Integrated miRNA-mRNA networks underlie attenuation of chronic ß-adrenergic stimulation-induced cardiac remodeling by minocycline.

Adverse cardiac remodeling contributes to heart failure development and progression, partly due to inappropriate sympathetic nervous system activation. Although ß-adrenergic receptor (ß-AR) blockade is a common heart failure therapy, not all patients respond, prompting exploration of alternative treatments. Minocycline, an FDA-approved antibiotic, has pleiotropic properties beyond antimicrobial action. Recent evidence suggests it may alter gene expression via changes in miRNA expression. Thus, we hypothesized that minocycline could prevent adverse cardiac remodeling induced by the ß-AR agonist isoproterenol, involving miRNA-mRNA transcriptome alterations. Male C57BL/6J mice received isoproterenol (30 mg/kg/day sc) or vehicle via osmotic minipump for 21 days, along with daily minocycline (50 mg/kg ip) or sterile saline. Isoproterenol induced cardiac hypertrophy without altering cardiac function, which minocycline prevented. Total mRNA sequencing revealed isoproterenol altering gene networks associated with inflammation and metabolism, with fibrosis activation predicted by integrated miRNA-mRNA sequencing, involving miR-21, miR-30a, miR-34a, miR-92a, and miR-150, among others. Conversely, the cardiac miRNA-mRNA transcriptome predicted fibrosis inhibition in minocycline-treated mice, involving antifibrotic shifts in Atf3 and Itgb6 gene expression associated with miR-194 upregulation. Picrosirius red staining confirmed isoproterenol-induced cardiac fibrosis, prevented by minocycline. These results demonstrate minocycline's therapeutic potential in attenuating adverse cardiac remodeling through miRNA-mRNA-dependent mechanisms, especially in reducing cardiac fibrosis. NEW & NOTEWORTHY We demonstrate that minocycline treatment prevents cardiac hypertrophy and fibrotic remodeling induced by chronic ß-adrenergic stimulation by inducing antifibrotic shifts in the cardiac miRNA-mRNA transcriptome.

Functional characterization of the disease-associated CCL2 rs1024611G-rs13900T haplotype: The role of the RNA-binding protein HuR.

CC-chemokine ligand 2 (CCL2) is involved in the pathogenesis of several diseases associated with monocyte/macrophage recruitment, such as HIV-associated neurocognitive disorder (HAND), tuberculosis, and atherosclerosis. The rs1024611 (alleles:A>G; G is the risk allele) polymorphism in the CCL2 cis-regulatory region is associated with increased CCL2 expression in vitro and ex vivo, leukocyte mobilization in vivo, and deleterious disease outcomes. However, the molecular basis for the rs1024611-associated differential CCL2 expression remains poorly characterized. It is conceivable that genetic variant(s) in linkage disequilibrium (LD) with rs1024611 could mediate such effects. Previously, we used rs13900 (alleles:_C>T) in the CCL2 3' untranslated region (3' UTR) that is in perfect LD with rs1024611 to demonstrate allelic expression imbalance (AEI) of CCL2 in heterozygous individuals. Here we tested the hypothesis that the rs13900 could modulate CCL2 expression by altering mRNA turnover and/or translatability. The rs13900 T allele conferred greater stability to the CCL2 transcript when compared to the rs13900 C allele. The rs13900 T allele also had increased binding to Human Antigen R (HuR), an RNA-binding protein, in vitro and ex vivo. The rs13900 alleles imparted differential activity to reporter vectors and influenced the translatability of the reporter transcript. We further demonstrated a role for HuR in mediating allele-specific effects on CCL2 expression in overexpression and silencing studies. The presence of the rs1024611G-rs13900T conferred a distinct transcriptomic signature related to inflammation and immunity. Our studies suggest that the differential interactions of HuR with rs13900 could modulate CCL2 expression and explain the interindividual differences in CCL2-mediated disease susceptibility.

Empagliflozin Reverses Oxidized LDL-Induced RECK Suppression, Cardiotrophin-1 Expression, MMP Activation, and Human Aortic Smooth Muscle Cell Proliferation and Migration.

