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JOURNAL OF ETHNOPHARMACOLOGY · 2021 · IF 4.36

Luteolin and apigenin derived glycosides from Alphonsea elliptica abrogate LPS-induced inflammatory responses in human plasma

Ali Attiq,Juriyati Jalil,Khairana Husain,Hazni Falina Mohamad,Abrar Ahmad

Ethnopharmacological relevance Numerous Alphonsea species including Alphonsea elliptica (mempisang) leaves and fruits are indigenously used in inflammatory conditions such as postpartum swelling and rheumatism in southeast Asian countries. In our previous in-vitro findings, A. elliptica methanol extract exhibited platelet-activating factor inhibition, suggesting the presence of phyto-constituents with anti-inflammatory potential. Aim of the study However, so far there is no literature available on the anti-inflammatory activity of this species. Henceforth, based on the above background and our previous laboratory findings, we hypothesize that phytoconstituents of A. elliptica could possess anti-inflammatory potential against inflammatory mediators including prostaglandin-E 2 (PGE 2 ), cyclooxegenase-2 (COX-2) and cytokines (IL-1β and IL-6). Materials and methods Vacuum and column chromatography techniques were employed for the isolation of phytoconstituents. The structure elucidation was carried out using HRESI-MS, 1 H and 13 C-NMR analysis and compared with the published literature. For cytotoxicity analysis, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed on peripheral blood mononuclear cells. In-vitro anti-inflammatory activities were evaluated against the levels of PGE 2 , COX-2, IL-1β and IL-6 in lipopolysaccharide (LPS)-induced human plasma using enzyme-linked immunosorbent assay and radioimmunoassay . Results Unprecedentedly, chromatographic purification of methanolic leaves extract afforded five flavones namely vitexin , isovitexin , orientin, isoorientin , schaftoside with three flavanols ; kaempferol , myricetin and rutin from A elliptica . In cell viability analysis, isolates did not present cytotoxicity up to 50 μM. In anti-inflammatory evaluation, orientin and isoorientin exhibited strong (≥70%), while isovitexin and vitexin produced strong to moderate (50–69%) PGE 2 , COX-2, IL-1β and IL-6 inhibition at 25 and 50 μM. Isoorientin, orientin, isovitexin, and vitexin showed significant (p < 0.05) and concentration-dependent PGE 2 inhibition with IC 50 values (μM) of 11.40, 14.71, 17.70 and 20.58 against indomethacin (8.80). Furthermore, isoorientin, orientin, isovitexin, and vitexin produced significant concentration-dependent inhibition with IC 50 values (μM) of COX-2: 7.13, 9.51, 12.81, 16.61; IL-1β 4.80, 6.20, 10.85, 14.51; IL-6: 4.01, 5.90, 11.51 and 14.88 as compared to dexamethasone : 5.29, 2.93, 3.72, respectively (p < 0.05). Conclusion Conclusively, isolated phytoconstituents are reported for the first time from the A. elliptica. Moreover, isovitexin, vitexin orientin and isoorientin abrogated LPS-induced inflammatory responses in human plasma at non-cytotoxic concentrations.

研究领域: 药理学 · 民族药理学 · 生物化学 · 免疫学 · 植物化学
✓ 已验证 DOI PubMed 高影响因子
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TOXICOLOGY · 2020 · IF 4.099

