SCIENCE OF THE TOTAL ENVIRONMENT
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2023
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IF 9.8
Xiaoxun Lu,Jiabin Hong,Jing Zhang,Qian Liu,Ganzhong Liao,Yanwei Shi,Huanwen Tang,Xiaoshan Liu
Triphenyl phosphate (TPhP) is an organophosphate flame retardant widely distributed in the environment. The neurodevelopmental toxicity of TPhP has been observed in animals and humans. Previously, we found that prenatal TPhP exposure disturbed placental tryptophan metabolism, impaired neurodevelopment in male offspring, and induced abnormal neurobehavior; however, the underlying mechanisms are unknown. In this study, using the trophoblast cell line JEG-3, we found that TPhP altered gene and protein expression in the tryptophan metabolism pathway, inhibited the tryptophan-serotonin pathway, and activated the tryptophan-kynurenine pathway. Meanwhile, TPhP induced oxidative stress by activating monoamine oxidase A (MAOA), promoting inflammatory factors including nuclear factor kappa-B (NFκB), interleukin-6, and tumor necrosis factor α. The NFκB inhibitor sulfasalazine could alleviate the effects of TPhP on tryptophan metabolism disturbance. The MAOA inhibitor clorgyline or the antioxidant N -acetylcysteine can mitigate oxidative stress and eliminate TPhP-induced inflammatory factors and tryptophan metabolism disturbances. The data above suggest that TPhP disturbed tryptophan metabolism by activating NFκB through MAOA-mediated oxidative stress. Finally, using the mouse intrauterine exposure model, the results confirmed that TPhP induced oxidative stress, activated inflammatory factors, disturbed tryptophan metabolism, and increased the levels of the tryptophan metabolites serotonin, kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid in the placenta during the second trimester of pregnancy. Overall, TPhP can disturb placental tryptophan metabolism by activating the inflammatory factor NFkB, which was induced by MAOA-induced oxidative stress. The results of this study confirm that indirect exposure to xenobiotic compounds at an early life stage can impair offspring development and provide a novel perspective on the neurodevelopmental toxicity of TPhP.
研究领域:
毒理学
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生殖生物学
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神经科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Kexin Shi,Bentian Jing,Yifan Feng,Yong Yu
Ethnopharmacological relevance Within Anemarrhena asphodeloides Bunge (AAB), the pivotal bioactive constituents are identified as Anemarrhena asphodeloides Bunge total saponins (ABS). In traditional pharmacology, ABS has exhibited notable anti-inflammatory, hypoglycemic, and cardioprotective properties. Despite these observed effects, the specific protective mechanisms of ABS against metabolic diseases and improving the endocrine system remain largely uncharted. Aim to study This work intends to shed light on the effects and intrinsic mechanisms of ABS on metabolic diseases. Materials and methods The characterization of ABS components was achieved through High-Performance Liquid Chromatography/Mass Spectrometry (HPLC/MS). To evaluate ABS's anti-inflammatory efficacy, mouse macrophages underwent analysis using the Griess method. Induced differentiation of mouse fibroblasts was assessed through Oil Red O staining. In an obesity model with C57BL/6 N mice, ABS administration prompted measurements of glucose and insulin tolerance. Western blot analysis quantified lipolysis and anti-inflammatory protein expression. Nile red staining gauged body fat content in C. elegans post-ABS treatment. The mechanism of ABS action was elucidated through mRNA sequencing, further validated using RNA interference technology, and nematode mutants. Results ABS showcased the ability to diminish Nitric Oxide (NO) production in inflammatory macrophages and shrink adipocyte lipid droplets. In mice experiments, ABS was effective in alleviating fat accumulation and affecting serum lipid metabolism in diabetic mice. It enhanced oral glucose tolerance and insulin tolerance while increasing lipolysis-associated protein expression. ABS notably reduced fat content in C. elegans . Mechanistically, ABS downregulated NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and monoamine oxidase A (MAOA) expression while enhancing UGT, ilys-2 , and ilys-3 . Lipolysis emerged as a pivotal pathway for ABS in the therapeutic intervention of metabolic diseases. Conclusions Our investigation has revealed that ABS exert a role in combating metabolic diseases by enhancing the body's defense mechanisms. ABS activate the NLRP3-neurotransmitter-visceral adipose pathway in mice, thereby bolstering resistance and diminishing fat accumulation. In C. elegans , ABS downregulated the expression of MAOA, bolstered resistance, and augmented glucuronidase activity, consequently leading to a reduction in fat content.
