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ABSTRACT: While caloric restriction (CR) is associated with a prolonged lifespan in multiple species by regulating metabolism, a comprehensive profile of metabolism under CR conditions remains largely unclear. Therefore, in this study we aimed to characterize the metabolomic profiling associated with CR using a rat model.
Rapid resolution liquid chromatography/electrospray ionization quadrupole-time of flight mass spectrometry (RRLC/ESI-Q-TOFMS) was employed to analyze metabolomic profiling of urine samples from aging rats who underwent caloric restriction (CR; n=7) or were provided a normal diet (N; n=8) for 12 weeks time. Multivariate data analysis was performed on the mass data of metabolomic profiles to uncover the differences between the CR and N groups.
CR treatment led to manifest metabolic changes in aging rats, and fifteen urinary metabolites including hypoxanthine, hippurate, dimethylglycine and creatinine were significantly different in the rat groups.
Our study demonstrates the high reliability of the HPLC-based metabolomic approach towards the study of anti-aging effects induced by CR, while the urinary metabolites we identified may become potential biomarkers of aging.
Aging clinical and experimental research 02/2011; 24(1):79-84. · 1.55 Impact Factor
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ABSTRACT: Although pioglitazone, a PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) agonist, has been shown to prolong survival in two rapidly progressive pkd1 (polycystic kidney disease 1)-knockout mice models through disparate mechanisms, these studies lacked data on therapeutic potential and long-term safety because of a short observation period. In the present study, we have used another potent PPAR-gamma agonist, rosiglitazone, to treat Han:SPRD rats, a slowly progressive ADPKD (autosomal dominant PKD) animal model, and confirmed that short-term treatment was able to delay the progression of kidney cysts and protect renal function, which may relate to down-regulating the abnormally activated beta-catenin signalling pathway and its anti-inflammatory and anti-fibrosis effects. Long-term administration significantly prolonged the survival of Han:SPRD rats. Moreover, early therapy in rats with normal renal function had a better outcome than delayed therapy, while initiating therapy in rats with mild impaired renal function still protected renal function. The efficacy of rosiglitazone depended on continuous drug administration; withdrawal of the drug caused accelerated deterioration of renal function in effectively treated rats and shortened their survival to an untreated state. Long-term administration led to cardiac enlargement, probably due to rosiglitazone-mediated sodium re-absorption. In conclusion, these results indicate that rosiglitazone was able to effectively delay the progression of kidney disease and protect renal function in Han:SPRD rats, but its adverse effect of inducing cardiac enlargement should also be monitored closely.
Clinical Science 10/2010; 119(8):323-33. · 4.61 Impact Factor
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ABSTRACT: Due to chemotherapy resistance in osteosarcoma subgroups, the prognosis of these patients is still poor, and the development of new agents is of utmost importance. The aim of our study was to test the antitumor effects of two novel alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives as peroxisome proliferator-activated receptor (PPAR) gamma agonists, together with rosiglitazone, a well-known thiazolidinedione (TZD) acting on several osteosarcoma cell lines.
The MTT assay revealed that cell viability was inhibited in a dose-dependent manner with IC(50) 6.2-15.8 microM for the two novel compounds and rosiglitazone (48.4-83.5 microM). Exposure to DG8 and DH9 at low micromolar concentrations induced a dose-dependent block of DNA synthesis and colony formation. In these antitumor assays, DG8 and DH9 were more effective than rosiglitazone, although the PPARgamma agonistic activity of rosiglitazone is much higher. The SiRNA approach to downregulate specifically PPARgamma in U-2OS cells did not affect the cytotoxic efficiency of either the two novel compounds or rosiglitazone.
These observations suggest that non-TZDs with less PPARgamma agonistic activity might show more potent antitumor efficacy independent of PPARgamma in human osteosarcoma cells, which supports the possibility that they could be beneficial in the treatment of osteosarcoma patients.
Chemotherapy 12/2009; 55(6):468-76. · 1.82 Impact Factor
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ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that exclusively progresses to renal failure. An important target for the treatment of ADPKD is to reduce cystic cell proliferation. PPARγ agonists such as TZDs are insulin sensitizing agents that have also been reported to decrease tumor growth. Here we tested DH9, a newly synthesized PPARγ agonist on the proliferation of an ADPKD cell line, WT9-12. DH9 showed a potent anti-proliferative activity against ADPKD cells. At high concentration, DH9 also induced apoptotic cell death. The effect of DH9 on cell proliferation was mediated by a PPARγ independent mechanism. Since DH9 decreased the levels of β-catenin in cells via a GSK3β mediated degradation pathway, this acts as a mechanism for growth inhibition by DH9.
