Toxicology and applied pharmacology最新文献_第3页

Baicalin nanoemulsion mitigates cisplatin-induced hepatotoxicity by alleviating oxidative stress, inflammation, and restoring cellular integrity 黄芩苷纳米乳通过减轻氧化应激、炎症和恢复细胞完整性来减轻顺铂诱导的肝毒性。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2025.117231

Hadir Farouk , Maha Nasr , Marawan Abd Elbaset , Marwa E. Shabana , Omar A.H. Ahmed-Farid , Rania F. Ahmed

Cisplatin is a widely used chemotherapeutic agent, but its clinical utility is limited by side effects affecting different systems and organs, including hepatotoxicity in some cases. Baicalin, a flavonoid isolated from Scutellaria baicalensis, possesses antioxidant, anti-inflammatory and hepatoprotective properties, but its low bioavailability limits its therapeutic use. This study aimed to investigate whether a nanoemulsion formulation of baicalin could enhance its efficacy against cisplatin-induced hepatic injury in rats. Rats were orally treated daily with baicalin either in nanoformulation (10 or 20 mg/kg body weight per day) or conventional form (100 mg/kg body weight per day) for 12 days. Cisplatin (10 mg/kg body weight) was injected intraperitoneally on day six and day twelve to induce hepatic injury. Samples were collected on day thirteen. Serum markers, oxidative stress parameters, inflammatory markers, cellular energy status, histopathology, and other endpoints were evaluated. Results revealed that cisplatin caused elevated serum enzymes, oxidative stress, inflammation, DNA damage, depleted cellular energy levels, and induced severe hepatic histological changes. The baicalin nanoemulsion especially the higher 20 mg/kg dose, significantly ameliorated cisplatin-induced abnormalities across the various parameters. The conventional baicalin suspension also provided protection, albeit to a lesser degree than the nanoemulsion. In conclusion, administering baicalin as a nanoemulsion potentiated its hepatoprotective effects against cisplatin toxicity. The nanoemulsion formulation strategy was proven promising for enhancing baicalin's therapeutic utility.

顺铂是一种广泛使用的化疗药物，但其临床应用受到影响不同系统和器官的副作用的限制，在某些情况下包括肝毒性。黄芩苷是黄芩中分离的一种黄酮类化合物，具有抗氧化、抗炎和保护肝脏的作用，但其生物利用度较低，限制了黄芩苷的临床应用。本研究旨在探讨黄芩苷纳米乳制剂是否能增强其对顺铂所致大鼠肝损伤的保护作用。每日口服黄芩苷纳米制剂（10或20 mg/kg体重/天）或常规制剂（100 mg/kg体重/天），持续12天。第6天和第12天分别腹腔注射顺铂（10 mg/kg体重）诱导肝损伤。第13天采集样品。评估血清标志物、氧化应激参数、炎症标志物、细胞能量状态、组织病理学和其他终点。结果显示，顺铂引起血清酶升高、氧化应激、炎症、DNA损伤、细胞能量水平降低，并引起严重的肝脏组织学改变。黄芩苷纳米乳特别是高剂量20 mg/kg时，显著改善了顺铂诱导的各参数异常。传统的黄芩苷悬浮液也提供了保护，尽管程度不如纳米乳。综上所述，黄芩苷纳米乳可增强其抗顺铂毒性的肝保护作用。研究结果表明，采用纳米乳剂配方可以提高黄芩苷的治疗效果。

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引用次数: 0

Cadmium-induced iron dysregulation contributes to functional impairment in brain endothelial cells via the ferroptosis pathway