Inhibition of ferroptosis attenuates busulfan-induced oligospermia in mice

Xi Zhao,Zhenhua Liu,Jie Gao,Hu Li,Xiaorong Wang,Yinchuan Li,Fei Sun

Busulfan is commonly used for cancer chemotherapy, nevertheless it cause male infertility via damaging the germ cells. Therefore, the underlying mechanism should be explored. In the present study, we demonstrated for the first time that ferroptosis was involved in busulfan-induced oligospermia in mice. Mice were given testicular injection of busulfan on both sides at the dose of 4 mg/kg body weight to establish the model of oligospermia. Four weeks later, the results showed that busulfan-treated mice exhibited decreased sperm concentration and motility, along with features of typical ferroptosis in testis, such as increased malondialdehyde (MDA) content and prostaglandin-endoperoxide synthase (PTGS2) mRNA expression, and decreased NADPH content. Inhibition of ferroptosis by ferrostatin-1 (Fer-1) or deferoxamine (DFO) partially alleviated busulfan-induced oligospermia in mice. Additionally, we also revealed that busulfan treatment induced spermatogenic cells ferroptosis by down-regulating nuclear factor-E2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4) expressions, and decreasing iron efflux through reduction of ferroportin 1 (FPN1) expression. Fer-1 or DFO obviously reversed busulfan-induced ferroptosis by increasing Nrf2, GPX4 and FPN1 expressions. Furthermore, after activation of Nrf2 by sulforaphane, sperm concentration and motility in busulfan-treated mice increased, accompanied by enhanced expressions of GPX4 and FPN1. These findings imply that busulfan-induced ferroptosis might be mediated via inhibition of Nrf2-GPX4 (FPN1) signaling pathway, and highlight that targeting ferroptosis serves as a potential strategy for prevention of busulfan-induced damage and male infertility.

CAS / MDL: 4478-93-7
研究领域: 药理学 · 生殖生物学 · 毒理学
✓ 已验证 产品关联 DOI PubMed 高影响因子
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Biomed Research International · 2019 · IF 2.197

Galangin Suppresses Renal Inflammation via the Inhibition of NF-κB, PI3K/AKT and NLRP3 in Uric Acid Treated NRK-52E Tubular Epithelial Cells

Hao Lu,Hui Yao,Rong Zou,Xiwen Chen,Hanlin Xu

Renal inflammation can result in renal injury. Uric acid (UA) is the final product of purine metabolism in humans and because of the lack of urate oxidase, UA may accumulate in tissues, including kidney, causing inflammation. Galangin was isolated from a traditional Chinese medicine plant and possesses several beneficial effects, working as an anti-oxidant, anti-mutagenic, anti-tumor, anti-inflammatory, anti-microbial, and anti-viral agent. Therefore, this study aimed at investigating the molecular mechanism of galangin in the attenuation of UA induced renal inflammation in normal rat kidney epithelial cells NRK-52E. Our findings suggested that galangin treatment efficiently protected NRK-52E cells against UA induced renal inflammation by decreasing tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-18, prostaglandin E2 (PGE2), and nitric oxide (NO) release, and it inhibited nitric oxide synthase (iNOS), prostaglandin endoperoxide synthase 2 (PTGS2), TNF-α, IL-1β, and IL-18 mRNA expression. In addition, galangin was not exerting any cytotoxicity at the concentrations that were effective against inflammation as assessed by CCK8 assay. Moreover, western blotting showed that galangin treatment effectively inhibited nuclear factor-kappa B (NF-κB), phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) and nucleotide-binding domain- (NOD-) like receptor protein 3 (NLRP3) signaling pathway activation. Taken together, these findings suggested that galangin plays a pivotal role in renal inflammation by suppressing inflammatory responses, which might be closely associated with the inhibition of NLRP3 inflammasome, NF-κB and PI3K/AKT signaling pathway activation.

CAS / MDL: 548-83-4 69-93-2
研究领域: 药理学 · 肾病学 · 炎症研究
✓ 已验证 产品关联 DOI PubMed 高影响因子
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Acta Pharmaceutica Sinica B · 2022 · IF 14.903

Tumor-microenvironment activated duplex genome-editing nanoprodrug for sensitized near-infrared titania phototherapy

Zekun Li,Yongchun Pan,Shiyu Du,Yayao Li,Chao Chen,Hongxiu Song,Yueyao Wu,Xiaowei Luan,Qin Xu,Xiaoxiang Guan,Yujun Song,Xin Han

