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 ...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.展开更多
Obesity and osteoporosis are associated with estrogen deficiency following menopause. Therefore, it is important to prevent and treat both disorders to maintain a healthy life in postmenopausal women. Nobiletin, a pol...Obesity and osteoporosis are associated with estrogen deficiency following menopause. Therefore, it is important to prevent and treat both disorders to maintain a healthy life in postmenopausal women. Nobiletin, a polymethoxylated flavone, exhibits various pharmacologic effects, including anti-tumor and anti-inflammatory activities. Therefore, in this study, we examined the effects of nobiletin on obesity, obesity-related metabolic disorders, and bone mass in ovariectomized (OVX) mice. Mice were divided into four groups and underwent sham operation or OVX. OVX mice were treated with 50 or 100 mg/kg nobiletin, or received vehicle alone (0.3% carboxyl methyl cellulose/0.5% dimethyl sulfoxide). Nobiletin decreased body weight gain and white adipose tissue weight in OVX mice. Nobiletin also decreased triglyceride levels, and tended to reduce plasma total cholesterol and glucose levels. Additionally, nobiletin prevented the reduction in bone mineral density of the trabecular region of the femur in OVX mice. Taken together, our results suggest that nobiletin improves adiposity, dyslipidemia, hyperglycemia, and prevents bone loss in OVX mice. Therefore, nobiletin is expected to have beneficial effects for the prevention and improvement of metabolic disorders and osteoporosis in postmenopausal women.展开更多
Some citrus flavonoids have been reported to possess antioxidant activities that moderate endothelial dysfunction and show protective effects on cardiovascular disease. We have investigated the protective effects of n...Some citrus flavonoids have been reported to possess antioxidant activities that moderate endothelial dysfunction and show protective effects on cardiovascular disease. We have investigated the protective effects of nobiletin (5,6,7,8,3’,4’-hexamethoxy flavone) derived from the peel of Citrus depressa Hayata (Shiikuwasha), a citrus fruit produced in Okinawa prefecture in Japan on hypertension and thrombogenicity in cerebral vessels of stroke-prone spontaneously hypertensive rats (SHRSP). Nobiletin was added to the diet of male SHRSP (7 weeks old) for 4 weeks. The age-related increase in systolic blood pressure usually observed in SHRSP was significantly suppressed in the treated animals. Thrombogenesis in pial blood vessels, determined using a He-Ne laser technique, and antioxidant activity, assessed by measuring urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG), were significantly reduced after treatment. Urinary nitric oxide (NO) metabolites and acetylcholine-induced endothelial relaxation were increased after dietary intervention. These results strongly suggested that antihypertensive and antithrombotic effects of nobiletin may be related to an increase in bioavailable NO, possibly mediated by the scavenging of reactive oxygen species (ROS).展开更多
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 unbiase...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.展开更多
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...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.展开更多
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 ...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.展开更多
Our recent studies demonstrated that the natural product nobiletin(NOB)served as a promising multidrug resistance(MDR)reversal agent and improved the effectiveness of cancer chemotherapy in vitro.However,low aqueous s...Our recent studies demonstrated that the natural product nobiletin(NOB)served as a promising multidrug resistance(MDR)reversal agent and improved the effectiveness of cancer chemotherapy in vitro.However,low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent.To tackle these challenges,NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy.All the compounds showed improved sensitivity to paclitaxel(PTX)in P-glycoprotein(P-gp)overexpressing MDR cancer cells.Among them,compound 29 d exhibited water solubility 280-fold higher than NOB.A drug-resistance A549/T xenograft model showed that 29 d,at a dose of 50 mg/kg co-administered with PTX(15 mg/kg),inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition.Moreover,Western blot experiments revealed that 29 d inhibited expression of NRF2,phosphorylated ERK and AKT in MDR cancer cells,thus implying 29 d of multiple mechanisms to reverse MDR in lung cancer.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.81772702 and 81502214)。
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.