Persistent oxidative stress and inflammation contribute causally to smooth muscle cell (SMC) proliferation and migration, the characteristic features of vascular proliferative diseases. Oxidatively modified low-density lipoproteins (OxLDL) elevate oxidative stress levels, inflammatory responses, and matrix metallopeptidase (MMP) activation, resulting ultimately in SMC migration, proliferation, and phenotype change. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a membrane-anchored MMP inhibitor. Empagliflozin is an SGLT2 inhibitor and exerts pleiotropic cardiovascular protective effects, including antioxidant and anti-inflammatory effects. Here, we investigated (i) whether OxLDL regulates RECK expression, (ii) whether ectopic expression of RECK reverses OxLDL-induced SMC migration and proliferation, and (iii) whether pretreatment with empagliflozin reverses OxLDL-induced RECK suppression, MMP activation, and SMC migration, proliferation, and differentiation. Indeed, results show that OxLDL at pathophysiological concentration promotes SMC migration and proliferation via NF-κB/miR-30b-dependent RECK suppression. Moreover, OxLDL changed the SMC phenotype to a more pro-inflammatory type, and this effect is blunted by RECK overexpression. Further, treatment with empagliflozin reversed OxLDL-induced miR-30b induction, RECK suppression, MMP activation, SMC migration, proliferation, and proinflammatory phenotype changes. OxLDL-induced cardiotrophin (CT)-1 expression and CT-1 stimulated SMC proliferation and migration in part via leukemia inhibitory factor receptor (LIFR) and glycoprotein 130 (gp130). Ectopic expression of RECK inhibited these effects by physically associating with LIFR and gp130, as evidenced by immunoprecipitation/immunoblotting and double immunofluorescence. Importantly, empagliflozin inhibited CT-1-induced mitogenic and migratory effects. Together, these results suggest the therapeutic potential of sustaining RECK expression or empagliflozin in vascular diseases characterized by SMC proliferation and migration.

Effect of Insulin Resistance on Abdominal Obesity, Liver Fat Infiltration, and Body Mass Index in Youngsters.

AIM: Evaluate insulin resistance (IR) as a mediator of the effect of body fat distribution on liver fat infiltration and stiffness (LSt) in young adults using structural equation modeling (SEM). METHODS: We invited 500 first year students from two universities and evaluated their family history to determine the risk for cardiometabolic disease. Of these, 174 students (age 19 ± 1 years) were assessed for total body fat percentage (BF%), LSt, fat infiltration (Coefficient attenuated parameter CAP), and serum biochemical analysis. We performed a mediation analysis using two different structural equation models to determine the relationship between BMI, BF%, abdominal obesity (AO), IR, LSt, and fat infiltration using standardized ß coefficients. The symbol "->" means "explains/causes". RESULTS: Model#1 supported that mediation analysis and had a better fit than the direct effect. AO->IR (b = 0.62, p = 0.005), AO->CAP (b = 0.63, p <0.001), and CAP->IR (b = 0.23, p = 0.007), with negligible effect of BMI on CAP and IR. Model#2 showed direct effect of BMI on LSt was a better fit than mediation. BMI->LSt (b = 0.17, p = 0.05) but no effect AO->LSt. Interestingly, LSt->IR (b = 0.18, p = 0.001), but bi-directional IR->LSt (b = 0.23, p = 0.001). CONCLUSIONS: AO and BMI in young adults have differential phenotypic effects on liver CAP and LSt. Visceral fat had a direct effect on IR and CAP. Meanwhile, BMI was associated with LSt. Our findings shed light on the complex interplay of factors influencing liver stiffness, particularly in young individuals. Further research is needed to elucidate the precise mechanisms underlying these associations and their implications for liver health.

Exosomes induce neurogenesis of pluripotent P19 cells.

Exosomes play a role in tissue/organ development and differentiation. Retinoic acid induces differentiation of P19 cells (UD-P19) to P19 neurons (P19N) that behave like cortical neurons and express characteristic neuronal genes such as NMDA receptor subunits. Here we report P19N exosome-mediated differentiation of UD-P19 to P19N. Both UD-P19 and P19N released exosomes with characteristic exosome morphology, size, and common protein markers. P19N internalized significantly higher number of Dil-P19N exosomes as compared to UD-P19 with accumulation in the perinuclear region. Continuous exposure of UD-P19 to P19N exosomes for six days induced formation of small-sized embryoid bodies that differentiated into MAP2-/GluN2B-positive neurons recapitulating RA-induction of neurogenesis. Incubation with UD-P19 exosomes for six days did not affect UD-P19. Small RNA-seq identified enrichment of P19N exosomes with pro-neurogenic non-coding RNAs (ncRNAs) such as miR-9, let-7, MALAT1 and depleted with ncRNAs involved in maintenance of stem cell characteristics. UD-P19 exosomes were rich with ncRNAs required for maintenance of stemness. P19N exosomes provide an alternative method to genetic modifications for cellular differentiation of neurons. Our novel findings on exosomes-mediated differentiation of UD-P19 to P19 neurons provide tools to study pathways directing neuron development/differentiation and develop novel therapeutic strategies in neuroscience.