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2025.117233

Junkyung Gil, Donghyun Kim, Sungbin Choi, Ok-Nam Bae

Cadmium (Cd²⁺) is a heavy metal that is a major hazardous environmental contaminant, ubiquitously present in the environment. Cd²⁺ exposure has been closely associated with an increased prevalence and severity of neurological and cardiovascular diseases (CVD). The blood-brain barrier (BBB) plays a crucial role in protecting the brain from external environmental factors. Mitochondria play an important role in maintaining the barrier function of brain endothelial cells by regulating energy metabolism and redox homeostasis. In this study, we aimed to assess the cytotoxic effects of Cd²⁺ on the integrity and function of brain endothelial cells. After 24 h of exposure, Cd²⁺ reduced cell survival, tight junction protein expression, and trans-endothelial electrical resistance (TEER) in bEnd.3 cells suggest a potential BBB integrity disruption by Cd²⁺ exposure. To clarify the underlying mechanism, we further investigated the role of mitochondria in iron overload-mediated cell death following Cd²⁺ exposure. Cd²⁺ induced a substantial reduction in mitochondrial basal respiration and ATP production in brain endothelial cells, suggesting mitochondrial dysfunction. In addition, Cd²⁺ exposure led to impaired autophagy, elevated iron levels, and increased lipid peroxidation, indicating the initiation of ferroptosis, a form of cell death triggered by iron. In summary, our research suggests that Cd²⁺ exposure can disrupt BBB function by causing mitochondrial dysfunction and disrupting iron homeostasis.

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引用次数: 0

Fucoxanthin ameliorates ulcerative colitis by maintaining the epithelial barrier via blocking JAK2/STAT3 signaling pathway 岩藻黄素通过阻断JAK2/STAT3信号通路维持上皮屏障来改善溃疡性结肠炎。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117213

Jingjing Ma , Simei Yue , Yinghui Liu , Lingjiao Gong , Pengzhan He , Yingjie Yang , Zhengxin Fu , Danxiang Han , Qiang Hu , Fei Liao , Lin Xu

Background

The clinical efficacies of Ulcerative colitis (UC) are far from satisfactory. Fucoxanthin (FUC) is a marine carotenoid that is abundant in seaweed and microalgae. It has been reported that FUC can possess anti-inflammatory and antioxidant. However, its mechanism and role in UC is yet to be clarified. This study aimed to investigate the protective effect and potential mechanism of FUC extracted from the diatom Phaeodactylum tricornutm on dextran sodium sulfate (DSS) -induced colitis.

Methods

Animal UC model was induced by DSS and cellular model was established by TNF-α. Immunohistochemical staining, Western blot, RT-qPCR, and immunofluorescence were used to assess the inflammatory responses and epithelial barrier in vivo and in vitro models.

Results

The results showed that FUC attenuates DSS-induced colitis by ameliorating the epithelial mucosal barrier. Moreover, FUC possessed antioxidant and anti-inflammatory effects on NCM460 cells. JAK/STAT activator RO8191 could reverse these changes.

Conclusion

FUC exerted anti-inflammatory and antioxidant effects via the JAK2/STAT3 signaling pathway, and served as a potential therapeutic agent for the treatment of UC.

背景：溃疡性结肠炎（UC）的临床疗效远不令人满意。岩藻黄素（FUC）是一种富含海藻和微藻的海洋类胡萝卜素。据报道，FUC具有抗炎和抗氧化的作用。但其在UC中的作用机制尚不清楚。本研究旨在探讨三角藻褐指藻提取物FUC对右旋糖酐硫酸钠（DSS）诱导结肠炎的保护作用及其可能机制。方法：DSS诱导动物UC模型，TNF-α建立细胞模型。采用免疫组织化学染色、western blots、RT-qPCR和免疫荧光法评估体内和体外模型的炎症反应和上皮屏障。结果：FUC通过改善上皮粘膜屏障来减轻dss诱导的结肠炎。FUC对NCM460细胞具有抗氧化和抗炎作用。JAK/STAT激活剂RO8191可以逆转这些变化。结论：FUC通过JAK2/STAT3信号通路发挥抗炎和抗氧化作用，是治疗UC的潜在药物。

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引用次数: 0

CALML3-AS1 enhances malignancies and stemness of small cell lung cancer cells through interacting with DAXX protein and promoting GLUT4-mediated aerobic glycolysis CALML3-AS1通过与DAXX蛋白相互作用，促进glut4介导的有氧糖酵解，增强小细胞肺癌细胞的恶性肿瘤和干性。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117177

