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    Cardiac troponin T predicts mortality in patients with end-stage renal disease. Dierkes J,Domröse U,Westphal S,Ambrosch A,Bosselmann H P,Neumann K H,Luley C Circulation BACKGROUND:Patients with end-stage renal disease have a high risk of premature death, mainly as the result of cardiovascular disease (CVD), which is not sufficiently explained by the conventional risk factors. We therefore prospectively investigated total mortality and cardiovascular events in 102 patients on hemodialysis and assessed the prognostic value of baseline disease status and laboratory variables including total homocysteine and cardiac troponin T. METHODS AND RESULTS:Patients were followed for 2 years or until their first event of CVD (for outcome variable cardiovascular events, n=33) or death (for outcome variable total mortality, n=28). Survival was computed by the Kaplan-Meier method. Cox proportional hazards model was used to determine independent predictors of CVD events or total mortality. Cardiac troponin T emerged as the most powerful predictor of mortality, resulting in an almost 7-fold risk increase at concentrations >0.10 ng/mL (hazard ratio 6.85, 95% CI 3. 04 to 15.45). Total homocysteine level greater than median was also associated with mortality (hazard ratio 2.44, 95% CI 1.10 to 5.40). These hazard ratios did not change substantially after adjustment for other risk factors. Significant predictors for CVD events were baseline diabetes, cerebrovascular disease, serum glucose, and triglycerides. After adjustment, only glucose and triglycerides remained significantly related to CVD events (hazard ratio with 95% CI 1.33 [1.12 to 1.57] and 1.14 [1.04 to 1.26], respectively, for a 1-mmol/L increase in concentration). CONCLUSIONS:We conclude that total homocysteine and particularly cardiac troponin T are important predictors of mortality in patients with end-stage renal disease, whereas other laboratory variables and baseline disease status have less prognostic value. 10.1161/01.cir.102.16.1964
    High ferritin and low transferrin saturation are associated with pre-diabetes among a national representative sample of U.S. adults. Cheung Ching-Lung,Cheung Tommy T,Lam Karen S L,Cheung Bernard M Y Clinical nutrition (Edinburgh, Scotland) BACKGROUND & AIMS:Iron overload is known to cause diabetes. However, the underlying mechanism is poorly understood. We therefore studied the association of different markers of iron metabolism, namely ferritin, erythrocyte protoporphyrin and transferrin saturation (TSAT, as defined by a percentage of transferrin that is saturated with iron) with pre-diabetes (preDM) in US adults without chronic kidney disease, anemia, and iron deficiency. METHODS:Data on 2575 participants of the National Health and Nutrition Examination Survey (NHANES) 1999-2002 who were free of diabetes, chronic kidney disease, iron deficiency, and anemia were analyzed. Data on 3876 participants of the NHANES III (1988-1994) were used as replication. Homeostasis model assessment of insulin resistance (HOMA-IR), blood glycosylated hemoglobin level (HbA1C), fasting glucose, insulin, and preDM (defined as a fasting plasma glucose 100-125 mg/dl or an HBA1C value 5.7-6.4%) were measured as the outcomes. RESULTS:Logistic regression analyses indicated independent associations of high ferritin (Ptrend = 0.028) and low TSAT (P(trend) = 0.029) with preDM after adjusting for sociodemographics, physical activity (active/sedementary), metabolic and inflammatory markers (triglycerides, total cholesterol, HDL cholesterol, mean arterial pressure, CRP, white cell count, and albumin), and liver enzymes (GGT, Alk phos, AST, and ALT). The NHANES III data showed similar associations. Combining the results showed a more significant association for high ferritin (P(meta) = 0.016) and low TSAT (P(meta) = 0.002). Moreover, TSAT was associated with HbA1C, fasting glucose, insulin, and HOMA-IR (P(meta) ≤ 0.001). CONCLUSIONS:Higher ferritin and lower TSAT are associated with higher risk of preDM in a general population without confounding diseases. Further research is needed to examine the underlying mechanism of these two indices, especially TSAT, in the pathophysiology of preDM. 10.1016/j.clnu.2012.11.024
    Vitamin D Deficiency in Patients with Diabetes in French Guiana: Epidemiology and Relation with Microvascular and Macrovascular Complications. Girard Elise,Nacher Mathieu,Bukasa-Kakamba John,Fahrasmane Aniza,Adenis Antoine,Massicard Mickael,Drak Alsibai Kinan,De Toffol Bertrand,Bekima Raissa,Thelusme Liliane,Okambabelle Diana,Demar Magalie,Aurelus Jean M,Sabbah Nadia Nutrients Vitamin D (VD) insufficiency is common among patients with diabetes in French Guiana. The study aimed to evaluate the prevalence of VD deficiency in the different type of diabetes encountered and to analyze the relationship between VD deficiency and diabetes complications. METHODS:An observational study was conducted between May 2019 and May 2020 in French Guiana, based on data from the CODIAM study (Diabetes Cohort in French Amazonia), describing the characteristics of patients with diabetes mellitus. Among 600 patients enrolled with diabetes, 361 had an available VD assay. RESULTS:The mean 25(OH)VD (hydroxycalciferol) level was 27.9 ng/mL. The level of VD was inversely proportional to the HbA1c (glycated hemoglobin) level. Patients with angina pectoris had a greater proportion of deficiencies VD < 20 ng/mL than those without angina. By contrast, patients with retinopathy had higher vitamin D concentrations than those without retinopathy. There was no association between vitamin D and arteriopathy, stroke, nephropathy and polyneuropathy. VD deficiency was more frequent in women, and in patients with a high school education. CONCLUSION:The prevalence of VD deficiency was high in patients with diabetes in French Guiana, emphasizing the importance of VD supplementation. 10.3390/nu13124302
    Vitamin D affects the neutrophil-to-lymphocyte ratio in patients with type 2 diabetes mellitus. Wang Si-Yang,Shen Ting-Ting,Xi Bei-Li,Shen Zhan,Zhang Xian Journal of diabetes investigation AIMS/INTRODUCTION:Chronic inflammation is an underlying feature of type 2 diabetes mellitus. Hypovitaminosis D is associated with type 2 diabetes mellitus, but whether it contributes to chronic inflammation is unclear. We examined the effects of vitamin D on various immune markers to evaluate its contribution to systemic inflammation in type 2 diabetes mellitus. MATERIALS AND METHODS:We retrospectively analyzed data from type 2 diabetes mellitus patients, people with prediabetes and control patients without diabetes (n = 9,746). Demographic and clinical variables were evaluated using descriptive statistics and generalized linear regression. A stratified analysis based on total serum vitamin D was also carried out. RESULTS:Neutrophil count was a significant predictor of 1,5-anhydroglucitol and glycated hemoglobin (HbA1c) in patients with prediabetes (1,5-anhydroglucitol: β = -0.719, P < 0.001 and HbA1c: β = -0.006, P = 0.002) and patients with diabetes (1,5-anhydroglucitol: β = 0.207, P = 0.004 and HbA1c: β = -0.067, P = 0.010). Lymphocyte count was a significant predictor of HbA1c in patients without diabetes (β = 0.056, P < 0.001) and patients with prediabetes (β = 0.038, P < 0.001). The neutrophil-to-lymphocyte ratio (NLR) was a significant predictor of HbA1c in patients without diabetes (β = -0.001, P = 0.032). No immune markers differed significantly based on vitamin D level among patients without diabetes (P> 0.05 for all). Among patients with prediabetes, those who were vitamin D-deficient had the highest NLR (P = 0.040). Among patients with diabetes, those who were vitamin D-deficient had the highest neutrophil count (P = 0.001), lowest lymphocyte count (P = 0.016) and highest NLR (P < 0.001). CONCLUSIONS:The NLR is strongly influenced by serum vitamin D level. Given the high prevalence of hypovitaminosis D and elevated NLR among chronic disease patients and the elderly, our results suggest that clinical interpretation of NLR as a predictive marker of type 2 diabetes mellitus-related inflammation should consider vitamin D level, age and pre-existing morbidity. 10.1111/jdi.13338
    Association Between 25(OH)Vitamin D, HbA1c and Albuminuria in Diabetes Mellitus: Data From a Population-Based Study (VIDAMAZON). Felício João Soares,de Rider Britto Hana Andrade,Cortez Pedro Celeira,de Souza Resende Fabrício,de Lemos Manuela Nascimento,de Moraes Lorena Vilhena,de Aquino Vitória Teixeira,de Souza Parente Fernanda,de Queiroz Natércia Neves Marques,Abrahão Neto João Felício,de Alcântara Angélica Leite,da Silva Wanderson Maia,de Souza Neto Norberto Jorge Kzan,Freire Piani Pedro Paulo,de Souza Ícaro José Araújo,Silva Lilian de Souza D'Albuquerque,de Oliveira Maria Clara Neres Iunes,Said Nivin Mazen,Nascimento de Lemos Gabriela,de Melo Franciane Trindade Cunha,Gomes Daniela Lopes,Contente Braga de Souza Ana Carolina,de Sá Oliveira Dos Reis Melissa,Leal Valéria Suênya Galvão,Lobato Isabel Jane Campos,Felício Karem Miléo Frontiers in endocrinology Background:The effect of glycemic control on diabetic kidney disease (DKD) is well known. Recent evidence has suggested that Vitamin D (VD) may have a nephroprotective effect in diabetes, but the relationship between VD, glycemic control, and albuminuria has yet to be clarified. Objective:Evaluate the relationship between 25-hydroxy-vitamin D [25(OH)D], HbA1c, and albuminuria in Diabetes Mellitus (DM). Patients and Methods:Cross-sectional study with 1576 individuals with DM who had 25(OH)D, HbA1c, and albuminuria levels measured. Patients with abnormal creatinine levels were excluded, in order to avoid interference on VD levels by impaired kidney function. Results:Patients with HbA1c ≥7% had lower 25(OH)D when compared to patients with HbA1c <7% (29.7 ± 10.2 28.1 ± 9.9 ng/ml, p = 0.003) and 25(OH)D levels seems to predict 1.5% of HbA1c behavior. The 25(OH)D concentrations in patients with normoalbuminuria were higher than the levels observed in those with micro or macroalbuminuria (29.8 ± 9.0 26.8 ± 8.6 and 25.1 ± 7.6, respectively, p = 0.001), patients who had 25(OH)D <20 ng/ml and 25(OH)D <30 ng/ml were at a higher risk of presenting albuminuria [OR = 2.8 (95% CI = 1.6 - 4.9), p<0.001, and OR = 2.1 (95% CI = 1.3 - 4.6), p<0.001, respectively]. In our regression model, albuminuria was influenced by HbA1c (r² = 0.076, p<0.00001) and 25(OH)D (r² = 0.018, p = 0.002) independently. Conclusion:Our study found an association between vitamin D levels, HbA1c and DKD. Additionally, our data suggest that the association between urinary albumin excretion and vitamin D levels is independent of glycemic control in patients with diabetes. Even though our patients presented normal creatinine levels, it is necessary further prospective studies to confirm if this association precedes or not the loss of renal function. 10.3389/fendo.2021.723502