Burden of Type 2 Diabetes and Associated Cardiometabolic Traits and Their Heritability Estimates in Endogamous Ethnic Groups of India: Findings From the INDIGENIUS Consortium.

To assess the burden of type 2 diabetes (T2D) and its genetic profile in endogamous populations of India given the paucity of data, we aimed to determine the prevalence of T2D and estimate its heritability using family-based cohorts from three distinct Endogamous Ethnic Groups (EEGs) representing Northern (Rajasthan [Agarwals: AG]) and Southern (Tamil Nadu [Chettiars: CH] and Andhra Pradesh [Reddys: RE]) states of India. For comparison, family-based data collected previously from another North Indian Punjabi Sikh (SI) EEG was used. In addition, we examined various T2D-related cardiometabolic traits and determined their heritabilities. These studies were conducted as part of the Indian Diabetes Genetic Studies in collaboration with US (INDIGENIUS) Consortium. The pedigree, demographic, phenotypic, covariate data and samples were collected from the CH, AG, and RE EEGs. The status of T2D was defined by ADA guidelines (fasting glucose ≥ 126 mg/dl or HbA1c ≥ 6.5% and/or use of diabetes medication/history). The prevalence of T2D in CH (N = 517, families = 21, mean age = 47y, mean BMI = 27), AG (N = 530, Families = 25, mean age = 43y, mean BMI = 27), and RE (N = 500, Families = 22, mean age = 46y, mean BMI = 27) was found to be 33%, 37%, and 36%, respectively, Also, the study participants from these EEGs were found to be at increased cardiometabolic risk (e.g., obesity and prediabetes). Similar characteristics for the SI EEG (N = 1,260, Families = 324, Age = 51y, BMI = 27, T2D = 75%) were obtained previously. We used the variance components approach to carry out genetic analyses after adjusting for covariate effects. The heritability (h2) estimates of T2D in the CH, RE, SI, and AG were found to be 30%, 46%, 54%, and 82% respectively, and statistically significant (P ≤ 0.05). Other T2D related traits (e.g., BMI, lipids, blood pressure) in AG, CH, and RE EEGs exhibited strong additive genetic influences (h2 range: 17% [triglycerides/AG and hs-CRP/RE] - 86% [glucose/non-T2D/AG]). Our findings highlight the high burden of T2D in Indian EEGs with significant and differential additive genetic influences on T2D and related traits.

Comparison of Carotid Intima-Media Thickness in Children and Adults With and Without Obesity: A Hysteresis Model.

OBJECTIVE: To describe a third-degree polynomial function (hysteresis) of the effect size of age, obesity, and insulin sensitivity over the carotid intima-media thickness (c-IMT), in the pediatric and adult groups. METHODS: A quasi-experimental study with fixed factor analysis of age (children aged 8-12 years, n = 73; adults aged 21-45 years, n = 82) and obesity (yes, n = 76; no, n = 79) was conducted to analyze the effect on the c-IMT and Matsuda insulin sensitivity index values. This quasi-experimental design was analyzed with robust regression modeling. RESULTS: The additive effect of obesity, independent of age, was evident in the case of the c-IMT values. There was no interaction effect, but a significant difference between participants with normal weight and those with obesity was found (P < .0001). The difference between adults and children was also significant, but the effect size was smaller. A model was created based on age, Tanner stage, and obesity using the c-IMT and Matsuda insulin sensitivity index values. A linear function fit as R2, and the cubic function estimated parameters like a polynomial model. CONCLUSION: This practical study design showed that children with obesity displayed the same levels of carotid intima-media abnormalities as adults with obesity. The polynomial shape of the model suggests potentially poor outcomes that resemble the hysteresis process and may predict chronic cardiometabolic events during early adulthood.