Guangxian Mao , Jixian Liu

The lncRNA CALML3 antisense RNA 1 (CALML3-AS1) is a biomarker for various cancers, including non-small cell lung cancer (NSCLC). However, the role of CALM3-AS1 in small cell lung cancer (SCLC) is still unclear. Here, we found that the CALML3-AS1 was upregulated in SCLC tissues and cells. SCLC cells (NCI-H69 and NCI-H466 cells) were transfected with small interfering RNA of CALML-AS1 (si-CALML3-AS1) and Death domain-associated protein (DAXX) (si-DAXX) or an overexpression vector of CALML-AS1 (dCas9-CALML3-AS1) and DAXX (dCas9-DAXX). The results showed that silencing CALML3-AS1 inhibited SCLC cell proliferation, colony formation, migration, invasion, and spheroid formation, and reduced the expression of stemness marker proteins (Nanog. Oct4, and Lin28). Moreover, silencing CALML3-AS1 reduced glycolysis rate, glucose utilization, and lactate production, and decreased the levels of key glycolytic regulatory proteins (GLUT1, GLUT4, HK2, and PKM2) in SCLC cells, while overexpression of CALML3-AS1 promoted malignant growth and stemness and enhanced glucose transporters type 4 (GLUT4)-mediated aerobic glycolysis by interacting with DAXX in NCI-H69 and NCI-H466 cells. Silencing DAXX or GLUT4, or treatment with 2-Deoxy-d-glucose (2-DG, a glycolysis inhibitor) reversed the effects of CALML3-AS1 overexpression on aerobic glycolysis, malignant growth, and stemness of SCLC cells. Finally, NCI-H69 cells transfected with CALML3-AS1, sh-CALML3-AS1, and sh-DAXX lentiviral vectors were subcutaneously injected into nude mice to construct xenograft models. Knockdown of CALML3-AS1 or DAXX inhibited tumor growth in SCLC in vivo. In conclusion, CALML3-AS1, an oncogene, promotes the malignancy and stemness of SCLC cells by interacting with DAXX to enhance GLUT4-mediated aerobic glycolysis, thereby promoting SCLC progression.

lncRNA CALML3反义RNA 1 （CALML3- as1）是多种癌症的生物标志物，包括非小细胞肺癌（NSCLC）。然而，CALM3-AS1在小细胞肺癌（SCLC）中的作用尚不清楚。在这里，我们发现CALML3-AS1在SCLC组织和细胞中上调。用calm - as1小干扰RNA （si-CALML3-AS1）和死亡结构域相关蛋白（DAXX）（si-DAXX）或过表达载体calm - as1 （dCas9-CALML3-AS1）和DAXX （dCas9-DAXX）转染SCLC细胞（NCI-H69和NCI-H466细胞）。结果表明，沉默CALML3-AS1可抑制SCLC细胞增殖、集落形成、迁移、侵袭和球体形成，并降低干性标记蛋白（Nanog）的表达。Oct4和Lin28)。此外，沉默CALML3-AS1降低了SCLC细胞的糖酵解速率、葡萄糖利用率和乳酸产量，降低了关键糖酵解调节蛋白（GLUT1、GLUT4、HK2和PKM2）的水平，而在NCI-H69和NCI-H466细胞中，过表达CALML3-AS1促进了恶性生长和干性，并通过与DAXX相互作用增强了葡萄糖转运蛋白4 （GLUT4）介导的有氧糖酵解。沉默DAXX或GLUT4，或用2-脱氧-d-葡萄糖（2-DG，一种糖酵解抑制剂）治疗可逆转CALML3-AS1过表达对SCLC细胞有氧糖酵解、恶性生长和干性的影响。最后，将转染CALML3-AS1、sh-CALML3-AS1和sh-DAXX慢病毒载体的NCI-H69细胞皮下注射到裸鼠体内，构建异种移植模型。下调CALML3-AS1或DAXX在体内抑制SCLC的肿瘤生长。综上所述，癌基因CALML3-AS1通过与DAXX相互作用，增强glut4介导的有氧糖酵解，从而促进SCLC的进展，从而促进SCLC细胞的恶性和干性。

