Chemico-Biological Interactions最新文献

Glycerophospholipid metabolic disorders and gender difference of cantharidin-induced hepatotoxicity in rats: Lipidomics and MALDI mass spectrometry imaging analysis 甘油磷脂代谢紊乱与安乃近诱导的大鼠肝毒性的性别差异：脂质组学和 MALDI 质谱成像分析

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2024-11-17 DOI: 10.1016/j.cbi.2024.111314

Qiyi Wang , Weina Cheng , Tianmu He , Shan Li , Jingwen Ao , Yanmei He , Cancan Duan , Xiaofei Li , Jianyong Zhang

The hepatotoxicity mechanism of cantharidin (CTD), a major active component of Mylabris was explored based on liver lipidome alterations and spatial distributions in female and male rats using lipidomics and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). After oral CTD exposure, the livers of female rats were screened for 104 differential lipids including lysophosphatidylethanolamine(LysoPE)(20:2/0:0) and diacylglycerol(DG)(18:2/22:4), whereas the livers of male rats were screened for 76 differential lipids including fatty acid(FA)(24:6) and DG(18:0/22:4). According to the MALDI-MSI results, female rats exhibited 12 differential lipids with alteration in the abundance and spatial distribution of phosphatylcholine(PC), phosphatidylethanolamine(PE), lysophosphatidylcholine(LysoPC), and LysoPE in the liver lesion area. On the other hand, male rats exhibited 8 differential lipids with changes in the abundance and spatial distribution of PC, PE, and FA in the liver lesion area. The lipidomics- and MALDI-MSI-detected differential lipids strongly disrupted glycerophospholipid metabolism in both female and male rats. Additionally, phosphatidate phosphatase (Lipin1), choline/ethanolamine phosphotransferase 1 (CEPT1), and phosphatidylethanolamine N-methyltransferase (PEMT) were screened to distinguish CTD hepatoxicity in female and male rats. Western blotting analysis demonstrated a significant elevation in Lipin1 expression in female and male rat livers, accompanied by a decrease in PEMT expression. Furthermore, CEPT1 expression increased significantly in female rat livers and decreased significantly in male rat livers. These findings suggested that CTD could disrupt lipid metabolism in a gender-specific manner. Moreover, the combination of lipidomics and MALDI-MSI could offer valuable insights into CTD-induced hepatotoxicity in rats.

利用脂质组学和基质辅助激光解吸电离质谱成像（MALDI-MSI）技术，基于雌性和雄性大鼠肝脏脂质体的改变和空间分布，探讨了Mylabris的主要活性成分坎他利定（CTD）的肝毒性机制。口服CTD后，雌性大鼠肝脏中的溶血磷脂酰乙醇胺（LysoPE）（20:2/0:0）和二酰甘油（DG）（18:2/22:4）等104种差异脂质被筛查出来，而雄性大鼠肝脏中的脂肪酸（FA）（24:6）和二酰甘油（DG）（18:0/22:4）等76种差异脂质被筛查出来。根据 MALDI-MSI 的结果，雌性大鼠肝脏病变区域的磷脂酰胆碱（PC）、磷脂酰乙醇胺（PE）、溶血磷脂酰胆碱（LysoPC）和溶血磷脂酰乙醇胺（LysoPE）的丰度和空间分布发生了变化，显示出 12 种差异脂质。另一方面，雄性大鼠表现出 8 种不同的脂质，其中 PC、PE 和 FA 在肝脏病变区域的丰度和空间分布发生了变化。脂质组学和 MALDI-MSI 检测到的差异脂质强烈干扰了雌性和雄性大鼠的甘油磷脂代谢。此外，还对磷脂酰磷酸酶（Lipin1）、胆碱/乙醇胺磷酸转移酶1（CEPT1）和磷脂酰乙醇胺N-甲基转移酶（PEMT）进行了筛选，以区分雌性和雄性大鼠的CTD肝毒性。Western 印迹分析表明，雌性和雄性大鼠肝脏中 Lipin1 的表达显著升高，同时 PEMT 的表达降低。此外，CEPT1 在雌性大鼠肝脏中的表达明显增加，而在雄性大鼠肝脏中则明显减少。这些发现表明，CTD 能以性别特异性的方式破坏脂质代谢。此外，脂质组学和 MALDI-MSI 的结合可为了解 CTD 诱导的大鼠肝毒性提供有价值的信息。

{"title":"Glycerophospholipid metabolic disorders and gender difference of cantharidin-induced hepatotoxicity in rats: Lipidomics and MALDI mass spectrometry imaging analysis","authors":"Qiyi Wang , Weina Cheng , Tianmu He , Shan Li , Jingwen Ao , Yanmei He , Cancan Duan , Xiaofei Li , Jianyong Zhang","doi":"10.1016/j.cbi.2024.111314","DOIUrl":"10.1016/j.cbi.2024.111314","url":null,"abstract":"<div><div>The hepatotoxicity mechanism of cantharidin (CTD), a major active component of <em>Mylabris</em> was explored based on liver lipidome alterations and spatial distributions in female and male rats using lipidomics and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). After oral CTD exposure, the livers of female rats were screened for 104 differential lipids including lysophosphatidylethanolamine(LysoPE)(20:2/0:0) and diacylglycerol(DG)(18:2/22:4), whereas the livers of male rats were screened for 76 differential lipids including fatty acid(FA)(24:6) and DG(18:0/22:4). According to the MALDI-MSI results, female rats exhibited 12 differential lipids with alteration in the abundance and spatial distribution of phosphatylcholine(PC), phosphatidylethanolamine(PE), lysophosphatidylcholine(LysoPC), and LysoPE in the liver lesion area. On the other hand, male rats exhibited 8 differential lipids with changes in the abundance and spatial distribution of PC, PE, and FA in the liver lesion area. The lipidomics- and MALDI-MSI-detected differential lipids strongly disrupted glycerophospholipid metabolism in both female and male rats. Additionally, phosphatidate phosphatase <strong>(</strong>Lipin1), choline/ethanolamine phosphotransferase 1 (CEPT1), and phosphatidylethanolamine N-methyltransferase (PEMT) were screened to distinguish CTD hepatoxicity in female and male rats. Western blotting analysis demonstrated a significant elevation in Lipin1 expression in female and male rat livers, accompanied by a decrease in PEMT expression. Furthermore, CEPT1 expression increased significantly in female rat livers and decreased significantly in male rat livers. These findings suggested that CTD could disrupt lipid metabolism in a gender-specific manner. Moreover, the combination of lipidomics and MALDI-MSI could offer valuable insights into CTD-induced hepatotoxicity in rats.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111314"},"PeriodicalIF":4.7,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Copper oxide nanoparticles induced reactive oxygen species generation: A systematic review and meta-analysis 氧化铜纳米粒子诱导活性氧的生成：系统综述和荟萃分析。