Association of HIV-1 Infection and Antiretroviral Therapy With Type 2 Diabetes in the Hispanic Population of the Rio Grande Valley, Texas, USA.

The Rio Grande Valley (RGV) in South Texas has one of the highest prevalence of obesity and type 2 diabetes (T2D) in the United States (US). We report for the first time the T2D prevalence in persons with HIV (PWH) in the RGV and the interrelationship between T2D, cardiometabolic risk factors, HIV-related indices, and antiretroviral therapies (ART). The PWH in this study received medical care at Valley AIDS Council (VAC) clinic sites located in Harlingen and McAllen, Texas. Henceforth, this cohort will be referred to as Valley AIDS Council Cohort (VACC). Cross-sectional analyses were conducted using retrospective data obtained from 1,827 registries. It included demographic and anthropometric variables, cardiometabolic traits, and HIV-related virological and immunological indices. For descriptive statistics, we used mean values of the quantitative variables from unbalanced visits across 20 months. Robust regression methods were used to determine the associations. For comparisons, we used cardiometabolic trait data obtained from HIV-uninfected San Antonio Mexican American Family Studies (SAMAFS; N = 2,498), and the Mexican American population in the National Health and Nutrition Examination Survey (HHANES; N = 5,989). The prevalence of T2D in VACC was 51% compared to 27% in SAMAFS and 19% in HHANES, respectively. The PWH with T2D in VACC were younger (4.7 years) and had lower BMI (BMI 2.43 units less) when compared to SAMAFS individuals. In contrast, VACC individuals had increased blood pressure and dyslipidemia. The increased T2D prevalence in VACC was independent of BMI. Within the VACC, ART was associated with viral load and CD4+ T cell counts but not with metabolic dysfunction. Notably, we found that individuals with any INSTI combination had higher T2D risk: OR 2.08 (95%CI 1.67, 2.6; p < 0.001). In summary, our results suggest that VACC individuals may develop T2D at younger ages independent of obesity. The high burden of T2D in these individuals necessitates rigorously designed longitudinal studies to draw potential causal inferences and develop better treatment regimens.

Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness.

OBJECTIVE: Cardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes, and both serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy. METHODS: Sixteen-week-old male Zucker Obese rats (ZO; n = 64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mg•kg-1•day-1; ZOSV); Group 3: valsartan (31 mg•kg-1•day-1; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mg•kg-1•day-1; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. RESULTS: Sac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val decreased aortic stiffness and reversed impairment in nitric oxide-induced vascular relaxation in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective than val in ameliorating DD. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, cytokine array revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val, suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val, but not val, increased IL-4, which is increasingly recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity-associated DD. CONCLUSIONS: These studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.

Serum carotenoids and Pediatric Metabolic Index predict insulin sensitivity in Mexican American children.

High concentrations of carotenoids are protective against cardiometabolic risk traits (CMTs) in adults and children. We recently showed in non-diabetic Mexican American (MA) children that serum α-carotene and ß-carotene are inversely correlated with obesity measures and triglycerides and positively with HDL cholesterol and that they were under strong genetic influences. Additionally, we previously described a Pediatric Metabolic Index (PMI) that helps in the identification of children who are at risk for cardiometabolic diseases. Here, we quantified serum lycopene and ß-cryptoxanthin concentrations in approximately 580 children from MA families using an ultraperformance liquid chromatography-photodiode array and determined their heritabilities and correlations with CMTs. Using response surface methodology (RSM), we determined two-way interactions of carotenoids and PMI on Matsuda insulin sensitivity index (ISI). The concentrations of lycopene and ß-cryptoxanthin were highly heritable [h2 = 0.98, P = 7 × 10-18 and h2 = 0.58, P = 1 × 10-7]. We found significant (P ≤ 0.05) negative phenotypic correlations between ß-cryptoxanthin and five CMTs: body mass index (- 0.22), waist circumference (- 0.25), triglycerides (- 0.18), fat mass (- 0.23), fasting glucose (- 0.09), and positive correlations with HDL cholesterol (0.29). In contrast, lycopene only showed a significant negative correlation with fasting glucose (- 0.08) and a positive correlation with HDL cholesterol (0.18). Importantly, we found that common genetic influences significantly contributed to the observed phenotypic correlations. RSM showed that increased serum concentrations of α- and ß-carotenoids rather than that of ß-cryptoxanthin or lycopene had maximal effects on ISI. In summary, our findings suggest that the serum carotenoids are under strong additive genetic influences and may have differential effects on susceptibility to CMTs in children.

