1. To investigate Genkwa Flos hepatotoxicity, a cell metabolomics strategy combined with serum pharmacology was performed on human HL-7702 liver cells in this study.
2. Firstly, cell viability and biochemical indicators were determined and the cell morphology was observed to confirm the cell injury and develop a cell hepatotoxicity model. Then, with the help of cell metabolomics based on UPLC-MS, the Genkwa Flos group samples were completely separated from the blank group samples in the score plots and seven upregulated as well as two down-regulated putative biomarkers in the loading plot were identified and confirmed. Besides, two signal molecules and four enzymes involved in biosynthesis pathway of lysophosphatidylcholine and the sphingosine kinase/sphingosine-1-phosphate pathway were determined to investigate the relationship between Genkwa Flos hepatotoxicity and these two classic pathways. Finally, the metabolic pathways related to specific biomarkers and two classic metabolic pathways were analyzed to explain the possible mechanism of Genkwa Flos hepatotoxicity.
3. Based on the results, lipid peroxidation and oxidative stress, phospholipase A2/lysophosphatidylcholine pathway, the disturbance of sphingosine-1-phosphate metabolic profile centered on sphingosine kinase/sphingosine-1-phosphate pathway and fatty acid metabolism might be critical participators in the progression of liver injury induced by Genkwa Flos. 相似文献
Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future. 相似文献
Low back pain (LBP) is a common complaint in clinical practice of multifactorial origin. Although obesity has been thought to contribute to LBP primarily by altering the distribution of mechanical loads on the spine, the additional contribution of obesity-related conditions such as diabetes mellitus (DM) to LBP has not been thoroughly examined.
Purpose
To determine if there is a relationship between DM and LBP that is independent of body mass index (BMI) in a large cohort of adult survey participants.
Study Design
Retrospective analysis of prospectively collected National Health and Nutrition Examination Survey (NHANES) data to characterize associations between LBP, DM, and BMI in adults subdivided into 6 subpopulations: normal weight (BMI 18.5–25), overweight (BMI 25–30), and obese (BMI >30) diabetics and nondiabetics. Diabetes was defined with glycohemoglobin A1c (HbA1c) ≥6.5%.
Patient Sample
11,756 participants from NHANES cohort.
Outcome Measures
Percentage of LBP reported.
Methods
LBP reported in the 1999-2004 miscellaneous pain NHANES questionnaire was the dependent variable examined. Covariates included HbA1c, BMI, age, and family income ratio to poverty as continuous variables as well as race, gender, and smoking as binary variables. Individuals were further subdivided by weight class and diabetes status. Regression and graphical analyses were performed on the study population as a whole and also on subpopulations.
Results
Increasing HbA1c did not increase the odds of reporting LBP in the full cohort. However, multivariate logistic regression of the 6 subpopulations revealed that the odds of LBP significantly increased with increasing HbA1c levels in normal weight diabetics. No other subpopulations reported significant relationships between LBP and HbA1c. LBP was also significantly associated with BMI for normal weight diabetics and also for obese subjects regardless of their DM status.
Conclusions
LBP is significantly related to DM status, but this relationship is complex and may interact with BMI. These results support the concept that LBP may be improved in normal weight diabetic subjects with improved glycemic control and weight loss, and that all obese LBP subjects may benefit from improved weight loss alone. 相似文献
Background: Intraductal carcinoma and cribriform (IDC/C) tumor features are well-established prognosticators of biochemical recurrence (BCR), metastasis, and prostate cancer (PCa)-specific mortality. However, approximately 70% of PCa patients undergoing a radical prostatectomy are IDC/C negative, yet up-to 20% of these patients progress and experience BCR. Thus, tumor histopathologic characteristics such as IDC/C alone are limited in their ability to predict disease progression. Conversely, several nomograms such as Cancer of the Prostate Risk Assessment-Surgery (CAPRA-S) have been developed to aid in the prognostication of BCR, but not yet widely applied in clinical settings. Materials and methods: In this study, we assessed the combined prognostic utility of IDC/C, and CAPRA-S for BCR in 3 PCa patient cohorts. Results: CAPRA-S+IDC/C improved the predictive accuracy of BCR in all 3 cohorts (P < .001). Specifically, among IDC/C negative cases, CAPRA-S improved the prognostication of BCR in low-risk (Cohort 1; P < .001, Cohort 2; P < .001, Cohort 3; P = .003), intermediate (Cohort 1; P < .001, Cohort 2; P = .006, Cohort 3; P = .03) and high-risk (Cohort 1-3; P < .001) patients. Conversely, IDC/C improved the prognostication of BCR among CAPRA-S low-risk (Cohorts 1; P < .001 and Cohort 3; P = .003) patients. Conclusion: Our results suggest the investigation of histopathological IDC/C features in CAPRA-S low-risk patients and conversely, nomogram CAPRA-S among IDC/C negative patients improves the identification of patients likely to experience BCR, which would otherwise be missed through current assessment regimens. These patients can be offered more intensive monitoring and adjuvant therapies upfront to circumvent the development of recurrent cancer or overtreatment at the time of surgery. 相似文献
ObjectiveIdentify factors associated with healthcare providers' frequency of depot medroxyprogesterone acetate (DMPA) provision to adolescents.Study designWe analyzed data from surveys mailed to a nationally representative sample of public-sector providers and office-based physicians (n=1984). We estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) of factors associated with frequent DMPA provision to adolescents in the past year.ResultsAlthough most providers (>95%) considered DMPA safe for adolescents, fewer reported frequent provision (89% of public-sector providers; 64% of office-based physicians). Among public-sector providers, factors associated with lower odds of frequent provision included working in settings without Title X funding (aOR 0.44, 95% CI 0.30–0.64), reporting primary care as their primary clinical focus versus reproductive or adolescent health (aOR 0.42, 95% CI 0.28–0.61), and providing fewer patients with family planning services. Among office-based physicians, factors associated with lower odds of frequent provision included specializing in obstetrics/gynecology (aOR 0.50, 95% CI 0.27–0.91) and family medicine (aOR 0.21, 95% CI 0.09–0.47) versus adolescent medicine, completing training ≥15 versus <5 years ago (aOR 0.27, 95% CI 0.09–0.83), and reporting that 0–24% of patients pay with Medicaid or other government healthcare assistance versus ≥50% (aOR 0.23, 95% CI 0.09–0.61). The reason most commonly reported by providers for infrequent DMPA provision was patient preference for another method.ConclusionsWhile most providers reported frequently providing DMPA to adolescents, training on evidence-based recommendations for contraception, focused on subgroups of providers with lower odds of frequent DMPA provision, may increase adolescents' access to contraception.ImplicationsAlthough >95% of providers considered depot medroxyprogesterone (DMPA) a safe contraceptive for adolescents, only 89% of public-sector providers and 64% of office-based physicians reported frequently providing DMPA to adolescents. Provider training on evidence-based recommendations for contraception counseling and provision may increase adolescents' access to DMPA and all methods of contraception. 相似文献