广泛应用的中草药雷公藤根浆中最丰富的生物活性成分。由于其抗氧化、抗炎和抗凋亡活性,CELA赋予细胞保护作用。本研究旨在探讨CELA对cst所致肾毒性的潜在肾保护作用。大鼠分为5组,按以下方法处理:第一组只给药;第二组仅接受CELA治疗;第三组仅给予CST,第四组和第五组给予CST和CELA(0.5或1 mg/kg)。H&; e染色肾切片显微镜检查显示,仅cst处理的动物肾脏组织学特征出现畸变;此外,马松三色、小天狼星红和周期性酸-希夫染色也突出了纤维化的变化。这与肾脏血清标志物(尿素、肌酐和胱抑素C)升高、诱导氧化应激(MDA水平升高、SOD和CAT活性降低、nif -2和HO-1蛋白水平降低)、炎症标志物(COX-2、iNOS、TNF-α和NF-κB)的免疫反应性升高以及刺激细胞凋亡(Bax和CASP3转录升高、Bcl-2转录降低)有关。相比之下,CELA预处理显著降低了组织病理学改变、氧化应激、炎症和细胞凋亡。因此,CELA对cst所致肾损伤具有明显的保护作用。
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引用次数: 0
Propofol suppresses esophageal cancer tumorigenesis by modulating circular RNA protein tyrosine kinase 2/microRNA-134-5p/poly ADP-ribose polymerase 9 axis. 异丙酚通过调节环状RNA蛋白酪氨酸激酶2/microRNA-134-5p/聚adp核糖聚合酶9轴抑制食管癌肿瘤发生。
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-11 DOI: 10.1002/jbt.23390
Chi Zhang, Lina Zheng, Yongmei Guo

Emerging evidence has pointed out the potential antitumor role of propofol in esophageal cancer (EC). Circular RNAs (circRNAs) have been reported as pivotal regulators in cancer development. This work explores the potential working mechanism between propofol and circular RNA protein tyrosine kinase 2 (circ-PTK2) in EC progression and chemoresistance. The cell vitality, clone formation, apoptosis, invasion, migration, tube formation capacity in EC cells after propofol treatment (0, 5, 10 or 15 µg/mL for 24 h) were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, flow cytometry, transwell, wound healing and tube formation assays, respectively. Propofol (0, 5, 10, or 15 µg/mL for 24 h) significantly inhibited cell vitality, clone formation, invasion, migration, tube formation capacity, and accelerated apoptosis in EC cells in vitro. The suppressive role of propofol (10 µg/mL for 24 h) in EC progression was partly overturned by circ-PTK2 overexpression, microRNA-134-5p (miR-134-5p) inhibitor, or poly ADP-ribose polymerase 9 (PARP9) overexpression. Circ-PTK2 directly interacted with miR-134-5p, and circ-PTK2 elevated PARP9 expression by its miRNA sponge role for miR-134-5p in EC cells. Propofol dramatically impeded EC tumor growth partly through reducing the circ-PTK2 level in vivo. Propofol exerted an antitumor role in EC advancement at least partly through the circ-PTK2/miR-134-5p/PARP9 axis, providing new insight into the involvement of circRNAs in propofol-mediated effect on EC progression. This study also provides evidence that circ-PTK2 could be developed as a potential therapeutic target for EC patients. This article is protected by copyright. All rights reserved.

