Peroxisome proliferator activated receptor-γ (PPARγ), a transcription factor of the nuclear receptor superfamily plays a significant role in colorectal cancer pathogenesis. In most experimental systems PPARγ activa...Peroxisome proliferator activated receptor-γ (PPARγ), a transcription factor of the nuclear receptor superfamily plays a significant role in colorectal cancer pathogenesis. In most experimental systems PPARγ activation has tumor suppressing effects in the colon. PPARγ is regulated at multiple levels by the ubiquitin-proteasome system (UPS). At a first level, UPS regulates PPARγ transcription. This regulation involves both PPARγ transcription specific factors and the general transcription machinery. At a second level UPS regulates PPARγ and its co-factors themselves, as PPARγ and many co-factors are proteasome substrates. At a third level of regulation, transduction pathways working in parallel but also having interrelations with PPARγ are regulated by the UPS, creating a network of regulation in the colorectal carcinogenesisrelated pathways that are under UPS control. Activation of PPARγ transcription by direct pharmacologic activators and by stabilization of its molecule by proteasome inhibitors could be strategies to be exploited in colorectal cancer treatment.展开更多
Studies concerning the pathophysiological connection between obesity and osteoporosis are currently an intriguing area of research.Although the onset of these two diseases can occur in a different way,recent studies h...Studies concerning the pathophysiological connection between obesity and osteoporosis are currently an intriguing area of research.Although the onset of these two diseases can occur in a different way,recent studies have shown that obesity and osteoporosis share common genetic and environmental factors.Despite being a risk factor for health,obesity has traditionally been considered positive to bone because of beneficial effect of mechanical loading,exerted by high body mass,on bone formation.However,contrasting studies have not achieved a clear consensus,suggesting instead that excessive fat mass derived from obesity condition may not protect against osteoporosis or,even worse,could be rather detrimental to bone.On the other hand,it is hitherto better established that,since adipocytes and osteoblasts are derived from a common mesenchymal stem cell precursor,molecules that lead to osteoblastogenesis inhibit adipogenesis and vice versa.Here we will discuss the role of the key molecules regulating adipocytes and osteoblasts differentiation,which are peroxisome proliferators activated receptor-γand Wnts,respectively.In particular,wewill focus on the role of both canonical and non-canonical Wnt signalling,involved in mesenchymal cell fate regulation.Moreover,at present there are no experimental data that relate any influence of the Wnt inhibitor Sclerostin to adipogenesis,although it is well known its role on bone metabolism.In addition,the most common pathological condition in which there is a simultaneous increase of adiposity and decrease of bone mass is menopause.Given that postmenopausal women have high Sclerostin level inversely associated with circulating estradiol level and since the sex hormone replacement therapy has proved to be effective in attenuating bone loss and reversing menopause-related obesity,we hypothesize that Sclerostin contribution in adipogenesis could be an active focus of research in the coming years.展开更多
This study was aimed to explore the associations between the combined effects of several polymorphisms in the PPAR-γ and RXR-α gene and environmental factors with the risk of metabolic syndrome by back-error propaga...This study was aimed to explore the associations between the combined effects of several polymorphisms in the PPAR-γ and RXR-α gene and environmental factors with the risk of metabolic syndrome by back-error propaga- tion artificial neural network （BPANN）. We established the model based on data gathered from metabolic syndrome patients （n = 1012） and normal controls （n = 1069） by BPANN. Mean impact value （MIV） for each input variable was calculated and the sequence of factors was sorted according to their absolute MIVs. Generalized multifactor dimensionality reduction （GMDR） confirmed a joint effect of PPAR-9＂ and RXR-a based on the results from BPANN. By BPANN analysis, the sequences according to the importance of metabolic syndrome risk fac- tors were in the order of body mass index （BMI）, serum adiponectin, rs4240711, gender, rs4842194, family history of type 2 diabetes, rs2920502, physical activity, alcohol drinking, rs3856806, family history of hypertension, rs1045570, rs6537944, age, rs17817276, family history of hyperlipidemia, smoking, rs1801282 and rs3132291. However, no polymorphism was statistically significant in multiple logistic regression analysis. After controlling for environmental factors, A1, A2, B1 and B2 （rs4240711, rs4842194, rs2920502 and rs3856806） models were the best models （cross-validation consistency 10/10, P = 0.0107） with the GMDR method. In conclusion, the interaction of the PPAR-γ and RXR-α gene could play a role in susceptibility to metabolic syndrome. A more realistic model is obtained by using BPANN to screen out determinants of diseases of multiple etiologies like metabolic syndrome.展开更多