Further evidence supporting a potential role for ADH1B in obesity.

Insulin is an essential hormone that regulates glucose homeostasis and metabolism. Insulin resistance (IR) arises when tissues fail to respond to insulin, and it leads to serious health problems including Type 2 Diabetes (T2D). Obesity is a major contributor to the development of IR and T2D. We previously showed that gene expression of alcohol dehydrogenase 1B (ADH1B) was inversely correlated with obesity and IR in subcutaneous adipose tissue of Mexican Americans. In the current study, a meta-analysis of the relationship between ADH1B expression and BMI in Mexican Americans, African Americans, Europeans, and Pima Indians verified that BMI was increased with decreased ADH1B expression. Using established human subcutaneous pre-adipocyte cell lines derived from lean (BMI < 30 kg m-2) or obese (BMI ≥ 30 kg m-2) donors, we found that ADH1B protein expression increased substantially during differentiation, and overexpression of ADH1B inhibited fatty acid binding protein expression. Mature adipocytes from lean donors expressed ADH1B at higher levels than obese donors. Insulin further induced ADH1B protein expression as well as enzyme activity. Knockdown of ADH1B expression decreased insulin-stimulated glucose uptake. Our findings suggest that ADH1B is involved in the proper development and metabolic activity of adipose tissues and this function is suppressed by obesity.

Lactation Plays a Fundamental Role in Developmental Programming.

Breast milk has been considered the best source of nutrition for newborns. Several epidemiological and basic experimental studies have been conducted to understand the nutritional advantages of breast milk. Previous findings have emphasized the importance of good maternal nutrition. Maternal milk provides macromolecules, minerals, immune cells, antibodies, hormones, and regular flora to strengthen their offspring preventing various diseases. Maternal milk helps to facilitate physiological, and molecular maturation of several systems, which are important for the final maturation of organs and newborn body development. Currently, breastfeeding is being abandoned for various reasons, such as lower milk production, lack of time, abandonment of the family, social or emotional problems and adverse environmental conditions. These permanent alterations during a critical developmental window have negative consequences in regard to the development of the offspring and organ maturation leading to metabolic, reproductive, hormonal and physiological problems from early life to adulthood. This review describes the advantages of breast milk and the importance for the mother to maintain an adequate diet during pregnancy and lactation, in addition to maintaining a healthy lifestyle and harmonious family relationships. Such an environment will contribute to the complete maturation and development of the offspring.

The SGLT2 inhibitor Empagliflozin attenuates interleukin-17A-induced human aortic smooth muscle cell proliferation and migration by targeting TRAF3IP2/ROS/NLRP3/Caspase-1-dependent IL-1ß and IL-18 secretion.

Chronic inflammation and persistent oxidative stress contribute to the development and progression of vascular proliferative diseases. We hypothesized that the proinflammatory cytokine interleukin (IL)-17A induces oxidative stress and amplifies inflammatory signaling in human aortic smooth muscle cells (SMC) via TRAF3IP2-mediated NLRP3/caspase-1-dependent mitogenic and migratory proinflammatory cytokines IL-1ß and IL-18. Further, we hypothesized that these maladaptive changes are prevented by empagliflozin (EMPA), an SGLT2 (Sodium/Glucose Cotransporter 2) inhibitor. Supporting our hypotheses, exposure of cultured SMC to IL-17A promoted proliferation and migration via TRAF3IP2, TRAF3IP2-dependent superoxide and hydrogen peroxide production, NLRP3 expression, caspase-1 activation, and IL-1ß and IL-18 secretion. Furthermore, NLRP3 knockdown, caspase-1 inhibition, and pretreatment with IL-1ß and IL-18 neutralizing antibodies and IL-18BP, each attenuated IL-17A-induced SMC migration and proliferation. Importantly, SMC express SGLT2, and pre-treatment with EMPA attenuated IL-17A/TRAF3IP2-dependent oxidative stress, NLRP3 expression, caspase-1 activation, IL-1ß and IL-18 secretion, and SMC proliferation and migration. Importantly, silencing SGLT2 attenuated EMPA-mediated inhibition of IL-17A-induced cytokine secretion and SMC proliferation and migration. EMPA exerted these beneficial antioxidant, anti-inflammatory, anti-mitogenic and anti-migratory effects under normal glucose conditions and without inducing cell death. These results suggest the therapeutic potential of EMPA in vascular proliferative diseases.

