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Natural Compounds as Nephroprotective Agents: Therapeutic Potential Against Drug-Induced Kidney Injury 天然化合物作为肾保护剂:治疗药物性肾损伤的潜力。
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-20 DOI: 10.1002/jbt.70649
Mukul Shyam, Abantika Pal, Dishari Dey, Kiruba J, Vidhi Sharma, Jyoti Wadhwa, Prathap Srirangan, Sabina Evan Prince

Drug-induced nephrotoxicity poses a significant clinical challenge that limits the therapeutic application of various critical medications, such as antibiotics, chemotherapeutic agents, and nonsteroidal anti-inflammatory drugs. It accounts for 19%–26% of Acute Kidney Injury cases and may advance to chronic kidney disease if not promptly addressed. The kidneys are particularly vulnerable to injury caused by xenobiotics due to their role in drug metabolism and excretion. The mechanisms of nephrotoxicity include oxidative stress, mitochondrial dysfunction, apoptosis, inflammation, crystal nephropathy, and vascular injury, all of which impair renal structure and function. Contemporary therapeutic approaches are primarily confined to supportive care and depend on traditional renal biomarkers, including serum creatinine and blood urea nitrogen, which exhibit insufficient sensitivity for early detection. Thus, there is an increasing demand for efficacious nephroprotective measures and dependable diagnostic indicators. Phytochemicals have garnered considerable interest due to their renoprotective capabilities, which are attributed to their antioxidant, anti-inflammatory, and anti-apoptotic properties. Compounds like quercetin, silymarin, resveratrol, and curcumin have shown encouraging results in experimental models of nephrotoxicity. Furthermore, innovative biomarkers such as NGAL, KIM-1, IL-18, and cystatin C enhance diagnostic accuracy for early renal injury. This narrative review examines nephroprotective phytochemicals, novel biomarkers, and nanotechnology-based delivery methods to improve therapeutic efficacy.

药物引起的肾毒性是一个重大的临床挑战,限制了各种关键药物的治疗应用,如抗生素、化疗药物和非甾体抗炎药。它占急性肾损伤病例的19%-26%,如果不及时处理,可能会发展为慢性肾脏疾病。由于肾脏在药物代谢和排泄中的作用,它们特别容易受到外源性药物引起的损伤。肾毒性的机制包括氧化应激、线粒体功能障碍、细胞凋亡、炎症、晶体肾病和血管损伤,这些都损害了肾脏的结构和功能。目前的治疗方法主要局限于支持治疗,并依赖于传统的肾脏生物标志物,包括血清肌酐和血尿素氮,这些标志物对早期检测的敏感性不足。因此,对有效的肾保护措施和可靠的诊断指标的需求日益增加。植物化学物质因其抗氧化、抗炎和抗细胞凋亡的保护功能而受到广泛关注。槲皮素、水飞蓟素、白藜芦醇和姜黄素等化合物在肾毒性实验模型中显示出令人鼓舞的结果。此外,创新的生物标志物如NGAL、KIM-1、IL-18和胱抑素C提高了早期肾损伤的诊断准确性。本文综述了肾保护植物化学物质、新型生物标志物和基于纳米技术的递送方法,以提高治疗效果。
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引用次数: 0
Caspase-1 Dependent Neutrophil Pyroptosis Contributes to Fine Particulate Matter-Induced Lung Inflammation Caspase-1依赖性中性粒细胞焦亡与细颗粒物诱导的肺部炎症有关。
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-19 DOI: 10.1002/jbt.70639
Jia Mai, Shenshen Zhu, Zhaoke Wu, Peiyu Zhu, Yujie Li, Weidong Wu, Junxi Zhang, Yuefei Jin, Yacong Bo

