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1.
Sci Rep ; 13(1): 16552, 2023 10 02.
Article in English | MEDLINE | ID: mdl-37783777

ABSTRACT

Basal cell carcinoma (BCC) is the most common cancer with a rising incidence among white-skinned individuals. A number of epidemiological studies have suggested that obesity and serum 25-hydroxy-vitamin D (25(OH)D) levels may affect the arising of BCC. To address this, we selected 443 and 96 single nucleotide polymorphisms (SNPs) associated with body mass index (BMI) and serum level of 25(OH)D from large-scale genome-wide association studies (GWAS), respectively. The univariable and multivariable two-sample Mendelian randomization (MR) analyses were conducted with a series of sensitivity analyses to ensure the results were reliable and reproducible. The results of univariable two-sample MR analysis showed that higher BMI was related to lower risk for BCC (Odds ratio(OR) = 0.90; 95% confidence interval (CI),[0.81,0.99]; p = 0.02). In addition, this causal effect of BMI on BCC still remained (OR = 0.88; 95%CI,[- 0.22, - 0.03], p-value = 0.008) after adjusting for 25(OH)D level in the multivariable MR analysis. However, the results suggested that 25(OH)D level was not associated with BCC(OR = 1.02; 95%CI, [0.94,1.09], p-value = 0.67). In conclusion, similar to the conclusions of retrospective observational studies, the MR results indicate that high BMI is an independent protective factor for BCC. Meanwhile, vitamin D levels may not be causally associated with the risk of basal cell carcinoma and increasing vitamin D supplementation is unlikely to reduce the risk.


Subject(s)
Carcinoma, Basal Cell , Genome-Wide Association Study , Humans , Body Mass Index , Mendelian Randomization Analysis/methods , Retrospective Studies , Vitamin D , Calcifediol , Carcinoma, Basal Cell/epidemiology , Carcinoma, Basal Cell/genetics , Polymorphism, Single Nucleotide
2.
PLoS Genet ; 19(2): e1010629, 2023 02.
Article in English | MEDLINE | ID: mdl-36787291

ABSTRACT

Pharmacological vitamin C (VC) is a potential natural compound for cancer treatment. However, the mechanism underlying its antitumor effects remains unclear. In this study, we found that pharmacological VC significantly inhibits the mTOR (including mTORC1 and mTORC2) pathway activation and promotes GSK3-FBXW7-mediated Rictor ubiquitination and degradation by increasing the cellular ROS. Moreover, we identified that HMOX1 is a checkpoint for pharmacological-VC-mediated mTOR inactivation, and the deletion of FBXW7 or HMOX1 suppresses the regulation of pharmacological VC on mTOR activation, cell size, cell viability, and autophagy. More importantly, it was observed that the inhibition of mTOR by pharmacological VC supplementation in vivo produces positive therapeutic responses in tumor growth, while HMOX1 deficiency rescues the inhibitory effect of pharmacological VC on tumor growth. These results demonstrate that VC influences cellular activities and tumor growth by inhibiting the mTOR pathway through Rictor and HMOX1, which may have therapeutic potential for cancer treatment.


Subject(s)
Ascorbic Acid , Neoplasms , Humans , F-Box-WD Repeat-Containing Protein 7/metabolism , Ascorbic Acid/pharmacology , Glycogen Synthase Kinase 3/metabolism , Rapamycin-Insensitive Companion of mTOR Protein/genetics , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Mechanistic Target of Rapamycin Complex 2/genetics , Mechanistic Target of Rapamycin Complex 2/metabolism , Neoplasms/drug therapy , Neoplasms/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism , Transcription Factors/metabolism , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism
3.
J Bone Miner Res ; 20(6): 1022-31, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15883643