Acanthosis nigricans as a composite marker of cardiometabolic risk and its complex association with obesity and insulin resistance in Mexican American children.

AIM: Acanthosis nigricans (AN) is a strong correlate of obesity and is considered a marker of insulin resistance (IR). AN is associated with various other cardiometabolic risk factors (CMRFs). However, the direct causal relationship of IR with AN in obesity has been debated. Therefore, we aimed to examine the complex causal relationships among the troika of AN, obesity, and IR in Mexican Americans (MAs). METHODS: We used data from 670 non-diabetic MA children, aged 6-17 years (49% girls). AN (prevalence 33%) severity scores (range 0-5) were used as a quasi-quantitative trait (AN-q) for analysis. We used the program SOLAR for determining phenotypic, genetic, and environmental correlations between AN-q and CMRFs (e.g., BMI, HOMA-IR, lipids, blood pressure, hs-C-reactive protein (CRP), and Harvard physical fitness score (PFS)). The genetic and environmental correlations were subsequently used in mediation analysis (AMOS program). Model comparisons were made using goodness-of-fit indexes. RESULTS: Heritability of AN-q was 0.75 (p<0.0001). It was positively/significantly (p<0.05) correlated with traits such as BMI, HOMA-IR, and CRP, and negatively with HDL-C and PFS. Of the models tested, indirect mediation analysis of BMI→HOMA-IR→AN-q yielded lower goodness-of-fit than a partial mediation model where BMI explained the relationship with both HOMA-IR and AN-q simultaneously. Using complex models, BMI was associated with AN-q and IR mediating most of the CMRFs; but no relationship between IR and AN-q. CONCLUSION: Our study suggests that obesity explains the association of IR with AN, but no causal relationship between IR and AN in Mexican American children.

CARDIOMETABOLIC RISK FACTORS ASSOCIATED WITH RENAL FUNCTION IN APPARENTLY HEALTHY YOUNG STUDENTS: A CROSS-SECTIONAL STUDY.

BACKGROUND: Cardiometabolic risk factors (CMRFs) appear decades before developing chronic kidney disease (CKD) in adulthood. OBJECTIVE: The objective of the study was to identify the prevalence and association between CMRFs and kidney function in apparently healthy young adults (18-25 years old). METHODS: We included 5531 freshman year students. Data collected on CMRFs included central obesity, high body mass index (hBMI >25), blood pressure, glycemia, lipids, uric acid (UA >6.8 mg/dL), and insulin. Glomerular filtration rate (GFR) was estimated by CKD-Epidemiology Collaboration formula. We used logistic regression and a log linear for odds ratio (OR) (95% confidence level) and probabilities. RESULTS: The presence of any CMRF was observed in 78% (4312) of individuals; GFR ≥120/130 mL/min/1.73 m2sc was found in 33%, GFR <90 mL/min/1.73 m2sc in 3%, and proteinuria in 3%. Factors associated with high GFR were hBMI (OR 1.3 [1.14, 1.47]), UA (OR 0.2 [0.15, 0.26]), high-density lipoprotein (HDL) (OR 1.4 [1.2, 1.6]), and insulin resistance (OR 1.3 [1.05, 1.7]). CMRF associated with low GFR was UA (OR 1.8 [1.3, 2.6]), low-density lipoprotein cholesterol (OR 1.66 [1.05, 2.6]), and proteinuria (OR 3.4 [2.07, 5.7]). Proteinuria was associated with high UA (OR 1.59 [1.01, 2.5]) and hypercholesterolemia (OR 1.8 [1.03, 3.18]). The sole presence of hBMI+UA predicted low GFR with p = 0.6 and hBMI+UA+low HDL predicted proteinuria with p = 0.55. CONCLUSIONS: CMRFs were highly prevalent among this freshman student population and were associated with proteinuria and GFR abnormalities. Future studies should focus on public health programs to prevent or delay the development of CKD.