Near-infrared (NIR)-light-triggered nanomedicine, including photodynamic therapy (PDT) and photothermal therapy (PTT), is growing an attractive approach for cancer therapy due to its high spatiotemporal controllability and minimal invasion, but the tumor eradication is limited by the intrinsic anti-stress response of tumor cells. Herein, we fabricate a tumor-microenvironment responsive CRISPR nanoplatform based on oxygen-deficient titania (TiO 2- x ) for mild NIR-phototherapy. In tumor microenvironment, the overexpressed hyaluronidase (HAase) and glutathione (GSH) can readily destroy hyaluronic acid (HA) and disulfide bond and releases the Cas9/sgRNA from TiO 2- x to target the stress alleviating regulators, i.e. , nuclear factor E2-related factor 2 (NRF2) and heat shock protein 90 α (HSP90 α ), thereby reducing the stress tolerance of tumor cells. Under subsequent NIR light illumination, the TiO 2- x demonstrates a higher anticancer effect both in vitro and in vivo . This strategy not only provides a promising modality to kills cancer cells in a minimal side-effects manner by interrupting anti-stress pathways but also proposes a general approach to achieve controllable gene editing in tumor region without unwanted genetic mutation in normal environments.

研究领域: 癌症治疗 · 纳米技术 · 基因编辑 · 光疗 · 生物材料
✓ 已验证 产品关联 DOI PubMed 高影响因子
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MATERIALS & DESIGN · 2022 · IF 9.417

Branched AuAg nanoparticles coated by metal–phenolic networks for treating bacteria-induced periodontitis via photothermal antibacterial and immunotherapy

Hanchi Wang,Dongyang Wang,Huimin Huangfu,Huixin Lv,Qiuyue Qin,Sicong Ren,Yidi Zhang,Lin Wang,Yanmin Zhou

Periodontitis is an inflammatory disease caused by bacteria. The prolonged and repeated occurrence of this disease results from immune system disorders and leads to the destruction of surrounding tissues. Research on new antibacterial materials that can regulate autoimmunity and promote repair can effectively treat periodontal inflammation. Hence, metal–phenolic networks (MPNs) were loaded onto the surface of branched AuAg nanoparticles (NPs), denoted as [email protected] The procyanidin (PC)-Fe network not only enhanced the photothermal properties of AuAg NPs to achieve effective photothermal antibacterial activity against periodontal pathogens but also alleviated oxidative stress and excessive inflammation. The mechanism of action is as follows: [email protected] promotes the polarisation of alternatively activated macrophages by activating the phosphoinositide 3-kinase/protein kinase B signaling pathway and upregulates nuclear factor erythroid 2-related factor 2, scavenging reactive oxygen species and subsequently inhibiting the nuclear factor kappa-B signaling pathway to regulate immunity. The ability of periodontal inflammatory tissue to repair was improved in vivo. This design provides new ideas for applying MPNs to photothermal therapy and immunotherapy. It presents a new therapeutic platform for treating periodontitis and other infectious diseases.

研究领域: 纳米技术 · 牙科学 · 免疫学 · 药学 · 材料科学
✓ 已验证 产品关联 DOI 高影响因子
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CHEMICAL ENGINEERING JOURNAL · 2023 · IF 15.1

Photothermal enhanced polyphenol-based nanofibers ameliorate catalytic efficiency of ferroptosis for synergistic tumor therapy

Kai Sun,Jiaying Yu,Jinzhong Hu,Wanxiang Yang,Xianfeng Chu,Lucheng Chen,Xiongwei Deng,Baiwang Sun,Zhifei Wang

