Dipeptidyl Peptidase 4/Midline-1 Axis Promotes T Lymphocyte Motility in Atherosclerosis.

T cells play a crucial role in atherosclerosis, with its infiltration preceding the formation of atheroma. However, how T-cell infiltration is regulated in atherosclerosis remains largely unknown. Here, this work demonstrates that dipeptidyl peptidase-4 (DPP4) is a novel regulator of T-cell motility in atherosclerosis. Single-cell ribonucleic acid (RNA) sequencing and flow cytometry show that CD4+ T cells in atherosclerotic patients display a marked increase of DPP4. Lack of DPP4 in hematopoietic cells or T cells reduces T-cell infiltration and atherosclerotic plaque volume in atherosclerosis mouse models. Mechanistically, DPP4 deficiency reduces T-cell motility by suppressing the expression of microtubule associated protein midline-1 (Mid1) in T cells. Deletion of either DPP4 or Mid1 inhibits chemokine-induced shape change and motility, while restitution of Mid1 in Dpp4-/- T cell largely restores its migratory ability. Thus, DPP4/Mid1, as a novel regulator of T-cell motility, may be a potential inflammatory target in atherosclerosis.

DPP-4 inhibitors and GLP-1RAs: cardiovascular safety and benefits.

Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors are commonly used treatments for patients with type 2 diabetes mellitus (T2DM). Both anti-diabetic treatments function by playing key modulatory roles in the incretin system. Though these drugs have been deemed effective in treating T2DM, the Food and Drug Administration (FDA) and some members of the scientific community have questioned the safety of these therapeutics relative to important cardiovascular endpoints. As a result, since 2008, the FDA has required all new drugs for glycemic control in T2DM patients to demonstrate cardiovascular safety. The present review article strives to assess the safety and benefits of incretin-based therapy, a new class of antidiabetic drug, on the health of patient cardiovascular systems. In the process, this review will also provide a physiological overview of the incretin system and how key components function in T2DM.

Predictive factors of radioiodine therapy failure in Graves' Disease: A meta-analysis.

BACKGROUND: I-131 therapy is a common treatment modality for adults with Graves' Disease (GD). Utilizing meta-analysis, we examined patient specific factors that predict I-131 therapy failure. METHODS: Literature search followed PRISMA. Comprehensive Meta-analysis (version 3.0) was used. Mantel-Haenszel test with accompanying risk ratio and confidence intervals evaluated categorical variables. Continuous data was analyzed using inverse variance testing yielding mean difference or standardized mean difference. Decision tree algorithms identified variables of high discriminative performance. RESULTS: 4822 collective patients across 18 studies were included. Male sex (RR = 1.23, 95%CI = 1.08-1.41, p = 0.002), I-131 therapy 6 months after GD diagnosis (RR = 2.10, 95%CI = 1.45-3.04, p < 0.001) and history of anti-thyroid drugs (RR = 2.05, 95%CI = 1.49-2.81, p < 0.001) increased the risk of I-131 therapy failure. Elevated free thyroxine, 24-h radioactive iodine uptake scan ≥60.26% and thyroid volume ≥35.77 mL were also associated with failure. CONCLUSION: Patient characteristics can predict the likelihood of I-131 therapy failure in GD. Definitive surgical treatment may be a reasonable option for those patients.

Discordantly normal ApoB relative to elevated LDL-C in persons with metabolic disorders: A marker of atherogenic heterogeneity.

OBJECTIVE: A significant proportion of persons with metabolic syndrome (MetS), prediabetes, or type 2 diabetes (T2D) do not develop atherosclerotic cardiovascular disease (ASCVD).We sought to determine whether discordantly normal apolipoprotein B (ApoB) relative to elevated LDL-C may help to explain heterogeneity in ASCVD risk among persons with metabolic disorders. METHODS: There were 278 Bogalusa Heart Study participants with MetS (n=95), prediabetes (n=233), or T2D (n=31) and LDL-C ≥100 mg/dL who were free of carotid plaque at baseline (2001-02) and underwent carotid ultrasound at follow-up (2013-16). Multivariable modified Poisson regression estimated the long-term absence of carotid plaque for lower ApoB, continuously and categorically. RESULTS: Participants were on average 36.1 years old at baseline, 61.5% were women, and 31.7% were black. A total of 50.7% had discordantly normal ApoB (<90 mg/dL) and the mean ApoB and LDL-C concentrations were 91.6 mg/dL and 137.7 mg/dL, respectively. In addition to having higher HDL-C and lower triglyceride values, individuals with ApoB <90 were more likely to maintain persistent absence of plaque compared to those with ApoB ≥90 (73.1% versus 58.4%, p=0.01). Contrastingly, there was no significant difference in the proportion of individuals who remained free of plaque with increasing LDL-C (p=0.45). Independent of traditional risk factors including LDL-C, each 10 mg/dL lower ApoB (RR=1.11, 95% CI: 1.03-1.19) and ApoB <90 (RR=1.22, 95% CI: 1.00-1.43) were significantly associated with the persistent absence of carotid plaque. CONCLUSIONS: One-half of young persons with metabolic disorders and elevated LDL-C had discordantly normal ApoB and a low burden of carotid atherosclerosis over 13 years, suggesting that ApoB better represents the atherogenic lipid burden compared to LDL-C in this patient population. These results suggest a utility for assessing whether routine ApoB measurement can improve ASCVD risk stratification in young persons with metabolic disorders who have high triglycerides and low HDL-cholesterol.

