CHEMOSPHERE
·
2023
·
IF 8.8
Mingzhao Li,Ren Wang,Pan Wang
Endocrine disruptors are environmental chemicals that can interfere with the endocrine system. However, research on endocrine disruptors that interfere with androgen's actions is still limited. The purpose of this study is to use in silico computation, i.e. , molecular docking to facilitate the identification of environmental androgens. Computational docking was used to study the binding interactions of environmental/industrial compounds with the three dimensional structure of human androgen receptor (AR). Then reporter assay and cell proliferation assay using AR-expressing LNCaP prostate cancer cells were used to determine their in vitro androgenic activity. Animal studies using immature male rats were also carried out to test their in vivo androgenic activity. Two novel environmental androgens were identified. As a photoinitiator, 2-benzyl-2-(dimethylamino)-4′-morpholinobutyrophenone (Irgacure 369, abbreviated as IC-369) is widely used in the packaging and electronics industries. Galaxolide (HHCB) is widely used in the production of perfume, fabric softeners and detergents. We found that both IC-369 and HHCB could activate AR transcriptional activity and promote cell proliferation in AR-sensitive LNCaP cells. Furthermore, IC-369 and HHCB could induce cell proliferation and histological changes of seminal vesicles in immature rats. RNA sequencing and qPCR analysis showed that androgen-related genes in seminal vesicle tissue were up-regulated by IC-369 and HHCB. In conclusion, IC-369 and HHCB are new environmental androgens that bind AR and induce AR transcriptional activity, thereby exerting toxicological effects on the development of male reproductive organs.
研究领域:
环境科学
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毒理学
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分子生物学
·
内分泌学
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DOI
PubMed
高影响因子
Scientific Reports
·
2026
·
IF 4.9
Zhang Panpan,Zhang Xun,Ma Siyu,Jiang Mengqiang,Zhao Wenhong
Astaxanthin (ATX), a natural antioxidant whose benefits in age-related liver and kidney damage remain unclear. We established a D-galactose-induced ageing model in rats and observed the daily behaviour of the rats. Using staining methods to detect ROS, apoptosis and histopathological changes in liver and brain tissue. Determination of antioxidant levels of IL-2, IL-6 and AGES in rats. Assessment of cognitive function using the Morris water maze and ChAT. The mRNA and protein expression levels of Nrf2, Bach1, SOD1, SOD2, HO-1 were determined by real-time PCR and Western blotting. To investigate the role of the Nrf2/Bach1-ARE pathway, we used ML385, a specific inhibitor of the Nrf2 pathway, to treat rats in the inhibitor group. Aging rats showed impaired learning and memory, along with decreased levels of neurotransmitters and antioxidant enzymes. ATX and vitamin E (VE) interventions significantly alleviated these symptoms and activated the Nrf2/Bach1-ARE pathway in liver and brain tissues of aged SD rats. Furthermore, the protective effects of ATX were attenuated by the addition of the Nrf2 inhibitor ML385. ATX reduces oxidative stress and ameliorates liver and brain damage in aged rats via activation of the Nrf2/Bach1-ARE pathway.
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DOI
PubMed
高影响因子
Pharmacognosy Magazine
·
2024
·
IF 0.6
Zhao Chenghe,Wang Yao,Jing Shu,Lin Huijiao,Li He,Chen Jianguang,Xia Wei
Background: Drug-induced liver injury (DILI) is extremely common in clinical practice and needs to be focused. Anwulignan is a unique lignan monomer of Schisandrae Sphenantherae Fructus and is used as the main active ingredient of Wuzhi tablet, which is used for liver protection in clinical practice. In this study, an acute liver injury mouse model induced by acetaminophen and paracetamol (APAP) was used to observe its effects.Materials and Methods: An acute liver injury mouse model was established by intraperitoneally injecting APAP. Mice were divided into blank control (CON) group, APAP model (MOD) group, Anwulignan CON group, and Anwulignan MOD group. Anwulignan (6 mg/kg) or sodium carboxymethylcellulose (10 mL/kg) was intragastrically given to mice once a day, successively for 14 days. On day 14, 250 mg/kg APAP solution (10 mL/kg) or saline was injected intraperitoneally, and 12 h later, the mice were killed. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the serum of mice were tested. The liver index of mice was calculated, and the pathology of liver injury was evaluated by HE staining in mice. The activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) as well as the content of malondialdehyde (MDA) in the liver tissue were tested. The levels of kelch-like ECH-associated protein 1 (Keap-1), nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), BCL2 associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), caspase-3 and tumor suppressor protein (P53) mRNAs in the liver tissues of mice were detected by reverse transcription-PCR (RT-PCR), and the expression levels of Keap-1, Nrf2, HO-1, Bax, Bcl-2, caspase-3 and P53 proteins in the liver tissue of mice were detected by Western blot.Results: Anwulignan can alleviate the acute liver injury of mice. The down-regulation of the cyclophosphamide (CYP2E1) expression in the liver tissue of mice to reduce the hepatotoxicity of APAP, and the regulation of Nrf2-ARE signaling pathway-related gene expressions to play an antioxidant role and apoptosis-related gene expressions to inhibit the liver cell apoptosis may be involved in the mechanism through which Anwulignan can exert its effect.Conclusion: Anwulignan can alleviate the liver injury induced by APAP in mice, and this study may provide evidence for researching and developing some drugs and nutraceuticals used for preventing and treating liver injury.