    General glycosylated hemoglobin goals potentially increase myocardial infarction severity in diabetes patients with comorbidities: Insights from a nationwide multicenter study. Che Qianzi,Zhang Yan,Wang Jianan,Wan Zheng,Fu Xianghua,Chen Jiyan,Yan Hongbing,Chen Yundai,Ge Junbo,Chen Dafang,Huo Yong Journal of diabetes investigation AIMS/INTRODUCTION:We aimed to investigate the relationship between glycemic status and coronary artery disease (CAD) extent and severity in ST-elevation myocardial infarction (STEMI) patients, and further examine whether diabetes patients could benefit from glycosylated hemoglobin (HbA1c) below the recommended level. MATERIALS AND METHODS:Consecutive STEMI patients admitted in 2015-2017 across 244 hospitals were included in the China STEMI Care Project-2. We carried out a cross-sectional study comprising 8,370 participants with a record of HbA1c testing after admission. CAD extent and severity were assessed by admission heart rate, Killip classification and the number of stenosed vessels based on the coronary angiogram. RESULTS:Diabetes patients showed a greater risk for higher Killip class, admission tachycardia (admission heart rate ≥100 b.p.m.) and multivessel CAD (presence of left main and/or triple vessel disease). Likewise, HbA1c level was significantly associated with CAD extent and severity. While dividing diabetes patients according to general HbA1c targets (HbA1c ≤6.5, 6.5-7.0 and ≥7.0%), diabetes patients with HbA1c ≤6.5% showed a 1.30-fold higher risk for multivessel CAD (adjusted odds ratio 1.30, 95% confidence interval 1.05-1.62). In stratified analysis, the association was even stronger in patients with hypertension (adjusted odds ratio 1.41, 95% confidence interval 1.08-1.86) or hyperlipidemia (adjusted odds ratio 1.57, 95% confidence interval 1.17-2.12). CONCLUSIONS:HbA1c level is independently correlated with CAD extent and severity in STEMI patients. HbA1c below generally recommended levels might still increase the risk of CAD progression, especially for diabetes patients with hypertension or hyperlipidemia. 10.1111/jdi.13287
    Gender- and age-related differences in homocysteine concentration: a cross-sectional study of the general population of China. Xu Ranran,Huang Fei,Wang Yiru,Liu Qingquan,Lv Yongman,Zhang Qian Scientific reports The primary goals of this study were to evaluate the gender- and age-related differences in homocysteine concentration in the general population of China and possible influencing factors. A total of 7872 subjects, divided into male and female groups, participated in this retrospective study. The average homocysteine level, prevalence of hyperhomocysteinemia, and independent factors affecting homocysteine concentration were analyzed. The homocysteine level was significantly higher in males than in females in each age range (aged 20-30, aged 30-40, aged 40-50, aged 50-60, aged 60-80, aged over 80) (P < 0.0001), and the trend did not abate with age. The homocysteine concentration first decreased and then increased, being lowest at 30-50 years of age and significantly increased after 50 years of age. Factors associated with homocysteine concentration in males were smoking status (current smokers versus ex-smokers: β: 0.112), estimated glomerular filtration rate (β =  - 0.192), blood urea nitrogen (β =  - 0.14), diastolic blood pressure (β =  - 0.113), free triiodothyronine (β =  - 0.091), serum potassium (β =  - 0.107) and cystatin C (β = 0.173). In females, independent factors associated with homocysteine concentration were cystatin C (β = 0.319), albumin (β = 0.227), free thyroxine (β = 0.179), age (β = 0.148), free triiodothyronine (β =  - 0.217) and serum potassium (β =  - 0.153). The homocysteine level was significantly higher in males than in females and increased markedly after 50 years of age in both groups. The independent factors associated with increased homocysteine concentration differed between males and females. 10.1038/s41598-020-74596-7
    The Relationship between Folic Acid and Vitamin B12 Serum Levels with High Sensitivity C-reactive Protein and Homocysteine in Chronic Hemodialysis Patients: A Cross-sectional Study. Lydia Aida,Priantono Dimas,Harimurti Kuntjoro,Alwi Idrus Acta medica Indonesiana BACKGROUND:Folic acid (FA) and vitamin B12 treatment have been routinely prescribed to lower serum homocysteine levels and to reduce inflammation. However, no study has been conducted to determine serum folic acid (SFA) and vitamin B12 (B12) levels in patients who have twice-weekly hemodialysis. The aim of our study was to assess serum folate and B12  levels in chronic hemodialysis patients and their relationship with hsCRP and homocysteine levels. METHODS:Our study was a cross-sectional study involcing patients who had twice-weekly hemodialysis in Dr Cipto Mangunkusumo National Hospital Jakarta, Indonesia. Predialysis blood samples were taken to measure SFA, B12, homocysteine and hsCRP levels. Patients with medical conditions affecting the assays were excluded. Spearman correlation was used to compare variables. RESULTS:Eighty subjects enrolled in this study. Among those of non-given folic acid and vitamin B-12 supplementation, only 3.85% of subjects had low folic acid levels, and none had low vitamin B12 levels. A moderate negative correlation between serum folic acid and homocysteine level (p≤0.001; r=-0.42) and a weak correlation between serum vitamin B12 and homocysteine level (p=0.009; r=-0.29) was found. Among the high-risk cardiovascular group (CRP>3, n=49), there is a moderate negative correlation between serum folic acid and homocysteine level (p≤0.001; r=-0.561) and a weak negative correlation between vitamin B12 and homocysteine level (p=0.018; r=-0.338). CONCLUSION:There is a significant negative correlation between serum vitamin B12 and folic acid with homocysteine levels, especially in high-risk cardiovascular group.
    TG: HDL-C Ratio as Insulin Resistance Marker for Metabolic Syndrome in Children With Obesity. Frontiers in endocrinology Insulin resistance (IR) is an important variable in the diagnosis of metabolic syndrome (MetS). Currently, IR is not part of the existing pediatric definition of MetS, instead elevated fasting blood glucose (FBG) is measured as an indicator of hyperglycemia. Arguably, many obese children with severe IR are still able to regulate their FBG well. Hence, this study aimed to assess the utility of triglyceride-to-high-density lipoprotein cholesterol (TG : HDL-C) ratio as an IR marker in the modeling of pediatric MetS among children with obesity using structural equation modeling (SEM). A total of 524 blood samples from children with obesity (age 10-16 years old) were analyzed for FBG, lipids, insulin, leptin, and adiponectin. Both exploratory (EFA) and confirmatory factor analysis (CFA) were used to examine TG : HDL-C ratio as an IR marker in pediatric MetS. EFA shows that TG: HDL-C ratio (standardized factor loading = 0.904) groups together with homeostasis model assessment-estimated insulin resistance (HOMA-IR) (standardized factor loading = 0.664), indicating a strong correlation to the IR factor. Replacing FBG with TG: HDL-C ratio improved the modeling of MetS structure in children with obesity. Our MetS model of TG: HDL-C ratio as IR component shows comparable model fitness indices (goodness of fit, Akaike's information criterion, and Bayesian information criterion) with leptin:adiponectin ratio (platinum standard for adiposity:IR marker) model. The least model fit was seen when using FBG as an IR surrogate. TG : HDL-C ratio performed better as IR surrogate in MetS structures (standardized factor loading = 0.39) compared to FBG (standardized factor loading = 0.27). TG: HDL-C ratio may be considered as an IR component in pediatric MetS. 10.3389/fendo.2022.852290
    Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron. Stefanova Deborah,Raychev Antoan,Arezes Joao,Ruchala Piotr,Gabayan Victoria,Skurnik Mikael,Dillon Barbara J,Horwitz Marcus A,Ganz Tomas,Bulut Yonca,Nemeth Elizabeta Blood The iron-regulatory hormone hepcidin is induced early in infection, causing iron sequestration in macrophages and decreased plasma iron; this is proposed to limit the replication of extracellular microbes, but could also promote infection with macrophage-tropic pathogens. The mechanisms by which hepcidin and hypoferremia modulate host defense, and the spectrum of microbes affected, are poorly understood. Using mouse models, we show that hepcidin was selectively protective against siderophilic extracellular pathogens ( O9) by controlling non-transferrin-bound iron (NTBI) rather than iron-transferrin concentration. NTBI promoted the rapid growth of siderophilic but not nonsiderophilic bacteria in mice with either genetic or iatrogenic iron overload and in human plasma. Hepcidin or iron loading did not affect other key components of innate immunity, did not indiscriminately promote intracellular infections (), and had no effect on extracellular nonsiderophilic O8 or Hepcidin analogs may be useful for treatment of siderophilic infections. 10.1182/blood-2017-03-772715
    Vitamin K status, all-cause mortality, and cardiovascular disease in adults with chronic kidney disease: the Chronic Renal Insufficiency Cohort. The American journal of clinical nutrition BACKGROUND:Vascular calcification contributes to cardiovascular disease (CVD) and mortality in individuals with chronic kidney disease (CKD). Vitamin K-dependent proteins function as calcification inhibitors in vascular tissue. OBJECTIVES:We sought to determine the association of vitamin K status with mortality and CVD events in adults with CKD. METHODS:Plasma dephospho-uncarboxylated matrix gla protein ((dp)ucMGP), which increases when vitamin K status is low, and plasma phylloquinone (vitamin K1), which decreases when vitamin K status is low, were measured in 3066 Chronic Renal Insufficiency Cohort participants (median age = 61 y, 45% female, 41% non-Hispanic black, median estimated glomerular filtration rate [eGFR] = 41 mL/min/1.73m2). The association of vitamin K status biomarkers with all-cause mortality and atherosclerotic-related CVD was determined using multivariable Cox proportional hazards regression. RESULTS:There were 1122 deaths and 599 atherosclerotic CVD events over the median 12.8 follow-up years. All-cause mortality risk was 21-29% lower among participants with plasma (dp)ucMGP <450 pmol/L (n = 2361) compared with those with plasma (dp)ucMGP ≥450 pmol/L (adjusted HRs [95% CIs]: <300 pmol/L = 0.71 [0.61, 0.83], 300-449 pmol/L = 0.77 [0.66, 0.90]) and 16-19% lower among participants with plasma phylloquinone ≥0.50 nmol/L (n = 2421) compared to those with plasma phylloquinone <0.50 nmol/L (adjusted HRs: 0.50, 0.99 nmol/L = 0.84 [0.72, 0.99], ≥1.00 nmol/L = 0.81 [0.70, 0.95]). The risk of atherosclerotic CVD events did not significantly differ across plasma (dp)ucMGP or phylloquinone categories. CONCLUSIONS:Two biomarkers of vitamin K status were associated with a lower all-cause mortality risk but not atherosclerotic CVD events. Additional studies are needed to clarify the mechanism underlying this association and evaluate the impact of improving vitamin K status in people with CKD. 10.1093/ajcn/nqab375