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引用次数: 0

Exposure to environmentally relevant concentrations of di-(2-ethylhexyl) phthalate (DEHP) induced reproductive toxicity in female koi carp (Cyprinus carpio) 暴露于环境相关浓度的邻苯二甲酸二（2-乙基己基）酯（DEHP）诱导雌性锦鲤（Cyprinus carpio）的生殖毒性。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117200

Kampan Bisai , Vikash Kumar , Basanta Kumar Das , Bijay Kumar Behera , Manoj Kumar Pati

A frequently utilized plasticizer is di-(2-ethylhexyl) phthalate (DEHP), considered a ubiquitous contaminant in the environment and reported to have severe impacts on animals. Although it disrupts the female reproductive system in mammals, little is known about how it effects on fish reproduction. The reproductive parameters of female adult koi carp (Cyprinus carpio) were investigated in this study subjected to environmentally relevant exposure of DEHP (1, 10 and 100 μg/L). After 60 days experiment, significantly lower GSI was recorded in females of 10 and 100 μg/L DEHP-exposed groups. The examination of ovarian histology showed defective histoarchitecture, which included the existence of atretic oocytes, the emergence of intra-oocyte vacuoles as well as necrosis. The groups exposed to DEHP (10 and 100 μg/L) showed significant decreases in fecundity and ova-diameter values. Significant changes in the biochemical (total protein, glucose and cholesterol) and ionic (sodium, potassium, calcium and magnesium) composition were noticed in the ovarian fluid of exposed groups. The groups treated with DEHP showed higher levels of 11-ketotestosterone along with reduced levels of 17β-estradiol. Using real-time PCR, the mRNA expression of several genes linked to reproduction, such as Fshr, Lhr, Ar, Erα and Erβ were assessed and observed that there was a concentration-dependent alternation. The pairing of exposed females with untreated males significantly lowered the rates of fertilization, hatching and larval survival. In summary, the results of this investigation validated that exposure to DEHP in a nominal concentration could potentially reduce the reproductive health of female fish.

一种常用的增塑剂是邻苯二甲酸二（2-乙基己基）酯（DEHP），它被认为是环境中普遍存在的污染物，据报道对动物有严重影响。尽管它会扰乱哺乳动物的雌性生殖系统，但人们对它对鱼类繁殖的影响知之甚少。本研究研究了DEHP（1、10和100 μg/L）对鲤雌成鱼生殖参数的影响。实验60 d后，10和100 μg/L dehp暴露组雌鼠GSI显著降低。卵巢组织学检查显示组织结构存在缺陷，包括卵母细胞闭锁，卵母细胞内出现空泡和坏死。DEHP（10和100 μg/L）暴露组的繁殖力和卵圆直径值显著降低。暴露组卵巢液的生化（总蛋白、葡萄糖、胆固醇）和离子（钠、钾、钙、镁）组成均发生显著变化。DEHP组11-酮睾酮水平升高，17 - β-雌二醇水平降低。利用实时荧光定量PCR技术，对Fshr、Lhr、Ar、Erα和Erβ等生殖相关基因的mRNA表达量进行了检测，发现存在浓度依赖性变化。暴露的雌虫与未处理的雄虫配对显著降低了受精率、孵化率和幼虫存活率。总之，本调查结果证实，暴露于名义浓度的DEHP可能会降低雌鱼的生殖健康。

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引用次数: 0

Investigating the anticancer properties of urolithin B in triple negative breast cancer: In vivo and in vitro insights 研究尿素B在三阴性乳腺癌中的抗癌特性：体内和体外观察。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117224

Saeide Mansoori , Seyed Isaac Hashemy , Moein Eskandari , Azar Khorrami , Masoud Homayouni , Atefeh Ghahremanloo