Objective： To explore the molecular mechanism of puerarin （Pue） in improving insulin resistance through observing its effect on the insulin resistance of 3T3-Li lipocyte induced by free fatty acid （FFA）. Methods...Objective： To explore the molecular mechanism of puerarin （Pue） in improving insulin resistance through observing its effect on the insulin resistance of 3T3-Li lipocyte induced by free fatty acid （FFA）. Methods： 3T3-L1 preadipocyte was induced by a culture solution containing insulin, isobutyo-menthyl-xanthine, and dexamethasone to mature lipocyte, and it was divided into six groups： the control group （normal cells）, the model group （untreated model cells）, and the four drug treatment group exposed to dimethyl biguanide （Met group）, high- dose pueradn （PueH group）, low-dose puerarin （PueL group）, and propylene glycol （PG group）, respectively. Mature lipocytes in various groups, except those in the normal group, were established into insulin resistance model by FFA induction and treated respectively with corresponding drugs. Peroxisome proliferator-activated receptor- γ （PPAR- γ） mRNA expressions at the fourth, sixth, and eighth day were observed using reverse transcription polymerase chain reaction （RT-PCR）; glucose transportation in various groups were observed by 2-deoxy-[3H]-D-glucose intake method; mRNA expression of Cbl binding protein （CAP） was determined by RT-PCR; and glucose transporter-4 （Glut-4） transposition was detected by immune-fluorescence method. Results： PPAR- γmRNA expression increased gradually, and it showed lower levels at the fourth, sixth, and eighth day in all treatment groups than that in the model group. Glucose transportation determination showed that the transportation in the model group was 2.23 ± 0.63, significantly lower than that in the normal group 5.05 ± 0.66 （P〈0.01）; as compared with the model group, they were significantly higher in the PueH and the PueL groups. In addition, the CAP mRNA expression and membranous distribution of Glut-4 were higher in the two Pue treated groups than those in the model group, respectively. Conclusion： Pue could markedly improve the insulin resistance of 3T3-L1 lipocyte, which is realized possibly by way of inactivating CAP path, promoting Glut-4 transposition to cell membrane to increase the transportation of glucose.展开更多
文摘Peroxisome proliferator activated receptor-γ (PPARγ), a transcription factor of the nuclear receptor superfamily plays a significant role in colorectal cancer pathogenesis. In most experimental systems PPARγ activation has tumor suppressing effects in the colon. PPARγ is regulated at multiple levels by the ubiquitin-proteasome system (UPS). At a first level, UPS regulates PPARγ transcription. This regulation involves both PPARγ transcription specific factors and the general transcription machinery. At a second level UPS regulates PPARγ and its co-factors themselves, as PPARγ and many co-factors are proteasome substrates. At a third level of regulation, transduction pathways working in parallel but also having interrelations with PPARγ are regulated by the UPS, creating a network of regulation in the colorectal carcinogenesisrelated pathways that are under UPS control. Activation of PPARγ transcription by direct pharmacologic activators and by stabilization of its molecule by proteasome inhibitors could be strategies to be exploited in colorectal cancer treatment.
文摘Studies concerning the pathophysiological connection between obesity and osteoporosis are currently an intriguing area of research.Although the onset of these two diseases can occur in a different way,recent studies have shown that obesity and osteoporosis share common genetic and environmental factors.Despite being a risk factor for health,obesity has traditionally been considered positive to bone because of beneficial effect of mechanical loading,exerted by high body mass,on bone formation.However,contrasting studies have not achieved a clear consensus,suggesting instead that excessive fat mass derived from obesity condition may not protect against osteoporosis or,even worse,could be rather detrimental to bone.On the other hand,it is hitherto better established that,since adipocytes and osteoblasts are derived from a common mesenchymal stem cell precursor,molecules that lead to osteoblastogenesis inhibit adipogenesis and vice versa.Here we will discuss the role of the key molecules regulating adipocytes and osteoblasts differentiation,which are peroxisome proliferators activated receptor-γand Wnts,respectively.In particular,wewill focus on the role of both canonical and non-canonical Wnt signalling,involved in mesenchymal cell fate regulation.Moreover,at present there are no experimental data that relate any influence of the Wnt inhibitor Sclerostin to adipogenesis,although it is well known its role on bone metabolism.In addition,the most common pathological condition in which there is a simultaneous increase of adiposity and decrease of bone mass is menopause.Given that postmenopausal women have high Sclerostin level inversely associated with circulating estradiol level and since the sex hormone replacement therapy has proved to be effective in attenuating bone loss and reversing menopause-related obesity,we hypothesize that Sclerostin contribution in adipogenesis could be an active focus of research in the coming years.