As a pollutant, Fine particulate matter (PM2.5) directly deposits in alveoli to induce lung inflammation, yet its pathogenic mechanism remains unclear. PM2.5-induced pulmonary inflammation will trigger the activation of Caspase-1 (Casp1). We seek to elucidate the role of pyroptosis in PM2.5-induced lung inflammation by employing Casp1 knock-out (KO) mice and a specific pyroptosis inhibitor (Disulfiram, DSF). We found the typical pathological changes were comparatively alleviated in the Casp1 KO mice. Notably, in Casp1 KO mice, there was a significant downregulation of gasdermin D (GSDMD) and GSDMD-N at the protein levels. The Casp1 KO mice exhibited a decrease in the numbers of pyroptotic neutrophils. After administrating with DSF, we observed the downregulation of GSDMD and GSDMD-N, along with a decreased number of pyroptotic neutrophils. These findings suggest that neutrophils contribute to PM2.5-induced lung inflammation depending on Caspase-1/pyroptosis signaling pathway. These results demonstrate that PM2.5 triggers lung inflammation via the neutrophil Caspase-1/pyroptosis pathway, revealing a novel mechanism of PM2.5-mediated inflammation and suggesting DSF as a potential therapeutic agent for PM2.5-induced pneumonia.

细颗粒物(PM2.5)作为一种污染物,直接沉积在肺泡内诱发肺部炎症,其致病机制尚不清楚。pm2.5诱导的肺部炎症会触发Caspase-1 (Casp1)的激活。我们试图通过Casp1敲除(KO)小鼠和一种特定的焦亡抑制剂(Disulfiram, DSF)来阐明焦亡在pm2.5诱导的肺部炎症中的作用。我们发现Casp1 KO小鼠的典型病理改变相对减轻。值得注意的是,在Casp1 KO小鼠中,gasdermin D (GSDMD)和GSDMD- n在蛋白水平上显著下调。Casp1 KO小鼠表现出嗜热性中性粒细胞数量的减少。给药后,我们观察到GSDMD和GSDMD- n的下调,同时嗜热性中性粒细胞数量减少。这些发现表明,中性粒细胞通过Caspase-1/焦亡信号通路参与pm2.5诱导的肺部炎症。这些结果表明,PM2.5通过中性粒细胞Caspase-1/焦亡途径触发肺部炎症,揭示了PM2.5介导炎症的新机制,并提示DSF可能是PM2.5诱导的肺炎的潜在治疗剂。
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引用次数: 0
N7-Methylguanine Modification of SHMT2 Mediated by GEMIN5 Inhibits Cell Ferroptosis of Colorectal Cancer Cells GEMIN5介导的n7 -甲基鸟嘌呤修饰SHMT2抑制结直肠癌细胞铁下垂。
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-19 DOI: 10.1002/jbt.70647
Zhiquan Wang, Quanwei Wu, Jing He, Sasa Zhu, Qiuxian Li

Colorectal cancer (CRC) is a common malignancy in the digestive tract. Serine hydroxymethyltransferase 2 (SHMT2) plays a critical role in CRC progression, and its regulatory mechanisms warrant further investigation.

The regulatory role of SHMT2 was investigated by assessing cell viability and ferroptosis. RNA methylation detection was performed to determine the predominant methylation modification types. The interaction between GEMIN5 (which binds to the m7G cap) was analyzed through RNA immunoprecipitation (RIP) and dual luciferase reporter assays. Finally, the synergistic regulation of GEMIN5 and SHMT2 on the Wnt/β-catenin signaling pathway was examined.

SHMT2 was highly expressed in CRC tissues, and its inhibition suppressed cell viability while promoting ferroptosis. Quantitative analysis revealed significantly elevated m7G levels in CRC cells. GEMIN5 expression positively correlated with SHMT2 levels in CRC, and GEMIN5 overexpression increased m7G modification levels of SHMT2 mRNA. RIP assays demonstrated that SHMT2 mRNA could be enriched in GEMIN5 complexes, with GEMIN5 overexpression inhibiting SHMT2 mRNA degradation. SHMT2 overexpression counteracted the effects of GEMIN5 knockdown, while GEMIN5 overexpression prominently reversed the regulatory effects of SHMT2 knockdown on β-catenin and GSK3β protein expression.