Breast cancer (BC) is a leading cause of cancer-related mortality among women worldwide, with incidence rates rising globally. Urolithin B (UB), a bioactive metabolite of ellagic acid, has demonstrated promising anticancer effects in various cancer models. This study aimed to evaluate the effects of UB on the growth, angiogenesis, and metastasis of BC cells using both in vivo and in vitro approaches. Cytotoxic effects of UB were assessed on MDA-MB-231 cells and normal HFF cells using the MTT assay. Scratch assays and gelatin zymography demonstrated UB's suppression of cell migration and reduced enzymatic activities of MMP-2 and MMP-9. In a xenograft mouse model, UB significantly reduced tumor growth, enhanced necrosis, and decreased vascularity in tumor tissues. It downregulated mRNA expression levels of VEGF, VEGFR, MMP-2, and MMP-9, indicating potent anti-angiogenic and anti-metastatic properties. Additionally, UB exhibited antioxidant effects by increasing total thiol content and the activities of superoxide dismutase (SOD) and catalase (CAT) while reducing malondialdehyde (MDA) levels in tumor tissues. In conclusion, our results highlight the anticancer potential of UB, through its ability to suppress the proliferation, angiogenesis, and metastatic properties of BC both in vitro and in vivo. Coupled with its antioxidant properties, UB emerges as a promising and safe candidate for further pre-clinical and clinical research and therapeutic applications in BC management.

乳腺癌（BC）是全球女性癌症相关死亡的主要原因，全球发病率不断上升。尿素B （UB）是鞣花酸的一种生物活性代谢物，在多种癌症模型中显示出良好的抗癌作用。本研究旨在通过体内和体外两种方法评估UB对BC细胞生长、血管生成和转移的影响。采用MTT法评估UB对MDA-MB-231细胞和正常HFF细胞的细胞毒作用。划痕实验和明胶酶谱分析表明，UB抑制细胞迁移，降低MMP-2和MMP-9的酶活性。在异种移植小鼠模型中，UB显著降低肿瘤生长，增强坏死，并降低肿瘤组织中的血管。它下调VEGF、VEGFR、MMP-2和MMP-9的mRNA表达水平，表明其具有有效的抗血管生成和抗转移特性。此外，UB还通过提高肿瘤组织中总硫醇含量、超氧化物歧化酶（SOD）和过氧化氢酶（CAT）的活性，降低丙二醛（MDA）水平，表现出抗氧化作用。总之，我们的研究结果强调了UB的抗癌潜力，通过它在体外和体内抑制BC的增殖、血管生成和转移特性的能力。再加上其抗氧化特性，UB成为进一步临床前和临床研究以及BC治疗应用的有前途和安全的候选药物。

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引用次数: 0

Exploring the role of Bisphenol A in obesity-driven colorectal cancer progression: network toxicology and multi-organ pathology in animal models 探讨双酚A在肥胖驱动的结直肠癌进展中的作用：动物模型的网络毒理学和多器官病理学。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2025.117227

Muhamad Fikri Shazlan Saad , Muhammad Nazrul Hakim Abdullah , Vuanghao Lim , Hasnah Bahari , Boon Yin Khoo , Jun Jie Tan , Yoke Keong Yong

Bisphenol A (BPA), an endocrine disruptor, is linked to cancer progression in estrogen-responsive tissues, but its role in promoting colorectal cancer (CRC) progression in the context of obesity remains underexplored. This study examines BPA's influence on CRC in obese Sprague-Dawley rats using network toxicology and experimental models. Computational analysis using the Database for Annotation, Visualization, and Integrated Discovery identified pathways such as “CRC” and “chemical carcinogenesis-receptor activation”, implicating the PI3K-AKT pathway in IL-1 beta upregulation and BPA's role in CRC during obesity. Thirty male rats were grouped (n = 6) as follows: N (normal diet), NC (normal diet + CRC), HC (high-fat diet + CRC), NCB (normal diet + CRC + BPA), and HCB (high-fat diet + CRC + BPA). CRC was induced with 1,2-dimethylhydrazine (40 mg/kg), and BPA (25 mg/kg) was administered for 19 weeks. Although BPA exposure did not affect body weight or biochemical parameters, the HCB group exhibited significant histopathological changes in the colon, including lymphoid hyperplasia, liver damage, and increased IL-1β levels. Furthermore, diet influenced adipocyte size, exacerbating BPA's effects on CRC progression. Findings suggest BPA may worsen CRC progression in obese rats through identified pathways, promoting multi-organ pathology and underscoring the need for stricter regulations, especially for vulnerable populations.