越来越多的证据表明异丙酚在食管癌(EC)中具有潜在的抗肿瘤作用。环状rna (circRNAs)已被报道为癌症发展中的关键调节因子。本研究探讨了异丙酚与环状RNA蛋白酪氨酸激酶2 (circ-PTK2)在EC进展和化疗耐药中的潜在作用机制。采用3-(4,5-二甲基噻唑-2-酰基)-2,5-二苯基溴化四唑(MTT)、菌落形成、流式细胞术、transwell、伤口愈合和成管实验,分别测定异丙酚(0、5、10或15µg/mL)作用24 h后EC细胞的细胞活力、克隆形成、凋亡、侵袭、迁移和成管能力。异丙酚(0、5、10或15µg/mL,作用24 h)显著抑制体外EC细胞活力、克隆形成、侵袭、迁移、成管能力,并加速细胞凋亡。异丙酚(10µg/mL,持续24小时)对EC进展的抑制作用被circ-PTK2过表达、microRNA-134-5p (miR-134-5p)抑制剂或聚adp -核糖聚合酶9 (PARP9)过表达部分推翻。Circ-PTK2直接与miR-134-5p相互作用,Circ-PTK2通过miR-134-5p在EC细胞中的miRNA海绵作用提高PARP9的表达。异丙酚通过降低体内circ-PTK2水平显著抑制EC肿瘤生长。异丙酚至少部分通过circ-PTK2/miR-134-5p/PARP9轴在EC进展中发挥抗肿瘤作用,为circrna参与异丙酚介导的EC进展效应提供了新的见解。本研究也提供了circ-PTK2可作为EC患者潜在治疗靶点的证据。这篇文章受版权保护。版权所有。
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引用次数: 0
ARL4C depletion suppresses the resistance of ovarian cancer to Carboplatin by disrupting cholesterol transport and autophagy via Notch-RBP-Jκ-H3K4Me3-OSBPL5. ARL4C缺失通过Notch-RBP-Jκ-H3K4Me3-OSBPL5破坏胆固醇转运和自噬来抑制卵巢癌对卡铂的耐药性。
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-11 DOI: 10.1002/jbt.23466
Juan Yang, Shuping Peng, Keqiang Zhang

Increasing studies indicate that cholesterol plays an important role in drug resistance. ARL4C is implicated in the export and import of cholesterol, therefore this study aimed to explore the effect of ARL4C on the resistance of ovarian cancer (OVC) to Carboplatin. This study collected OVC tissue samples from patients who are sensitive or resistan to carboplatin, and established Carboplatin-resistant OVC cell lines, OVCAR3(R) and SKOV3(R) using OVCAR3 and SKOV3. High throughput sequencing was conducted to find genes that regulated by ARL4C. Cholesterol esterification was performed to evaluate the transprot of cholesterol from Lysosome (LY) to Endoplasmic reticulum (ER). The fluorescence of LC3-GFP-mRFP was used to evaluate the function of autophagy flux. As indicated by PCR, western blot and Immunohistochemistry, ARL4C was increased in the Carboplatin-resistant OVC tissues and cells. Knockdown of ARL4C attenuated the resistance of OVCAR3(R) and SKOV3(R) to Carboplatin. By suppressing Notch signal, ARL4C knockdown inhibited the transcritpional function of RBP-Jκ and RBP-Jκ-induced H3K4Me3, which collectively reduced OSBPL5 expression. OSBPL5 deficiency inhibited the transport of cholesterol from LYs to ER, which led to the accumulation of cholesterol in LYs and the dysfunction of autophagy. In summary, ARL4C knockdown attenuated the resistance of OVC to Carboplatin by disrupting cholesterol transport and autophagy. This study revealed a promising target to attenuate the resistance of OVC to Carboplatin and elucidated the potential mechanism. This article is protected by copyright. All rights reserved.

越来越多的研究表明,胆固醇在耐药性中起着重要作用。ARL4C参与胆固醇的输出和输入,因此本研究旨在探讨ARL4C对卵巢癌(OVC)对卡铂耐药的影响。本研究收集卡铂敏感或耐药患者的OVC组织样本,利用OVCAR3和SKOV3建立卡铂耐药OVC细胞系OVCAR3(R)和SKOV3(R)。通过高通量测序寻找受ARL4C调控的基因。采用胆固醇酯化法评价胆固醇从溶酶体(LY)向内质网(ER)的转运情况。采用LC3-GFP-mRFP荧光检测自噬通量的功能。PCR、western blot和免疫组化结果显示,ARL4C在卡铂耐药OVC组织和细胞中升高。敲低ARL4C可减弱OVCAR3(R)和SKOV3(R)对卡铂的耐药性。ARL4C敲低通过抑制Notch信号,抑制RBP-Jκ和RBP-Jκ诱导的H3K4Me3的转录功能,共同降低OSBPL5的表达。OSBPL5缺乏抑制了胆固醇从LYs向内质网的转运,导致胆固醇在LYs中积累,导致自噬功能障碍。综上所述,ARL4C敲低通过破坏胆固醇转运和自噬减弱OVC对卡铂的耐药性。本研究发现了一个有希望的靶点来减弱OVC对卡铂的耐药性,并阐明了其潜在的机制。这篇文章受版权保护。版权所有。
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引用次数: 0
Protective Role of Boldine Against 5-Fluorouracil-Induced Nephrotoxicity: In Vitro and In Vivo Approach Boldine对5-氟尿嘧啶引起的肾毒性的保护作用:体外和体内研究
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-10 DOI: 10.1002/jbt.70636
Rayar Arthina, Munusamy Karthick, Muthusethupathi Sharmila, Somasundaram Sanjay, Karthik Shree Harini, Kulanthaivel Langeswaran, Devaraj Ezhilarasan