    Sex-Specific Absolute Delta Thresholds for High-Sensitivity Cardiac Troponin T. Clinical chemistry BACKGROUND:Sex differences in high-sensitivity cardiac troponin (hs-cTn) concentrations from healthy populations have led to the establishment of sex-specific upper reference limits for hs-cTn assays. This study assessed the performance of sex-specific delta (i.e., changes in concentrations) thresholds for the hs-cTnT assay for ruling in acute myocardial infarction (AMI) in different emergency department (ED) populations. METHODS:This retrospective study consisted of 2 cohorts (Cohort 1 derivation and Cohort 2 validation). Cohort 1 consisted of 18 056 ED patients who had serial hs-cTnT measured using a 0-h/3-h algorithm at a US medical center, with Cohort 2 consisting of 1137 ED patients with 0-h/3-h sampling at a Canadian medical center. The primary outcome was AMI diagnosis with sex-specific deltas derived based on the Youden index and specificity estimates (i.e., ≥90%) in Cohort 1 and validated in Cohort 2. RESULTS:In Cohort 1, 42% of all patients had 0-h hs-cTnT above the sex-specific 99th percentile. Males had higher 0-h hs-cTnT (median 17 ng/L) and absolute deltas (median 2 ng/L) than females (0-h median 11 ng/L, P < 0.0001; deltas median 1 ng/L, P < 0.0001) in non-AMI patients but not in patients with AMI. For ruling in AMI, the sex-specific delta thresholds based on 90% specificity (14 ng/L for males, 11 ng/L for females) performed best and resulted in 91% diagnostic accuracy in both males and females. The sex-specific delta thresholds yielding high specificity estimates were confirmed in the validation data set. CONCLUSIONS:Sex-specific absolute delta thresholds can be used to rule in AMI and are robust across different study populations. 10.1093/clinchem/hvab230
    High-sensitivity cardiac troponin T is a biomarker for atherosclerosis in systemic lupus erythematous patients: a cross-sectional controlled study. Divard Gillian,Abbas Rachid,Chenevier-Gobeaux Camille,Chanson Noémie,Escoubet Brigitte,Chauveheid Marie-Paule,Dossier Antoine,Papo Thomas,Dehoux Monique,Sacre Karim Arthritis research & therapy BACKGROUND:Cardiovascular disease (CVD) is the main cause of death in systemic lupus erythematous (SLE) patients. The Framingham score underestimates the risk for CVD in this population. Our study aimed to determine whether serum high-sensitivity cardiac troponin T (HS-cTnT) might help to identify SLE patients at risk for CVD. METHODS:The presence of carotid plaques was prospectively assessed by ultrasound in 63 consecutive SLE patients asymptomatic for CVD and 18 controls. Serum HS-cTnT concentration was measured using the electrochemiluminescence method. Factors associated with carotid plaques were identified and multivariate analysis was performed. RESULTS:Framingham score was low in both SLE patients (median 1 (range 1-18%)) and controls (1 (1-13%)). Nevertheless, 23 (36.5%) SLE patients, but only 2 (11.1%) controls (p = 0.039), had carotid plaque detected by vascular ultrasound. In the multivariate analysis, only age (p = 0.006) and SLE status (p = 0.017) were independently associated with carotid plaques. Serum HS-cTnT concentration was detectable (i.e. >3 ng/L) in 37 (58.7%) SLE patients and 6 (33.3%) controls (p = 0.057). Interestingly, 87% of SLE patients with carotid plaques, but only 42.5% of SLE patients without plaques (p < 0.001), had detectable HS-cTnT. Conversely, 54.5% of SLE patients with detectable HS-cTnT, but only 11.5% with undetectable HS-cTnT (p < 0.001), had a carotid plaque. In the multivariate analysis, only body mass index (p = 0.006) and HS-cTnT (p = 0.033) were statistically associated with carotid plaques in SLE patients. Overall, the risk of having a carotid plaque was increased by 9 (odds ratio 9.26, 95% confidence interval 1.55-90.07) in SLE patients in whom HS-cTnT was detectable in serum. CONCLUSION:Serum HS-cTnT level is high and associated with carotid plaques in SLE patients who are at an apparently low risk for CVD according to the Framingham score. HS-cTnT may be a useful biomarker for SLE-associated atherosclerosis. 10.1186/s13075-017-1352-7
    Early elevation in plasma high-sensitivity troponin T and morbidity after elective noncardiac surgery: prospective multicentre observational cohort study. Ackland Gareth L,Abbott Tom E F,Jones Timothy F,Leuwer Martin,Pearse Rupert M, , , , British journal of anaesthesia BACKGROUND:Elevated high-sensitivity troponin (hsTnT) after noncardiac surgery is associated with higher mortality, but the temporal relationship between early elevated troponin and the later development of noncardiac morbidity remains unclear. METHODS:Prospective observational study of patients aged ≥45 yr undergoing major noncardiac surgery at four UK hospitals (two masked to hsTnT). The exposure of interest was early elevated troponin, as defined by hsTnT >99th centile (≥15 ng L) within 24 h after surgery. The primary outcome was morbidity 72 h after surgery, defined by the Postoperative Morbidity Survey (POMS). Secondary outcomes were time to become morbidity-free and Clavien-Dindo ≥grade 3 complications. RESULTS:Early elevated troponin (median 21 ng L [16-32]) occurred in 992 of 4335 (22.9%) patients undergoing elective noncardiac surgery (mean [standard deviation, sd] age, 65 [11] yr; 2385 [54.9%] male). Noncardiac morbidity was more frequent in 494/992 (49.8%) patients with early elevated troponin compared with 1127/3343 (33.7%) patients with hsTnT <99th centile (odds ratio [OR]=1.95; 95% confidence interval [CI], 1.69-2.25). Patients with early elevated troponin had a higher risk of proven/suspected infectious morbidity (OR=1.54; 95% CI, 1.24-1.91) and critical care utilisation (OR=2.05; 95% CI, 1.73-2.43). Clavien-Dindo ≥grade 3 complications occurred in 167/992 (16.8%) patients with early elevated troponin, compared with 319/3343 (9.5%) patients with hsTnT <99th centile (OR=1.78; 95% CI, 1.48-2.14). Absence of early elevated troponin was associated with morbidity-free recovery (OR=0.44; 95% CI, 0.39-0.51). CONCLUSIONS:Early elevated troponin within 24 h of elective noncardiac surgery precedes the subsequent development of noncardiac organ dysfunction and may help stratify levels of postoperative care in real time. 10.1016/j.bja.2020.02.003
    Platelets as therapeutic targets to prevent atherosclerosis. Nording Henry,Baron Lasse,Langer Harald F Atherosclerosis Cardiovascular disease remains the main cause of death worldwide. For this reason, strategies for the primary prevention of atherosclerosis and atherosclerosis-related pathologies like stroke or myocardial infarction are needed. Platelets are key players of atherosclerosis-related vascular thrombotic pathologies and their role as targets in secondary prevention of atherosclerosis-related complications is uncontested. However, platelets also play an important role in the initiation and progression of atherosclerosis. Currently, though, there is no generally valid recommendation for the use of antiplatelet therapy in primary prevention of cardiovascular disease. Recent clinical studies have shown that the benefit from antiplatelet therapy in primary prevention is counteracted by the entailed bleeding risk. This review addresses the important role platelets play in initiating and sustaining vascular inflammation, which drives atherosclerosis. Specifically, platelet-lipid interactions as well as platelet-endothelium interactions in the context of atherosclerosis are illustrated. We also depict how platelets help recruit immune cells like monocytes, neutrophils or dendritic cells to the subendothelial space. Finally, we portray the role of complement and platelets in atherosclerosis. Platelets appear to act as mediators of tissue homeostasis and may also modulate the microenvironment of the atherosclerotic plaque. Overall, this review addresses the role of platelets in atherosclerosis with particular focus on potential targets for pharmacological interventions into platelet functions distinct from aggregation. By eliminating the bleeding risk of antiplatelet therapy, platelets are likely to regain a role in primary prevention of cardiovascular disease. 10.1016/j.atherosclerosis.2020.05.018
    Cardiovascular disease biomarkers are associated with declining renal function in type 2 diabetes. Jenks Sara J,Conway Bryan R,McLachlan Stela,Teoh Wei Leng,Williamson Rachel M,Webb David J,Welsh Paul,Sattar Naveed,Strachan Mark W J,Price Jackie F Diabetologia AIMS/HYPOTHESIS:We investigated whether biochemical cardiovascular risk factors and/or markers of subclinical cardiovascular disease were associated with the development of reduced renal function in people with type 2 diabetes. METHODS:A cohort of 1066 Scottish men and women aged 60-74 years with type 2 diabetes from the Edinburgh Type 2 Diabetes Study were followed up for a median of 6.7 years. New-onset reduced renal function was defined as two eGFRs <60 ml min (1.73 m) at least 3 months apart with a > 25% decline from baseline eGFR. Ankle brachial pressure index (ABI), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) were measured at baseline. Pulse wave velocity (PWV) and carotid intima media thickness were measured 1 year into follow-up. Data were analysed using Cox proportional hazards models. RESULTS:A total of 119 participants developed reduced renal function during follow-up. ABI, PWV, NT-proBNP and hsTnT were all associated with onset of decline in renal function following adjustment for age and sex. These associations were attenuated after adjustment for additional diabetes renal disease risk factors (systolic BP, baseline eGFR, albumin:creatinine ratio and smoking pack-years), with the exception of hsTnT which remained independently associated (HR 1.51 [95% CI 1.22, 1.87]). Inclusion of hsTnT in a predictive model improved the continuous net reclassification index by 0.165 (0.008, 0.286). CONCLUSIONS/INTERPRETATION:Our findings demonstrate an association between hsTnT, a marker of subclinical cardiac ischaemia, and subsequent renal function decline. Further research is required to establish the predictive value of hsTnT and response to intervention. 10.1007/s00125-017-4297-0