Investigational New Drugs 09/2009; 28(6):783-90. · 3.36 Impact Factor
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Xishan Xiong,
Li Wang,
Yangliang Ye,
Lili Fu,
Minli Chen,
Qingyi Wang,
Moyan Liu,
Jing Tang,
Bing Dai,
Jianhua Shen,
Changlin Mei
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ABSTRACT: Numerous studies have documented that various naturally derived ligands or synthetic non-thiazolidinediones (TZD) as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have shown moderate or potent antitumor activities, which is PPARgamma independent or partially dependent. However, the PPARgamma agonistic or glucose-lowering activity is ranked first more often than antitumor activity to determine promising novel PPARgamma agonists for potential clinical use. In this study, we hypothesized that there might exist some compounds with less PPARgamma agonistic activity but potent antitumor activity. Thereafter, we evaluated the PPARgamma agonistic and antitumor activity of a novel series of alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives synthesized with the initial aim of developing novel PPARgamma agonists as hypoglycemic agents. MTT assay results revealed that several compounds were able to inhibit cell proliferation in a dose-dependent manner with IC(50) 12.7-29.7 microM, better than that of rosiglitazone (45.9-141 microM), although the PPARgamma agonistic activity of most compounds is much lower than rosiglitazone. Some compounds induced cell cycle arrest and apoptosis tested by Flow Cytometry. Oral administration of DH9 (100 mg/kg/d) for 21 days to BALB/c nude mice bearing xenografts including MGC-803, NCI-H460, HT-29 and OS-RC-2 cells significantly retarded tumor growth. DG8 and DJ5 showed benefits in some of the above four xenografts. Our findings demonstrate that these compounds have potent antitumor activity in vitro and in vivo and pyrimidinyl-arylpropionic acid derivatives might be viable resources in the development of new antineoplastic agents.
Investigational New Drugs 07/2009; 28(4):472-81. · 3.36 Impact Factor
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ABSTRACT: (E)-Ethyl 3,5-dimethyl-4-[(indolin-2-one-3-ylidene)methyl]-1H-pyrrole-2-carboxylate (B5) was one of the novel pyrrole-substituted indolinones synthesized in our research with the initial aim of developing selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKIs). However, B5 exhibited weak inhibitory potency against a variety of protein tyrosine kinases including EGFR, but potent kinase inhibition against several members of the cyclin-dependent kinase (CDK) family. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay demonstrated that B5 had approximately 500 times more potent antitumor activity than PD153035, a known standard EGFR-TKI, in a panel of ten epithelial cancer cell lines. B5 did not inhibit the phosphorylation of EGFR induced by EGF in vitro. DNA flow cytometric analysis revealed that B5 induced cell cycle arrest at G2/M phase and western blot analysis indicated that both CDK1 (Cdc2) and cyclin B1 proteins were decreased after B5 treatment. Our findings suggested the potential therapeutic applications of B5 in numerous cancers and a promising new template for further development of antitumor agents.
Investigational New Drugs 02/2009; 28(1):26-34. · 3.36 Impact Factor
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ABSTRACT: Epidermal growth factor receptor (EGFR) is one of the important protein tyrosine kinases (PTKs), whose blockade by tyrosine kinase inhibitors (TKIs) has been introduced in the treatment of advanced non-small-cell lung cancers (NSCLCs). However, intrinsic and acquired resistance to the clinically used erlotinib or gefitinib leads to poor overall prognosis. The novel EGFR-TKI will provide alternative choices in NSCLC treatment and might be beneficial. We have previously reported the design and synthesis of a novel class of PTK inhibitors featuring the N-(2-oxo-1,2-dihydro-quinolin-3-ylmethyl)-thiourea framework. In this study, we examined the antitumor effect of compound 5a (DC27) in a panel of human lung carcinoma cell lines. The results of a bromodeoxyurdine (BrdU) incorporation assay revealed that cell proliferation was inhibited in a dose-dependent manner, with an IC(50) of 2.5-12.9 microM, similar to gefitinib (1.1-15.6 microM). DC27 induced G(0)/G(1) arrest of cell cycle and apoptosis as tested by flow cytometry. DC27 markedly reduced tyrosine phosphorylation of EGFR and inhibited activation of Erk1/2 and AKT, two key downstream effectors of proliferation. In conclusion, DC27 has potent in vitro cytotoxicity against human lung carcinoma cells, possibly mediated by induction of apoptosis and cell cycle arrest in G(0)/G(1) phase.
Chemotherapy 11/2008; 54(6):463-74. · 1.82 Impact Factor
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Xishan Xiong,
Yangliang Ye,
Lili Fu,
Bing Dai,
Jieqiong Liu,
Jieshuang Jia,
Jing Tang,
Lin Li,
Li Wang,
Jianhua Shen,
Changlin Mei
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ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have shown benefit in treating diabetes mellitus, atherosclerosis and cancer. However, widespread use of thiazolidinediones (TZDs), the clinically used synthetic PPARgamma agonists, has been limited by adverse cardiovascular effects. Consequently, numerous novel non-TZD compounds were synthesized and antidiabetic efficacy was evaluated to identify PPARgamma agonists for potential clinical use. On the other hand, many studies have documented that the antitumor activity of PPARgamma agonists is PPARgamma independent. Here we hypothesized that there might exist some compounds with less PPARgamma agonistic activity or antidiabetic efficacy but potent antitumor activity. In this study, we evaluated the PPARgamma agonistic and antitumor activity of several newly synthesized alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives as PPARgamma agonists in a panel of human cancer cell lines, which showed promising antitumor activity without appreciable PPARgamma agonistic activity. The results of MTT assay revealed that cell viability was inhibited in a dose dependent manner with IC(50) 17.1-55.1 microM for all the novel compounds and rosiglitazone (17.2-165 microM). They induced cell cycle arrest and apoptosis tested by Flow Cytometry. In conclusion, our findings demonstrate that these compounds have potent in vitro cytotoxicity, the possible mechanism of which is through induction of apoptosis and cell cycle arrest.
