Evidence for low-density lipoprotein–induced expression of connective tissue growth factor in mesangial cells

Evidence for low-density lipoprotein–induced expression of connective tissue growth factor in mesangial cells.BackgroundAlthough hyperlipidemia is a risk factor for the progression of renal damage, the relationship between increased plasma lipoproteins and glomerular injury is poorly defined. Connective tissue growth factor (CTGF) is emerging as a key determinant of progressive fibrotic diseases and its expression is up-regulated by diabetes. To define the mechanisms through which low-density lipoproteins (LDLs) promote glomerular injury, we evaluated whether LDL can modulate the expression of CTGF and collagen I.MethodsThe effects of LDL on CTGF and collagen I expression were carried out in rat mesangial cells.ResultsTreatment of mesangial cells with LDL for 24 hours produced a significant increase in the protein levels of CTGF and collagen I compared to unstimulated controls. To explore if CTGF and collagen I are downstream targets for regulation by transforming growth factor-β (TGF-β), mesangial cells were treated with various concentration of TGF-β for 24 hours. TGF-β produced a concentration-dependent increase in the protein levels of CTGF and collagen I. The increase in CTGF and collagen I induced by LDL was significantly inhibited by neutralizing anti-TGF-β antibodies. Inhibition of p38mapk or p42/44mapk activities did not affect LDL-induced TGF-β1, CTGF, and collagen I expression, whereas inhibition of c-Jun NH2-terminal kinase (JNK) suppressed LDL-induced TGF-β, CTGF, and collagen I expression.ConclusionThese findings implicate JNK pathway and TGF-β1 as key players in LDL signaling leading to CTGF and collagen I expression in mesangial cells. The data also point to a potential mechanistic pathway through which lipoproteins may promote glomerular injury

Table_2_Social and racial inequalities in diabetes and cancer in the United States.DOCX

BackgroundCancer and diabetes are among the leading causes of morbidity and mortality worldwide. Several studies have reported diabetes as a risk factor for developing cancer, a relationship that may be explained by associated factors shared with both diseases such as age, sex, body weight, smoking, and alcohol consumption. Social factors referred to as social determinants of health (SDOH) were shown to be associated with the risk of developing cancer and diabetes. Despite that diabetes and social factors were identified as significant determinants of cancer, no studies examined their combined effect on the risk of developing cancer. In this study, we aim at filling this gap in the literature by triangulating the association between diabetes, indices of SDOH, and the risk of developing cancer.MethodsWe have conducted a quantitative study using data from the Behavioral Risk Factor Surveillance System (BRFSS), whereby information was collected nationally from residents in the United States (US) with respect to their health-related risk behaviors, chronic health conditions, and the use of preventive services. Data analysis using weighted regressions was conducted on 389,158 study participants.ResultsOur findings indicated that diabetes is a risk factor that increases the likelihood of cancer by 13% (OR 1.13; 95%CI: 1.05–1.21). People of White race had higher odds for cancer compared to African Americans (OR 0.44; 95%CI: 0.39–0.49), Asians (OR 0.27; 95%CI: 0.20–0.38), and other races (OR 0.56; 95%CI: 0.46–0.69). The indices of SDOH that were positively associated with having cancer encompassed unemployment (OR 1.78; 95%CI: 1.59–1.99), retirement (OR 1.54; 95%CI: 1.43–1.67), higher income levels with ORs ranging between 1.16–1.38, college education (OR 1.10; 95%CI: 1.02–1.18), college graduates (OR 1.31; 95%CI: 1.21–1.40), and healthcare coverage (OR 1.44; 95%CI: 1.22–1.71). On the other hand, the indices of SDOH that were protective against having cancer were comprised of renting a home (OR 0.86; 95%CI: 0.79–0.93) and never married (OR 0.73; 95%CI: 0.65–0.81).ConclusionThis study offers a novel social dimension for the association between diabetes and cancer that could guide setting strategies for addressing social inequities in disease prevention and access to healthcare.</p

Heteromerization fingerprints between bradykinin B2 and thromboxane TP receptors in native cells.