基金supported by the National Natural Science Foundation of China Grant No.30771858Jiangsu Provincial Natural Science Foundation Grant No.BK2007229Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)
文摘This study was aimed to explore the associations between the combined effects of several polymorphisms in the PPAR-γ and RXR-α gene and environmental factors with the risk of metabolic syndrome by back-error propaga- tion artificial neural network （BPANN）. We established the model based on data gathered from metabolic syndrome patients （n = 1012） and normal controls （n = 1069） by BPANN. Mean impact value （MIV） for each input variable was calculated and the sequence of factors was sorted according to their absolute MIVs. Generalized multifactor dimensionality reduction （GMDR） confirmed a joint effect of PPAR-9＂ and RXR-a based on the results from BPANN. By BPANN analysis, the sequences according to the importance of metabolic syndrome risk fac- tors were in the order of body mass index （BMI）, serum adiponectin, rs4240711, gender, rs4842194, family history of type 2 diabetes, rs2920502, physical activity, alcohol drinking, rs3856806, family history of hypertension, rs1045570, rs6537944, age, rs17817276, family history of hyperlipidemia, smoking, rs1801282 and rs3132291. However, no polymorphism was statistically significant in multiple logistic regression analysis. After controlling for environmental factors, A1, A2, B1 and B2 （rs4240711, rs4842194, rs2920502 and rs3856806） models were the best models （cross-validation consistency 10/10, P = 0.0107） with the GMDR method. In conclusion, the interaction of the PPAR-γ and RXR-α gene could play a role in susceptibility to metabolic syndrome. A more realistic model is obtained by using BPANN to screen out determinants of diseases of multiple etiologies like metabolic syndrome.
文摘Objective： To explore the molecular mechanism of puerarin （Pue） in improving insulin resistance through observing its effect on the insulin resistance of 3T3-Li lipocyte induced by free fatty acid （FFA）. Methods： 3T3-L1 preadipocyte was induced by a culture solution containing insulin, isobutyo-menthyl-xanthine, and dexamethasone to mature lipocyte, and it was divided into six groups： the control group （normal cells）, the model group （untreated model cells）, and the four drug treatment group exposed to dimethyl biguanide （Met group）, high- dose pueradn （PueH group）, low-dose puerarin （PueL group）, and propylene glycol （PG group）, respectively. Mature lipocytes in various groups, except those in the normal group, were established into insulin resistance model by FFA induction and treated respectively with corresponding drugs. Peroxisome proliferator-activated receptor- γ （PPAR- γ） mRNA expressions at the fourth, sixth, and eighth day were observed using reverse transcription polymerase chain reaction （RT-PCR）; glucose transportation in various groups were observed by 2-deoxy-[3H]-D-glucose intake method; mRNA expression of Cbl binding protein （CAP） was determined by RT-PCR; and glucose transporter-4 （Glut-4） transposition was detected by immune-fluorescence method. Results： PPAR- γmRNA expression increased gradually, and it showed lower levels at the fourth, sixth, and eighth day in all treatment groups than that in the model group. Glucose transportation determination showed that the transportation in the model group was 2.23 ± 0.63, significantly lower than that in the normal group 5.05 ± 0.66 （P〈0.01）; as compared with the model group, they were significantly higher in the PueH and the PueL groups. In addition, the CAP mRNA expression and membranous distribution of Glut-4 were higher in the two Pue treated groups than those in the model group, respectively. Conclusion： Pue could markedly improve the insulin resistance of 3T3-L1 lipocyte, which is realized possibly by way of inactivating CAP path, promoting Glut-4 transposition to cell membrane to increase the transportation of glucose.