    Association Between Renal Function and Troponin T Over Time in Stable Chronic Kidney Disease Patients. Chesnaye Nicholas C,Szummer Karolina,Bárány Peter,Heimbürger Olof,Magin Hasan,Almquist Tora,Uhlin Fredrik,Dekker Friedo W,Wanner Christoph,Jager Kitty J,Evans Marie, , Journal of the American Heart Association Background People with reduced glomerular filtration rate (GFR) often have elevated cardiac troponin T (cTnT) levels. It remains unclear how cTnT levels develop over time in those with chronic kidney disease (CKD). The aim of this study was to prospectively study the association between cTnT and GFR over time in older advanced-stage CKD patients not on dialysis. Methods and Results The EQUAL (European Quality Study) study is an observational prospective cohort study in stage 4 to 5 CKD patients aged ≥65 years not on dialysis (incident estimated GFR, <20 mL/min/1.73 m²). The EQUAL cohort used for the purpose of this study includes 171 patients followed in Sweden between April 2012 and December 2018. We used linear mixed models, adjusted for important groups of confounders, to investigate the effect of both measured GFR and estimated GFR on high-sensitivity cTnT (hs-cTnT) trajectory over 4 years. Almost all patients had at least 1 hs-cTnT measurement elevated above the 99th percentile of the general reference population (≤14 ng/L). On average, hs-cTnT increased by 16%/year (95% CI, 13-19; <0.0001). Each 15 mL/min/1.73 m lower mean estimated GFR was associated with a 23% (95% CI, 14-31; <0.0001) higher baseline hs-cTnT and 9% (95% CI, 5-13%; <0.0001) steeper increase in hs-cTnT. The effect of estimated GFR on hs-cTnT trajectory was somewhat lower than a previous myocardial infarction (15%), but higher than presence of diabetes mellitus (4%) and male sex (5%). Conclusions In CKD patients, hs-cTnT increases over time as renal function decreases. Lower CKD stage (each 15 mL/min/1.73 m lower) is independently associated with a steeper hs-cTnT increase over time in the same range as other established cardiovascular risk factors. 10.1161/JAHA.119.013091
    Platelet phagocytosis by leukocytes in a patient with cerebral hemorrhage and thrombocytopenia caused by gram-negative bacterial infection. Wu Xiuji,Li Youjun,Yang Xiaoyang The Journal of international medical research Bacteria-induced thrombocytopenia is a common clinical disease that is often ignored by clinical and scientific research. Thus, exploring the mechanism and principle of bacteria-induced thrombocytopenia could facilitate the development of new diagnostic, preventative, and treatment modalities for thrombocytopenia. This case report describes a case of platelet phagocytosis by neutrophils and monocytes in a patient with cerebral hemorrhage and thrombocytopenia caused by gram-negative bacterial infection. After the infection was eradicated, platelet phagocytosis was alleviated, and his platelet count normalized. Cellular immunity may be an important cause of bacteria-induced thrombocytopenia in patients with cerebral hemorrhage. 10.1177/03000605221079102
    The prognostic impact of uric acid in acute heart failure according to coexistence of diabetes mellitus. Cidade-Rodrigues Catarina,Cunha Filipe M,Elias Catarina,Oliveira Diana,Bettencourt Paulo,Lourenço Patrícia Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIMS:Increased uric acid levels predict higher mortality in heart failure (HF) patients. Patients with diabetes mellitus (DM) appear to have increased xanthine oxidase activity. We aimed to study if the association between uric acid and mortality in acute HF was different according to the coexistence of DM. METHODS AND RESULTS:We studied a cohort of patients hospitalized due to acute HF in 2009-2010. Patients with no uric acid measurement upon admission were excluded from the analysis. FOLLOW-UP:2 years; endpoint: all-cause mortality. Patients with elevated uric acid (>80.0 mg/L) were compared with those with lower values. We used a multivariate Cox-regression analysis to assess the prognostic impact of uric acid (both continuous and categorical variable: cut-off 80.0 mg/L). The analysis was stratified according to coexistence of DM. We studied 569 acute HF patients, 44.6%male, mean age 76 years, 290 were diabetic. Median admission uric acid: 81.2 mg/L and 52.2%had uric acid >80.0 mg/L. Elevated uric acid predicted all-cause mortality in acute HF only in patients with DM. The multivariate-adjusted HR of 2-year mortality was 1.68 (95 % CI: 1.15-2.46) for diabetic HF patients with uric acid>80.0 mg/L compared to those with lower levels (p = 0.008) and 1.10 (95 % CI: 1.03-1.18) per each 10 mg/L increase in uric acid (p = 0.007). In non-diabetic HF patients, uric acid was not associated with mortality. CONCLUSIONS:Increased uric acid predicts ominous outcome in acute HF patients with diabetes, however, it is not prognostic associated in non-diabetics. Uric acid may play a different role in acute HF depending on DM status. 10.1016/j.numecd.2021.07.032
    Association between uric acid level and incidence of albuminuria in patients with type 2 diabetes mellitus: A 4.5-year cohort study. Lai Yun-Ju,Chen Yu-Yen,Ku Po-Wen,Chen Li-Jung,Yen Yung-Feng Medicine ABSTRACT:Using animal models and molecular biology researches, hyperuricemia has been shown to instruct renal arteriolopathy, arterial hypertension, and microvascular injury involving the renin-angiotensin system and resulting in renal function impairment. Nevertheless, the association between uric acid levels and the development of albuminuria has been under-investigated in patients with type 2 diabetes mellitus. Patients with type 2 diabetes and regular outpatient visits were recruited from the Puli Branch of the Taichung Veterans General Hospital in Taiwan since January 2014. Demographics, lifestyle features, and medical history were gathered by well-trained interviewers. All participants underwent comprehensive physical examinations, including a biochemical assay of venous blood specimens and urine samples after an 8-hour overnight fast. Participants were followed until June 2018. The primary outcome was the albuminuria incidence. Univariable and multivariable Cox regression analysis were employed to explore the relation between uric acid and incident albuminuria. Uric acid cutoffs for incident albuminuria were determined with the receiver operator characteristic curve. We included 247 qualified subjects (mean age: 64.78 years old [standard deviation = 11.29 years]; 138 [55.87%] men). During a 4.5-year follow-up duration, 20 subjects with incident albuminuria were recognized. Serum uric acid was significantly associated with an increased risk of incident albuminuria (adjusted hazard ratio = 2.39; 95% confidence interval: 1.53-3.75; P < .001) with potential confounders adjustment. The uric acid cutoff point was 6.9 mg/dL (area under the curve 0.708, sensitivity 60.0%, specificity 84.58%) for incident albuminuria. Serum uric acid was associated with incident albuminuria among patients with type 2 diabetes. 10.1097/MD.0000000000027496
    Albumin, bilirubin, uric acid and cancer risk: results from a prospective population-based study. Kühn Tilman,Sookthai Disorn,Graf Mirja E,Schübel Ruth,Freisling Heinz,Johnson Theron,Katzke Verena,Kaaks Rudolf British journal of cancer BACKGROUND:It has long been proposed that albumin, bilirubin and uric acid may inhibit cancer development due to their anti-oxidative properties. However, there is a lack of population-based studies on blood levels of these molecules and cancer risk. METHODS:Associations between pre-diagnostic serum albumin, bilirubin and uric acid and the risks of common cancers as well as cancer death in the EPIC-Heidelberg cohort were evaluated by multivariable Cox regression analyses. A case-cohort sample including a random subcohort (n=2739) and all incident cases of breast (n=627), prostate (n=554), colorectal (n=256), and lung cancer (n=195) as well as cancer death (n=761) that occurred between baseline (1994-1998) and 2009 was used. RESULTS:Albumin levels were inversely associated with breast cancer risk (hazard ratio (95% CI): 0.71 (0.51, 0.99), P=0.004) and overall cancer mortality (HR (95% CI): 0.64 (0.48, 0.86), P<0.001) after multivariable adjustment. Uric acid levels were also inversely associated with breast cancer risk (HR (95% CI): 0.72 (0.53, 0.99), P=0.043) and cancer mortality (HR (95% CI): 0.75 (0.58, 0.98), P=0.09). There were no significant associations between albumin or uric acid and prostate, lung and colorectal cancer. Serum bilirubin was not associated with any cancer end point. CONCLUSIONS:The present findings indicate that higher levels of albumin and uric acid are related to lower risks of breast cancer and cancer mortality. Further studies are needed to assess whether the observed associations are causal. 10.1038/bjc.2017.313
    High level of individual lipid profile and lipid ratio as a predictive marker of poor glycemic control in type-2 diabetes mellitus. Artha I Made Junior Rina,Bhargah Agha,Dharmawan Nyoman Khrisna,Pande Utami Wijayaswari,Triyana Komang Agus,Mahariski Pande Agung,Yuwono Jessica,Bhargah Varennia,Prabawa I Putu Yuda,Manuaba Ida Bagus Amertha Putra,Rina I Ketut Vascular health and risk management Diabetes is often accompanied by undiagnosed dyslipidemia. The aim of the study is to investigate the clinical relevance of lipid profiles and lipid ratios as predictive biochemical models for glycemic control in patients with type 2 diabetes mellitus (T2DM). This is a retrospective study recruiting 140 patients with T2DM during a one-year period, 2018-2019, at the Diabetic Center Sanglah General Hospital and Internal Medicine Polyclinic Puri Raharja General Hospital. Demographic characteristics, glycosylated hemoglobin (HBA1c) , and lipid profile were recorded and analyzed using SPSS version 25.0 for Windows. The sample is then classified into good (HBA1c≤7) and poor (HBA1c>7) glycemic control. Risk analysis model, receiver operator characteristics (ROC) analysis, and correlation test were used to evaluate the association of HBA1c level with lipid profile and lipid ratio parameters. Lipid profile findings such as total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) , triglycerides (TG), and lipid ratio parameter (LDL-C to high-density lipoprotein cholesterol (HDL-C) ratio) were higher in patients in the poor glycemic control group (<0.05) and HDL-C was significantly lower in patients with poor glycemic control (=0.001). There is a significant positive correlation between LDL, total cholesterol, LDL-C, TG, and TC to HDL-C ratio, triglycerides, and TC/HDL-C ratio with HBA1c level. Meanwhile, a negative correlation was observed on HDL-C with the HBA1c level. Only TC/HDL-C ratio and LDL-C/HDL-C ratio parameters may be used as predictive models (AUC>0.7), with cutoff point, sensitivity, and specificity of 4.68 (77%; 52%) and 3.06 (98%; 56%) respectively. A risk analysis model shows that the LDL-C/HDL-C ratio parameter is the most influential risk factor in the occurrence of poor glycemic control (adjusted OR =38.76; 95% CI: 27.32-56.64; <0.001). Lipid profiles (LDL-C) and lipid ratios (LDL-C/HDL-C and TC/HDL-C ratio) show potential markers that can be used in predicting glycemic control in patients with T2DM. 10.2147/VHRM.S209830