Investigational New Drugs 09/2008; 27(3):223-32. · 3.36 Impact Factor
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ABSTRACT: Protein phosphorylation is a very important PTM. Phosphorylation/dephosphorylation of a protein can alter its behavior in almost every conceivable way. Previous studies indicate that abnormal phosphorylation is involved in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). However, large-scale proteomic analysis of altered phosphoproteins in ADPKD has not been reported. In this study, total proteins from ADPKD cystic kidney tissues (n = 5) and normal kidney tissues (n = 5) were extracted and phosphoproteins were enriched by phosphate metal affinity chromatography, then separated by 2-DE and identified by LC-MS/MS. Between the two groups, 48 protein spots showing more than a twofold difference were detected. Among them, 28 spots were up-regulated and 20 down-regulated in ADPKD kidney tissues. Of these, 38 different proteins were identified including cell signaling proteins, cytoskeleton proteins, mitochondria metabolic enzymes, antioxidant proteins, molecular chaperones, transcription factors and regulators. Two differential phosphoproteins, annexin II and tropomyosin, were further confirmed by immunoprecipitation and Western blot analysis. The results show that there are many kinds of abnormal phosphoproteins in ADPKD cystic kidney tissues. More studies on the functions of the differential phosphoproteins may provide us new clues for ADPKD pathogenesis and treatment.
Proteomics. Clinical applications 07/2008; 2(7-8):1153-66. · 1.97 Impact Factor
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ABSTRACT: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has led to dramatic clinical improvement in selected patients with non-small cell lung cancer (NSCLC). However, intrinsic and acquired resistance to EGFR-TKI remains a common phenomenon. Novel EGFR-TKI, structurally different with erlotinib or gefitinib might be beneficial for patients with NSCLC. In this study, we examined the antitumor effect of a newly synthesized novel EGFR tyrosine kinase inhibitor (Zhao260054). In vitro studies in a panel of four different human lung cancer cell lines revealed that Zhao260054 inhibited cell proliferation with high potency and induced G(0)/G(1) arrest of cell cycle and apoptosis. Zhao260054 markedly reduced phosphorylation of EGFR and inhibited activation of ERK1/2 and AKT. Oral administration of Zhao260054 (200 mg/kg/day) to BALB/c nude mice bearing SPC-A1 xenografts significantly retarded tumor growth. In conclusion, Zhao260054 has potent antitumor activity on human lung cancer in vitro and in vivo.
Investigational New Drugs 06/2008; 27(1):1-11. · 3.36 Impact Factor
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ABSTRACT: We aimed to explore the effect of Mycophenolate mofetil (MMF) on loss of renal function and cyst progression compared to rapamycin in Han: SPRD rats. We also sought to assess whether the effect of combination therapy of MMF plus rapamycin was better than that of monotherapy.
Sixty heterozygous (Cy/+) and littermate control (+/+) male Han: SPRD rats were weaned at 4 weeks of age, then divided into four groups randomly to receive different treatments by intragastric administration for 2 months: vehicle-treated group as control, MMF-treated group (20mg/kg/day), rapamycin-treated group (2mg/kg/day), and MMF+Rapa- treated group (MMF 20mg/kg/day plus Rapamycin 2mg/kg/day). RESULLS: After 2 months of treatment, rapamycin caused a 22 % decrease in body weight in comparison to the control group, whereas MMF had no significant effect on weight gain. The steady increase of BUN in Cy/+ rats was reduced by 15% in MMF-treated Cy/+ rats. However, rapamycin and combination therapy reduced BUN by 42% and 43%, respectively. CCr was 0.93+/-0.11ml/min in vehicle-treated Cy/+ rats, 1.67+/-0.23 ml/min in MMF-treated Cy/+ rats (P<0.05), 1.72+/-0.44 ml/min and 1.83+/-0.21 ml/min in rapamycin- and MMF+Rapa-treated Cy/+ rats, respectively (.P<0.01). Cyst volume density was 57.1 % in vehicle-treated Cy/+ rats, 45.2% in MMF-treated Cy/+ rats (P<0.05), 32.9% and 37.7% in rapamycin- and MMF+Rapa-treated Cy/+ rats, respectively (P<0.01). MMF markedly ameliorated interstitial inflammation and fibrosis. Rapamycin showed a similar effect on interstitial inflammation and fibrosis, but to a lesser degree.
MMF is more tolerable than rapamycin and can retard deterioration of renal function in Han: SPRD rats, though its effect is weaker than that of rapamycin. Combination therapy does not exert more favorable effect than monotherapy.
Biological research 42(4):437-44. · 1.03 Impact Factor