Overexpression of TC-PTP in murine epidermis attenuates skin tumor formation.

T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, has been shown to function as a tumor suppressor during skin carcinogenesis. In the current study, we generated a novel epidermal-specific TC-PTP-overexpressing (K5HA.Ptpn2) mouse model to show that TC-PTP contributes to the attenuation of chemically induced skin carcinogenesis through the synergistic regulation of STAT1, STAT3, STAT5, and PI3K/AKT signaling. We found overexpression of TC-PTP increased epidermal sensitivity to DMBA-induced apoptosis and it decreased TPA-mediated hyperproliferation, coinciding with reduced epidermal thickness. Inhibition of STAT1, STAT3, STAT5, or AKT reversed the effects of TC-PTP overexpression on epidermal survival and proliferation. Mice overexpressing TC-PTP in the epidermis developed significantly reduced numbers of tumors during skin carcinogenesis and presented a prolonged latency of tumor initiation. Examination of human papillomas and squamous cell carcinomas (SCCs) revealed that TC-PTP expression was significantly reduced and TC-PTP expression was inversely correlated with the increased grade of SCCs. Our findings demonstrate that TC-PTP is a potential therapeutic target for the prevention of human skin cancer given that it is a major negative regulator of oncogenic signaling.

Cardiometabolic risk factors associated with renal function in apparently healthy young students: a cross-sectional study

ABSTRACT Background: Cardiometabolic risk factors (CMRFs) appear decades before developing chronic kidney disease (CKD) in adulthood. Objective: The objective of the study was to identify the prevalence and association between CMRFs and kidney function in apparently healthy young adults (18-25 years old). Methods: We included 5531 freshman year students. Data collected on CMRFs included central obesity, high body mass index (hBMI >25), blood pressure, glycemia, lipids, uric acid (UA >6.8 mg/dL), and insulin. Glomerular filtration rate (GFR) was estimated by CKD-Epidemiology Collaboration formula. We used logistic regression and a log linear for odds ratio (OR) (95% confidence level) and probabilities. Results: The presence of any CMRF was observed in 78% (4312) of individuals; GFR ≥120/130 mL/min/1.73 m2sc was found in 33%, GFR <90 mL/min/1.73 m2sc in 3%, and proteinuria in 3%. Factors associated with high GFR were hBMI (OR 1.3 [1.14, 1.47]), UA (OR 0.2 [0.15, 0.26]), high-density lipoprotein (HDL) (OR 1.4 [1.2, 1.6]), and insulin resistance (OR 1.3 [1.05, 1.7]). CMRF associated with low GFR was UA (OR 1.8 [1.3, 2.6]), low-density lipoprotein cholesterol (OR 1.66 [1.05, 2.6]), and proteinuria (OR 3.4 [2.07, 5.7]). Proteinuria was associated with high UA (OR 1.59 [1.01, 2.5]) and hypercholesterolemia (OR 1.8 [1.03, 3.18]). The sole presence of hBMI+UA predicted low GFR with p = 0.6 and hBMI+UA+low HDL predicted proteinuria with p = 0.55. Conclusions: CMRFs were highly prevalent among this freshman student population and were associated with proteinuria and GFR abnormalities. Future studies should focus on public health programs to prevent or delay the development of CKD.

RECK suppresses interleukin-17/TRAF3IP2-mediated MMP-13 activation and human aortic smooth muscle cell migration and proliferation.

Sustained inflammation and matrix metalloproteinase (MMP) activation contribute to vascular occlusive/proliferative disorders. Interleukin-17 (IL-17) is a proinflammatory cytokine that signals mainly via TRAF3 Interacting Protein 2 (TRAF3IP2), an upstream regulator of various critical transcription factors, including AP-1 and NF-κB. Reversion inducing cysteine rich protein with kazal motifs (RECK) is a membrane-anchored MMP inhibitor. Here we investigated whether IL-17A/TRAF3IP2 signaling promotes MMP-13-dependent human aortic smooth muscle cell (SMC) proliferation and migration, and determined whether RECK overexpression blunts these responses. Indeed, IL-17A treatment induced (a) JNK, p38 MAPK, AP-1, NF-κB, and CREB activation, (b) miR-21 induction, (c) miR-27b and miR-320 inhibition, (d) MMP-13 expression and activation, (e) RECK suppression, and (f) SMC migration and proliferation, all in a TRAF3IP2-dependent manner. In fact, gain of TRAG3IP2 function, by itself, induced MMP-13 expression and activation, and RECK suppression. Furthermore, treatment with recombinant MMP-13 stimulated SMC migration in part via ERK activation. Importantly, RECK gain-of-function attenuated MMP-13 activity without affecting its mRNA or protein levels, and inhibited IL-17A- and MMP-13-induced SMC migration. These results indicate that increased MMP-13 and decreased RECK contribute to IL-17A-induced TRAF3IP2-dependent SMC migration and proliferation, and suggest that TRAF3IP2 inhibitors or RECK inducers have the potential to block the progression of neointimal thickening in hyperplastic vascular diseases.