GEMIN5-mediated m7G modification stabilizes high SHMT2 expression, which inhibits CRC cell ferroptosis and activates the Wnt/β-catenin signaling pathway in vitro.

结直肠癌(CRC)是一种常见的消化道恶性肿瘤。丝氨酸羟甲基转移酶2 (SHMT2)在结直肠癌的进展中起关键作用,其调控机制有待进一步研究。通过评估细胞活力和铁下垂来研究SHMT2的调节作用。进行RNA甲基化检测以确定主要的甲基化修饰类型。通过RNA免疫沉淀(RIP)和双荧光素酶报告基因分析GEMIN5(与m7G帽结合)之间的相互作用。最后,我们考察了GEMIN5和SHMT2对Wnt/β-catenin信号通路的协同调控作用。SHMT2在结直肠癌组织中高表达,其抑制抑制细胞活力,促进铁下垂。定量分析显示CRC细胞中m7G水平显著升高。结直肠癌中GEMIN5的表达与SHMT2水平呈正相关,GEMIN5过表达增加了SHMT2 mRNA的m7G修饰水平。RIP实验表明SHMT2 mRNA在GEMIN5复合物中富集,GEMIN5过表达抑制SHMT2 mRNA降解。SHMT2过表达抵消了GEMIN5敲低的作用,而GEMIN5过表达显著逆转了SHMT2敲低对β-catenin和GSK3β蛋白表达的调节作用。gemin5介导的m7G修饰稳定了SHMT2的高表达,在体外抑制CRC细胞铁凋亡并激活Wnt/β-catenin信号通路。
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引用次数: 0
Pyrimidine Based Inhibitors Targeting Glutathione S-Transferase in Phase II Detoxification: Antioxidant, ADMET, Docking, and Molecular Dynamics Evaluation 在II期解毒中靶向谷胱甘肽s -转移酶的嘧啶类抑制剂:抗氧化、ADMET、对接和分子动力学评估。
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-17 DOI: 10.1002/jbt.70652
Fikret Türkan, Adnan Cetin, Meryem Ayan Ustun

The present study has been conducted to investigate the inhibitory effects and antioxidant capacities of two pyrimidine derivatives, 4,6-Dichloro-2-(methylthio) pyrimidine-5-carbonyl chloride (p1) and 4,6-Dichloro-2-(methylthio) pyrimidine-5-carboxyamide (p2), against the glutathione S-transferase (GST) enzyme for exploring their potential as therapeutic agents in conditions related to oxidative stress and drug resistance mediated through GST. The data are compared with that of ethacrynic acid (EA), a well-documented GST inhibitor. The IC50 values for molecules p1, p2, and EA were computed to be 38.5 nM, 46.2 nM, and 5.82 nM, respectively. During the second part of the inhibition study, Ki values calculated from IC50 plots became 57.61 nM for molecule p1, 43.75 nM for molecule p2, and 4.43 nM for EA. Molecules p1 and p2 depicted non-competitive mechanisms, while EA followed competitive inhibition. Moreover, antioxidant capacities of molecules were tested by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay method. Using the DPPH method scavenging activity in both p1 and p2 was comparable to that of the reference standard, ascorbic acid (AA). Other than this, biological activities of GST enzyme complexes were further validated using molecular docking, molecular dynamics, and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses. These complementary studies gave further insight into binding affinities, dynamic stability, and pharmacokinetic properties, reinforcing the impact of p1 and p2 complexation on GST structural and functional characteristics.