Drug-induced nephrotoxicity is a significant clinical complication associated with several chemotherapeutic agents, including 5-fluorouracil (5-FU). This study was aimed to investigate the nephroprotective potential of boldine, an aporphine alkaloid, against 5-FU-induced renal toxicity using in vitro (HEK293 cells) and in vivo (Wistar rats) models. In vitro cytotoxicity was evaluated using the MTT assay, AO/EB and DAPI staining was performed to identify apoptotic alterations. The expression of apoptotic and antioxidant genes was analyzed by quantitative and semi-quantitative PCR. For the in vivo study, rats were divided into five groups. One group received a single intraperitoneal dose of 5-FU (150 mg/kg) to induce nephrotoxicity. In the remaining groups, 5-FU was administered followed by oral treatment with boldine (10 or 20 mg/kg) or silymarin (100 mg/kg) for 7 days. Biochemical markers including creatinine, urea, blood urea nitrogen, uric acid in serum and oxidative stress indicators in kidney tissue were analyzed. MAPK pathway-related gene expression and histopathological changes were assessed. Treatment of HEK cells with 5-FU markedly reduced cell viability and induced apoptosis, while co-treatment with boldine restored viability and normal cell morphology. Boldine modulated the 5-FU-induced downregulation of SOD, CAT, GPx, and Bcl-2 and upregulation of Bax and caspase-3. In vivo, boldine treatment normalized elevated nephrotoxic markers in serum, enhanced antioxidant enzyme activities, and inhibited activation of ASK1, ERK1, c-Jun, and NF-κB1. Histopathological findings further confirmed that boldine preserved renal tissue integrity and prevented tubular and glomerular damage. Overall, boldine significantly protected against 5-FU-induced renal injury via anti-apoptotic, antioxidant, and anti-inflammatory mechanisms.

药物性肾毒性是与包括5-氟尿嘧啶(5-FU)在内的几种化疗药物相关的重要临床并发症。本研究旨在通过体外(HEK293细胞)和体内(Wistar大鼠)模型研究阿啡类生物碱boldine对5- fu诱导的肾毒性的保护作用。采用MTT法评估体外细胞毒性,AO/EB和DAPI染色检测细胞凋亡改变。采用定量和半定量PCR分析凋亡基因和抗氧化基因的表达。在体内研究中,将大鼠分为五组。一组小鼠单次腹腔注射5-FU (150 mg/kg)诱导肾毒性。在其余组中,5-FU在口服博尔定(10或20 mg/kg)或水飞蓟素(100 mg/kg)后给予7天。分析血清肌酐、尿素、血尿素氮、尿酸等生化指标及肾组织氧化应激指标。评估MAPK通路相关基因表达和组织病理学变化。5-FU处理HEK细胞可显著降低细胞活力并诱导凋亡,而与boldine共同处理可恢复细胞活力和正常细胞形态。Boldine调节了5- fu诱导的SOD、CAT、GPx和Bcl-2的下调以及Bax和caspase-3的上调。在体内,boldine治疗使血清肾毒性标志物升高正常化,增强抗氧化酶活性,抑制ASK1、ERK1、c-Jun和NF-κB1的激活。组织病理学结果进一步证实,波定保留了肾组织的完整性,防止了肾小管和肾小球的损伤。总体而言,boldine通过抗凋亡、抗氧化和抗炎机制显著保护5- fu诱导的肾损伤。
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引用次数: 0
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Journal of Biochemical and Molecular Toxicology
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