Advances in Genomics Research of Blood Pressure Responses to Dietary Sodium and Potassium Intakes.

More than half of US adults have hypertension by 40 years of age and a subsequent increase in atherosclerotic cardiovascular disease risk. Dietary sodium and potassium are intricately linked to the pathophysiology of hypertension. However, blood pressure responses to dietary sodium and potassium, phenomena known as salt and potassium sensitivity of blood pressure, respectively, are heterogenous and normally distributed in the general population. Like blood pressure, salt and potassium sensitivity are complex phenotypes, and previous research has shown that up to 75% of individuals experience a blood pressure change in response to such dietary minerals. Previous research has also implicated both high salt sensitivity and low salt sensitivity (or salt resistance) of blood pressure to an increased risk of hypertension and potentially atherosclerotic cardiovascular disease risk. Given the clinical challenges required to accurately measure the sodium and potassium response phenotypes, genomic characterization of these traits has become of interest for hypertension prevention initiatives on both the individual and population levels. Here, we review advances in human genomics research of blood pressure responses to dietary sodium and potassium by focusing on 3 main areas, including the phenotypic characterization of salt sensitivity and resistance, clinical challenges in diagnosing such phenotypes, and the genomic mechanisms that may help to explain salt and potassium sensitivity and resistance. Through this process, we hope to further underline the value of leveraging genomics and broader multiomics for characterizing the blood pressure response to sodium and potassium to improve precision in lifestyle approaches for primordial and primary atherosclerotic cardiovascular disease prevention.

Achieving Dietary Sodium Recommendations and Atherosclerotic Cardiovascular Disease Prevention through Culinary Medicine Education.

Sodium-reduction initiatives have been a cornerstone of preventing hypertension and broader atherosclerotic cardiovascular disease (ASCVD) since the early 1970s. For nearly 50 years, public health and clinical guidelines have concentrated on consumer education, behavioral change, and, to a lesser extent, food policy to help reduce sodium intake among Americans. While these efforts undoubtedly helped improve awareness, average sodium consumption remains at approximately 4200 mg/day in men and 3000 mg/day in women, well above the United States Dietary Guidelines of 2300 mg/day. Culinary medicine is an emerging discipline in clinical and public-health education that provides healthcare professionals and community members with food-based knowledge and skills. With the hands-on teaching of kitchen education to individuals, culinary medicine provides eaters with tangible strategies for reducing sodium through home cooking. Here, we review opportunities for culinary medicine to help improve both individual- and population-level sodium-reduction outcomes through five main areas: increasing adherence to a plant-forward dietary pattern, food literacy, the enhancement of complementary flavors, disease-specific teaching-kitchen modules, and the delivery of culturally specific nutrition education. Through this process, we hope to further underline the value of formal, hands-on teaching-kitchen education among healthcare professionals and community members for ASCVD prevention.

Nuclear morphometry in indeterminate thyroid nodules.

BACKGROUND: Up to 30% of thyroid nodules undergoing fine needle aspiration (FNA) yield an indeterminate result. Recent research efforts have suggested that nuclear morphometry and morphology may enhance the diagnostic accuracy of FNA as an objective adjunct. We applied nuclear morphometric analysis on a diverse cohort of patients to evaluate the association between nuclear morphometry and malignancy. METHODS: Forty-five randomly selected patients, who underwent thyroid surgery after an indeterminate FNA result (Bethesda III & IV) between 2012-2015, were reviewed. One hundred representative nuclei per FNA of a thyroid nodule were analyzed using ImageJ. Seven validated morphometric parameters were collected: nuclear area, perimeter, circularity, aspect ratio, roundness, and maximum/minimum Feret's diameter. L/S ratio was subsequently calculated. All 8 nuclear parameters were reported as averages with standard errors of the mean (SEM). A Student's t-test was used to assess the association of nuclear parameters with final surgical pathology. RESULTS: The mean age of all patients was 56.31±15.39 years, with female patients comprising 68.9% of the cohort. Twenty-two patients had malignant thyroid nodules. The mean perimeter of nuclei for the cohort was 18.48±0.45 µm, the mean area was 22.19±0.93 µm, and the mean maximum Feret's diameter was 6.67±0.13 µm. No significant differences in the 8 nuclear parameters were observed between the malignant and non-malignant groups. CONCLUSIONS: In the population examined, our results suggest that nuclear morphometry is not yet a tool of reliable diagnostic value in accessing malignant and non-malignant thyroid nodules. Further investigation is necessary to identify objective parameters that will enhance diagnostic accuracy of indeterminate FNA cytology to minimize the number of diagnostic thyroid surgery.