本研究研究了4,6-二氯-2-(甲基硫)嘧啶-5-羰基氯(p1)和4,6-二氯-2-(甲基硫)嘧啶-5-羧酰胺(p2)这两种嘧啶衍生物对谷胱甘肽s -转移酶(GST)酶的抑制作用和抗氧化能力,以探索它们作为GST介导的氧化应激和耐药性相关疾病的治疗药物的潜力。这些数据与乙稀酸(EA)的数据进行了比较,乙稀酸是一种有据可查的GST抑制剂。分子p1、p2和EA的IC50值分别为38.5 nM、46.2 nM和5.82 nM。在抑制研究的第二部分,从IC50图中计算的Ki值为分子p1为57.61 nM,分子p2为43.75 nM,分子EA为4.43 nM。分子p1和p2描述非竞争性机制,而EA遵循竞争性抑制。此外,采用2,2-二苯基-1-苦味酰肼(DPPH)自由基清除法检测分子的抗氧化能力。DPPH法对p1和p2的清除活性与参考标准抗坏血酸(AA)相当。除此之外,通过分子对接、分子动力学和ADMET(吸收、分布、代谢、排泄和毒性)分析进一步验证了GST酶复合物的生物活性。这些互补研究进一步深入了解了结合亲和力、动态稳定性和药代动力学特性,强化了p1和p2络合对GST结构和功能特征的影响。
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引用次数: 0
Exosomes From Hepatitis B Virus-Infected Hepatocytes Induce Liver Fibrosis Through METTL3-Mediated m6A Modification of P2RX7 mRNA 乙型肝炎病毒感染肝细胞外泌体通过mettl3介导的P2RX7 mRNA的m6A修饰诱导肝纤维化
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-17 DOI: 10.1002/jbt.70645
Caixia Li, Jiaxin Zeng, Yongbo Liu, Zhibin Chen

Exosomes derived from hepatitis B virus (HBV)-infected hepatocytes (HBV-Exo) promote liver fibrosis. Emerging evidence implicates METTL3 and P2RX7 as critical drivers of liver fibrosis. However, the molecular mechanisms by which HBV-Exo drive hepatic fibrosis remain poorly understood. This study investigated the mechanistic involvement of METTL3 and P2RX7 in this fibrotic process. Exosomes from pHBV1.3-transfected, HBV-replicating THLE-2 hepatocytes (HBV-THLE-2-Exo) were isolated and used to incubate LX-2 hepatic stellate cells (HSCs). Impacts on LX-2 cells were evaluated by detecting cell viability, proliferation, invasion, migration, and fibrosis marker expression. MeRIP, RIP, RNA pull-down, and mRNA stability assays were used to assess the METTL3/P2RX7 mRNA interaction. A CCl4-induced mouse model of liver fibrosis was generated to elucidate the role in vivo. HBV-THLE-2-Exo elevated METTL3 levels in recipient LX-2 HSCs. HBV-THLE-2-Exo enhanced the proliferation, invasion, migration, and fibrosis marker expression in LX-2 HSCs in vitro. Moreover, METTL3-depleted exosomes (si-METTL3-HBV-THLE-2-Exo) attenuated LX-2 cell proliferation, invasion, migration, and expression of fibrotic markers compared to HBV-THLE-2-Exo. Mechanistically, METTL3 stabilized P2RX7 in an IGF2BP1-m6A-dependent manner. P2RX7 overexpression reversed si-METTL3-HBV-THLE-2-Exo-mediated alterations in LX-2 cell proliferation, invasion, migration, and fibrosis marker expression in vitro. Additionally, HBV-THLE-2-Exo exacerbated liver fibrosis in CCl4-induced mice. Our findings unveil a novel METTL3/P2RX7 axis by which HBV-Exo drive HSC activation and liver fibrosis. These findings elucidate a novel exosome-mediated regulatory axis in liver fibrosis, suggesting the therapeutic potential of targeting METTL3/P2RX7 axis.

