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| 1 | Nobiletin downregulates the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma显示文摘Objective:Natural extracts,including nobiletin,have been reported to enhance the efficacy and sensitivity of chemotherapeutic drugs.However,whether and how nobiletin affects tumor growth and progression in renal cell carcinoma(RCC)are still unclear.Methods:Cell proliferation,cell cycle and apoptosis analyses,colony-formation assays,immunoblotting analysis,and q RT-PCR analysis were performed to investigate how nobiletin affected RCC cell proliferation in vitro.The nude mouse model was used to test the efficacy of nobiletin alone or in combination with palbociclib.Results:Nobiletin inhibited cell proliferation by inducing G1 cell cycle arrest and cell apoptosis in RCC cells.Mechanistically,nobiletin decreased SKP2 protein expression by reducing its transcriptional level.The downregulated SKP2 caused accumulation of its substrates,p27 and p21,which further inhibited the activity of the G1 phase-related protein,CDK2,leading to inhibition of cell proliferation and tumor formation.A higher SKP2 protein level indicated less sensitivity to the CDK4/6 inhibitor,palbociclib.A combination of nobiletin and palbociclib showed a synergistic tumor inhibition in vitro and in an in vivo model.Conclusions:Nobiletin downregulated the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and showed synergistic tumor inhibition effects with the CDK4/6 inhibitor,palbociclib,on RCC,which indicates a potential new therapeutic strategy. | Tingting Chen Liu Liu Yonghong Zou Xiaoyan Hu Wenfeng Zhang Tao Zhou Xi Luo Weihua Fu Jie Xu | 2021 | Cancer Biology & Medicine2021，18，1： | 3 |
| 2 | Novel treatment for refractory rheumatoid arthritis with total glucosides of paeony and nobiletin codelivered in a self-nanoemulsifying drug delivery system显示文摘Patients with refractory rheumatoid arthritis(RA)remain a substantial clinical problem,while the overexpression of P-glycoprotein(P-gp)on their lymphocytes may contribute to resistance to anti-rheumatic drugs.This study aims to develop a novel treatment for refractory RA consisting of the combination of total glucosides of paeony(TGPs)and the P-gp inhibitor nobiletin(N),which are codelivered in a self-nanoemulsifying drug delivery system(SNEDDS).Based on the solubility,compatibility,and pseudoternary phase diagram tests,a nano-SNEDDS formulation composed of capryol 90-cremophor EL35-tcranscutol HP(CET)to codeliver TGP and N was developed,and this formulation increased the bioavailability of TGP by 435.04%(indicated with paeoniflorin).A modified adjuvant-induced arthritis(AIA)rat model was verified for the overexpression of P-gp in lymphocytes and resistance to methotrexate(MTX)treatment at the reported anti-inflammatory dosage.CET formulation not only increased the solubility and permeability of TGP but also inhibited the function and expression of P-gp,leading to enhanced bioavailability and intracellular concentration in the lymphocytes of AIA rats and consequently boosting the anti-arthritic effects of TGP.Moreover,TGP and N coloaded CET reduced the expression of P-gp in AIA rats partly by inhibiting the phosphorylated AKT and HIF-1αpathways.In summary,TGP-N coloaded SNEDDS is a novel and effective treatment for refractory RA. | Biao Qu Xiao-lin Wang De-chong Zheng Chu-tian Mai Zhong-qiu Liu Hua Zhou Ying Xie | 2022 | Acta Pharmacologica Sinica2022，43，8： | 1 |
| 3 | Natural sources,refined extraction,biosynthesis,metabolism,and bioactivities of dietary polymethoxyflavones(PMFs)显示文摘Polymethoxyflavones(PMFs)are a type of uncommon dietary flavonoids,characterized by more than one methoxy group,which exist in limited plant species,like Citrus species and Kaempferia parviflora.In addition,different PMFs,such as nobiletin,sinensetin,tangeretin,and casticin,have been isolated from these natural sources.PMFs have received increasing attention due to their multiple bioactivities,such as antioxidant,anti-inflammatory,anti-cancer,metabolic regulatory,immunoregulatory,neuroprotective,and skin protective effects.These bioactivities of PMFs should be associated with the regulation of critical molecular targets and the interaction with gut microbiota.In order to provide a comprehensive and updated review of PMFs,their natural sources,refined extraction,biosynthesis,metabolism,and bioactivities are summarised and discussed,with the emphasis on the molecular mechanisms of PMFs on regulating different chronic diseases.Overall,PMFs may be promising flavonoids to the forefront of nutraceuticals for the prevention and/or treatment of certain human chronic diseases. | Renyou Gan Yi Liu Hang Li Yu Xia Huan Guo Fang Geng Qiguo Zhuang Huabin Li Dingtao Wu | 2024 | Food Science and Human Wellness2024，13，1： | 1 |