文摘Obesity and osteoporosis are associated with estrogen deficiency following menopause. Therefore, it is important to prevent and treat both disorders to maintain a healthy life in postmenopausal women. Nobiletin, a polymethoxylated flavone, exhibits various pharmacologic effects, including anti-tumor and anti-inflammatory activities. Therefore, in this study, we examined the effects of nobiletin on obesity, obesity-related metabolic disorders, and bone mass in ovariectomized (OVX) mice. Mice were divided into four groups and underwent sham operation or OVX. OVX mice were treated with 50 or 100 mg/kg nobiletin, or received vehicle alone (0.3% carboxyl methyl cellulose/0.5% dimethyl sulfoxide). Nobiletin decreased body weight gain and white adipose tissue weight in OVX mice. Nobiletin also decreased triglyceride levels, and tended to reduce plasma total cholesterol and glucose levels. Additionally, nobiletin prevented the reduction in bone mineral density of the trabecular region of the femur in OVX mice. Taken together, our results suggest that nobiletin improves adiposity, dyslipidemia, hyperglycemia, and prevents bone loss in OVX mice. Therefore, nobiletin is expected to have beneficial effects for the prevention and improvement of metabolic disorders and osteoporosis in postmenopausal women.
文摘Some citrus flavonoids have been reported to possess antioxidant activities that moderate endothelial dysfunction and show protective effects on cardiovascular disease. We have investigated the protective effects of nobiletin (5,6,7,8,3’,4’-hexamethoxy flavone) derived from the peel of Citrus depressa Hayata (Shiikuwasha), a citrus fruit produced in Okinawa prefecture in Japan on hypertension and thrombogenicity in cerebral vessels of stroke-prone spontaneously hypertensive rats (SHRSP). Nobiletin was added to the diet of male SHRSP (7 weeks old) for 4 weeks. The age-related increase in systolic blood pressure usually observed in SHRSP was significantly suppressed in the treated animals. Thrombogenesis in pial blood vessels, determined using a He-Ne laser technique, and antioxidant activity, assessed by measuring urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG), were significantly reduced after treatment. Urinary nitric oxide (NO) metabolites and acetylcholine-induced endothelial relaxation were increased after dietary intervention. These results strongly suggested that antihypertensive and antithrombotic effects of nobiletin may be related to an increase in bioavailable NO, possibly mediated by the scavenging of reactive oxygen species (ROS).
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.
基金supported by the National Key R&D Program of China (No. 2019YFA0110600)National Natural Science Foundation of China (Nos. 82171006, 81970986)Sichuan Province Youth Science and Technology Innovation Team (No. 2022JDTD0021)。
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.
基金supported by the Local Financial Funds of National Agricultural Science and Technology Center,Chengdu,China(NASC2021KR01)the Agricultural Science and Technology Innovation Program(ASTIP-IUA-2022002)。
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.
基金supported by National Key R&D Program of China(2017YFB0202600)Macao Science and Technology Development Fund,Macao Special Administrative Region(003/2017/A1to Ying Xie,China)+1 种基金National Natural Science Foundation of China(21572279,21877134,81602955 and 81703341)Guangdong Province Higher Vocational Colleges&Schools Pearl River Scholar Funded Scheme(2016,China).
文摘Our recent studies demonstrated that the natural product nobiletin(NOB)served as a promising multidrug resistance(MDR)reversal agent and improved the effectiveness of cancer chemotherapy in vitro.However,low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent.To tackle these challenges,NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy.All the compounds showed improved sensitivity to paclitaxel(PTX)in P-glycoprotein(P-gp)overexpressing MDR cancer cells.Among them,compound 29 d exhibited water solubility 280-fold higher than NOB.A drug-resistance A549/T xenograft model showed that 29 d,at a dose of 50 mg/kg co-administered with PTX(15 mg/kg),inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition.Moreover,Western blot experiments revealed that 29 d inhibited expression of NRF2,phosphorylated ERK and AKT in MDR cancer cells,thus implying 29 d of multiple mechanisms to reverse MDR in lung cancer.