研究领域:
药理学
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肝脏病学
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分子生物学
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DOI
高影响因子
TOXICOLOGY LETTERS
·
2016
·
IF 3.522
Linling Que,Liu He,Chenshu Yu,Wencheng Yin,Liwen Ma,Baoshan Cao,Siwang Yu
Myelosuppression is the most common dose-limiting adverse effect of chemotherapies. In the present study, we investigated the involvement of nuclear erythroid 2-related factor 2 (Nrf2) in cyclophosphamide-induced myelosuppression in mice, and evaluated the potential of activating Nrf2 signaling as a preventive strategy. The whole blood from Nrf2 −/− mice exhibited decreased antioxidant capacities, while the bone marrow cells, peripheral blood mononuclear cells and granulocytes from Nrf2 −/− mice were more susceptible to acrolein-induced cytotoxicity than those from wild type mice. Single dosage of cyclophosphamide induced significantly severer acute myelosuppression in Nrf2 −/− mice than in wild type mice. Furthermore, Nrf2 −/− mice exhibited greater loss of peripheral blood nucleated cells and recovered slower from myelosuppression nadir upon multiple consecutive dosages of cyclophosphamide than wild type mice did. This was accompanied with decreased antioxidant and detoxifying gene expressions and impaired colony formation ability of Nrf2 −/− bone marrow cells. More importantly, activation of Nrf2 signaling by CDDO-Me significantly alleviated cyclophosphamide-induced myelosuppression, while this alleviation was diminished in Nrf2 −/− mice. In conclusion, the present study shows that Nrf2 plays a protective role in cyclophosphamide-induced myelosuppression and activation of Nrf2 is a promising strategy to prevent or treat chemotherapy-induced myelosuppression.
研究领域:
药理学
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肿瘤学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Reproductive and Developmental Medicine
·
2024
·Vol. 9
·期 1
·22
·
IF 0.7
Chen Xi,Zuo Wei-Wen,Zhang Guo-Dong,Xu Cong-Jian
Objective: Immune dysfunction plays an important role in the pathogenesis of endometriosis. C5a, a by-product of complement activation, binds to its receptor (C5a receptor 1, C5aR1) in various cells, including macrophages. The combination of C5a and C5aR1 in macrophages induces M2 polarization. There is no consistent conclusion regarding macrophage polarization status and its participation in the pathogenesis of endometriosis. Methods: We analyzed the expression of C5aR1 and the immunophenotype of macrophages in samples from patients with endometriosis using immunohistochemistry and flow cytometry. We tested the equivalent item in a mouse model and the THP-1 cell line in vivo and in vitro . Single-cell RNA sequencing (scRNA-seq) from the Gene Expression Omnibus (GEO, GSE213216) was used to investigate the phenotype and function of C5aR1 + macrophages. Results: The infiltration of C5aR1 + macrophages was associated with the severity of endometriosis. C5aR1 + macrophages polarized more toward the M2 phenotype and transformed into an immunosuppressive state. Inhibiting C5aR1 using PMX-53 decreased the expression of C5aR1 + macrophages and reduced their polarization to the M2 phenotype, consequently shrinking lesion size in a mouse model. Conclusion: Our study emphasizes the importance of C5aR1 and the macrophage phenotype in the pathogenesis of endometriosis. We propose PMX-53 as a potential therapeutic agent for endometriosis.