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2024-11-15 DOI: 10.1016/j.cbi.2024.111311

Srimathi Murugesan, Satheeswaran Balasubramanian, Ekambaram Perumal

Copper oxide nanoparticles (CuO NPs) are widely employed in various industrial and biomedical applications owing to their enhanced physicochemical characteristics. However, concerns regarding their adverse effects on biological systems upon entering the environment remain unexplored. The generation of reactive oxygen species (ROS) is one of the primary mechanisms in CuO NPs induced toxicity. This meta-analysis was conducted to assess the associative link between CuO NPs exposure and ROS generation. A literature survey was performed in PubMed, Web of Science, Scopus, and Google Scholar, following PRISMA guidelines. After comprehensive initial and primary screening, 28 in vitro studies were selected for meta-analysis. Overall, our results show a substantial increase of ROS in the experimental group when compared to control (SMD = 3.3; 95 % CI: 2.82−3.77, p = 0.00001), with substantial heterogeneity (82 %). Subgroup analysis revealed that larger-sized NPs, higher dosages, and longer exposure duration were associated with ROS generation. Meta-regression analysis identified size, and dosage as significant factors influencing ROS levels. Sensitivity analysis revealed an outlier study and the funnel plot results suggested potential publication bias. Overall, our results provide valuable insights of CuO NPs induced ROS generation, and the relation of variables such as size, dose, and duration in nanotoxicity assessments.

氧化铜纳米粒子（CuO NPs）因其增强的物理化学特性而被广泛应用于各种工业和生物医学领域。然而，人们对其进入环境后对生物系统产生的不利影响仍有疑虑。活性氧（ROS）的产生是 CuO NPs 引发毒性的主要机制之一。本荟萃分析旨在评估氧化铜氧化物氮氧化物暴露与 ROS 生成之间的关联。按照 PRISMA 指南，在 PubMed、Web of Science、Scopus 和 Google Scholar 上进行了文献调查。经过全面的初步筛选和初选，选出了 28 项体外研究进行荟萃分析。总体而言，我们的结果显示，与对照组相比，实验组的 ROS 显著增加（SMD = 3.3；95% CI：2.82-3.77，p = 0.00001），异质性很大（82%）。亚组分析显示，较大尺寸的 NPs、较高的剂量和较长的暴露时间与 ROS 的产生有关。元回归分析发现，尺寸和剂量是影响 ROS 水平的重要因素。敏感性分析发现了一项离群研究，漏斗图结果表明可能存在发表偏差。总之，我们的研究结果对氧化铜氮氧化物诱导的 ROS 生成以及纳米毒性评估中大小、剂量和持续时间等变量之间的关系提供了有价值的见解。

{"title":"Copper oxide nanoparticles induced reactive oxygen species generation: A systematic review and meta-analysis","authors":"Srimathi Murugesan, Satheeswaran Balasubramanian, Ekambaram Perumal","doi":"10.1016/j.cbi.2024.111311","DOIUrl":"10.1016/j.cbi.2024.111311","url":null,"abstract":"<div><div>Copper oxide nanoparticles (CuO NPs) are widely employed in various industrial and biomedical applications owing to their enhanced physicochemical characteristics. However, concerns regarding their adverse effects on biological systems upon entering the environment remain unexplored. The generation of reactive oxygen species (ROS) is one of the primary mechanisms in CuO NPs induced toxicity. This meta-analysis was conducted to assess the associative link between CuO NPs exposure and ROS generation. A literature survey was performed in PubMed, Web of Science, Scopus, and Google Scholar, following PRISMA guidelines. After comprehensive initial and primary screening, 28 <em>in vitro</em> studies were selected for meta-analysis. Overall, our results show a substantial increase of ROS in the experimental group when compared to control (SMD = 3.3; 95 % CI: 2.82−3.77, p = 0.00001), with substantial heterogeneity (82 %). Subgroup analysis revealed that larger-sized NPs, higher dosages, and longer exposure duration were associated with ROS generation. Meta-regression analysis identified size, and dosage as significant factors influencing ROS levels. Sensitivity analysis revealed an outlier study and the funnel plot results suggested potential publication bias. Overall, our results provide valuable insights of CuO NPs induced ROS generation, and the relation of variables such as size, dose, and duration in nanotoxicity assessments.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111311"},"PeriodicalIF":4.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Exploring the nephrotoxicity and molecular mechanisms of Di-2-ethylhexyl phthalate: A comprehensive review 探索邻苯二甲酸二-2-乙基己酯的肾毒性和分子机制：全面综述。

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2024-11-15 DOI: 10.1016/j.cbi.2024.111310

Yun Liu , Xu Zhang , Ruhan Yi , Qing Tian , Jiawei Xu , Xinyu Yan , Jiaxuan Ma , Shaopeng Wang , Guang Yang

Di-2-ethylhexyl phthalate (DEHP), a widely applied plasticizer in various products, can be absorbed into the human body through several channels and accumulate in the lungs, liver, testes, and kidneys, potentially impairing the function of these organs. Recently, the nephrotoxicity of DEHP has received heightened attention. Numerous epidemiologic findings have demonstrated that DEHP exposure may contribute to renal damage, leading to structural and functional abnormalities and exacerbating the progression of kidney disease. Recent research has discovered the mechanisms behind DEHP-induced nephrotoxicity may involve a variety of pathways, including apoptosis, autophagy, ferroptosis, oxidative stress, inflammation, DNA damage, and lipid metabolism disorders. This review discusses the impact of DEHP on kidney function and delves into the molecular mechanisms of nephrotoxicity mediated by DEHP in recent years. In addition, the review examines evidence for the antioxidant and anti-inflammatory capacities of lycopene, green tea polyphenols, and quercetin in ameliorating DEHP-induced renal injury is reviewed, providing a basis for further research.

邻苯二甲酸二-2-乙基己酯（DEHP）是一种广泛应用于各种产品的增塑剂，可通过多种途径被人体吸收，并在肺部、肝脏、睾丸和肾脏中蓄积，可能损害这些器官的功能。最近，DEHP 的肾毒性受到了高度关注。大量流行病学研究结果表明，接触 DEHP 可能会造成肾脏损伤，导致结构和功能异常，加剧肾脏疾病的恶化。最新研究发现，DEHP 诱发肾毒性的机制可能涉及多种途径，包括细胞凋亡、自噬、铁变态反应、氧化应激、炎症、DNA 损伤和脂质代谢紊乱。本综述讨论了 DEHP 对肾功能的影响，并深入探讨了近年来 DEHP 介导的肾毒性分子机制。此外，综述还研究了番茄红素、绿茶多酚和槲皮素在改善 DEHP 引起的肾损伤方面的抗氧化和抗炎能力，为进一步的研究提供了依据。