Bradykinin (BK) and thromboxane-A2 (TX-A2) are two vasoactive mediators that modulate vascular tone and inflammation via binding to their cognate "class A" G-protein coupled receptors (GPCRs), BK-B2 receptors (B2R) and TX-prostanoid receptors (TP), respectively. Both BK and TX-A2 lead to ERK1/2-mediated vascular smooth muscle cell (VSMC) proliferation and/or hypertrophy. While each of B2R and TP could form functional dimers with various GPCRs, the likelihood that B2R-TP heteromerization could contribute to their co-regulation has never been investigated. The main objective of this study was to investigate the mode of B2R and TP interaction in VSMC, and its possible impact on downstream signaling. Our findings revealed synergistically activated ERK1/2 following co-stimulation of rat VSMC with a subthreshold dose of BK and effective doses of the TP stable agonist, IBOP, possibly involving biased agonist signaling. Single detection of each of B2R and TP in VSMC, using in-situ proximity ligation assay (PLA), provided evidence of the constitutive expression of nuclear and extranuclear B2R and TP. Moreover, inspection of B2R-TP PLA signals in VSMC revealed agonist-modulated nuclear and extranuclear proximity between B2R and TP, whose quantification varied substantially following single versus dual agonist stimulations. B2R-TP interaction was further verified by the findings of co-immunoprecipitation (co-IP) analysis of VSMC lysates. To our knowledge, this is the first study that provides evidence supporting the existence of B2R-TP heteromerization fingerprints in primary cultured VSMC

Table_1_Social and racial inequalities in diabetes and cancer in the United States.DOCX

BackgroundCancer and diabetes are among the leading causes of morbidity and mortality worldwide. Several studies have reported diabetes as a risk factor for developing cancer, a relationship that may be explained by associated factors shared with both diseases such as age, sex, body weight, smoking, and alcohol consumption. Social factors referred to as social determinants of health (SDOH) were shown to be associated with the risk of developing cancer and diabetes. Despite that diabetes and social factors were identified as significant determinants of cancer, no studies examined their combined effect on the risk of developing cancer. In this study, we aim at filling this gap in the literature by triangulating the association between diabetes, indices of SDOH, and the risk of developing cancer.MethodsWe have conducted a quantitative study using data from the Behavioral Risk Factor Surveillance System (BRFSS), whereby information was collected nationally from residents in the United States (US) with respect to their health-related risk behaviors, chronic health conditions, and the use of preventive services. Data analysis using weighted regressions was conducted on 389,158 study participants.ResultsOur findings indicated that diabetes is a risk factor that increases the likelihood of cancer by 13% (OR 1.13; 95%CI: 1.05–1.21). People of White race had higher odds for cancer compared to African Americans (OR 0.44; 95%CI: 0.39–0.49), Asians (OR 0.27; 95%CI: 0.20–0.38), and other races (OR 0.56; 95%CI: 0.46–0.69). The indices of SDOH that were positively associated with having cancer encompassed unemployment (OR 1.78; 95%CI: 1.59–1.99), retirement (OR 1.54; 95%CI: 1.43–1.67), higher income levels with ORs ranging between 1.16–1.38, college education (OR 1.10; 95%CI: 1.02–1.18), college graduates (OR 1.31; 95%CI: 1.21–1.40), and healthcare coverage (OR 1.44; 95%CI: 1.22–1.71). On the other hand, the indices of SDOH that were protective against having cancer were comprised of renting a home (OR 0.86; 95%CI: 0.79–0.93) and never married (OR 0.73; 95%CI: 0.65–0.81).ConclusionThis study offers a novel social dimension for the association between diabetes and cancer that could guide setting strategies for addressing social inequities in disease prevention and access to healthcare.</p

Table_3_Social and racial inequalities in diabetes and cancer in the United States.docx

BackgroundCancer and diabetes are among the leading causes of morbidity and mortality worldwide. Several studies have reported diabetes as a risk factor for developing cancer, a relationship that may be explained by associated factors shared with both diseases such as age, sex, body weight, smoking, and alcohol consumption. Social factors referred to as social determinants of health (SDOH) were shown to be associated with the risk of developing cancer and diabetes. Despite that diabetes and social factors were identified as significant determinants of cancer, no studies examined their combined effect on the risk of developing cancer. In this study, we aim at filling this gap in the literature by triangulating the association between diabetes, indices of SDOH, and the risk of developing cancer.MethodsWe have conducted a quantitative study using data from the Behavioral Risk Factor Surveillance System (BRFSS), whereby information was collected nationally from residents in the United States (US) with respect to their health-related risk behaviors, chronic health conditions, and the use of preventive services. Data analysis using weighted regressions was conducted on 389,158 study participants.ResultsOur findings indicated that diabetes is a risk factor that increases the likelihood of cancer by 13% (OR 1.13; 95%CI: 1.05–1.21). People of White race had higher odds for cancer compared to African Americans (OR 0.44; 95%CI: 0.39–0.49), Asians (OR 0.27; 95%CI: 0.20–0.38), and other races (OR 0.56; 95%CI: 0.46–0.69). The indices of SDOH that were positively associated with having cancer encompassed unemployment (OR 1.78; 95%CI: 1.59–1.99), retirement (OR 1.54; 95%CI: 1.43–1.67), higher income levels with ORs ranging between 1.16–1.38, college education (OR 1.10; 95%CI: 1.02–1.18), college graduates (OR 1.31; 95%CI: 1.21–1.40), and healthcare coverage (OR 1.44; 95%CI: 1.22–1.71). On the other hand, the indices of SDOH that were protective against having cancer were comprised of renting a home (OR 0.86; 95%CI: 0.79–0.93) and never married (OR 0.73; 95%CI: 0.65–0.81).ConclusionThis study offers a novel social dimension for the association between diabetes and cancer that could guide setting strategies for addressing social inequities in disease prevention and access to healthcare.</p