研究领域:
免疫学
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生殖医学
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分子生物学
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DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2018
·
IF 3.412
Shan Liang,Yu Huang,Youn Young Shim,Xiang Ma,Martin J. T. Reaney,Yong Wang
Nanocomposites, based on iron salts and soluble flaxseed gum (FG), were prepared as potential treatments of iron deficiency anemia (IDA). FG was extracted, characterized, and formulated into iron-loading nanocomposites via ion-exchange against FeCl3, Fe2(SO4)3, FeCl2, and FeSO4·7H2O. FG-iron nanocomposites preparation condition was optimized, and physicochemical properties of the nanocomposites were investigated. In vitro release kinetics of iron in simulated gastric fluid (SGF) was also evaluated. FG heteropolysaccharide, consisting of rhamnose (33.73%), arabinose (24.35%), xylose (14.23%), glucose (4.54%), and galactose (23.15%) monosaccharides, linked together via varieties of glycosidic bonds, was a good recipient for both ferric and ferrous irons under screened conditions (i.e., 80 °C, 2 h, I/G = 1:2). Iron loaded contents in the nanocomposites prepared from FG-FeCl3, FG-Fe2(SO4)3, FG-FeCl2, and FG-FeSO4·7H2O were 25.51%, 10.36%, 5.83%, and 22.83%, respectively. Iron in these nanocomposites was mostly in a bound state, especially in FG-FeCl3, due to chelation forming bonds between iron and polysaccharide hydroxyl or carboxyl groups and formed stable polysaccharide-iron crystal network structures. Free iron ions were effectively removed by ethanol treatments. Because of chelation, the nanocomposites delayed iron release in SGF and the release kinetics were consistent with Korsmeyer-Peppas model. This indicates that such complexes might reduce side effects of free iron in human stomach. Altogether, this study indicates that these synthetic FG-iron nanocomposites might be developed as novel iron supplements for iron deficiency, in which FG-FeCl3 is considered as the best option.
研究领域:
食品科学
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医学
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材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
XENOBIOTICA
·
2022
·
IF 1.997
Siyu Ding,Siyu Liu,Yaxuan Chen,Ying Peng,Jiang Zheng
Anastrozole (ANA), is an inhibitor of non-steroidal aromatase, widely employed for the treatment of breast cancer. However, ANA-associated liver injury cases have been documented in the application of the drug.The major purposes of the present study were to identify the structure of reactive metabolites derived from ANA and to study related metabolic pathways of ANA.We found ANA itself is an electrophilic species reactive to GSH. ANA can be metabolised to ANA-N+-glucuronide (1) catalysed by UGT1A4. An ANA GSH conjugate (2) was detected in bile and livers of rats treated with ANA. UGT1A4 participated in the phase II metabolic pathway.This work allowed us to better understand the mechanisms of the hepatotoxicity of ANA and provided new avenue to define the possible role of metabolic activation in hepatotoxicity.
研究领域:
药理学
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毒理学
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药物化学
·
癌症研究
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DOI
PubMed
高影响因子
Cell Reports
·
2020
·
IF 8.109
Yan Li,Yi Han,Runping Su,Yiqiong Liu,Gaowei Chong,Dailin Xu,Ruiqing He,Ying Liu,Haiqing Dong,Donglu Shi,Yongyong Li
Summary By incorporating an artificial reactive oxygen species (ROS) generation mechanism, a biotic/abiotic integration is designed to improve the anti-tumor effect of neutrophils by artificially potentiating their ROS effector mechanism in a remotely controlled route. Specifically, the photosensitizer Ce6 is nano-packaged by the albumin BSA to achieve biocompatible and efficient integration with neutrophils (NEs). Reinfusion of the engineered NEs into 4T1 tumor-bearing mice led to more Ce6 accumulation in tumors relative to Ce6 nanoformulation. At the peak of accumulation, tumor illumination activates the embedded Ce6 for ROS generation and NETosis formation. Because of the ROS-intensified cytolytic effect, the growth of 4T1 tumors is inhibited significantly. The photo-controlled process largely avoids the off-target effects observed frequently in current cell therapies. The strategy directly generates ROS effector molecules with spatiotemporal precision. This engineering approach is able to potentiate the native capacity of immune cells independent of the tumor microenvironment.