{"title":"Exploring the nephrotoxicity and molecular mechanisms of Di-2-ethylhexyl phthalate: A comprehensive review","authors":"Yun Liu , Xu Zhang , Ruhan Yi , Qing Tian , Jiawei Xu , Xinyu Yan , Jiaxuan Ma , Shaopeng Wang , Guang Yang","doi":"10.1016/j.cbi.2024.111310","DOIUrl":"10.1016/j.cbi.2024.111310","url":null,"abstract":"<div><div>Di-2-ethylhexyl phthalate (DEHP), a widely applied plasticizer in various products, can be absorbed into the human body through several channels and accumulate in the lungs, liver, testes, and kidneys, potentially impairing the function of these organs. Recently, the nephrotoxicity of DEHP has received heightened attention. Numerous epidemiologic findings have demonstrated that DEHP exposure may contribute to renal damage, leading to structural and functional abnormalities and exacerbating the progression of kidney disease. Recent research has discovered the mechanisms behind DEHP-induced nephrotoxicity may involve a variety of pathways, including apoptosis, autophagy, ferroptosis, oxidative stress, inflammation, DNA damage, and lipid metabolism disorders. This review discusses the impact of DEHP on kidney function and delves into the molecular mechanisms of nephrotoxicity mediated by DEHP in recent years. In addition, the review examines evidence for the antioxidant and anti-inflammatory capacities of lycopene, green tea polyphenols, and quercetin in ameliorating DEHP-induced renal injury is reviewed, providing a basis for further research.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111310"},"PeriodicalIF":4.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Sevoflurane postconditioning mitigates neuronal hypoxic-ischemic injury via regulating reactive astrocytic STAT3 protein modification 七氟醚后处理通过调节反应性星形胶质细胞 STAT3 蛋白修饰减轻神经元缺氧缺血性损伤

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2024-11-12 DOI: 10.1016/j.cbi.2024.111308

Yufei Jia, Yanhong Song, Hang Xue, Xingyue Li, Yinong Zhang, Shiyue Fan, Xu Yang, Zixuan Ding, Yue Qiu, Ziyi Wu, Ping Zhao

Astrocyte activation plays a pivotal role in accelerating the cascade of neuroinflammation associated with the development of hypoxic-ischemic brain injury. This study aimed to investigate the mechanism by which sevoflurane postconditioning mitigates neuronal damage through astrocytes by regulating reactive astrocytic Signal Transducer and Activator of Transcription 3 (STAT3) modifications. A modified Rice‒Vannucci model in rats and a conditioned culture system established by subjecting primary astrocytes to oxygen glucose deprivation, followed by using the conditioned medium to culture the neuron cell line SH-SY5Y were used to simulate HI insult in vivo and in vitro, respectively. These models were followed by 30 min of 2.5 % sevoflurane treatment. Stattic was used to inhibit STAT3 phosphorylation, and (Z)-PUGNAc or OSMI-1 was added to regulate O-linked-β-N-acetylglucosamine modification (O-GlcNAcylation) in primary astrocytes in vitro. Neurobehavioral tests, Nissl staining, CCK8 assay, and flow cytometry for apoptosis were used to assess neuronal function. Immunofluorescence staining was used to detect astrocyte reactivity and the intracellular distribution of STAT3. Immunoprecipitation combined with Western blotting was used to evaluate the O-GlcNAcylation of STAT3. Protein expression and phosphorylation levels were detected by Western blotting. ELISA was conducted to detect the detrimental cytokines IL-6 and IL-1β in astrocyte-conditioned medium. Sevoflurane postconditioning enhanced the O-GlcNAcylation of astrocytic STAT3 following HI insult via the manner of OGT. Crosstalk between O-GlcNAcylation and phosphorylation of STAT3 showed that O-GlcNAcylation inhibited STAT3 phosphorylation. The inhibitory effect on astrocytes suppressed STAT3 nuclear translocation, reduced astrocyte reactivity, decreased the release of the inflammatory cytokines IL6 and IL-1β, attenuated neuronal apoptosis following HI insult, and improved neuron viability. Sevoflurane postconditioning increased astrocytic STAT3 O-GlcNAcylation level to competitively inhibit STAT3 phosphorylation. This deactivated downstream inflammation pathways and reduced astrocyte reactivity, thereby mitigating HI insult in neurons both in vivo and in vitro.

星形胶质细胞活化在加速与缺氧缺血性脑损伤发展相关的神经炎症级联反应中起着关键作用。本研究旨在探究七氟醚后处理通过调节反应性星形胶质细胞信号转换器和转录激活因子3（STAT3）修饰来减轻神经元损伤的机制。研究人员使用改良的大鼠 Rice-Vannucci 模型和通过对原代星形胶质细胞进行氧葡萄糖剥夺而建立的条件培养系统，然后使用条件培养基培养神经元细胞系 SH-SY5Y，分别在体内和体外模拟 HI 损伤。在这些模型之后进行 30 分钟的 2.5% 七氟醚处理。Stattic 用于抑制 STAT3 磷酸化，(Z)-PUGNAc 或 OSMI-1 用于调节体外原发性星形胶质细胞中的 O-连-β-N-乙酰葡糖胺修饰（O-GlcNAcylation）。神经行为测试、Nissl 染色、CCK8 检测和流式细胞术检测细胞凋亡被用来评估神经元功能。免疫荧光染色用于检测星形胶质细胞的反应性和 STAT3 在细胞内的分布。免疫沉淀结合 Western 印迹技术用于评估 STAT3 的 O-GlcNAcylation 情况。蛋白表达和磷酸化水平由 Western 印迹法检测。用 ELISA 检测星形胶质细胞条件培养基中的有害细胞因子 IL-6 和 IL-1β。七氟醚后条件通过OGT的方式增强了HI损伤后星形胶质细胞STAT3的O-GlcNA酰化。O-GlcNAcylation与STAT3磷酸化之间的相互影响表明，O-GlcNAcylation抑制了STAT3的磷酸化。对星形胶质细胞的抑制作用抑制了 STAT3 的核转位，降低了星形胶质细胞的反应性，减少了炎症细胞因子 IL6 和 IL-1β 的释放，减轻了 HI 损伤后神经元的凋亡，提高了神经元的存活率。七氟烷后条件增加了星形胶质细胞 STAT3 O-GlcNAcylation 水平，从而竞争性地抑制了 STAT3 磷酸化。这使下游炎症通路失活，降低了星形胶质细胞的反应性，从而减轻了体内和体外神经元的高频损伤。