乙型肝炎病毒(HBV)感染的肝细胞(HBV- exo)衍生的外泌体促进肝纤维化。新出现的证据表明METTL3和P2RX7是肝纤维化的关键驱动因素。然而,HBV-Exo驱动肝纤维化的分子机制仍然知之甚少。本研究探讨了METTL3和P2RX7参与该纤维化过程的机制。从phbv1.3转染、hbv复制的THLE-2肝细胞(HBV-THLE-2-Exo)中分离外泌体,用于培养LX-2肝星状细胞(hsc)。通过检测细胞活力、增殖、侵袭、迁移和纤维化标志物表达来评估对LX-2细胞的影响。采用MeRIP、RIP、RNA拉下和mRNA稳定性分析来评估METTL3/P2RX7 mRNA的相互作用。建立了ccl4诱导的小鼠肝纤维化模型,以阐明其在体内的作用。HBV-THLE-2-Exo升高受体LX-2 hsc中METTL3水平。HBV-THLE-2-Exo增强LX-2 hsc的增殖、侵袭、迁移和纤维化标志物的体外表达。此外,与HBV-THLE-2-Exo相比,mettl3缺失的外泌体(si-METTL3-HBV-THLE-2-Exo)减弱了LX-2细胞的增殖、侵袭、迁移和纤维化标志物的表达。在机制上,METTL3以依赖igf2bp1 - m6a的方式稳定了P2RX7。P2RX7过表达逆转了si- mettl3 - hbv - thle -2- exo介导的LX-2细胞增殖、侵袭、迁移和纤维化标志物表达的改变。此外,HBV-THLE-2-Exo加重了ccl4诱导小鼠的肝纤维化。我们的发现揭示了一种新的METTL3/P2RX7轴,HBV-Exo通过该轴驱动HSC激活和肝纤维化。这些发现阐明了一种新的外泌体介导的肝纤维化调节轴,提示靶向METTL3/P2RX7轴的治疗潜力。
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引用次数: 0
Parthenolide Mitigates Doxorubicin-Induced Cardiotoxicity in Rats With Associated Activation of Nrf2 and Inhibition of Ferroptosis Parthenolide减轻阿霉素诱导的大鼠心脏毒性与Nrf2的激活和铁下沉的抑制。
IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-17 DOI: 10.1002/jbt.70626
Jiayu Sun, Lei Qian, Feijie Guo, Fengjuan Gai, Peilin Lin

Doxorubicin (DOX) is a widely used anticancer agent, but its clinical utility is limited by significant cardiotoxicity. Parthenolide (PTL), a sesquiterpene lactone, has garnered significant attention due to its broad pharmacological potential. This study aimed to investigate the potential cardioprotective effects of PTL against DOX-induced cardiotoxicity in rats, focusing on its impact on Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and ferroptosis. Male Sprague-Dawley rats were divided into a control group, a DOX group, and DOX + PTL (10 mg/kg, 25 mg/kg, or 50 mg/kg) groups. DOX (4 mg/kg) was administered via intraperitoneal injection once weekly for 4 weeks. Cardiac function was assessed using echocardiography, and histopathological changes were examined through hematoxylin and eosin and Masson trichrome staining. Oxidative stress markers, inflammatory cytokines, and ferroptosis-related proteins—including acyl-CoA synthetase long-chain family member 4 (ACSL4), NADPH oxidase 4 (Nox4), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11)—were measured by ELISA and Western blotting. Additionally, Nrf2 and its downstream targets were analyzed to elucidate the molecular mechanisms underlying PTL's effects. PTL treatment significantly improved DOX-induced cardiac dysfunction, as evidenced by improved echocardiographic parameters and reduced histopathological damage. PTL also markedly decreased oxidative stress and inflammatory cytokines, while upregulating Nrf2 signaling and downregulating ferroptosis-related protein expression. These results suggested that the cardioprotective effects of PTL might be associated with the activation of Nrf2 signaling and suppression of ferroptosis. PTL demonstrated significant cardioprotective effects against DOX-induced cardiotoxicity, likely through Nrf2 activation and ferroptosis inhibition. PTL is a promising therapeutic agent for mitigating DOX-induced cardiac dysfunction.