MRP14 enhances the ability of macrophage to recruit T cells and promotes obesity-induced insulin resistance.

OBJECTIVE: Myeloid-related protein-14 (MRP14) and its binding partner MRP8 play an essential role in innate immune function and have been implicated in a variety of inflammatory diseases. However, the role of MRP14 in obesity-induced inflammation and insulin resistance is not well defined. This study investigated the role of MRP14 in macrophage-mediated adipose tissue inflammation and obesity-induced insulin resistance. SUBJECTS AND RESULTS: Wild-type (WT) and Mrp14-/- mice were fed with a high-fat diet or normal chow for 12 weeks. Tissue-resident macrophages in both adipose tissue and liver from obese WT mice expressed higher levels of MRP14 in the visceral adipose fat and liver compared with the lean mice. Mrp14-/- mice demonstrated a significantly improved postprandial insulin sensitivity, as measured by intraperitoneal glucose tolerance test and insulin tolerance testing. Macrophages secreted MRP14 in response to inflammatory stimuli, such as LPS. Extracellular MRP8/14 induced the production of CCL5 and CXCL9. Deficiency of MRP14 did not affect macrophage proliferation, mitochondrial respiration, and glycolytic function, but Mrp14-/- macrophages showed a reduced ability to attract T cells. Depletion of the extracellular MRP14 reduced the T cell attracting ability of WT macrophages to a level similar to Mrp14-/- macrophages. CONCLUSION: Our data indicate that MRP14 deficiency decreases obesity-induced insulin resistance and MRP8/14 regulates T-cell recruitment through the induction of T-cell chemoattractant production from macrophages.

Alpha2B-Adrenergic Receptor Regulates Neutrophil Recruitment in MSU-Induced Peritoneal Inflammation.

Gout is one of the most common metabolic disorders in human. Previous studies have shown that the disease activity is closely associated with sympathetic nervous system (SNS). α2B-adrenergic receptor (α2BAR), a subtype of α2 adrenergic receptor, plays a critical role in many diseases. However, the role of α2BAR in the pathogenesis of gout remains unclear. Here, we assessed the role of α2BAR in the monosodium urate (MSU) crystals-induced peritonitis that mimics human gout by using the α2BAR-overexpressing mice (α2BAR-Tg). We found that the number of recruited neutrophils was significantly increased in the α2BAR-Tg mice after MSU treatment, when compared with wild type mice. In contrast, the number of macrophages was not changed. Importantly, there is no difference in the IL-1ß levels and caspase-1 activity between wild type and α2BAR-Tg mice in the gout animal model. Notably, the enhanced neutrophil migration in α2BAR-Tg mice was dependent on the α2BAR overexpression in neutrophils, but not resulted from other tissues or cells with α2BAR overexpression. In conclusion, our data provide a direct evidence that α2BAR plays a critical role in neutrophil migration and MSU-induced inflammation.

Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathways.

BACKGROUND: We and others have shown that dipeptidyl peptidase-IV (DPP4) expression is increased in obesity/atherosclerosis and is positively correlated with atherosclerotic burden. However, the mechanism by which DPP4 expression is regulated in obesity remains unclear. In this study, we investigated the pathways regulating the expression of DPP4 on macrophages. METHODS: Flowsight® Imaging Flow Cytometry was employed for the detection of DPP4 and immunophenotyping. DPP4 enzymatic activity was measured by a DPPIV-Glo™ Protease Assay kit. FINDINGS: Human monocytes expressed a moderate level of membrane-bound DPP4. Obese patients with body mass index (BMI) ≥ 30 had a higher level of monocyte DPP4 expression, in parallel with higher levels of HOMA-IR, blood glucose, triglycerides, and non-HDL cholesterol, compared to those in the non-obese (BMI < 30) patients. Oxidized low-density lipoprotein (oxLDL), but not native LDL, up-regulated DPP4 expression on macrophages with a preferential increase in CD36+ cells. OxLDL mediated DPP4 up-regulation was considerably diminished by Toll-like receptor-4 (TLR4) knockdown and CD36 deficiency. TRIF deficiency, but not MyD88 deficiency, attenuated oxLDL-induced DPP4 increase. INTERPRETATION: Our study suggests a key role for oxLDL and downstream CD36/TLR4/TRIF in regulating DPP4 expression. Increased DPP4 in response to oxidized lipids may represent an integrated mechanism linking post-prandial glucose metabolism to lipoprotein abnormality-potentiated atherosclerosis.