    Pulmonary surfactant protein B carried by HDL predicts incident CVD in patients with type 1 diabetes. Journal of lipid research Atherosclerotic CVD is the major cause of death in patients with type 1 diabetes mellitus (T1DM). Alterations in the HDL proteome have been shown to associate with prevalent CVD in T1DM. We therefore sought to determine which proteins carried by HDL might predict incident CVD in patients with T1DM. Using targeted MS/MS, we quantified 50 proteins in HDL from 181 T1DM subjects enrolled in the prospective Coronary Artery Calcification in Type 1 Diabetes study. We used Cox proportional regression analysis and a case-cohort design to test associations of HDL proteins with incident CVD (myocardial infarction, coronary artery bypass grafting, angioplasty, or death from coronary heart disease). We found that only one HDL protein-SFTPB (pulmonary surfactant protein B)-predicted incident CVD in all the models tested. In a fully adjusted model that controlled for lipids and other risk factors, the hazard ratio was 2.17 per SD increase of SFTPB (95% confidence interval, 1.12-4.21, P = 0.022). In addition, plasma fractionation demonstrated that SFTPB is nearly entirely bound to HDL. Although previous studies have shown that high plasma levels of SFTPB associate with prevalent atherosclerosis only in smokers, we found that SFTPB predicted incident CVD in T1DM independently of smoking status and a wide range of confounding factors, including HDL-C, LDL-C, and triglyceride levels. Because SFTPB is almost entirely bound to plasma HDL, our observations support the proposal that SFTPB carried by HDL is a marker-and perhaps mediator-of CVD risk in patients with T1DM. 10.1016/j.jlr.2022.100196
    Milk polar lipids reduce lipid cardiovascular risk factors in overweight postmenopausal women: towards a gut sphingomyelin-cholesterol interplay. Vors Cécile,Joumard-Cubizolles Laurie,Lecomte Manon,Combe Emmanuel,Ouchchane Lemlih,Drai Jocelyne,Raynal Ketsia,Joffre Florent,Meiller Laure,Le Barz Mélanie,Gaborit Patrice,Caille Aurélie,Sothier Monique,Domingues-Faria Carla,Blot Adeline,Wauquier Aurélie,Blond Emilie,Sauvinet Valérie,Gésan-Guiziou Geneviève,Bodin Jean-Pierre,Moulin Philippe,Cheillan David,Vidal Hubert,Morio Béatrice,Cotte Eddy,Morel-Laporte Françoise,Laville Martine,Bernalier-Donadille Annick,Lambert-Porcheron Stéphanie,Malpuech-Brugère Corinne,Michalski Marie-Caroline Gut OBJECTIVE:To investigate whether milk polar lipids (PL) impact human intestinal lipid absorption, metabolism, microbiota and associated markers of cardiometabolic health. DESIGN:A double-blind, randomised controlled 4-week study involving 58 postmenopausal women was used to assess the chronic effects of milk PL consumption (0, 3 or 5 g-PL/day) on lipid metabolism and gut microbiota. The acute effects of milk PL on intestinal absorption and metabolism of cholesterol were assessed in a randomised controlled crossover study using tracers in ileostomy patients. RESULTS:Over 4 weeks, milk PL significantly reduced fasting and postprandial plasma concentrations of cholesterol and surrogate lipid markers of cardiovascular disease risk, including total/high-density lipoprotein-cholesterol and apolipoprotein (Apo)B/ApoA1 ratios. The highest PL dose preferentially induced a decreased number of intestine-derived chylomicron particles. Also, milk PL increased faecal loss of coprostanol, a gut-derived metabolite of cholesterol, but major bacterial populations and faecal short-chain fatty acids were not affected by milk PL, regardless of the dose. Acute ingestion of milk PL by ileostomy patients shows that milk PL decreased cholesterol absorption and increased cholesterol-ileal efflux, which can be explained by the observed co-excretion with milk sphingomyelin in the gut. CONCLUSION:The present data demonstrate for the first time in humans that milk PL can improve the cardiometabolic health by decreasing several lipid cardiovascular markers, notably through a reduced intestinal cholesterol absorption involving specific interactions in the gut, without disturbing the major bacterial phyla of gut microbiota. TRIAL REGISTRATION NUMBER:NCT02099032 and NCT02146339; Results. 10.1136/gutjnl-2018-318155
    SOAT1 is a new prognostic factor of colorectal cancer. Wang Xin-Chun,Luo Lin-Ming,Huang Tao-Sheng,Feng Li-Feng Irish journal of medical science Colorectal cancer (CRC) is one of the most common malignant gastrointestinal cancers. Metastasis is the major leading cause of death in patients with CRC, and many patients treated with radical surgery were diagnosed with metastasis during follow-up. However, the underlying molecular mechanisms regulating CRC metastasis are still elusive. Sterol o-acyltransferase 1 (SOAT1) is a critical participant in maintaining intracellular cholesterol balance. Here, by analyzing the clinical specimens and in vitro cell line experiments, we evaluated the clinical relevance and role of SOAT1 in regulating CRC metastasis. The results revealed that SOAT1 was overexpressed in colon cancer tissues compared to peritumor tissues at mRNA and protein levels. High intratumor SOAT1 expression correlates to lymph node metastasis and indicates poor patient disease-free survival and overall survival. The silencing of SOAT1 strongly inhibited the migration and invasion ability of CRC tumor cells. These results demonstrated that SOAT1 was upregulated in colon cancer. Upregulation of SOAT1 expression may promote CRC progression by enhancing the migration and invasion ability of CRC. Our results indicate that targeting SOAT1 activity may be applied as a promising therapeutic strategy for preventing the metastasis of CRC after radical surgical treatment. 10.1007/s11845-021-02746-5
    Platelet number is positively and independently associated with glycated hemoglobin in non-diabetic overweight and obese subjects. De Pergola G,Giagulli V A,Guastamacchia E,Bartolomeo N,Tatoli R,Lampignano L,Silvestris F,Triggiani V Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIMS:A significant increase in platelet count may be a risk factor for atherosclerotic cardiovascular disease. This study investigates the association between platelet number and glucose metabolism, evaluated by glycated hemoglobin (HbA1c) levels, in a apparently healthy population represented by overweight and obese subjects with normal glucose and HbA1c levels. METHODS AND RESULTS:As many as 240 subjects, 177 women and 63 men, aged 18-70 years, were enrolled. Body mass index (BMI), waist circumference (WC), systolic and diastolic blood pressure levels, platelet count and fasting blood glucose, insulin, insulin resistance, HbA1c, uric acid, triglyceride, total cholesterol, high and low density lipoprotein cholesterol concentrations were evaluated. Concerning the univariate correlation analyses between platelets number and all other variables, platelet count was significantly (and positively) correlated only with HbA1c (P < 0.05) and female sex (P < 0.01). HbA1c (P < 0.05), female sex (P < 0.001), and diastolic blood pressure (P < 0.01), positively, and age (P < 0.05) and systolic blood pressure (P < 0.05), negatively, were significantly and independently associated to platelet count in a final multiple regression analysis. CONCLUSION:This is the first study showing a strong positive and independent relationship between HbA1c and platelet number in non-diabetic overweight and obese subjects. 10.1016/j.numecd.2018.12.007
    High-density lipoprotein as a modulator of platelet and coagulation responses. van der Stoep Marco,Korporaal Suzanne J A,Van Eck Miranda Cardiovascular research Platelets and coagulation factors are involved in the process of haemostasis, which ensures undisturbed blood flow upon vessel wall damage. However, excessive platelet aggregation and/or coagulation may lead to arterial or venous thrombosis. Pro-atherogenic lipoproteins, including native and oxidized low-density lipoprotein (LDL), are associated with an increased susceptibility to thrombosis. In contrast, numerous epidemiological studies have established an inverse correlation between high-density lipoprotein (HDL) levels and the risk for thrombosis. In addition to its role in reverse cholesterol transport, HDL also interacts with platelets, the coagulation cascade, and the vascular endothelium. Native HDL prevents platelet hyperreactivity by limiting intraplatelet cholesterol overload, as well as by modulating platelet signalling pathways after binding platelet HDL receptors such as scavenger receptor class B type I (SR-BI) and apoER2'. The antithrombotic properties of native HDL are also related to the suppression of the coagulation cascade and stimulation of clot fibrinolysis. Furthermore, HDL stimulates the endothelial production of nitric oxide and prostacyclin, which are potent inhibitors of platelet activation. Thus, HDL's antithrombotic actions are multiple and therefore, raising HDL may be an important therapeutic strategy to reduce the risk of arterial and venous thrombosis. 10.1093/cvr/cvu137
    The relation of mean platelet volume with microalbuminuria and glomerular filtration rate in obese individuals without other metabolic risk factors: the role of platelets on renal functions. Esen Bennur,Atay Ahmet Engin,Gunoz Nalan,Gokmen Emel Saglam,Sari Hakan,Cakir Ilkay,Kayabasi Hasan,Sit Dede Clinical nephrology INTRODUCTION:Mean platelet volume (MPV) is an indirect indicator of platelet activity that plays a major role in the pathogenesis of endothelial injury. Obese individuals have higher microalbuminuria which is the initial step of renal endothelial injury. We aimed to analyze the relation of microalbuminuria and MPV in obese individuals without metabolic risk factors. METHODS:A total of 290 obese individuals (body mass index (BMI)>30 kg/m2) without an accompanying chronic disorder, and 204 nonobese healthy subjects were enrolled into the study. All participants underwent physical examination. Biochemical, hemogram, and hormonal parameters along with urine albumin analysis were performed. Glomerular filtration rate (GFR) was measured by Cockcroft-Gault (GFRC&G), modification of diet in renal disease (MDRD). The BMI was calculated as weight/height2 (kg/m2). Logistic regression analysis was used to analyze relation of variables. RESULTS:The patient group consisted of 171 (59%) female (mean age: 37.15±8.05 years) and 119 (41%) male (mean age 38.98±10.68 years) obese individuals. 130 (63.7%) age matched female (mean age 36.18±8.26 years) and 74 (36.3%) age matched male (mean age 36.49±10.25 years) controls were assigned to the control group. There was a significant difference between groups with regard to BMI, spot microalbuminuria, spot urine microalbuminuria/creatinine ratio but not with to MPV and spot urine creatinine (p: 0.01, 0.004, 0.002; respectively). GFR measured by MDRD and Cockcroft-Gault formula were significantly higher in the obese group (p<0.001 for both). Correlation analysis revealed a significant correlation between BMI and spot urine microalbuminuria, spot urine microalbuminuria/creatinine ratio, GFR (Cockcroft-Gault Formula), Homeostasis Model Assessment of Insulin resistance (HOMA-IR), insulin, C-peptide, diastolic blood pressure, glucose, uric acid, total cholesterol, low density lipoprotein (LDL)-cholesterol, c-reactive protein (CRP), thyroid stimulating hormone (TSH), leukocyte count, platelet count. MPV was inversely and significantly correlated with spot urine creatinine, systolic blood pressure, triglyceride, C-peptide, and platelet count. Mean urea, creatinine, uric acid, triglyceride, total cholesterol, LDL-cholesterol, insulin, C-peptide, HOMA-IR were significantly higher in obese male individuals while obese female individuals had higher levels of mean high density lipoprotein (HDL), CRP, TSH, platelet count, spot urine microalbumin/creatinine rate, and GFR measured by MDRD. CONCLUSIONS:Obese individuals have higher microalbuminuria and nonsignificantly elevated MPV, however, urine albumin loss is independent of MPV. 10.5414/CN108534