{"title":"Sevoflurane postconditioning mitigates neuronal hypoxic-ischemic injury via regulating reactive astrocytic STAT3 protein modification","authors":"Yufei Jia, Yanhong Song, Hang Xue, Xingyue Li, Yinong Zhang, Shiyue Fan, Xu Yang, Zixuan Ding, Yue Qiu, Ziyi Wu, Ping Zhao","doi":"10.1016/j.cbi.2024.111308","DOIUrl":"10.1016/j.cbi.2024.111308","url":null,"abstract":"<div><div>Astrocyte activation plays a pivotal role in accelerating the cascade of neuroinflammation associated with the development of hypoxic-ischemic brain injury. This study aimed to investigate the mechanism by which sevoflurane postconditioning mitigates neuronal damage through astrocytes by regulating reactive astrocytic Signal Transducer and Activator of Transcription 3 (STAT3) modifications. A modified Rice‒Vannucci model in rats and a conditioned culture system established by subjecting primary astrocytes to oxygen glucose deprivation, followed by using the conditioned medium to culture the neuron cell line SH-SY5Y were used to simulate HI insult in vivo and in vitro, respectively. These models were followed by 30 min of 2.5 % sevoflurane treatment. Stattic was used to inhibit STAT3 phosphorylation, and (Z)-PUGNAc or OSMI-1 was added to regulate O-linked-β-N-acetylglucosamine modification (O-GlcNAcylation) in primary astrocytes in vitro. Neurobehavioral tests, Nissl staining, CCK8 assay, and flow cytometry for apoptosis were used to assess neuronal function. Immunofluorescence staining was used to detect astrocyte reactivity and the intracellular distribution of STAT3. Immunoprecipitation combined with Western blotting was used to evaluate the O-GlcNAcylation of STAT3. Protein expression and phosphorylation levels were detected by Western blotting. ELISA was conducted to detect the detrimental cytokines IL-6 and IL-1β in astrocyte-conditioned medium. Sevoflurane postconditioning enhanced the O-GlcNAcylation of astrocytic STAT3 following HI insult via the manner of OGT. Crosstalk between O-GlcNAcylation and phosphorylation of STAT3 showed that O-GlcNAcylation inhibited STAT3 phosphorylation. The inhibitory effect on astrocytes suppressed STAT3 nuclear translocation, reduced astrocyte reactivity, decreased the release of the inflammatory cytokines IL6 and IL-1β, attenuated neuronal apoptosis following HI insult, and improved neuron viability. Sevoflurane postconditioning increased astrocytic STAT3 O-GlcNAcylation level to competitively inhibit STAT3 phosphorylation. This deactivated downstream inflammation pathways and reduced astrocyte reactivity, thereby mitigating HI insult in neurons both in vivo and in vitro.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111308"},"PeriodicalIF":4.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Toxicological effects and potential reproductive risk of microplastic-induced molecular changes in protamine-like proteins and their DNA binding 微塑料诱导的原胺样蛋白分子变化及其 DNA 结合的毒理效应和潜在生殖风险。

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2024-11-12 DOI: 10.1016/j.cbi.2024.111309

Carmela Marinaro , Giulia Scarciello , Anna Rita Bianchi , Bruno Berman, Teresa Chianese, Rosaria Scudiero, Luigi Rosati , Anna De Maio , Gennaro Lettieri, Marina Piscopo

Today, plastic pollution is a widespread problem in all ecosystems and has a particularly severe impact on marine ecosystems and external fertilisers such as the mussel Mytilus galloprovincialis. The present study aims to assess the toxicological reproductive health effects in this organism following exposure to two concentrations of polystyrene microplastics (PS-MPs) (0.5 and 1 μg/L), representative of conditions in the Mediterranean Sea. After exposure, the electrophoretic pattern of protamine-like (PL) proteins, the major basic protein component of Mytilus galloprovincialis sperm chromatin, was analysed. Compared to the unexposed condition, differences were observed by SDS-PAGE and an increased ability of PL to bind and protect DNA from oxidative damage was then measured, particularly for PL from mussels exposed to 1 μg/L PS-MPs. At this dose of PS-MPs, a reduced release of all PLs from the sperm nuclei was also observed, whereas the digestion by micrococcal nuclease did not show any significant differences between the exposed and the unexposed conditions. Finally, the possibility of poly(ADP)-ribosylation of the PLs was investigated. PL-II showed an increase in poly(ADP)-ribosylation after PS-MPs exposure, which may account for the difference in the ability of the PLs to bind DNA. In conclusion, while all the results might suggest a molecular mechanism of gametic plasticity occurring upon exposure of mussels to PS-MPs 1 μg/L, they also indicate that this dose of exposure could be extremely detrimental to the reproductive health of Mytilus galloprovincialis because it could prevent the release of basic nuclear proteins from the sperm DNA at fertilisation.

如今，塑料污染是所有生态系统中普遍存在的问题，对海洋生态系统和外部肥料（如贻贝）的影响尤为严重。本研究旨在评估该生物在接触两种浓度的聚苯乙烯微塑料（PS-MPs）（0.5 和 1 μg/L）后对生殖健康的毒理学影响。接触后，分析了原胺样蛋白（PL）的电泳图谱，原胺样蛋白是五步蛇精子染色质的主要基本蛋白成分。与未暴露的情况相比，SDS-PAGE 观察到了差异，然后测量了 PL 结合和保护 DNA 免受氧化损伤的能力，尤其是暴露于 1 μg/L PS-MPs 的贻贝的 PL。在这一剂量的 PS-MPs 下，还观察到精子细胞核中所有聚乳酸的释放量减少，而用微球核酸酶消化的结果显示，暴露和未暴露条件下的聚乳酸没有任何显著差异。最后，研究人员还调查了聚乳酸发生聚（ADP）核糖基化的可能性。暴露于 PS-MPs 后，PL-II 的聚（ADP）-核糖基化增加，这可能是 PLs 结合 DNA 的能力不同的原因。总之，虽然所有结果都可能表明，贻贝接触 1 微克/升的 PS-MPs 后，会出现配子可塑性的分子机制，但这些结果也表明，这一剂量的接触可能会对五步蛇的生殖健康极为不利，因为它可能会阻止精子 DNA 释放基本核蛋白。

