JOURNAL OF HAZARDOUS MATERIALS
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2021
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IF 10.588
Sinuo Tian,Sen Yan,Zhiyuan Meng,Shiran Huang,Wei Sun,Ming Jia,Miaomiao Teng,Zhiqiang Zhou,Wentao Zhu
Bisphenols (BPs), as widely used plastic additives, penetrate into our daily lives. BPs are considered endocrine disruptors and could potentially induce obesity. In this study, the effects of bisphenol A (BPA) and tetrabromobisphenol A (TBBPA) on food intake and lipid metabolism in zebrafish were determined. Moreover, the impact of BPA and TBBPA on the endocannabinoid system (ECS) of zebrafish was further explored by metabolomics, transcriptomics, and molecular docking analysis. Here we show that exposure to BPA and TBBPA at concentrations commonly found in the environment (20, 100, and 500 μg/L) led to hyperphagia and obesity in adult male zebrafish. Metabolomics and histopathological analysis revealed significant lipid accumulation in the liver of zebrafish exposed to BPA and TBBPA. The expression of ECS-related genes, in conjunction with RNA-Seq results, further indicated that BPA and TBBPA increased appetite and induced obesity by activating cannabinoid receptor type 1(CB1). Furthermore, molecular docking revealed that six representative BPs including BPA and TBBPA could bind to the CB1 receptor. Collectively, these findings indicate that CB1 may be a potential target for BPs to induce obesity.
研究领域:
环境科学
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毒理学
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分子生物学
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PubMed
高影响因子
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
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2017
·Vol. 42
·期 6
·2281-2294
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IF 5.104
He Xiaolie,Yang Li,Wang Mei,Zhuang Xizhen,Huang Ruiqi,Zhu Rongrong,Wang Shilong
Background/Aims: This study investigated the underlying mechanisms of the antidepressant effects of curcumin and dexanabinol-loaded solid lipid nanoparticles in corticosterone-induced cell and mice depression models. Methods: Curcumin and dexanabinol-loaded solid lipid nanoparticles (Cur/SLNs-HU-211) were synthesized via an emulsifcation and low-temperature solidification method. Antidepressant activities of nanoparticles in a corticosterone-induced major depression model were investigated by MTT assay, cellular uptake by flow cytometry, behaviour by Forced Swimming Test and rotarod test, neurotransmitters by High Performance Liquid Chromatography, Western blotting, qPCR and immunofluorescence. Results: Treatment with Cur/SLNs-HU-211 induced greater dopamine (DA)/5-hydroxytryptamine (5-HT) release with reduced corticosterone-induced apoptotic cell death in PC12 cells. Additionally, in vivo Cur/SLNs-HU-211 significantly induced recovery from depressive behaviour with increased DA/5-HT levels, CB1 mRNA levels and CB1, p-MEK1 and p-ERK1/2 protein expression levels in the hippocampus and striatum. Cur/SLNs-HU-211 improved CB1 expression and inspired the proliferation of astrocytes in the hippocampus and striatum, exerted neuroprotective effects by preventing corticosterone -induced BDNF/NeuN expression reduction. Conclusion: Our study implies that Cur/SLNs-HU-211 may be a useful approach for treatment of major depression
研究领域:
药理学
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神经科学
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分子生物学
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纳米技术
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高影响因子
CELL
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2026
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IF 45.1
Yu-Ying Liao,Jinxin Che,Yun-Tao Gao,Jianheng Xue,Linjie Li,Lin-Lin Wu,Jia-Xue Hu,Meng-Ting Hu,Linghua Xie,Huibing Zhang,Dan-Dan Shen,Yingjun Dong,Shaokun Zang,Na Zhang,Hao Wang,Yan Zhang,Xiaowu Dong,Xiao-Ming Li
The cannabinoid receptor 1 (CB1) has emerged as a promising candidate for next-generation non-opioid therapies. However, the development of therapeutics targeting CB1 has been consistently hindered by significant adverse effects. Here, through structure-activity relationship analyses focused on biased signaling, we rationally design two G i -biased CB1 agonists, LZD503 and LZD505. Our design strategy employed structural spatial tuning of the agonist scaffold to disrupt specific molecular interactions and minimize steric conflicts with critical tip residues within the ligand-binding pocket, thereby promoting preferential G i -pathway signaling. Cryo-electron microscopy structures of the CB1-G-protein complexes bound to these designed agonists confirmed that their anticipated conformational poses favored G i -biased signaling. Both designed compounds demonstrated promising results by alleviating pain and mitigating unwanted responses in mice. The elucidated CB1 complex structures and the resulting insights establish a comprehensive framework for the structure-guided development of innovative CB1-targeted analgesics with reduced adverse effect profiles.