    Relationship between serum cholesterol and indices of erythrocytes and platelets in the US population. Fessler Michael B,Rose Kathryn,Zhang Yanmei,Jaramillo Renee,Zeldin Darryl C Journal of lipid research Whereas dyslipidemia has been associated with leukocytosis, the relationship between serum cholesterol and other hematopoietic lineages is poorly defined. Erythrocytes and platelets, anucleate cells relegated to nonspecific diffusional exchange of cholesterol with serum, have been proposed to have a distinct relationship to cholesterol from leukocytes. We examined the relationship between serum cholesterol and circulating erythrocyte/platelet indices in 4,469 adult participants of the National Health and Nutrition Examination Survey (NHANES) 2005-2006. In linear regression analyses, serum non-high density lipoprotein-cholesterol (non-HDL-C) was positively associated with mean erythrocyte number, hematocrit, hemoglobin concentration, platelet count, and platelet crit independently of age, gender, race/ethnicity, smoking, body mass index, serum folate, and C-reactive protein. The magnitude of the relationship was most marked for platelets, with lowest versus highest non-HDL-C quartile subjects having geometric mean platelet counts of 258,000/μl versus 281,000/μl, respectively (adjusted model, P < 0.001 for trend). These associations persisted in a sensitivity analysis excluding several conditions that affect erythrocyte/platelet and/or serum cholesterol levels, and were also noted in an independent analysis of 5,318 participants from NHANES 2007-2008. As non-HDL-C, erythrocytes, and platelets all impact cardiovascular disease risk, there is a need for advancing understanding of the underlying interactions that govern levels of these three blood components. 10.1194/jlr.P037614
    The platelet to high density lipoprotein -cholesterol ratio is a valid biomarker of nascent metabolic syndrome. Jialal Ishwarlal,Jialal Ganesh,Adams-Huet Beverley Diabetes/metabolism research and reviews AIMS:The metabolic syndrome (MetS) is a major global problem, and inflammation and insulin resistance appear to be key underpinnings in this cardio-metabolic cluster. MetS predisposes to an increased risk of diabetes and atherosclerotic cardiovascular disease (ASCVD). It has a procoagulant diathesis which included increased platelet activity and impaired fibrinolysis. High density lipoprotein (HDL) appears to be anti-thrombotic. Accordingly, we examined the ratios between platelets to HDL-cholesterol(C) and adiponectin (Adipo) in patients with nascent MetS without the confounding of diabetes, ASCVD and smoking to determine their validity as biomarkers of MetS. METHODS:Patients with nascent MetS (n = 58) and matched controls (n = 44) were recruited. Fasting blood samples were obtained for complete blood counts, basic metabolic panel, lipids, insulin, and Adipo. Ratios of platelets to HDL-C and Adipo were calculated. RESULTS:Following adjustment for adiposity, only the platelet: HDL ratio was significantly increased in MetS and increased with severity of MetS. Receiver operating characteristic curve analysis showed that the platelet: HDL-C area under the curve (AUC) significantly added to both platelets and platelet lymphocyte ratio AUCs. Also the platelet: HDL-C ratio correlated with all cardio-metabolic features of MetS, high sensitivity C-reactive protein, insulin resistance chemerin, and leptin. CONCLUSIONS:The ratio of platelets: HDL-C is significantly increased in patients with nascent MetS and appear to be a valid biomarker of MetS. It could also emerge as a biomarker for athero-thrombotic risk. However, these preliminary findings need confirmation in large prospective studies. 10.1002/dmrr.3403
    Prediction of gestational diabetes mellitus in the first 19 weeks of pregnancy using machine learning techniques. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians AIM:Our objective was to develop a first 19 weeks risk prediction model with several potential gestational diabetes mellitus (GDM) predictors including hepatic and renal and coagulation function measures. METHODS:A total of 490 pregnant women, 215 with GDM and 275 controls, participated in this case-control study. Forty-three blood examination indexes including blood routine, hepatic and renal function, and coagulation function were obtained. Support vector machine (SVM) and light gradient boosting machine (lightGBM) were applied to estimate possible associations with GDM and build the predict model. Cutoff points were estimated using receiver operating characteristic curve analysis. RESULTS:It was observed that a cutoff of Prothrombin time (PAT-PT) and Activated partial thromboplastin time (PAT-APTT) could reliably predict GDM with sensitivity of 88.3% and specificity of 99.47% (AUC of 94.2%). If we only use hepatic and renal function examination, a cutoff of DBIL and FPG with sensitivity of 82.6% and specificity of 90.0% (AUC of 91.0%) was obvious and a negative correlation with PAT-PT (=-0.430549) and patient activated partial thromboplastin time (PAT-APTT) (=-0.725638). A negative correlation with direct bilirubin (DBIL) (=-0.379882) and positive correlation with fasting plasma glucose (FPG) ( = 0.458332) neglect coagulation function examination. CONCLUSION:The results of this study point out the possible roles of PAT-PT and PAT-APTT as potential novel biomarkers for the prediction and earlier diagnosis of GDM. A first 19 weeks risk prediction model, which incorporates novel biomarkers, accurately identifies women at high risk of GDM, and relevant measures can be applied early to achieve the prevention and control effects. 10.1080/14767058.2020.1786517
    A unified framework identifies new links between plasma lipids and diseases from electronic medical records across large-scale cohorts. Nature genetics Plasma lipids are known heritable risk factors for cardiovascular disease, but increasing evidence also supports shared genetics with diseases of other organ systems. We devised a comprehensive three-phase framework to identify new lipid-associated genes and study the relationships among lipids, genotypes, gene expression and hundreds of complex human diseases from the Electronic Medical Records and Genomics (347 traits) and the UK Biobank (549 traits). Aside from 67 new lipid-associated genes with strong replication, we found evidence for pleiotropic SNPs/genes between lipids and diseases across the phenome. These include discordant pleiotropy in the HLA region between lipids and multiple sclerosis and putative causal paths between triglycerides and gout, among several others. Our findings give insights into the genetic basis of the relationship between plasma lipids and diseases on a phenome-wide scale and can provide context for future prevention and treatment strategies. 10.1038/s41588-021-00879-y
    Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II-Induced Microvascular Dysfunction. Senchenkova Elena Y,Russell Janice,Yildirim Alper,Granger D Neil,Gavins Felicity N E Hypertension (Dallas, Tex. : 1979) Hypertension is an established risk factor for subsequent cardiovascular diseases, with Ang II (angiotensin II) playing a major role in mediating thrombotic and inflammatory abnormalities. Although T cells and IL-6 (interleukin-6) play an important role in adaptive immune responses, little is known about their role(s) in the thromboinflammatory responses associated with Ang II. Here we show using intravital microscopy coupled with the light/dye injury model that Rag-1 deficient (Rag-1) and IL-6 deficient (IL-6) mice are afforded protection against Ang II-induced thrombosis. Blocking IL-6 receptors (using CD126 and gp130 antibodies) significantly diminished Ang II-mediated thrombosis and inflammatory cell recruitment in mice. Furthermore, the adoptive transfer of IL-6-derived T cells into Rag-1 mice failed to accelerate Ang II-induced thrombosis compared with Rag-1 mice reconstituted with wild-type-derived T cells, suggesting T cell IL-6 mediates the thrombotic abnormalities associated Ang II hypertension. Interestingly, adoptive transfer of WT T cells into Rag-1/Ang II mice resulted in increased numbers of immature platelets, which constitutes a more active platelet population, that is, prothrombotic and proinflammatory. To translate our in vivo findings, we used clinical samples to demonstrate that IL-6 also predisposes platelets to an interaction with collagen receptors, thereby increasing the propensity for platelets to aggregate and cause thrombosis. In summary, we provide compelling evidence for the involvement of IL-6, IL-6R, and T-cell-dependent IL-6 signaling in Ang II-induced thromboinflammation, which may provide new therapeutic possibilities for drug discovery programs for the management of hypertension. 10.1161/HYPERTENSIONAHA.118.12286
    Diabetic ketoacidosis. Dhatariya Ketan K,Glaser Nicole S,Codner Ethel,Umpierrez Guillermo E Nature reviews. Disease primers Diabetic ketoacidosis (DKA) is the most common acute hyperglycaemic emergency in people with diabetes mellitus. A diagnosis of DKA is confirmed when all of the three criteria are present - 'D', either elevated blood glucose levels or a family history of diabetes mellitus; 'K', the presence of high urinary or blood ketoacids; and 'A', a high anion gap metabolic acidosis. Early diagnosis and management are paramount to improve patient outcomes. The mainstays of treatment include restoration of circulating volume, insulin therapy, electrolyte replacement and treatment of any underlying precipitating event. Without optimal treatment, DKA remains a condition with appreciable, although largely preventable, morbidity and mortality. In this Primer, we discuss the epidemiology, pathogenesis, risk factors and diagnosis of DKA and provide practical recommendations for the management of DKA in adults and children. 10.1038/s41572-020-0165-1