Minocycline inhibits PDGF-BB-induced human aortic smooth muscle cell proliferation and migration by reversing miR-221- and -222-mediated RECK suppression.

Minocycline, a tetracycline antibiotic, is known to exert vasculoprotective effects independent of its anti-bacterial properties; however the underlying molecular mechanisms are not completely understood. Reversion Inducing Cysteine Rich Protein with Kazal Motifs (RECK) is a cell surface expressed, membrane anchored protein, and its overexpression inhibits cancer cell migration. We hypothesized that minocycline inhibits platelet-derived growth factor (PDGF)-induced human aortic smooth muscle cell (SMC) proliferation and migration via RECK upregulation. Our data show that the BB homodimer of recombinant PDGF (PDGF-BB) induced SMC migration and proliferation, effects significantly blunted by pre-treatment with minocycline. Further investigations revealed that PDGF-BB induced PI3K-dependent AKT activation, ERK activation, reactive oxygen species generation, Nuclear Factor-κB and Activator Protein-1 activation, microRNA (miR)-221 and miR-222 induction, RECK suppression, and matrix metalloproteinase (MMP2 and 9) activation, effects that were reversed by minocycline. Notably, minocycline induced RECK expression dose-dependently within the therapeutic dose of 1-100 µM, and silencing RECK partially reversed the inhibitory effects of minocycline on PDGF-BB-induced MMP activation, and SMC proliferation and migration. Further, targeting MMP2 and MMP9 blunted PDGF-BB-induced SMC migration. Together, these results demonstrate that minocycline inhibits PDGF-BB-induced SMC proliferation and migration by restoring RECK, an MMP inhibitor. These results indicate that the induction of RECK is one of the mechanisms by which minocycline exerts vasculoprotective effects.

Interaction of Breast Cancer and Insulin Resistance on PD1 and TIM3 Expression in Peripheral Blood CD8 T Cells.

Epidemiological evidence points to a link between insulin resistance (IR) and breast cancer (BrCA). Insulin plays a role in CD8+ T cells (CD8T) differentiation and function and affects adipocytokines levels. CD8T activity in BrCA is associated with favorable outcome; while PD1 and TIM3 are markers of CD8T exhaustion and play critical roles in the negative regulation of T cell responses. Patients with (BrCA) have high expression levels of PD1 on circulating. Therefore, we hypothesized that BrCA and IR could affect PD1 and/or TIM3 expression on circulating CD8T. We determine PD1 and TIM3 expression on CD8T and analyze the relationship of CD8T phenotype with serum insulin and plasma adipocytokines levels in the different groups. We enrolled four groups of treatment-naive patients: women without neoplasms (Neo-)/without IR (IR-), Neo-/with IR (IR+), BrCa/IR- and BrCa/IR+. We found interactions between BrCA and IR with respect to TIM3 on naïve and central memory (CM) CD8T subsets. Furthermore, BrCA had a greater PD1 + TIM3- CD8T frequency in CD8T subsets than Neo-. IR+ presented a significantly lower PD1 + TIM3- frequency in CD8T subsets compare to Non-IR. In addition, we found a negative correlation between insulin levels, HOMA and frequency of PD1 + TIM3- in CD8T and a positive correlation between adiponectin levels and the frequency PD1 + TIM3- in CD8T. The increased expression of PD1 on different subsets of CD8T from BrCa patients is consistent with immunological tolerance, whereas IR has a contrary effect. IR could have a deleterious role in the activation of CD8T that can be relevant to new BrCa immunotherapy.