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高影响因子
Frontiers in Nutrition
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2026
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IF 5.5
Qingjie Wu,Yuxin Shao,Lin Zhu,Xinzhe Guo,Shengquan Mi,Yanzhen Zhang,Ping Chang,Changying Xie,Junxia Guo
Introduction Obesity, driven by adipose tissue dysfunction, is a major global health challenge and a key contributor to metabolic disorders. Although taurine shows anti-obesity potential, its precise mechanisms for attenuating adipocyte lipid accumulation remain unclear. Methods In this study, high-fat diet (HFD)-induced obese mice were treated orally with taurine (700 mg/kg/day) for 14 weeks. Systemic obesity-related parameters were evaluated, with a focus on epididymal white adipose tissue (eWAT). UPLC-MS-based metabolomics combined with multivariate analysis was employed to characterize metabolic alterations in eWAT. Additionally, 3T3-L1 adipocyte spheroids were treated with taurine (0–0.5 mM), either alone or in combination with the cannabinoid receptor type 1 (CB1) agonist CP55940 or antagonist AM6545, to assess its effects on lipid accumulation and underlying mechanisms. Results Focusing on adipose tissue, taurine treatment effectively countered HFD-induced metabolic disturbances, particularly by suppressing epididymal fat mass accumulation and ameliorating adipocyte hypertrophy. Metabolomic profiling of eWAT revealed that taurine treatment reversed 15 out of 35 metabolic alterations, including the reduction of three anandamide (AEA) precursors, implying that taurine may alter endocannabinoid (eCB) biosynthesis by limiting precursor availability. Moreover, taurine suppressed lipid accumulation by inhibiting CB1 signaling, a mechanism supported by downregulation of lipogenic genes (including Srebf1 , Acaca , Cd36 , and Pparg ) and upregulation of lipolytic genes (including Pnpla2 , Lipe , and Ppargc1a ). Conclusion Collectively, our findings demonstrate that taurine exerts its anti-obesity effects partially via modulation of eCB-CB1 signaling, coordinately inhibiting lipogenesis and promoting lipolysis, thereby highlighting its therapeutic potential for obesity management.
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International Journal of Nanomedicine
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2023
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IF 8
Xiaolie He,Yanjing Zhu,Mei Wang,Guoxin Jing,Rongrong Zhu,Shilong Wang
Major depression is a complex neuropsychiatric disorder with few treatment approaches. The use of nontargeted antidepressants induced many side effects with their low efficacy. A more precise targeting strategy is to develop nanotechnology-based drug delivery systems; hence, we employed solid lipid nanoparticles (SLNs) to encapsulate HU-211 and curcumin (Cur). The antidepressant effects of the dual-drug nanoparticles (Cur/SLNs-HU-211) for major depression treatment were investigated in corticosterone-induced cellular and animal models of major depression. Cur/SLNs-HU-211 can effectively protect PC12 cells from corticosterone-induced apoptosis and can release more dopamine, which may be associated with the higher uptake of Cur/SLNs-HU-211 shown by cellular uptake behavior analysis. Additionally, Cur/SLNs-HU-211 significantly reduced the immobility time in forced swim test, enhanced fall latency in rotarod test, and improved the level of dopamine in mice blood. Cur/SLNs-HU-211 can deliver more Cur to the brain and thus produce a significant increase in neurotransmitters level in brain tissue, especially in the hippocampus and striatum. The results of Western blot and immunofluorescence revealed that Cur/SLNs-HU-211 can significantly enhance the expression of CB1, p-MEK1, and p-ERK1/2. Our study suggests that Cur/SLNs-HU-211 may have great potential for major depression treatment.
研究领域:
药理学
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纳米技术
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神经科学
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精神病学
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高影响因子
International Journal of Nanomedicine
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2023
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IF 8
Xinyu Fan,Jiachen Shi,Ye Liu,Mengqiu Zhang,Min Lu,Ding Qu
Background Berberine (BR) shows promise as a candidate for treating irritable bowel syndrome with diarrhea (IBS-D). However, the undesired physicochemical properties and poor oral absorption limit its clinical translation. A ketogenic diet (KD) can induce intestinal overexpression of cannabidiol (CB) receptors, which may offer a potential target for IBS-D-specific delivery of BR.Methods The microemulsions loaded with BR and decorated with cannabidiol (CBD/BR-MEs) were developed through a one-step emulsion method. The pharmaceutical behaviors of the CBD/BR-MEs were measured using dynamic light scattering and high-performance liquid chromatography. The efficacy of the anti-IBS-D therapy was evaluated by assessing fecal water content, Bristol score, and AWR score. The intestinal permeability were assessed through immunofluorescent staining of CB1 and ZO-1, respectively. The signaling of CREB/BDNF/c-Fos was also studied along with immunofluorescent and immunohistochemical examination of brain sections.Results The CBD/BR-MEs, which had a particle size of approximately 30 nm and a surface density of 2% (wt%) CBD, achieved greater than 80% (wt%) encapsulation efficiency of BR. The pharmacokinetics performance of CBD/BR-MEs was significantly improved in the KD-fed IBS-D rats than the standard diet-fed ones, which is highly related to intestinal expression of CB1 receptors. The treatment with CBD/BR-MEs and KD exhibited evident comprehensive advantages over the other groups in terms of anti-IBS-D efficacy. CBD/BR-MEs and KD synergistically decreased intestinal permeability. Moreover, the treatment with CBD/BR-MEs and KD not only blocked the CREB/BDNF/c-Fos signaling in the brain but also decreased the levels of neurotrophic factors, neurotransmitters, and inflammatory cytokines in the serum of IBS-D model rats.Conclusion Such a design represents the first attempt at IBS-D-targeted drug delivery for improved oral absorption and efficacy through KD-induced target exposure, which holds promising potential for the treatment of IBS-D.
研究领域:
药学
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胃肠病学
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营养科学
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分子生物学
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高影响因子
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