阿霉素(DOX)是一种广泛使用的抗癌药物,但其显著的心脏毒性限制了其临床应用。Parthenolide (PTL)是一种倍半萜内酯,由于其广泛的药理潜力而引起了人们的极大关注。本研究旨在探讨PTL对dox诱导的大鼠心脏毒性的潜在保护作用,重点研究其对核因子红系2相关因子2 (Nrf2)信号传导和铁凋亡的影响。雄性sd大鼠分为对照组、DOX组和DOX + PTL (10 mg/kg、25 mg/kg和50 mg/kg)组。DOX (4mg /kg)每周腹腔注射1次,连续4周。超声心动图评价心脏功能,苏木精、伊红、马松三色染色观察组织病理变化。采用ELISA和Western blotting检测氧化应激标志物、炎症因子和铁中毒相关蛋白,包括酰基辅酶a合成酶长链家族成员4 (ACSL4)、NADPH氧化酶4 (Nox4)、谷胱甘肽过氧化物酶4 (GPX4)和溶质载体家族7成员11 (SLC7A11)。此外,研究人员还分析了Nrf2及其下游靶点,以阐明PTL作用的分子机制。PTL治疗可显著改善dox诱导的心功能障碍,超声心动图参数的改善和组织病理学损伤的减少证明了这一点。PTL还能显著降低氧化应激和炎症细胞因子,上调Nrf2信号,下调铁中毒相关蛋白的表达。这些结果表明,PTL的心脏保护作用可能与Nrf2信号的激活和铁下垂的抑制有关。PTL对dox诱导的心脏毒性具有显著的心脏保护作用,可能是通过激活Nrf2和抑制铁下垂。PTL是一种很有前景的治疗dox诱导心功能障碍的药物。
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引用次数: 0
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
{"title":"Investigation of the Effects of Saxagliptin in In Vitro and In Vivo Models of Diabetic Neuropathy","authors":"Samet Oz,&nbsp;Seval Ulku Orhan,&nbsp;Asli Taslidere,&nbsp;Mete Ozcan,&nbsp;Suat Tekin","doi":"10.1002/jbt.70653","DOIUrl":"10.1002/jbt.70653","url":null,"abstract":"<div>\u0000 \u0000 <p>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 <i>Wistar Albino</i> 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 (<i>n</i> = 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 (<i>p</i> &lt; 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 (<i>p</i> &lt; 0.05). Additionally, caspase-3 expression in pancreatic tissue was suppressed, and histopathological damage was markedly reduced (<i>p</i> &lt; 0.0001). These findings suggest that Sax suppresses inflammation, inhibits oxidative damage and apoptosis, thereby reducing hyperalgesia, and may have therapeutic effects against DN.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 12","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145774678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
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。
{"title":"DLX6 Drives Lung Adenocarcinoma Progression via the p27Kip1/CDK2-CCNE1 Signaling Pathway","authors":"Zedong Sun,&nbsp;Feifan Ji,&nbsp;Jiayu Chen,&nbsp;Ningdan Song,&nbsp;Mingrui Liu,&nbsp;Minmin Zhou,&nbsp;Can Wang,&nbsp;Simian He,&nbsp;Ming Li,&nbsp;Quanli Zhang,&nbsp;Binhui Ren","doi":"10.1002/jbt.70640","DOIUrl":"10.1002/jbt.70640","url":null,"abstract":"<div>\u0000 \u0000 <p>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 p27<sup>Kip1</sup>/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/p27<sup>Kip1</sup>/CDK2-CyclinE signal axis as a potential therapeutic target for LUAD management.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 12","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
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Journal of Biochemical and Molecular Toxicology
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