研究领域:
生物医学工程
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免疫学
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2021
·Vol. 178
·期 24
·4808-4825
·
IF 8.74
Yan-Fei Yang,Hui Dong,Yan Shen,Lei Li,Michael Lazarus,Wei-Min Qu,Zhi-Li Huang
Background and Purpose Modafinil is a potent eugeroic (wakefulness-promoting) drug that is prescribed to treat narcolepsy and has a low incidence of abuse. Although previous studies have shown that modafinil-induced arousal depends on the dopamine receptors and transporters, the specific part/s of the dopamine transmitter system underlying this mechanism remained unclear. Here, we investigated the role of mesencephalic dopamine neurons in modafinil-evoked arousal. Experimental Approach A dopamine indicator (dLight1.1) was employed to detect dopamine changes in the nucleus accumbens (NAc) and dorsal striatum. We specifically lesioned mesencephalic dopamine neurons via diphtheria toxin (DTA) in the dopamine transporter (DAT)-Cre mice. Then, the sleep–wake states were recorded to evaluate the effect of modafinil on arousal. Finally, the extent of DTA-induced lesions was determined by immunohistochemistry. Key Results Modafinil promptly increased dopamine levels in the NAc and dorsal striatum in a dose-dependent manner. Lesioning of dopamine neurons in the substantia nigra pars compacta (SNc) or ventral tegmental area (VTA) had no significant effects on physiological sleep–wake cycles. Modafinil at 90 mg·kg −1 increased continuous wakefulness for 355 min in control mice. However, these effects were slightly decreased by 6.7% in the SNc-lesioned mice and were prominently diminished by 32.8% in VTA-lesioned mice. Furthermore, the modafinil-induced arousal was completely blocked in the SNc-VTA-lesioned mice, whereas lesions of the dorsal raphé nucleus had no effect. Conclusion and Implications Taken together, our findings indicate that mesencephalic dopamine neurons are essential for modafinil-induced arousal. Graphical
研究领域:
神经科学
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药理学
·
睡眠医学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Inflammation Research
·
2021
·
IF 6.922
Yongqing Cai,Bin Li,Dan Peng,Xianfeng Wang,Pan Li,Mingchun Huang,Haiyan Xing,Jianhong Chen
Background Nrf2-Bach1 antioxidant signaling pathway is considered as one of the most important mechanisms of cellular resistance to oxidative injury. The effect of hyperoside (Hyp) on the expression and distribution of Bach1, the relationship of Hyp’s antioxidative effect and the influence of Bach1 remains unclear. Purpose The aim of this study was to investigate the role and mechanisms of Bach1 in the protective effect of Hyp on oxidative liver injury. Methods The protective effect of Hyp on oxidative stress injury was observed in vivo and in vitro. Next, the influence of Hyp on Bach1 expression and distribution, and competitive combination of Nrf2-Bach1 with ARE in H 2 O 2 -induced L02 cell was studied by Western blot, RT-PCR, immunofluorescence and CHIP assay. Finally, the expressions of Crm1, ERK and p38 and their roles on Hyp mediated nuclear export of Bach1 were investigated by Western blot. Results Hyp ameliorated the pathological damage, reduced the liver index, AST, ALT and MDA activities, and increased SOD and GSH levels in the CCl 4 -induced acute liver injury mouse model. Hyp attenuated H 2 O 2 -induced oxidative stress injury in L02 cells. Hyp promoted the early rapid redistribution of Bach1 from nucleus to cytoplasm. CHIP analyses demonstrated that Hyp enhanced the levels of Nrf2-ARE complex, and weakened the levels of Bach1-ARE complex within three hours. In addition, Hyp enhanced transport protein Crm1 expression and ERK1/2 activity. And LMB, a Crm1 inhibitor, attenuated the effect of Hyp on Bach1 nuclear export and anti-oxidation. U0126, an ERK1/2 inhibitor, reduced the effect of Hyp on Crm1 expression and the Bach1 redistribution. Conclusion The hepatoprotective mechanism of Hyp was related to improve Bach1 nuclear export depending on ERK1/2-Crm1 to upregulate the level of Nrf2 binding to ARE.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