{"title":"Toxicological effects and potential reproductive risk of microplastic-induced molecular changes in protamine-like proteins and their DNA binding","authors":"Carmela Marinaro , Giulia Scarciello , Anna Rita Bianchi , Bruno Berman, Teresa Chianese, Rosaria Scudiero, Luigi Rosati , Anna De Maio , Gennaro Lettieri, Marina Piscopo","doi":"10.1016/j.cbi.2024.111309","DOIUrl":"10.1016/j.cbi.2024.111309","url":null,"abstract":"<div><div>Today, plastic pollution is a widespread problem in all ecosystems and has a particularly severe impact on marine ecosystems and external fertilisers such as the mussel <em>Mytilus galloprovincialis</em>. The present study aims to assess the toxicological reproductive health effects in this organism following exposure to two concentrations of polystyrene microplastics (PS-MPs) (0.5 and 1 μg/L), representative of conditions in the Mediterranean Sea. After exposure, the electrophoretic pattern of protamine-like (PL) proteins, the major basic protein component of <em>Mytilus galloprovincialis</em> sperm chromatin, was analysed. Compared to the unexposed condition, differences were observed by SDS-PAGE and an increased ability of PL to bind and protect DNA from oxidative damage was then measured, particularly for PL from mussels exposed to 1 μg/L PS-MPs. At this dose of PS-MPs, a reduced release of all PLs from the sperm nuclei was also observed, whereas the digestion by micrococcal nuclease did not show any significant differences between the exposed and the unexposed conditions. Finally, the possibility of poly(ADP)-ribosylation of the PLs was investigated. PL-II showed an increase in poly(ADP)-ribosylation after PS-MPs exposure, which may account for the difference in the ability of the PLs to bind DNA. In conclusion, while all the results might suggest a molecular mechanism of gametic plasticity occurring upon exposure of mussels to PS-MPs 1 μg/L, they also indicate that this dose of exposure could be extremely detrimental to the reproductive health of <em>Mytilus galloprovincialis</em> because it could prevent the release of basic nuclear proteins from the sperm DNA at fertilisation.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111309"},"PeriodicalIF":4.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Diosgenin attenuates nonalcoholic fatty liver disease through mTOR-mediated inhibition of lipid accumulation and inflammation 薯蓣皂苷通过 mTOR 介导的脂质积累和炎症抑制作用减轻非酒精性脂肪肝。

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2024-11-12 DOI: 10.1016/j.cbi.2024.111306

Guoliang Yin , Hongyi Liang , Yiran Cheng , Suwen Chen , Xin Zhang , Decheng Meng , Wenfei Yu , Hongshuai Liu , Chaoyuan Song , Fengxia Zhang

Excessive hepatic lipid accumulation and inflammatory injury are significant pathological manifestations of nonalcoholic fatty liver disease (NAFLD). Our previous research discovered that diosgenin, a natural steroidal saponin derived from Chinese herbs, can reduce hepatic lipid accumulation and steatosis; however, the exact mechanism remains unclear. This study aimed to investigate the protective mechanisms of diosgenin against NAFLD. We utilized network pharmacology and molecular docking approaches to identify the pathways through which diosgenin improves NAFLD. In high-fat diet (HFD)-fed rats, we measured biochemical markers in the serum and liver. Liver histopathology was assessed using HE and oil-red O staining. In free fatty acids (FFAs)-induced HepG2 cells, we employed the cell transfection overexpression method to verify the regulatory relationship of the identified pathways. The mechanisms in vitro and in vivo were examined using quantitative polymerase chain reaction and Western blot analyses. Bioinformatics analysis indicated that the mTOR-FASN/HIF-1α/RELA/VEGFA pathway may be the target pathway for diosgenin in alleviating NAFLD. Diosgenin inhibited hepatic lipid accumulation and pro-inflammatory cytokines in HFD-fed rats, and reduced intracellular lipid accumulation as well as TG, TC, IL-1β, and TNF-α levels in FFAs-induced HepG2 cells. Mechanistically, diosgenin downregulated the expression of p-mTOR, FASN, HIF-1α, RELA, and VEGFA, which are associated with lipid synthesis and inflammation. Overexpression of mTOR abolished the beneficial effects of diosgenin on lipid reduction and inflammation, as well as its inhibitory effects on the expression of FASN, HIF-1α, RELA, and VEGFA. In conclusion, diosgenin alleviates NAFLD through mTOR-mediated inhibition of lipid accumulation and inflammation.

肝脏脂质过度积聚和炎症损伤是非酒精性脂肪肝（NAFLD）的重要病理表现。我们之前的研究发现，从中草药中提取的天然甾体皂苷--薯蓣皂苷能减少肝脏脂质堆积和脂肪变性，但其确切机制仍不清楚。本研究旨在探讨薯蓣皂苷抗非酒精性脂肪肝的保护机制。我们利用网络药理学和分子对接方法确定了薯蓣皂苷改善非酒精性脂肪肝的途径。在高脂饮食（HFD）喂养的大鼠中，我们测量了血清和肝脏中的生化指标。肝脏组织病理学采用 HE 和油红 O 染色法进行评估。在游离脂肪酸（FFAs）诱导的 HepG2 细胞中，我们采用了细胞转染过表达的方法来验证已确定通路的调控关系。我们使用定量聚合酶链式反应和 Western 印迹分析检验了体外和体内的机制。生物信息学分析表明，mTOR-FASN/HIF-1α/RELA/VEGFA通路可能是薯蓣皂苷缓解非酒精性脂肪肝的靶通路。薯蓣皂苷抑制了高密度脂蛋白饮食大鼠的肝脏脂质积累和促炎细胞因子，降低了FFAs诱导的HepG2细胞的细胞内脂质积累以及TG、TC、IL-1β和TNF-α水平。从机理上讲，薯蓣皂苷能下调与脂质合成和炎症相关的 p-mTOR、FASN、HIF-1α、RELA 和 VEGFA 的表达。过量表达 mTOR 会消除薯蓣皂苷对降脂和炎症的有益作用，以及对 FASN、HIF-1α、RELA 和 VEGFA 表达的抑制作用。总之，薯蓣皂苷能通过 mTOR 介导的脂质积累和炎症抑制作用缓解非酒精性脂肪肝。

{"title":"Diosgenin attenuates nonalcoholic fatty liver disease through mTOR-mediated inhibition of lipid accumulation and inflammation","authors":"Guoliang Yin , Hongyi Liang , Yiran Cheng , Suwen Chen , Xin Zhang , Decheng Meng , Wenfei Yu , Hongshuai Liu , Chaoyuan Song , Fengxia Zhang","doi":"10.1016/j.cbi.2024.111306","DOIUrl":"10.1016/j.cbi.2024.111306","url":null,"abstract":"<div><div>Excessive hepatic lipid accumulation and inflammatory injury are significant pathological manifestations of nonalcoholic fatty liver disease (NAFLD). Our previous research discovered that diosgenin, a natural steroidal saponin derived from Chinese herbs, can reduce hepatic lipid accumulation and steatosis; however, the exact mechanism remains unclear. This study aimed to investigate the protective mechanisms of diosgenin against NAFLD. We utilized network pharmacology and molecular docking approaches to identify the pathways through which diosgenin improves NAFLD. In high-fat diet (HFD)-fed rats, we measured biochemical markers in the serum and liver. Liver histopathology was assessed using HE and oil-red O staining. In free fatty acids (FFAs)-induced HepG2 cells, we employed the cell transfection overexpression method to verify the regulatory relationship of the identified pathways. The mechanisms <em>in vitro</em> and in vivo were examined using quantitative polymerase chain reaction and Western blot analyses. Bioinformatics analysis indicated that the mTOR-FASN/HIF-1α/RELA/VEGFA pathway may be the target pathway for diosgenin in alleviating NAFLD. Diosgenin inhibited hepatic lipid accumulation and pro-inflammatory cytokines in HFD-fed rats, and reduced intracellular lipid accumulation as well as TG, TC, IL-1β, and TNF-α levels in FFAs-induced HepG2 cells. Mechanistically, diosgenin downregulated the expression of p-mTOR, FASN, HIF-1α, RELA, and VEGFA, which are associated with lipid synthesis and inflammation. Overexpression of mTOR abolished the beneficial effects of diosgenin on lipid reduction and inflammation, as well as its inhibitory effects on the expression of FASN, HIF-1α, RELA, and VEGFA. In conclusion, diosgenin alleviates NAFLD through mTOR-mediated inhibition of lipid accumulation and inflammation.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111306"},"PeriodicalIF":4.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Exploring the mechanism of ursolic acid in preventing liver fibrosis and improving intestinal microbiota based on NOX2/NLRP3 inflammasome signaling pathway 基于NOX2/NLRP3炎性体信号通路探索熊果酸预防肝纤维化和改善肠道微生物群的机制