Analysis of longitudinal semicontinuous data using marginalized two-part model

Abstract Background Connective tissue growth factor (CTGF), is a secreted matricellular factor that has been linked to increased risk of cardiovascular disease in diabetic subjects. Despite the biological role of CTGF in diabetes, it still remains unclear how CTGF expression is regulated. In this study, we aim to identify the clinical parameters that modulate plasma CTGF levels measured longitudinally in type 1 diabetic patients over a period of 10 years. A number of patients had negligible measured values of plasma CTGF that formed a point mass at zero, whereas others had high positive values of CTGF that were measured on a continuous scale. The observed combination of excessive zero and continuous positively distributed non-zero values in the CTGF outcome is referred to as semicontinuous data. Methods We propose a novel application of a marginalized two-part model (mTP) extended to accommodate longitudinal semicontinuous data in which the marginal mean is expressed in terms of the covariates and estimates of their effect on the mean responses are generated. The continuous component is assumed to follow distributions that stem from the generalized gamma family whereas the binary measure is analyzed using logistic model and both have correlated random effects. Other approaches including the one- and two-part with uncorrelated and correlated random effects models were also applied and their estimates were all compared. Results Our results using the mTP model identified intensive glucose control treatment and smoking as clinical factors that were associated with decreased and increased odds of observing non-zero CTGF values respectively. In addition, hemoglobin A1c, systolic blood pressure, and high density lipoprotein were all shown to be significant risk factors that contribute to increasing CTGF levels. These findings were consistently observed under the mTP model but varied with the distributions for the other models. Accuracy and precision of the mTP model was further validated using simulation studies. Conclusion The mTP model identified new clinical determinants that modulate the levels of CTGF in diabetic subjects. Applicability of this approach can be extended to other biomarkers measured in patient populations that display a combination of negligible zero and non-zero values

Renal kallikrein: a risk marker for nephropathy in children with sickle cell disease

Although improvements in the management of sickle cell disease (SCD) have increased patient survival into adulthood, morbidity and mortality from end-organ damage remain major concerns. One of the most serious complications of SCD is renal failure, affecting about 20% of patients. The clinical manifestations of sickle cell nephropathy (SCN) involve changes in glomerular ultrastructure, albuminuria, and a progressive decline in glomerular hemodynamics. The mechanisms or factors that promote SCN are not fully elucidated. In the present study, the role of renal kallikrein as a risk marker for promoting SCN was explored in a cross-sectional study. We measured the urinary excretion rate of active kallikrein in 73 children with sickle cell anemia (hemoglobin SS, SC, or S thalassemia) and in 30 control healthy African American children. The findings demonstrated that a significant difference in the excretion rate of log kallikrein in male versus female patients with SCD, P<0.0078 was observed. In children with SCD, cross-sectional analysis revealed a positive and significant correlation between the excretion rate of active kallikrein and log albumin excretion rate (AER), P<0.0088. Regression analysis also determined that the excretion rate of active kallikrein negatively correlates with hemoglobin in children with SCD, P<0.0096. In addition, an inverse relationship between log AER and hemoglobin was observed in male patients with SCD, P<0.0143. In children with SCD, cross-sectional analysis revealed a positive and significant correlation between log AER and age, suggesting age as a risk marker for AER in SCD. In multivariate regression analysis, our findings demonstrate a strong association between log AER and age and log kallikrein in children with SCD. About 20% of the variability in log AER in SCD patients is influenced by age and 6% is influenced by log kallikrein, P<0.0001 and P<0.02, respectively. These findings provide the first evidence that the excretion rate of active kallikrein is positively and independently correlated with log AER in children with SCD, and suggest that kallikrein could be a marker for progressive nephropathy. Longitudinal studies are essential to address this issue