研究领域:
药理学
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代谢学
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分子生物学
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生物化学
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民族药理学
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DOI
PubMed
高影响因子
TOXICOLOGY
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2024
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IF 4.8
Linjing Xu,Huan Liu,Yifeng Rang,Lizi Zhou,Xukai wang,Yinhuan Li,Chunhong Liu
Nonylphenol (NP) and octylphenol (OP) are environmental contaminants with potential endocrine disrupting effects. However, there is limited research on the mechanisms and intervention of combined NP and OP exposure-induced neurotoxicity. This study aims to explore the cytotoxicity of combined NP and OP exposure and evaluate the potential of Lycium barbarum polysaccharides (LBP) in mitigating the aforementioned toxicity. In present study, LBP (62.5, 125 and 250 µg/mL) were applied to intervene rat adrenal pheochromocytoma (PC-12) cells treated with combined NP and OP (NP: OP = 4:1, w/w; 1, 2, 4 and 8 µg/mL). The results showed that NP and OP induced oxidative stress, disrupted the 5-hydroxytryptamine (5-HT) and cholinergic systems in PC-12 cells. Additionally, they activated the p38 protein kinase (p38) and suppressed the expression of silent information regulation type 1 (SIRT1), monoamine oxidase A (MAOA), phosphorylated cyclic-AMP response binding protein (p-CREB), brain-derived neurotrophic factor (BDNF) and phosphorylated tropomyosin-related kinase receptor type B (p-TrkB). However, N-acetyl-L-cysteine (NAC) treatment counteracted the changes of signalling molecule p38, SIRT1/MAOA and CREB/BDNF/TrkB pathways-related proteins induced by NP and OP. LBP pretreatment ameliorated combined NP and OP exposure-induced oxidative stress and neurotransmitter imbalances. Furthermore, the application of LBP and administration of a p38 inhibitor both reversed the alterations in the signaling molecule p38, as well as the proteins associated to the SIRT1/MAOA and CREB/BDNF/TrkB pathways. These results implied that LBP may have neuroprotective effects via p38-mediated SIRT1/MAOA and CREB/BDNF/TrkB pathways.
研究领域:
毒理学
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神经科学
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药理学
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环境科学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2022
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IF 6.51
Chan Jin,Jinbo Li,Xiaoguang Yang,Shuang Zhou,Chang Li,Jiang Yu,Zhaomeng Wang,Dun Wang,Zhonggui He,Yiguo Jiang,Yongjun Wang
Immune checkpoint inhibitors (ICIs) represent a new class of immunotherapy drugs, and are used to relieve immune suppression or enhance the immune response through the blockade of checkpoint ligands or receptors. ICIs have achieved great success in clinical cancer treatment. Monoamine oxidase A (MAOA) is a potent immune checkpoint of immunotherapy. Recently, it has been reported that MAOA inhibitors could enhance CD8 + T cell activity by upregulating 5-HT autocrine pathway in T cells. In this study, we synthesized doxorubicin (DOX) and isoniazid (INH, a MAOA inhibitor) conjugates through a pH sensitive hydrazone bond. Results of the in vivo studies showed that DOX-INH could effectively enhance the activity of CD8 + T cells and perform a synergistic anti-tumor effect with PD-L1 small molecular inhibitor (BMS202). In addition, in an orthotopic 4T1 breast cancer model, it was demonstrated that DOX-INH could inhibit the epithelial-mesenchymal transition process by blocking Shh, IL-6, and TGF-β signaling pathways, thereby inhibiting the growth and metastasis of breast cancer. Thus, a simple and effective small molecule conjugate produced by the combination of a chemotherapy drug and a MAOA inhibitor shows broad prospect in cancer therapy.
研究领域:
癌症免疫治疗
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肿瘤学
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药理学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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