    Risk factors for retinopathy in hemodialysis patients with type 2 diabetes mellitus. Scientific reports There is limited knowledge on the prevalence and risk factors of diabetic retinopathy (DR) in dialysis patients. We have investigated the association between diabetes mellitus and lipid-related biomarkers and retinopathy in hemodialysis patients. We reviewed 1,255 hemodialysis patients with type 2 diabetes mellitus (T2DM) who participated in the German Diabetes and Dialysis Study (4D Study). Associations between categorical clinical, biochemical variables and diabetic retinopathy were examined by logistic regression. On average, patients were 66 ± 8 years of age, 54% were male and the HbA1c was 6.7% ± 1.3%. DR, found in 71% of the patients, was significantly and positively associated with fasting glucose, HbA1c, time on dialysis, age, systolic blood pressure, body mass index and the prevalence of other microvascular diseases (e.g. neuropathy). Unexpectedly, DR was associated with high HDL cholesterol and high apolipoproteins AI and AII. Patients with coronary artery disease were less likely to have DR. DR was not associated with gender, smoking, diastolic blood pressure, VLDL cholesterol, triglycerides, and LDL cholesterol. In summary, the prevalence of DR in patients with type 2 diabetes mellitus requiring hemodialysis is higher than in patients suffering from T2DM, who do not receive hemodialysis. DR was positively related to systolic blood pressure (BP), glucometabolic control, and, paradoxically, HDL cholesterol. This data suggests that glucose and blood pressure control may delay the development of DR in patients with diabetes mellitus on dialysis. 10.1038/s41598-020-70998-9
    Zinc, copper, and oxysterol levels in patients with type 1 and type 2 diabetes mellitus. Samadi Afshin,Isikhan Selen Yilmaz,Tinkov Alexey A,Lay Incilay,Doşa Monica Daniela,Skalny Anatoly V,Skalnaya Margarita G,Chirumbolo Salvatore,Bjørklund Geir Clinical nutrition (Edinburgh, Scotland) BACKGROUND:The present study has the objective to assess the zinc (Zn), copper (Cu), and oxysterols plasma levels in type 1 (DM1) (n = 26) and type 2 (DM2) (n = 80) diabetes patients, as compared to healthy controls (n = 71), in order to testify whether metal levels may have a significant impact on the association between oxysterols and diabetes. METHODS:Plasma trace elements and plasma oxysterols were assessed using atomic absorption spectrometry and LC-MS/MS, respectively. Lifestyle, smoking status, alcohol intake, and drug usage, as well as microvascular complications, were also monitored and reported. RESULTS:The obtained data demonstrated that both DM1 and DM2 patients were characterized by significantly elevated HbA1c, FBG, TC, LDL-C, VLDL-C, and TG levels as compared to controls. Plasma Zn levels and Zn/Cu ratio in DM1 and DM2 patients were about 3- and 2-fold lower than controls. No significant differences in plasma Cu levels were reported. The 7-ketocholesterol (7-kchol) levels in DM1 and DM2 patients exceeded these values in healthy individuals by 2.5 and 5-fold, respectively. Similarly, cholestan-3β, 5α, 6β-triol (chol-triol) levels were more than 3- and 6-fold higher when compared to the respective values in non-diabetic controls. In regression models decreased plasma Zn and elevated oxysterol levels were significantly associated with HbA1c and fasting plasma glucose levels, after adjustment for anthropometric and clinical variables, as well as routine biochemical markers. CONCLUSIONS:Plasma Zn concentration is inversely associated with both 7-kchol and chol-triol levels. Assessment of Zn and oxysterol levels may be used both for risk assessment and as targets for the treatment of diabetes mellitus. 10.1016/j.clnu.2019.07.026
    Association of gamma-glutamyl transferase and alanine aminotransferase with type 2 diabetes mellitus incidence in middle-aged Japanese men: 12-year follow up. Journal of diabetes investigation AIMS/INTRODUCTION:To prospectively investigate whether simultaneous elevation of gamma-glutamyl transferase (GGT) and alanine aminotransferase (ALT) is associated with the increase of type 2 diabetes mellitus incidence independent of alcohol drinking, body mass index and triglycerides. METHODS:A total of 2,775 Japanese male workers who had no history of type 2 diabetes mellitus were followed. High GGT and ALT were defined as the top tertiles (GGT cutpoint: 49 IU/L, ALT cutpoint: 28 IU/L). Three groups were created using these dichotomized GGT and ALT cutpoints: both low, either high or both high. Multivariable Cox proportional hazards models were carried out adjusted for potential confounding factors. RESULTS:A total of 276 type 2 diabetes mellitus cases were identified during 12 years (27,040 person-years) of follow up. Participants with simultaneously elevated GGT and ALT had a significantly higher incidence of type 2 diabetes mellitus, even after adjustment for fasting insulin and fasting blood glucose compared with the group without GGT or ALT elevation. Similar associations were observed in non- or light-to-moderate alcohol drinkers, as well as in participants with normal weight. However, the association was weaker in participants with triglycerides <150 mg/dL. We then evaluated whether the addition of GGT and ALT would improve the prediction of type 2 diabetes mellitus incidence, and found that their inclusion significantly increased the C-statistic, net reclassification improvement and integrated discrimination improvement. CONCLUSIONS:Simultaneous elevation of GGT and ALT was significantly associated with type 2 diabetes mellitus incidence, independent of potential confounding factors, including alcohol drinking and obesity, although the association might require concomitant elevation of triglycerides. Inclusion of GGT and ALT improved type 2 diabetes mellitus risk prediction. 10.1111/jdi.12930
    Higher level of GGT during mid-pregnancy is associated with increased risk of gestational diabetes mellitus. Kong Man,Liu Chaoqun,Guo Yanfang,Gao Qing,Zhong Chunrong,Zhou Xuezhen,Chen Renjuan,Xiong Guoping,Yang Xuefeng,Hao Liping,Yang Nianhong Clinical endocrinology OBJECTIVE:This study was to explore the link between gamma-glutamyl transferase (GGT), alanine transaminase (ALT) and aspartate transaminase (AST) levels during early-middle pregnancy and subsequent risk of gestational diabetes mellitus (GDM). METHODS:In a prospective cohort study, pregnant women enrolled prior to 16 weeks of gestation were followed up until delivery. GGT, AST and ALT levels were tested during weeks 14-18 of gestation and oral glucose tolerance test was conducted during 24-28 weeks to screen GDM. RESULTS:The GDM rate was 8.1% (122/1512). Mean GGT level was higher in GDM than non-GDM women (18.7 ± 13.0 vs 14.5 ± 7.0, P < .001). The higher GGT level was 26.9~74.0 U/L, which was significantly associated with increased risk of GDM. The adjusted RR (95% CI) comparing higher GGT level versus lower was 5.40 (3.36-8.68). No significant correlation was found between ALT or AST levels and the risk of GDM. CONCLUSIONS:The results suggest that pregnant women with higher serum GGT during early-middle pregnancy have higher risk of developing GDM. A GGT level >26.9 U/L may indicate an increased risk of developing GDM later and should be further concerned. 10.1111/cen.13558
    Could non-HDL-cholesterol be a better marker of atherogenic dyslipidemia in obstructive sleep apnea? Basoglu Ozen K,Tasbakan Mehmet S,Kayikcioglu Meral Sleep medicine BACKGROUND/OBJECTIVE:Obstructive sleep apnea (OSA) is independently associated with dyslipidemia, a surrogate marker of atherosclerosis. Low-density lipoprotein (LDL)-cholesterol is accepted as a major independent risk factor for cardiovascular disease. However, non-high-density lipoprotein (HDL)-cholesterol is a better marker of atherogenic dyslipidemia and recommended as a target of lipid lowering therapy. We aimed to assess the prevalence of atherogenic dyslipidemia, and relationship between OSA severity and serum LDL-cholesterol and non-HDL cholesterol levels in OSA patients. METHODS:We retrospectively evaluated treatment naïve 2361 subjects admitted to the sleep laboratory of a university hospital for polysomnography. All subjects' lipid profile including total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, and non-HDL-cholesterol were measured. RESULTS:Out of 2361 patients (mean age 49.6 ± 11.9 years; 68.9% male, apnea-hypopnea index 36.6 ± 28.4/h), 185 (7.8%) had no OSA and 2176 (92.2%) had OSA. Atherogenic dyslipidemia prevalence was high (57-66%) in OSA patients, and especially increased in severe OSA compared to other groups (p < 0.05). Though total and LDL-cholesterol did not differ between those with and without OSA, non-HDL-cholesterol (p = 0.020), and triglycerides (p = 0.001) were higher and HDL-cholesterol levels (p = 0.018) were lower in OSA patients than non-OSA. Non-HDL-cholesterol was significantly correlated with OSA severity (p < 0.001) and hypoxia parameters (p < 0.01), whereas LDL-cholesterol showed no correlation. CONCLUSIONS:Atherogenic dyslipidemia is highly prevalent and non-HDL-cholesterol levels are significantly increased, predominantly in severe OSA patients. Non-HDL-cholesterol but not LDL-cholesterol, is significantly correlated with OSA severity and hypoxia parameters. Therefore, it could be better to use non-HDL-cholesterol, which is a guideline recommended target of lipid therapy, as a marker of atherosclerotic cardiovascular risk in OSA patients. 10.1016/j.sleep.2021.09.021
    The role of the plasma glycosylated hemoglobin A1c/Apolipoprotein A-l ratio in predicting cardiovascular outcomes in acute coronary syndrome. Song Feier,Zhou Yu,Zhang Kunyi,Liang Yuan-Feng,He Xuyu,Li Liwen Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIMS:Glucose and lipid metabolism are major prognostic indicators of coronary heart disease. The ratio of plasma glycosylated hemoglobin A1c (HbA1c) to apolipoprotein A-l (ApoA-l) is an indirect measure of insulin resistance. The study aimed to evaluate whether the HbA1c/ApoA-1 ratio can predict the prognosis in patients with the acute coronary syndrome (ACS). METHODS AND RESULTS:A total of 476 ACS patients diagnosed by coronary angiography were enrolled in this longitudinal, observational, retrospective study. Plasma HbA1c, fasting blood glucose and lipid profile were measured. Patients were stratified according to the tertiles of HbA1c/ApoA-l levels. Cox proportional hazard model was used to examine the predictive value of HbA1c/ApoA-l for study endpoints. The association between the Log HbA1c/ApoA-l ratio and major adverse cardiovascular events (MACEs) was estimated using multiple logistic regression. Baseline characteristics showed a mean age of 66 ± 8 years, and 52.5% were hypertensive, 26.8% diabetic, and 54.5% current or prior smokers. During a mean follow-up period of 22.3 ± 1.7 months, 59 deaths occurred. After adjusting for age, gender, smoking, hypertension, diabetes, and coronary artery disease severity, patients in the highest HbA1c/ApoA-l ratio tertile had a 4.36-fold increased risk of mortality compared with those in the lowest tertile. The multivariate logistic regression showed that the Log HbA1c/ApoA-l ratio was associated with MACEs (Odds ratio 2.95, p = 0.013). CONCLUSION:After adjusting for traditional cardiovascular risk factors and ACS severity scores, the HbA1c/ApoA-1 ratio remained an independent predictor of all-cause mortality and MACEs in the ACS patients undergoing angiography. 10.1016/j.numecd.2020.10.008