Environmental implication

Bisphenol A (BPA), a widespread environmental contaminant, is increasingly linked to serious health issues, including cancer, in susceptible populations. Our study highlights BPA's role in promoting obesity-driven colorectal cancer (CRC) progression, demonstrating its carcinogenic potential in high-risk contexts. These findings emphasize the urgent need for regulatory scrutiny of BPA exposure, particularly in obese individuals, and support the development of safer alternatives. Addressing BPA's impact can contribute to preventive health strategies and inform policies aimed at reducing environmental and public health risks associated with endocrine-disrupting chemicals.

双酚A （BPA）是一种内分泌干扰物，与雌激素应答组织的癌症进展有关，但其在肥胖背景下促进结直肠癌（CRC）进展的作用仍未得到充分研究。本研究采用网络毒理学和实验模型研究了BPA对肥胖大鼠结直肠癌的影响。使用Database for Annotation， Visualization， and Integrated Discovery进行计算分析，确定了“CRC”和“化学致癌-受体激活”等通路，暗示PI3K-AKT通路参与IL-1 β上调和BPA在肥胖期间CRC中的作用。30只雄性大鼠（n = 6）分为：n（正常饮食）、NC（正常饮食+结直肠癌）、HC（高脂饮食+结直肠癌）、NCB（正常饮食+结直肠癌 + BPA）和HCB（高脂饮食+结直肠癌 + BPA）。1,2-二甲基肼（40 mg/kg）和BPA（25 mg/kg）诱导结直肠癌19 周。尽管BPA暴露不影响体重或生化参数，但HCB组在结肠中表现出显著的组织病理学变化，包括淋巴样增生、肝损伤和IL-1β水平升高。此外，饮食影响脂肪细胞大小，加剧了BPA对结直肠癌进展的影响。研究结果表明，BPA可能通过确定的途径恶化肥胖大鼠的结直肠癌进展，促进多器官病理，并强调需要更严格的法规，特别是对弱势群体。环境影响：双酚A （BPA）是一种广泛存在的环境污染物，在易感人群中与包括癌症在内的严重健康问题联系越来越紧密。我们的研究强调了BPA在促进肥胖驱动的结直肠癌（CRC）进展中的作用，证明了其在高风险环境中的致癌潜力。这些发现强调了对BPA暴露进行监管审查的迫切需要，特别是在肥胖人群中，并支持开发更安全的替代品。解决双酚a的影响有助于制定预防保健战略，并为旨在减少与内分泌干扰化学品有关的环境和公众健康风险的政策提供信息。

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引用次数: 0

Fangchinoline alleviates the progression of osteoarthritis through the nuclear factor kappa B signaling pathway

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2025.117241

Wei He , Xinhuo Li , Qiannan Ding , Tan Zhang , Jiewen Zheng , Xuanyuan Lu , Jianlei Li , Cong Jin , Yangjun Xu

Osteoarthritis is a progressive, chronic joint disease characterized by pain, stiffness, and limited mobility, which can lead to physical disability in severe cases. Owing to its complex pathological features, effective treatments for osteoarthritis are lacking. Fangchinoline is a natural alkaloid found in the tuberous roots of plants belonging to the Menispermaceae family. Fangchinoline reportedly possesses anti-inflammatory, antioxidant, and anticancer properties; however, its role in osteoarthritis progression remains unclear. In this study, we investigated the protective effects and potential mechanisms of fangchinoline against osteoarthritis. In vitro, we confirmed that fangchinoline alleviates interleukin-1β-induced cartilage inflammation, reduces the levels of metabolic factors, such as inducible nitric oxide synthase and matrix metalloproteinase-3, and modulates the expression of aggrecan, which enhances extracellular matrix synthesis. In vivo, we demonstrated that fangchinoline can ameliorate articular cartilage degeneration and reduce inflammatory destruction in a destabilization of the medial meniscus mouse model. The nuclear factor kappa B (NF-κB) signaling pathway in osteoarthritis has been a primary target for drug development, and our results suggest that fangchinoline exerts anti-inflammatory effects by inhibiting the activity of IKKα/β. Using an in vitro human cartilage culture model, we further validated that fangchinoline significantly mitigates cartilage degeneration and inflammation by modulating the NF-κB signaling pathway. This evidence highlights its dual action in preserving cartilage integrity and suppressing inflammatory responses. These findings collectively underscore fangchinoline as a potent inhibitor of NF-κB, capable of attenuating key pathological processes associated with osteoarthritis. Therefore, fangchinoline emerges as a promising therapeutic candidate for slowing the progression of osteoarthritis.