ABSTRACT

UNLABELLED: The intracellular signaling pathways controlling chondrocyte physiology are largely unknown. Here we show that the small GTPases, Rac1 and Cdc42, accelerate the rate of chondrocyte differentiation and apoptosis, thereby antagonizing the activity of RhoA. These results identify Rac1 and Cdc42 pathways as novel regulators of cartilage development. INTRODUCTION: Proliferation, hypertrophic differentiation, and ultimate apoptosis of chondrocytes regulate endochondral bone growth and development, but the intracellular signaling pathways controlling chondrocyte biology are incompletely understood. In this study, we investigated the role of the small GTPases Rac1 and Cdc42 in chondrocytes. MATERIALS AND METHODS: Rac1 and Cdc42 expression during chondrogenic differentiation was assessed by RT-PCR and Western blotting. Effects of Rac1 and Cdc42 on parameters of chondrocyte biology were studied using transient transfections into primary mouse chondrocytes and stable transfections of the chondrogenic cell line ATDC5. Luciferase assays, RT-PCR, cell proliferation, alkaline phosphatases assays, staining procedures, TUNEL assays, and caspase activity assays were performed to study the chondrocyte response to overexpression of Rac1 and Cdc42 proteins. Activation of the p38 pathway was analyzed using Western blotting with phospho-specific antibodies, and mitogen-activated protein (MAP) kinase pathways were inhibited using pharmacological approaches. RESULTS AND CONCLUSIONS: Rac1 and Cdc42 activities are required for maximal activity of the collagen X promoter, a hypertrophic marker, in primary chondrocytes, suggesting essential roles of these GTPases in chondrocyte hypertrophy. Overexpression of Rac1 or Cdc42 in chondrogenic ATDC5 cells results in reductions in cell numbers and marked acceleration of hypertrophic differentiation, thus opposing the effects of the related GTPase RhoA. Rac1 and Cdc42 also induce accelerated chondrocyte apoptosis, as shown by TUNEL and caspase activity assays and changes in cell morphology and actin organization. Rac1 and Cdc42 overexpression results in activation of the p38 MAP kinase pathway in ATDC5 cells, and pharmacological inhibition of p38 signaling blocks the effects of Rac1 and Cdc42 overexpression on hypertrophy and apoptosis. Our results therefore suggest that Rac1 and Cdc42 signaling accelerates progression through the chondrocyte life cycle in a p38-dependent fashion and antagonizes RhoA signaling pathways in chondrocyte proliferation, hypertrophy, and apoptosis.


Subject(s)
Chondrocytes/cytology , cdc42 GTP-Binding Protein/physiology , rac1 GTP-Binding Protein/physiology , rhoA GTP-Binding Protein/physiology , Actins/metabolism , Alkaline Phosphatase/metabolism , Animals , Apoptosis , Blotting, Western , Cell Differentiation , Cell Line , Cell Proliferation , Collagen Type X/genetics , DNA, Complementary/metabolism , Enzyme Activation , Hypertrophy , In Situ Nick-End Labeling , Luciferases/metabolism , Mice , Promoter Regions, Genetic , RNA/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Transfection , p38 Mitogen-Activated Protein Kinases/metabolism
4.
Zhongguo Zhong Yao Za Zhi ; 28(8): 738-40, 2003 Aug.
Article in Chinese | MEDLINE | ID: mdl-15015355

ABSTRACT

OBJECTIVE: To determine the content of shionone in Radix Aster from several different locations and markets. METHOD: The HPLC analysis was used to determine shionone directly, using Polaris C18 column and acetonitrile as the mobile phase with a flow rate of 1.0 mL.min-1, and the UV detection wavelength was 200 nm. RESULT AND CONCLUSION: The content of shionone was from 0.06% to 0.18%, depending on different locations and markets.


Subject(s)
Aster Plant/chemistry , Plants, Medicinal/chemistry , Triterpenes/analysis , China , Chromatography, High Pressure Liquid/methods , Drugs, Chinese Herbal/analysis , Ecosystem , Plant Roots/chemistry
5.
Zhongguo Zhong Yao Za Zhi ; 28(10): 946-8, 2003 Oct.
Article in Chinese | MEDLINE | ID: mdl-15620184

ABSTRACT

OBJECTIVE: To study the chemical constituents in root and rhizome of Aster tataricus. METHODS: Compounds were isolated and purified by silica gel and sephadex LH-20 column chromatography. Their structures were identified by physicochemical properties and spectral analysis. RESULT: Nine compounds were isolated and identified as quercetin (I), kaemferol (II), emodin (III), chrysophanol (IV), physcion (V), benzoic acid (VI), p-hydroxy-bezoic acid (VII), E-caffeic acid (VIII), E-ferulic acid hexacosyl ester (IX). CONCLUSION: Compounds IV, V, VI, VII, VIII, IX were isolated from A. tataricus for the first time.


Subject(s)
Anthraquinones/isolation & purification , Aster Plant/chemistry , Benzoic Acid/isolation & purification , Emodin/analogs & derivatives , Plants, Medicinal/chemistry , Anthraquinones/chemistry , Benzoic Acid/chemistry , Emodin/chemistry , Emodin/isolation & purification , Rhizome/chemistry
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