·
2016
·Vol. 60
·期 10
·
IF 4.415
Xi Yang,Zhiyuan Ma,Sisi Zhou,Yayun Weng,Hongmei Lei,Su Zeng,Liping Li,Huidi Jiang
Entecavir (ETV) is a first-line antiviral agent for the treatment of chronic hepatitis B virus infection. Renal excretion is the major elimination path of ETV, in which tubular secretion plays the key role. However, the secretion mechanism has not been clarified. We speculated that renal transporters mediated the secretion of ETV. Therefore, the aim of our study was to elucidate which transporters contribute to the renal disposition of ETV. Our results revealed that ETV (50 μM) remarkably reduced the accumulation of probe substrates in MDCK cells stably expressing human multidrug and toxin efflux extrusion proteins (hMATE1/2-K), organic cation transporter 2 (hOCT2), and carnitine/organic cation transporters (hOCTNs) and increased the substrate accumulation in cells transfected with multidrug resistance-associated protein 2 (hMRP2) or multidrug resistance protein 1 (hMDR1). Moreover, ETV was proved to be a substrate of the above-described transporters. In transwell studies, the transport of ETV in MDCK-hOCT2-hMATE1 showed a distinct directionality from BL (hOCT2) to AP (hMATE1), and the cellular accumulation of ETV in cells expressing hMATE1 was dramatically lower than that of the mock-treated cells. The accumulation of ETV in mouse primary renal tubular cells was obviously affected by inhibitors of organic anion transporter 1/3 (Oat1/3), Oct2, Octn1/2, and Mrp2. Therefore, the renal uptake of ETV is likely mediated by OAT1/3 and OCT2 while the efflux is mediated by MATEs, MDR1, and MRP2, and OCTN1/2 may participate in both renal secretion and reabsorption.
研究领域:
药理学
·
肾脏生理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ANIMAL ECOLOGY
·
2024
·Vol. 94
·期 1
·112-124
·
IF 3.5
Gaoying Gu,Ziqi Wang,Tao Lin,Sainan Wang,Jianjun Li,Shihao Dong,James C. Nieh,Ken Tan
en This link goes to a English section zh This link goes to a Chinese section Predatory threats, even when they do not involve direct consumption (non-consumptive effects, NCEs), can profoundly influence the physiology and behaviour of prey. For example, honeybees that encounter hornet predators show responses similar to fear. However, the physiological mechanisms that are connected with this fear-like response and their effects on bee cognition and olfaction remain largely unknown. We show that bees decreased time spent near the hornet, demonstrated fearful behaviour and moved with greater velocity to escape. After a prolonged 24-h exposure, bees adopted defensive clustering, displayed greater predator avoidance, and experienced a decline in brain dopamine levels. Prolonged predator exposure also diminished bee olfactory sensitivity to odours and their mechanical sensitivity to air currents, contributing to impaired olfactory learning. However, boosting brain dopamine reversed one fear-like behaviour (average bee velocity in the presence of a hornet) and rescued olfactory sensitivity and learning. We therefore provide evidence linking dopamine to sensory and cognitive declines associated with fear in an insect. 摘要 en This link goes to a English section zh This link goes to a Chinese section 即便对猎物不构成直接捕杀(非消耗性捕食效应)，捕食者也可以对猎物的生理和行为造成严重的影响。例如，遭遇胡蜂捕食者时，蜜蜂会产生类似恐惧的反应。 然而，该类似恐惧反应相关的生理机制还没有详细研究，该类似恐惧反应对蜜蜂的认知嗅觉的影响也没有报道。 我们的实验结果表明，蜜蜂在遭遇胡蜂时表现出惧怕行为，表现为减少了在胡蜂附近的停留时间，并以更快的速度逃离。但在24小时的胡蜂胁迫后，蜜蜂表现出防御性集群行为，大脑多巴胺水平下降。长时间的捕食者暴露还降低了蜜蜂对气味的嗅觉敏感度以及气流的机械敏感性，导致嗅觉联想学习能力受损。 然而，人为提高蜜蜂大脑多巴胺水平缓解了它们对胡蜂的恐惧，并在一定程度上恢复了蜜蜂的嗅觉敏感度和学习能力。 因此，我们的研究表明多巴胺参与昆虫恐惧行为的调控，与嗅觉和认知下降密切相关。
研究领域:
昆虫学
·
神经生物学
·
行为生态学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）