Ferroptosis is an emerging antitumor treatment modality with the superiority for evading apoptotic cell death pathway. However, how to elevate catalytic efficacy of Fe 2+ -mediated Fenton reaction and efficiently elicit ferroptosis remain enormously challenging. Herein, inspired by hyperthermia-enhanced Fenton reaction kinetics, we firstly designed iron-polyphenol-aspirin-coordinated nanochelates for photothermal-enhanced ferroptosis antitumor immunotherapy. Specifically, we modulated optimal mass feeding ratio of gallic acid (GA), aspirin (ASA), Fe (II) and polyvinylpyrrolidone (PVP) to construct novel nanofibrous GA-ASA-Fe (II) metalchelates named GAFs. The variations in size and structure allowed the nanomedicines to avoid the risk of premature renal clearance in vivo, compared with the reported ultrasmall GA-Fe (II) nanocomplexes (GFs). Under NIR laser irradiation, GAFs could constantly amplify toxic hydroxyl radicals ( OH) generation and deplete excessive GSH to induce more accumulation of lethal lipid peroxidation (LPO), thereby triggering ferroptosis pathway in vitro and in vivo. Besides, the introduction of ASA could inhibit cyclooxygenase-2 (COX-2) and prostaglandin E 2 (PGE 2 ), in combination with photothermal-enhanced ferroptosis tumor therapy to induce immunogenic cell death (ICD), promote maturation of dendritic cells (DCs) and activate cytotoxic T cells for synergistic antitumor immunotherapy. GAFs with laser irradiation exhibited the capacity of inhibition of pulmonary metastasis. This work presented a strategy for incorporating small molecule immunomodulator into the metal-polyphenolic coordination to ameliorate its deficiencies, thereby inspiring a new design concept for tumor treatment.

研究领域: 癌症治疗 · 纳米技术 · 药学 · 免疫学
✓ 已验证 产品关联 DOI 高影响因子
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ENVIRONMENT INTERNATIONAL · 2020 · IF 7.577

Bisphenol A promotes autophagy in ovarian granulosa cells by inducing AMPK/mTOR/ULK1 signalling pathway

Miaoling Lin,Rui Hua,Jing Ma,Yao Zhou,Pei Li,Xiya Xu,Zhiqiang Yu,Song Quan

Background Bisphenol A (BPA) is a widespread endocrine-disrupting chemical with estrogen like effects, which could interfere with the human reproductive system by disrupting the normal function of granulosa cells (GCs) leading to abnormal ovarian function. However, the mechanism of its toxicity on human GCs has not been clearly described thus far. Methods 106 normogonadotropic infertile women undergoing their first in-vitro fertilization-embryo transfer (IVF-ET) cycle were recruited. Urinary BPA level and the early outcomes of IVF-ET were analysed. Patients were divided to low and high BPA exposure groups using the median urinary BPA concentration as the cut-off value. In-vivo and in-vitro studies were conducted using mice and human granulosa cell line (KGN cells). Female Kunming mice approximately 6–8 weeks of age were poisoned with BPA at different dosages (1, 10 or 100 μg/kg) by oral gavage once daily for 2 weeks, while KGN cells were exposed to BPA at the concentration of 1, 10 or 100 nM for 24 h, 48 h or 72 h. BPA-induced ovarian morphologic changes were analysed by histopathology investigation. Cell viability and apoptosis were evaluated using CCK-8, TUNEL and flowcytometric, respectively. Hormone levels were determined using ELISA and the molecular mechanism studies were conducted using immunofluorescence, RT-PCR and western blots. Results The oocyte retrieval rate, maturation rate and embryo implantation rate significantly decreased with the higher level of urinary BPA concentration. Peak E2 level was lower in high BPA group, but no statistical significance could be observed. In BPA treated mice, cystic dilation of the follicles with a decreased number of GCs could be observed histopathologically. Decreased E2, P4 and AMH level and GCs autophagy could be detected both in-vivo and in-vitro with the activation of AMPK/mTOR/ULK1 signalling pathway. As being confirmed in KGN cells, phosphorylated AMPK and ULK1 increased while phosphorylated mTOR decreased, and by inhibition autophagy using knockdown of AMPK or 3-MA, adverse effects of BPA exposure in-vitro could be reversed. Conclusion BPA exposure might abnormally influence human ovarian functions leading to abnormal folliculogenesis by activation of autophagy in GCs through AMPK/mTOR/ULK1 pathway.