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引用次数: 0

Dehydrodiisoeugenol inhibits PDGF-BB-induced proliferation and migration of human pulmonary artery smooth muscle cells via the mTOR/HIF1-α/HK2 signaling pathway 脱氢二异丁香酚通过mTOR/HIF1-α/HK2信号通路抑制pdgf - bb诱导的人肺动脉平滑肌细胞的增殖和迁移。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117212

Shishun Xie , Jianjun Zhao , Fan Zhang , Xiangjun Li , Xiaoyan Yu , Zhiyun Shu , Hongyuan Cheng , Siyao Liu , Shaomin Shi

Abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) leading to pulmonary vascular remodeling are critical factors in the development of pulmonary hypertension (pH). Dehydrodiisoeugenol (DEH), a natural phenolic compound, is renowned for its antioxidant and anti-inflammatory properties. However, the precise role and mechanisms of DEH in PH remain unclear. In this study, human PASMCs were exposed to PDGF-BB for 48 h to establish an in vitro model. Subsequently, cells were treated with DEH, and assessments of cell proliferation, migration, and apoptosis were performed using CCK-8/EdU assays, scratch/transwell assays, and flow cytometry. The results showed that PDGF-BB induced phenotypic modulation, proliferation, and migration of PASMCs while reducing apoptosis. Treatment with DEH effectively reversed these effects. Bioinformatics analysis identified mTOR as a target of DEH action. Western blot experiments were conducted to evaluate the expression of proteins involved in the mTOR/HIF1-α/HK2 signaling pathway, suggesting that DEH modulates this pathway by targeting and inhibiting mTOR. After treating cells with mTOR inhibitors, cellular glycolysis was assessed using the extracellular acidification rate (ECAR) assay. The results indicated that inhibition of mTOR phosphorylation decreased aerobic glycolysis in PASMCs and suppressed cell proliferation, migration, and apoptosis resistance, regardless of PDGF-BB treatment. Activation of mTOR reversed the inhibition of PDGF-BB-induced PASMC-related protein expression by DEH. These findings suggest that DEH inhibits aerobic glycolysis in PDGF-BB-induced PASMCs through the mTOR/HIF1-α/HK2 signaling pathway, thereby suppressing cell proliferation, migration, and resistance to apoptosis. Consequently, DEH holds promise as a novel therapeutic agent for treating pulmonary arterial hypertension.

肺动脉平滑肌细胞（PASMCs）异常增殖和迁移导致肺血管重构是肺动脉高压（pulmonary hypertension, pH）发生的关键因素。脱氢二异丁香酚（DEH）是一种天然酚类化合物，以其抗氧化和抗炎特性而闻名。然而，DEH在PH中的确切作用和机制尚不清楚。在本研究中，人类PASMCs暴露于PDGF-BB 48 h以建立体外模型。随后，用DEH处理细胞，并使用CCK-8/EdU测定、划痕/transwell测定和流式细胞术评估细胞增殖、迁移和凋亡。结果表明，PDGF-BB可诱导PASMCs的表型调节、增殖和迁移，同时减少凋亡。DEH治疗有效地逆转了这些影响。生物信息学分析确定mTOR是DEH作用的靶标。Western blot实验检测mTOR/HIF1-α/HK2信号通路相关蛋白的表达，提示DEH通过靶向抑制mTOR调控该通路。用mTOR抑制剂处理细胞后，使用细胞外酸化率（ECAR）测定评估细胞糖酵解。结果表明，无论PDGF-BB是否治疗，抑制mTOR磷酸化均可降低PASMCs的有氧糖酵解，抑制细胞增殖、迁移和细胞凋亡抵抗。mTOR的激活逆转了DEH对pdgf - bb诱导的pasmc相关蛋白表达的抑制作用。这些发现表明，DEH通过mTOR/HIF1-α/HK2信号通路抑制pdgf - bb诱导的PASMCs的有氧糖酵解，从而抑制细胞增殖、迁移和对凋亡的抵抗。因此，DEH有望成为治疗肺动脉高压的新型治疗剂。