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2024-11-03 DOI: 10.1016/j.cbi.2024.111305

Qi Liu , Lin-Xiang Liu , Bi-Min Li , Wang Zhang , Yue Zhang , Peng Chen , Chen-Kai Huang , Yuan Nie , Xuan Zhu

Early-stage liver fibrosis can be reversed; however, the underlying mechanisms remain incompletely understood. The intestinal tract hosts a substantial and diverse microbiota involved in various physiological activities and is closely linked to chronic liver disease. Previous studies have indicated that ursolic acid (UA), derived from herbal plants, possesses anti-inflammatory and antifibrotic properties; however, its precise mechanism remains to be elucidated. Consequently, liver fibrosis models were constructed utilizing both the methionine/choline deficieny (MCD) diet and carbon tetrachloride (CCl4) intraperitoneal injections. 16S rRNA was conducted to analyze the intestinal microbiota. Results indicated that UA attenuated liver injury and fibrosis, reduced indices related to liver fibrosis, and decreased the expression levels of NADPH oxidase 2 (NOX2) and NOD like receptor protein 3 (NLRP3). Hepatic fibrosis was alleviated in post-model NOX2 and NLRP3 gene knockout (NOX2^−/− and NLRP3^−/−) mice in comparison to post-model wild-type (WT) mice. Nonetheless, neither UA treatment nor control treatment significantly improved liver fibrosis in comparison to post-model knockout mice. Furthermore, the liver of NOX2^−/− mice exhibited lower levels of NLRP3 expression. Importantly, knockout mice displayed a higher diversity of intestinal microbiota, characterized by an increased presence of beneficial bacteria and a reduced presence of harmful bacteria compared to WT mice. In conclusion, UA exerts antifibrotic effects through the inhibition of the NOX2/NLRP3 inflammasome signaling pathway. UA has the potential to reverse liver fibrosis by modulating this signaling pathway, thereby enhancing the gut microbiota.

早期阶段的肝纤维化是可以逆转的；然而，人们对其基本机制仍不完全了解。肠道内有大量多样的微生物群，参与各种生理活动，与慢性肝病密切相关。以往的研究表明，从草本植物中提取的熊果酸（UA）具有抗炎和抗肝纤维化的特性，但其确切机制仍有待阐明。因此，利用蛋氨酸/胆碱缺乏（MCD）饮食和腹腔注射四氯化碳（CCl4）构建了肝纤维化模型。16S rRNA用于分析肠道微生物群。结果表明，UA减轻了肝损伤和肝纤维化，降低了与肝纤维化相关的指数，并降低了NADPH氧化酶2（NOX2）和NOD样受体蛋白3（NLRP3）的表达水平。与建模后的野生型（WT）小鼠相比，NOX2 和 NLRP3 基因敲除（NOX2-/- 和 NLRP3-/-）小鼠的肝纤维化有所缓解。然而，与模型敲除后的小鼠相比，UA 治疗和对照组治疗都不能明显改善肝纤维化。此外，NOX2-/-小鼠肝脏中的NLRP3表达水平较低。重要的是，与 WT 小鼠相比，基因敲除小鼠显示出更高的肠道微生物群多样性，其特点是有益菌增多，有害菌减少。总之，UA通过抑制NOX2/NLRP3炎性体信号通路发挥抗肝纤维化作用。通过调节这一信号通路，UA 有可能逆转肝纤维化，从而增强肠道微生物群。

{"title":"Exploring the mechanism of ursolic acid in preventing liver fibrosis and improving intestinal microbiota based on NOX2/NLRP3 inflammasome signaling pathway","authors":"Qi Liu , Lin-Xiang Liu , Bi-Min Li , Wang Zhang , Yue Zhang , Peng Chen , Chen-Kai Huang , Yuan Nie , Xuan Zhu","doi":"10.1016/j.cbi.2024.111305","DOIUrl":"10.1016/j.cbi.2024.111305","url":null,"abstract":"<div><div>Early-stage liver fibrosis can be reversed; however, the underlying mechanisms remain incompletely understood. The intestinal tract hosts a substantial and diverse microbiota involved in various physiological activities and is closely linked to chronic liver disease. Previous studies have indicated that ursolic acid (UA), derived from herbal plants, possesses anti-inflammatory and antifibrotic properties; however, its precise mechanism remains to be elucidated. Consequently, liver fibrosis models were constructed utilizing both the methionine/choline deficieny (MCD) diet and carbon tetrachloride (CCl4) intraperitoneal injections. 16S rRNA was conducted to analyze the intestinal microbiota. Results indicated that UA attenuated liver injury and fibrosis, reduced indices related to liver fibrosis, and decreased the expression levels of NADPH oxidase 2 (NOX2) and NOD like receptor protein 3 (NLRP3). Hepatic fibrosis was alleviated in post-model NOX2 and NLRP3 gene knockout (NOX2<sup>−/−</sup> and NLRP3<sup>−/−</sup>) mice in comparison to post-model wild-type (WT) mice. Nonetheless, neither UA treatment nor control treatment significantly improved liver fibrosis in comparison to post-model knockout mice. Furthermore, the liver of NOX2<sup>−/−</sup> mice exhibited lower levels of NLRP3 expression. Importantly, knockout mice displayed a higher diversity of intestinal microbiota, characterized by an increased presence of beneficial bacteria and a reduced presence of harmful bacteria compared to WT mice. In conclusion, UA exerts antifibrotic effects through the inhibition of the NOX2/NLRP3 inflammasome signaling pathway. UA has the potential to reverse liver fibrosis by modulating this signaling pathway, thereby enhancing the gut microbiota.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111305"},"PeriodicalIF":4.7,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Molybdenum interferes with MMPs/TIMPs expression to reduce the receptivity of porcine endometrial epithelial cells 钼可干扰 MMPs/TIMPs 的表达，从而降低猪子宫内膜上皮细胞的接受能力。