CAS / MDL: 80-05-7 8002-03-7
研究领域: 内分泌学 · 生殖生物学 · 毒理学 · 细胞生物学 · 分子生物学
✓ 已验证 产品关联 DOI PubMed 高影响因子
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International Journal of Nanomedicine · 2017 · IF 4.3

Capsaicin-loaded nanolipoidal carriers for topical application: design, characterization, and in vitro/in vivo evaluation

Xia-Rong Wang,Si-Qian Gao,Xiao-Qian Niu,Long-Jian Li,Xiao-Ying Ying,Zhong-Jie Hu,Jian-Qing Gao

Capsaicin has been used in clinical applications for the treatment of pain disorders and inflammatory diseases. Given the strong pungency and high oil/water partition coefficient of capsaicin, capsaicin-loaded nanolipoidal carriers (NLCs) were designed to increase permeation and achieve the analgesic, anti-inflammatory effect with lower skin irritation. Capsaicin-loaded NLCs were prepared and later optimized by the Box–Behnken design. The physicochemical characterizations, morphology, and encapsulation of the capsaicin-loaded NLCs were subsequently confirmed. Capsaicin-loaded NLCs and capsaicin-loaded NLCs gel exhibited sustained release and no cytotoxicity properties. Also, they could significantly enhance the penetration amount, permeation flux, and skin retention amounts of capsaicin due to the application of NLCs. To study the topical permeation mechanism of capsaicin, 3,3′-dioctadecyloxacarbocyanine perchlorate (Dio) was used as a fluorescent dye. Dio-loaded NLCs and Dio-loaded NLCs gel could effectively deliver Dio up to a skin depth of 260 and 210 μm, respectively, primarily through the appendage route on the basis of version skin sections compared with Dio solution, which only delivered Dio up to 150 μm. In vivo therapeutic experiments demonstrated that capsaicin-loaded NLCs and capsaicin-loaded NLCs gel could improve the pain threshold in a dose-dependent manner and inhibit inflammation, primarily by reducing the prostaglandin E2 levels in the tissue compared with capsaicin cream and capsaicin solution. Meanwhile, skin irritation was reduced, indicating that application of NLCs could decrease the irritation caused by capsaicin. Overall, NLCs may be a potential carrier for topical delivery of capsaicin for useful pain and inflammation therapy.

CAS / MDL: 31566-31-1 298-93-1
研究领域: 药剂学 · 药学 · 药物递送系统 · 药理学
✓ 已验证 产品关联 DOI PubMed 高影响因子
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PHYTOMEDICINE · 2024 · IF 6.7

Integrated metabolomics and lipidomics investigation of the mechanism of Danggui Sini Decoction on improving lipid homeostasis in primary dysmenorrhea

Junling Ren,Xia Wang,Yuran Sun,Le Yang,Hui Sun,Ye Sun,Ling Kong,Guangli Yan,Ying Han,Xijun Wang

Background Danggui Sini Decoction (DGSND) is a classic prescription for treating primary dysmenorrhea (PD), while, the ameliorating effects of DGSND on PD and its mechanisms are not yet fully understood. Purpose The present study is devoted to investigate the protective effect of DGSND against PD and the possible mechanism from the perspective of metabolomics as well as lipidomics. Methods DGSND was characterized by UPLC-Q-TOF/MS. The PD rat model was induced by estradiol benzoate and oxytocin, and traditional pharmacology, including writhing times, latency time, biochemical index, organ index, and histopathology were performed to evaluated the efficacy of DGSND on PD. Urine metabolomics strategy combined with functional analysis was adopted to delineate the therapeutic effect of DGSND on PD rats and anchor the crucial pathway, and lipidomics analysis was further performed with the uterine tissue as the research object to elucidate the protective mechanism of DGSND from the perspective of lipid homeostasis. Finally, western blot analysis was used to validate the expression of key metabolic enzymes in lipid metabolism. Results DGSND was effective in ameliorating writhing times, latency time, the value of prostaglandin F 2α (PGF 2α )/PGE 2 , uterus index, and morphological changes of PD rats. Metabolic signature of PD rats was primarily characterized by the disturbance of steroid hormone metabolism, amino acid metabolism, and lipid metabolism. Functional analysis revealed the urine biomarkers of PD were most related with lipid abnormality. Further lipidomics analysis indicated DGSND exerted anti-PD effects by remodeling lipid homeostasis, which might be due to the significant correlations between different kinds of lipids, especially the extremely high correlation of phosphatidylethanolamine, phosphatidylcholine, and fatty acids. Moreover, the key metabolic enzymes expression of CK, PLA 2 , LPCAT3, COX-2, and 5-LOX can be greatly downregulated by DGSND. Conclusion Our findings demonstrated a novel protective mechanism of DGSND against PD by regulating lipid homeostasis.