| 4 | Biological regulation on synovial fibroblast and the treatment of rheumatoid arthritis by nobiletin-loaded tetrahedral framework nucleic acids cargo tank显示文摘The hyperplasia and destruction of synovial tissue have an important impact on the development of rheumatoid arthritis(RA), the abnormal proliferation and migration of synovial fibroblast in synovial tissue is similar to tumor cells. Targeting anomalous synovial fibroblast and designing a high bioavailability nano drug delivery system can reduce the dosage for the treatment of rheumatoid arthritis and it is of great significance to reduce toxic and side effects and improve curative effect. In this experiment, the nobiletin-loaded tetrahedral framework nucleic acids cargo tank was established, carrying antiinflammatory small molecule monomer drug nobiletin with minimal bioavailability. Both in vitro cell experiments and in vivo animal studies proved the nano cargo tank enhance the role of nobiletin in reducing the invasiveness of pathological synovial fibroblast and promote their apoptosis, effectively alleviate the disease development of rheumatoid arthritis. | Yuting Wen Mei Zhang Yangxue Yao Yang Gao Xiaolin Zhang Yunfeng Lin Xiaoxiao Cai | 2023 | Chinese Chemical Letters2023，34，2： | 0 |
| 5 | Nobiletin and tangeretin(citrus polymethoxyflavones): an overview on their chemistry, pharmacology and cytotoxic activities against breast cancer显示文摘The fruit peel of Citrus species(Chenpi),particularly those of mandarin oranges,is a useful source of food and medicine in China.Flavonoids from the citrus fruit peel are mainly polymethoxyflavones(PMFs),of which nobiletin and tangeretin are the most abundant components.In the present review,we summarized the cytotoxic activities of these two PMFs to breast cancer cells.Studies have reported that these two compounds inhibit the growth of breast cancer cells by inducing apoptosis,cytostatic cell death and cell cycle arrest,or by inhibiting cell proliferation,metastasis and tumour angiogenesis,depending on the molecular subtypes of breast cancer.In vitro and in vivo cytotoxic activities involve different molecular targets and signalling pathways.Analyses on the structure-activity relationship(SAR)of nobiletin and tangeretin have shown that the presence of a methoxy group at C8 and a hydroxyl group at C3 or C5 are essential for anti-proliferative activity.Some future perspectives and research needs are suggested.Sources of information are from Pub Med,Pub Med Central,Science Direct,Google Scholar,J-Stage,Pub Chem and CNKI using keyword search. | Eric Wei Chiang Chan Oi Yoon Michelle Soo Yong Hui Tan Siu Kuin Wong Hung Tuck Chan | 2020 | Journal of Chinese Pharmaceutical Sciences2020，29，7： | 0 |
| 6 | Nobiletin protects against metabolic syndrome by enhancing circadian rhythms显示文摘OBJECTIVE Dysregulation of circadian rhythms is associated with metabolic dysfunction,yet it is unclear whether enhancing clock function by small molecules can ameliorate metabolic disorders.METHODS We used an unbiased chemical screen in fibroblasts expressing PER2::Luc to identify the Clock amplitude-Enhancing Small Mole⁃cule.In diet-induced obese mice and DB/DB mutant mice,we evaluated the effects of the Clock amplitude-Enhancing small Molecule on metabolic syndrome and locomotor activity.RESULTS We identified Nobiletin(NOB),a natural poly⁃methoxylated flavone,as a Clock amplitude-Enhancing Small Molecule by an unbiased chemical screen.In diet-induced obese mice,NOB strongly improved metabolic syndrome and enhanced locomotor activity in a Clock gene-dependent manner.Moreover,the clock is also required for the beneficial effects of NOB on metabolic disorders in DB/DB mutant mice.Notably,NOB enhanced clock protein levels and reprogramed metabolic gene expressions in the liver.Finally,we revealed retinoid acid receptor-related orphan receptors(RORα/γ)as direct targets of NOB.CONCLUSION Altogether,our results demonstrate that a pharmacological intervention that enhances circadian rhythms by small molecule may be as a novel strategy for combating metabolic disease. | HE Bao-kun | 2019 | 中国药理学与毒理学杂志2019，33，9： | 0 |
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