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2024-10-31 DOI: 10.1016/j.cbi.2024.111304

Xiao-Ying Gao , Yan Zhang , Wen-Peng Zhao, Er-Jie Tian, Mohammad Mehdi Ommati, Ji-Cang Wang, Hong-Wei Wang, Bian-Hua Zhou

To investigate the effect of trace element molybdenum (Mo) on the receptivity of porcine endometrial epithelial cells (PEECs) and evaluate Mo toxicity and its potential molecular mechanisms, Mo-treated PEECs models were established by incubating the cells with various concentrations of medium containing Mo (0, 0.005, 0.020, 0.200, and 5 mmol/L MoNa₂O₄·2H₂O). The results showed that Mo disrupted the morphology and ultrastructure of PEECs, triggered blurred cell edges, cell swelling, cell cycle arrest, and increased apoptosis. At the molecular level, Mo treatment activated the TGF-β1/SMAD2 and PI3K/AKT1 pathways, causing a significant increase in matrix metalloproteinase (MMP)-9 and MMP-2 protein expression. Accompanied by markedly increased tissue inhibitors matrix metalloproteinase (TIMP)-2 and decreased TIMP-1, the balance of MMP2/TIMP-2 and MMP-9/TIMP-1 were disrupted. Ultimately, the receptivity of PEECs was destroyed by excessive Mo, which is revealed by the significant decrease of receptive marker molecules, including leukemia inhibitory factor (LIF), integrins β3 (ITGβ3), heparin-binding epidermal growth factor (HB-EGF), and vascular endothelial growth factor (VEGF). To sum up, the current study demonstrated the potential toxicity of Mo to PEECs, indicating reproductive toxicity at high Mo concentrations and suggesting that the content of Mo should be evaluated as a potential risk factor.

为了研究微量元素钼（Mo）对猪子宫内膜上皮细胞（PEECs）接受性的影响，并评估钼的毒性及其潜在的分子机制，研究人员用不同浓度的含钼培养基（0、0.005、0.020、0.200和5mmol/L MoNa2O4-2H2O）培养猪子宫内膜上皮细胞，建立了钼处理的PEECs模型。结果表明，Mo 破坏了 PEECs 的形态和超微结构，导致细胞边缘模糊、细胞肿胀、细胞周期停滞和细胞凋亡增加。在分子水平上，Mo 处理激活了 TGF-β1/SMAD2 和 PI3K/AKT1 通路，导致基质金属蛋白酶（MMP）-9 和 MMP-2 蛋白表达显著增加。伴随着组织抑制基质金属蛋白酶（TIMP）-2 的明显增加和 TIMP-1 的减少，MMP2/TIMP-2 和 MMP-9/TIMP-1 的平衡被打破。最终，白血病抑制因子（LIF）、整合素β3（ITGβ3）、肝素结合表皮生长因子（HB-EGF）和血管内皮生长因子（VEGF）等接受性标志物分子显著减少，表明过量的 Mo 破坏了 PEECs 的接受性。总之，目前的研究证明了钼对 PEECs 的潜在毒性，表明高浓度钼具有生殖毒性，并建议将钼含量作为潜在风险因素进行评估。

{"title":"Molybdenum interferes with MMPs/TIMPs expression to reduce the receptivity of porcine endometrial epithelial cells","authors":"Xiao-Ying Gao , Yan Zhang , Wen-Peng Zhao, Er-Jie Tian, Mohammad Mehdi Ommati, Ji-Cang Wang, Hong-Wei Wang, Bian-Hua Zhou","doi":"10.1016/j.cbi.2024.111304","DOIUrl":"10.1016/j.cbi.2024.111304","url":null,"abstract":"<div><div>To investigate the effect of trace element molybdenum (Mo) on the receptivity of porcine endometrial epithelial cells (PEECs) and evaluate Mo toxicity and its potential molecular mechanisms, Mo-treated PEECs models were established by incubating the cells with various concentrations of medium containing Mo (0, 0.005, 0.020, 0.200, and 5 mmol/L MoNa<sub>2</sub>O<sub>4</sub>·2H<sub>2</sub>O). The results showed that Mo disrupted the morphology and ultrastructure of PEECs, triggered blurred cell edges, cell swelling, cell cycle arrest, and increased apoptosis. At the molecular level, Mo treatment activated the TGF-β1/SMAD2 and PI3K/AKT1 pathways, causing a significant increase in matrix metalloproteinase (MMP)-9 and MMP-2 protein expression. Accompanied by markedly increased tissue inhibitors matrix metalloproteinase (TIMP)-2 and decreased TIMP-1, the balance of MMP2/TIMP-2 and MMP-9/TIMP-1 were disrupted. Ultimately, the receptivity of PEECs was destroyed by excessive Mo, which is revealed by the significant decrease of receptive marker molecules, including leukemia inhibitory factor (LIF), integrins β3 (ITGβ3), heparin-binding epidermal growth factor (HB-EGF), and vascular endothelial growth factor (VEGF). To sum up, the current study demonstrated the potential toxicity of Mo to PEECs, indicating reproductive toxicity at high Mo concentrations and suggesting that the content of Mo should be evaluated as a potential risk factor.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111304"},"PeriodicalIF":4.7,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Multiomic analysis of Lewisite exposed human dermal equivalent tissues 对暴露于路易斯特的人体真皮等效组织进行多组学分析。

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2024-10-30 DOI: 10.1016/j.cbi.2024.111295

Elizabeth S. Dhummakupt, Conor C. Jenkins, Gabrielle M. Rizzo, Allison E. Clay, Jennifer R. Horsmon, Tyler D.P. Goralski, Julie A. Renner, Daniel J. Angelini

Lewisite (Military Code: L) is an arsenical vesicant chemical warfare agent (CWA) that was developed in the United States during World War I. Even though its use has not been documented in warfare, large stockpiles were created and still exist in various locations around the world. Given that large quantities exist as well as the relative straightforward process for its creation, Lewisite still presents itself as a serious threat agent. In this study, we examined the effects of Lewisite on human dermal equivalent tissues (EpiDerm™/EpiDerm™-FT) through the evaluation of cellular viability, histology, and multiomic analysis.