CAS / MDL: 64-18-6
研究领域: 药理学 · 代谢组学 · 脂质组学 · 中医 · 动物模型
✓ 已验证 产品关联 DOI PubMed 高影响因子
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JOURNAL OF NUTRITIONAL BIOCHEMISTRY · 2020 · IF 4.873

Conjugated linoleic acid attenuates 2,4-dinitrofluorobenzene-induced atopic dermatitis in mice through dual inhibition of COX-2/5-LOX and TLR4/NF-κB signaling

Liu Tang,Xiao-Lei Li,Zi-Xin Deng,Yao Xiao,Ya-Hong Cheng,Jing Li,Hong Ding

Conjugated linoleic acid (CLA), commonly found in beef, lamb and dairy products, has been reported to exhibit anti-inflammatory and antipruritus effects and to inhibit the release of chemical mediators such as histamine and eicosanoid in laboratory rodents. The chief objective of the study is to assess the efficacy of CLA on atopic dermatitis (AD) in mice and to explore possible mechanisms with CLA treatments . To develop a new therapy for AD, the anti-AD potential of CLA was investigated by inducing AD-like skin lesions in mice using 2,4-dinitrofluorobenzene. We evaluated dermatitis severity; histopathological changes; serum levels of T helper (Th) cytokines (interferon-γ, interleukin-4); changes in protein expression by western blotting and immunohistochemistry staining for cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), toll like receptor 4 (TLR-4), myeloid differentiation factor 88 (MyD88), nuclear factor-κB (NF-κB) and tumor necrosis factor α (TNF-α); and production of the proinflammatory lipid mediators, such as prostaglandin E 2 and leukotriene B4 , in the skin lesions. Treatment with CLA ameliorated the development of AD-like clinical symptoms and effectively inhibited epidermal hyperplasia and infiltration of mast cells and CD4 + T cells in the AD mouse skin. Total serum immunoglobulin E levels and the expression levels of Th1/Th2 cytokines and lipid mediators in dorsal skin were dramatically suppressed by CLA. Furthermore, CLA down-regulated the expressions of COX-2, 5-LOX, TLR4, MyD88, NF-κB and TNF-α. Taken together, our findings demonstrate the potential usefulness of CLA as an anti-inflammatory dietary supplement or drug for the prevention and management of AD skin diseases by modulating the COX-2/5-LOX and TLR4/MyD88/NF-κB signaling pathways .

研究领域: 免疫学 · 药理学 · 皮肤科 · 分子生物学
✓ 已验证 DOI PubMed 高影响因子
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BRITISH JOURNAL OF PHARMACOLOGY · 2024 · IF 6.8

Combination therapy enhances efficacy and overcomes toxicity of metal-based anti-diabetic agent

Bing Shang,Yaqiong Dong,Bo Feng,Jingyan Zhao,Zhi Wang,Debbie C. Crans,Xiaoda Yang