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引用次数: 0

Chronic cadmium exposure to minimal-risk doses causes dysfunction of epididymal adipose tissue and metabolic disorders 慢性暴露于最低风险剂量的镉会导致附睾脂肪组织功能障碍和代谢紊乱。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117203

Victor Enrique Sarmiento-Ortega , Daniel Issac Alcántara-Jara , Diana Moroni-González , Alfonso Diaz , Rubén Antonio Vázquez-Roque , Eduardo Brambila , Samuel Treviño

Cadmium (Cd) is among the top seven most hazardous environmental contaminants. Minimal risk levels for daily exposure have been established, such as no observable adverse effect level (NOAEL) and lowest observable adverse effect level (LOAEL). Chronic exposure to Cd, at both NOAEL and LOAEL doses, causes toxicity in diverse tissues. However, Cd toxicity in adipose tissue, an endocrine and metabolic organ, remains relatively understudied. We aimed to investigate the potentially toxic effects of chronic Cd exposure (at NOAEL and LOAEL doses) on epidydimal adipose tissue of adult male Wistar rats. Ninety male Wistar rats were divided into three groups (n = 30): Control Cd-free, NOAEL, and LOAEL that received CdCl₂ in drinking water for 15 days to 5 months. We evaluated over time zoometry, serum and adipose Cd concentration, redox balance, GLUT4 and Nrf2 expression, histology, leptin, adiponectin, adipose insulin resistance index, free fatty acids, and glucose tolerance. The higher dose group showed a more pronounced and sustained increase in serum and adipose tissue of Cd concentration. Zoometry was similarly affected in both Cd-exposed groups with adipocyte hypertrophy. The redox balance was maintained due to the augmenting of Nrf2 expression. Leptin concentration augmented, while adiponectin diminished. Adipose insulin resistance increased simultaneously to lipolysis and glucose intolerance despite high GLUT4 expression. In conclusion, this study provides strong evidence that chronic Cd exposure, even at minimal risk levels (LOAEL and NOAEL doses), has toxic effects, disrupting the function of epididymal adipose tissue and contributing to metabolic disorders.

镉（Cd）是七大最危险的环境污染物之一。已经确定了每日接触的最低风险水平，例如无可观察不良影响水平（NOAEL）和最低可观察不良影响水平（LOAEL）。慢性暴露于Cd，在NOAEL和LOAEL剂量下，引起多种组织的毒性。然而，Cd对脂肪组织（一种内分泌和代谢器官）的毒性研究仍相对不足。我们旨在研究慢性Cd暴露（在NOAEL和LOAEL剂量下）对成年雄性Wistar大鼠附睾脂肪组织的潜在毒性作用。将90只雄性Wistar大鼠分为3组（n = 30）：对照组无镉组、NOAEL组和LOAEL组，在饮用水中给予CdCl2 15 天至5 个月。随着时间的推移，我们评估了zozoometry、血清和脂肪Cd浓度、氧化还原平衡、GLUT4和Nrf2表达、组织学、瘦素、脂联素、脂肪胰岛素抵抗指数、游离脂肪酸和葡萄糖耐量。高剂量组血清和脂肪组织中Cd浓度的升高更为明显和持续。在两个cd暴露组中，脂肪细胞肥大对动物测量的影响相似。由于Nrf2表达的增加，氧化还原平衡得以维持。瘦素浓度增加，脂联素浓度降低。尽管GLUT4高表达，但脂肪胰岛素抵抗与脂肪分解和葡萄糖耐受不良同时增加。总之，本研究提供了强有力的证据，证明慢性Cd暴露，即使在最低风险水平（LOAEL和NOAEL剂量）下，也具有毒性作用，破坏附睾脂肪组织的功能并导致代谢紊乱。

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引用次数: 0