路易斯特（军用代号：L）是美国在第一次世界大战期间研制的一种砷类含泡化学战剂（CWA）。尽管没有战争使用路易斯特的记录，但美国还是制造了大量的路易斯特储存，至今仍存在于世界各地。鉴于其大量存在以及相对简单的制造过程，路易斯特仍然是一种严重的威胁物质。在本研究中，我们通过评估细胞活力、组织学和多组学分析，研究了路易斯特对人体真皮等效组织（EpiDerm™/EpiDerm™-FT）的影响。

引用次数: 0

Activation of protein kinase B rescues against thapsigargin-elicited cardiac dysfunction through regulation of NADPH oxidase and ferroptosis 通过调节 NADPH 氧化酶和铁氧化酶，激活蛋白激酶 B 可防止钠硫磷苷诱发的心脏功能障碍

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2024-10-29 DOI: 10.1016/j.cbi.2024.111292

Xiaohu Wang , Feng-Juan Li , Yong Cheng , Shuying Chen , Shuyi Zhu , Yingmei Zhang , Russel J. Reiter , Milad Ashrafizadeh , Jie Lin , Guizhen Wang , Ling Lin , Jun Ren

Endoplasmic reticulum (ER) stress is a known contributor to cardiac remodeling and contractile dysfunction. Although NADPH oxidase has been implicated in ER stress-induced organ damage, its specific role in myocardial complications resulting from ER stress remains unclear. This study aimed to investigate the possible involvement of NADPH oxidase in ER stress-induced myocardial abnormalities and to evaluate the impact of Akt constitutive activation on these myocardial defects. Mice with cardiac-specific overexpression of active mutant of Akt (Myr-Akt) and their wild-type (WT) littermates were treated with ER stress instigator thapsigargin (1 mg/kg, i. p. 72 hrs) before evaluating myocardial morphology and function. Our results noted that thapsigargin significantly impaired echocardiographic parameters and cell shortening indices, including elevated LVESD, decreased ejection fraction, fractional shortening, peak shortening, electrically-stimulated intracellular Ca²⁺ release, and cardiomyocyte survival. These functional deteriorations were accompanied by upregulation of NADPH oxidase, O₂⁻ production, mitochondrial damage, carbonyl formation, lipid peroxidation, apoptosis, and interstitial fibrosis, with unchanged myocardial size. Constitutive Akt hyperactivation did not generate any response on myocardial morphology and function, although it greatly suppressed or nullified thapsigargin-induced myocardial remodeling and dysfunction. Thapsigargin also triggered dephosphorylation of Akt and its downstream signal GSK3β, along with development of ferroptosis, all of which were nullified by Akt hyperactivation. In vitro studies further revealed that thapsigargin provoked cardiomyocyte mechanical anomalies and lipid peroxidation, similar to in vivo results. These effects were reverted by inhibitors of NADPH oxidase and ferroptosis (apocynin and LIP1). Collectively, our data denote an important protective role for Akt hyperactivation in thapsigargin-evoked myocardial anomalies, likely through NADPH oxidase-mediated regulation of ferroptosis.

众所周知，内质网（ER）应激是导致心脏重塑和收缩功能障碍的一个因素。虽然 NADPH 氧化酶与 ER 应激诱导的器官损伤有关，但它在 ER 应激导致的心肌并发症中的具体作用仍不清楚。本研究旨在研究 NADPH 氧化酶可能参与 ER 应激诱导的心肌异常，并评估 Akt 构成性激活对这些心肌缺陷的影响。在评估心肌形态和功能之前，用ER应激诱导剂thapsigargin（1毫克/千克，静脉注射72小时）处理心脏特异性过表达Akt活性突变体（Myr-Akt）的小鼠及其野生型同窝鼠。我们的研究结果表明，硫辛酸会显著损害超声心动图参数和细胞缩短指数，包括左心室收缩压升高、射血分数下降、缩短分数下降、缩短峰值下降、电刺激细胞内 Ca2+ 释放和心肌细胞存活率下降。伴随这些功能恶化的是 NADPH 氧化酶上调、O2-产生、线粒体损伤、羰基形成、脂质过氧化、细胞凋亡和间质纤维化，而心肌大小不变。尽管Akt亢进在很大程度上抑制或抵消了thapsigargin诱导的心肌重塑和功能障碍，但并没有对心肌形态和功能产生任何影响。硫代甘氨还会引发 Akt 及其下游信号 GSK3β 的去磷酸化，并导致铁变态反应，而 Akt 过度激活则会使所有这些反应无效。体外研究进一步显示，硫代甘氨可引起心肌细胞机械异常和脂质过氧化，这与体内研究结果相似。NADPH 氧化酶和铁氧化酶抑制剂（apocynin 和 LIP1）可逆转这些效应。总之，我们的数据表明 Akt 过度激活在硫辛酸诱发的心肌异常中起着重要的保护作用，这可能是通过 NADPH 氧化酶介导的铁变态反应调节实现的。

{"title":"Activation of protein kinase B rescues against thapsigargin-elicited cardiac dysfunction through regulation of NADPH oxidase and ferroptosis","authors":"Xiaohu Wang , Feng-Juan Li , Yong Cheng , Shuying Chen , Shuyi Zhu , Yingmei Zhang , Russel J. Reiter , Milad Ashrafizadeh , Jie Lin , Guizhen Wang , Ling Lin , Jun Ren","doi":"10.1016/j.cbi.2024.111292","DOIUrl":"10.1016/j.cbi.2024.111292","url":null,"abstract":"<div><div>Endoplasmic reticulum (ER) stress is a known contributor to cardiac remodeling and contractile dysfunction. Although NADPH oxidase has been implicated in ER stress-induced organ damage, its specific role in myocardial complications resulting from ER stress remains unclear. This study aimed to investigate the possible involvement of NADPH oxidase in ER stress-induced myocardial abnormalities and to evaluate the impact of Akt constitutive activation on these myocardial defects. Mice with cardiac-specific overexpression of active mutant of Akt (Myr-Akt) and their wild-type (WT) littermates were treated with ER stress instigator thapsigargin (1 mg/kg, i. p. 72 hrs) before evaluating myocardial morphology and function. Our results noted that thapsigargin significantly impaired echocardiographic parameters and cell shortening indices, including elevated LVESD, decreased ejection fraction, fractional shortening, peak shortening, electrically-stimulated intracellular Ca<sup>2+</sup> release, and cardiomyocyte survival. These functional deteriorations were accompanied by upregulation of NADPH oxidase, O<sub>2</sub><sup>−</sup> production, mitochondrial damage, carbonyl formation, lipid peroxidation, apoptosis, and interstitial fibrosis, with unchanged myocardial size. Constitutive Akt hyperactivation did not generate any response on myocardial morphology and function, although it greatly suppressed or nullified thapsigargin-induced myocardial remodeling and dysfunction. Thapsigargin also triggered dephosphorylation of Akt and its downstream signal GSK3β, along with development of ferroptosis, all of which were nullified by Akt hyperactivation. <em>In vitro</em> studies further revealed that thapsigargin provoked cardiomyocyte mechanical anomalies and lipid peroxidation, similar to <em>in vivo</em> results. These effects were reverted by inhibitors of NADPH oxidase and ferroptosis (apocynin and LIP1). Collectively, our data denote an important protective role for Akt hyperactivation in thapsigargin-evoked myocardial anomalies, likely through NADPH oxidase-mediated regulation of ferroptosis.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111292"},"PeriodicalIF":4.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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