Background and Purpose Metal-based therapeutic agents are limited by the required concentration of metal-based agents. Hereby, we determined if combination with 17β-oestradiol (E2) could reduce such levels and the therapy still be effective in type 2 diabetes mellitus (T2DM). Experimental Approach The metal-based agent (vanadyl acetylacetonate [VAC])– 17β-oestradiol (E2) combination is administered using the membrane-permeable graphene quantum dots (GQD), the vehicle, to form the active GQD–E2–VAC complexes, which was characterized by fluorescence spectra, infrared spectra and X-ray photoelectron spectroscopy. In db / db type 2 diabetic mice, the anti-diabetic effects of GQD–E2–VAC complexes were evaluated using blood glucose levels, oral glucose tolerance test (OGTT), serum insulin levels, homeostasis model assessment (homeostasis model assessment of insulin resistance [HOMA-IR] and homeostasis model assessment of β-cell function [HOMA-β]), histochemical assays and western blot. Key Results In diabetic mice, GQD–E2–VAC complex had comprehensive anti-diabetic effects, including control of hyperglycaemia, improved insulin sensitivity, correction of hyperinsulinaemia and prevention of β-cell loss. Co-regulation of thioredoxin interacting protein (TXNIP) activation by the combination of metal complex and 17β-oestradiol contributed to the enhanced anti-diabetic effects. Furthermore, a potent mitochondrial protective antioxidant, coniferaldehyde, significantly potentiates the protective effects of GQD–E2–VAC complexes. Conclusion and Implications A metal complex–E2 combinatorial approach achieved simultaneously the protection of β cells and insulin enhancement at an unprecedented low dose, similar to the daily intake of dietary metals in vitamin supplements. This study demonstrates the positive effects of combination and multi-modal therapies towards type 2 diabetes treatment. Graphical

研究领域: 药理学 · 糖尿病 · 治疗学 · 纳米技术 · 分子生物学
✓ 已验证 DOI PubMed 高影响因子
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ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY · 2015 · IF 2.084

Tetrachlorobenzoquinone exhibits neurotoxicity by inducing inflammatory responses through ROS-mediated IKK/IκB/NF-κB signaling

Juanli Fu,Qiong Shi,Xiufang Song,Xiaomin Xia,Chuanyang Su,Zixuan Liu,Erqun Song,Yang Song

Tetrachlorobenzoquinone (TCBQ) is a joint metabolite of persistent organic pollutants (POPs), hexachlorobenzene (HCB) and pentachlorophenol (PCP). Previous studies have been reported that TCBQ contributes to acute hepatic damage due to its pro-oxidative nature. In the current study, TCBQ showed the highest capacity on the cytotoxicity, ROS formation and inflammatory cytokines release among four compounds, i.e., HCB, PCP, tetrachlorohydroquinone (TCHQ, reduced form of TCBQ) and TCBQ, in PC 12 cells. Further mechanistic study illustrated TCBQ activates nuclear factor-kappa B (NF-κB) signaling. The activation of NF-κB was identified by measuring the protein expressions of inhibitor of nuclear factor kappa-B kinase (IKK) α/β, p-IKKα/β, an inhibitor of NF-κB (IκB) α, p-IκBα, NF-κB (p65) and p-p65. The translocation of NF-κB was assessed by Western blotting of p65 in nuclear/cytosolic fractions, electrophoretic mobility shift assay (EMSA) and luciferase reporter gene assay. In addition, TCBQ significantly induced protein and mRNA expressions of inflammatory cytokines and mediators, such as interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the production of nitric oxide (NO) and prostaglandin E2 (PGE2). Pyrrolidine dithiocarbamate (PDTC), a specific NF-κB inhibitor inhibited these effects efficiently, further suggested TCBQ-induced inflammatory responses involve NF-κB signaling. Moreover, antioxidants, i.e., N-acetyl- l -cysteine (NAC), Vitamin E and curcumin, ameliorated TCBQ-induced ROS generation as well as the activation of NF-κB, which implied that ROS serve as the upstream molecule of NF-κB signaling. In summary, TCBQ exhibits a neurotoxic effect by inducing oxidative stress-mediated inflammatory responses via the activation of IKK/IκB/NF-κB pathway in PC12 cells.

研究领域: 毒理学 · 神经科学 · 细胞生物学 · 药理学
✓ 已验证 DOI PubMed 高影响因子
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