    Associations between TG/HDL ratio and insulin resistance in the US population: a cross-sectional study. Endocrine connections BACKGROUND:Clinical data on the relationship between triglycerides (TG)/HDL ratio and insulin resistance (IR) suggest that TG/HDL ratio may be a risk factor for IR. However, there is evidence that different races have different risk of developing IR. The relationship on TG/HDL ratio and IR in various populations needs to be improved. Therefore, we investigated whether TG/HDL ratio was linked to IR in different groups in the United States after controlling for other covariates. METHODS:The current research was conducted in a cross-sectional manner. From 2009 to 2018, the National Health and Nutrition Examination Survey (NHANES) had a total of 49,696 participants, all of whom were Americans. The target-independent variable was TG/HDL ratio measured at baseline, and the dependent variable was IR. Additionally, the BMI, waist circumference, education, race, smoking, alcohol use, alanine transaminase, aspartate transaminase, and other covariates were also included in this analysis. RESULTS:The average age of the 10,132 participants was 48.6 ± 18.4 years, and approximately 4936 (48.7%) were males. After correcting for confounders, fully adjusted logistic regression revealed that TG/HDL ratio was correlated with IR (odds ratio = 1.51, 95% CI 1.42-1.59). A nonlinear interaction between TG/HDL ratio and IR was discovered, with a point of 1.06. The impact sizes and CIs on the left and right sides of the inflection point were 6.28 (4.66-8.45) and 1.69 (1.45-1.97), respectively. According to subgroup analysis, the correlation was strong in females, alcohol users, and diabetes patients. Meanwhile, the inverse pattern was observed in the aged, obese, high-income, and smoking populations. CONCLUSION:In the American population, the TG/HDL ratio is positively associated with IR in a nonlinear interaction pattern. 10.1530/EC-21-0414
    Is a High HDL-Cholesterol Level Always Beneficial? Franczyk Beata,Rysz Jacek,Ławiński Janusz,Rysz-Górzyńska Magdalena,Gluba-Brzózka Anna Biomedicines The specific interest concerning HDL cholesterol (HDL-C) is related to its ability to uptake and return surplus cholesterol from peripheral tissues back to the liver and, therefore, to its role in the prevention of cardiovascular diseases, such as atherosclerosis and myocardial infarction, but also transient ischemic attack and stroke. Previous epidemiological studies have indicated that HDL-C concentration is inversely associated with the risk of cardiovascular disease and that it can be used for risk prediction. Some genetic disorders are characterized by markedly elevated levels of HDL-C; however, they do not translate into diminished cardiovascular risk. The search of the potential causative relationship between HDL-C and adverse events has shifted the attention of researchers towards the composition and function of the HDL molecule/subfractions. HDL possesses various cardioprotective properties. However, currently, it appears that higher HDL-C is not necessarily protective against cardiovascular disease, but it can even be harmful in extremely high quantities. 10.3390/biomedicines9091083
    TG/HDL Ratio: A marker for insulin resistance and atherosclerosis in prediabetics or not? Journal of family medicine and primary care BACKGROUND:The spectrum of Diabetes Mellitus and various complications associated with it have been regarded as major global health challenges. Raised TG/HDL has been regarded as one of the valid markers for Insulin resistance. It leads to increased risk of CVD by causing Insulin resistance and also by its own effect on the vessel wall. Detection of raised TG/HDL ratio and early intervention before the patients develop clinical disease can help in mitigation of future consequences of CVD. AIMS:The aim of our study was to compare TG/HDL ratio between prediabetics and controls and further to look for any correlation between the TG/HDL ratio value with HOMA-IR and Carotid Intima Media Thickness (CIMT) in prediabetics. SETTINGS AND DESIGNS:A cross sectional study. METHODS AND MATERIAL:Study was done at ABVIMS and Dr RML Hospital, New Delhi. 60 prediabetics and 60 age, sex, BMI matched controls were employed. In both cases and controls fasting and postprandial blood glucose, glycated Hemoglobin (HbA1C) and fasting Insulin levels were measured. HOMA-IR values in both the groups were calculated using fasting glucose and Insulin levels. Serum lipid profile was obtained and TG/HDL ratio was analysed in two groups. Values obtained were compared between the two groups. CIMT was only measured in cases using B mode ultrasonography. STATISTICAL ANALYSIS AND RESULTS:Median (IQR) of fasting plasma Insulin (μIU/ml) in cases was 11.3 (10.175-13.505) versus that in controls being 5.73 (4.3-7.1). HOMA-IR (IQR) values in cases and controls were 3.12 (2.73 - 3.595) and 1.21 (0.918 - 1.505) respectively. Median (IQR) for TG/HDL ratio was 3.26 (2.712 - 4) for cases and 2.05 (1.755- 2.502) for controls. However no correlation was observed between either the mean CIMT (mm) or HOMA-IR with TG/HDL ratio. CONCLUSIONS:Diabetes Mellitus and its various complications are of a great burden to society. Diagnosing the risk factors early before the onset of these manifestations can help us in combating these major issues. One of the risk factors among them is raised TG/HDL ratio. Early detection of elevated TG/HDL in prediabetics may serve in early detection of atherosclerotic complications and help physicians in framing primary preventive strategies for tackling ASCVD in patients with prediabetes and full-blown Diabetes. 10.4103/jfmpc.jfmpc_165_21
    Disturbances of the transfer of cholesterol to high-density lipoprotein (HDL) in patients with peripheral artery disease with or without type 2 diabetes mellitus. Vascular medicine (London, England) INTRODUCTION:Low high-density lipoprotein (HDL)-cholesterol is frequent in patients with peripheral artery disease (PAD) and also in type 2 diabetes mellitus (T2DM), the major risk factor for PAD. The transfer of cholesterol from the other lipoproteins to HDL is an important aspect of HDL metabolism and function, and may contribute to atherogenic mechanisms that lead to PAD development. OBJECTIVE:The aim of this study was to investigate the status of cholesterol transfers in patients with PAD without or with T2DM. METHODS:Patients with PAD ( = 19), with PAD and T2DM (PAD + DM, = 19), and healthy controls ( = 20), all paired for age, sex, and BMI were studied. Transfer of both forms of cholesterol, unesterified (UC) and esterified (EC), was performed by incubating plasma with a donor nanoemulsion containing radioactive UC and EC, followed by chemical precipitation and HDL radioactive counting. RESULTS:Low-density lipoprotein (LDL)-cholesterol and triglycerides were similar in the three groups. Compared to controls, HDL-C was lower in PAD + DM ( < 0.05), but not in PAD. Transfer of UC was lower in PAD + DM than in PAD and controls (4.18 ± 1.17%, 5.13 ± 1.44%, 6.59 ± 1.25%, respectively, < 0.001). EC transfer tended to be lower in PAD + DM than in controls (2.96 ± 0.60 vs 4.12 ± 0.89%, = 0.05). Concentrations of cholesteryl ester transfer protein (CETP) and lecithin-cholesterol acyltransferase (LCAT), both involved in HDL metabolism, were not different among the three groups. CONCLUSION:Deficient cholesterol transfer to HDL may play a role in PAD pathogenesis. Since UC transfer to HDL was lower in PAD + DM compared to PAD alone, it is possible that defective HDL metabolism may contribute to the higher PAD incidence in patients with T2DM.Keywords. 10.1177/1358863X211021142
    The Reciprocal Relationship between LDL Metabolism and Type 2 Diabetes Mellitus. Bonilha Isabella,Hajduch Eric,Luchiari Beatriz,Nadruz Wilson,Le Goff Wilfried,Sposito Andrei C Metabolites Type 2 diabetes mellitus and insulin resistance feature substantial modifications of the lipoprotein profile, including a higher proportion of smaller and denser low-density lipoprotein (LDL) particles. In addition, qualitative changes occur in the composition and structure of LDL, including changes in electrophoretic mobility, enrichment of LDL with triglycerides and ceramides, prolonged retention of modified LDL in plasma, increased uptake by macrophages, and the formation of foam cells. These modifications affect LDL functions and favor an increased risk of cardiovascular disease in diabetic individuals. In this review, we discuss the main findings regarding the structural and functional changes in LDL particles in diabetes pathophysiology and therapeutic strategies targeting LDL in patients with diabetes. 10.3390/metabo11120807
    Peri-operative monocyte count is a marker of poor prognosis in gastric cancer: increased monocytes are a characteristic of myeloid-derived suppressor cells. Urakawa Shinya,Yamasaki Makoto,Goto Kumiko,Haruna Miya,Hirata Michinari,Morimoto-Okazawa Akiko,Kawashima Atsunari,Iwahori Kota,Makino Tomoki,Kurokawa Yukinori,Yamada Tomomi,Mori Masaki,Doki Yuichiro,Wada Hisashi Cancer immunology, immunotherapy : CII Gastric cancer (GC) is the most common malignant tumor in digestive organs, and the prognosis of GC patients who have undergone surgery remains poor because of frequent recurrence. Therefore, the identification of new markers to predict the outcome of these patients is needed. Monocyte count is a negative prognostic factor associated with inflammation. We investigated the relationship between peripheral monocytes in the peri-operative period and prognosis in GC patients. A high pre-operative monocyte count was identified as a prognostic factor in a retrospective analysis of 278 stage II and III GC patients who underwent curative gastrectomy. In contrast, an increased post-operative monocyte count compared to the pre-operative monocyte count was a marker of poor prognosis, particularly for early relapse. In a prospective analysis of 75 GC patients, a subset of the increased post-operative monocytes was similar to CD14 HLA-DR CD11b CD33 cells by flow cytometry, and these monocytes produced IDO and arginase and suppressed T cell functions; therefore, we classified these cells as monocytic myeloid-derived suppressive cells (M-MDSCs). Peri-operative neutrophils and C-reactive protein (CRP), which are also related to inflammation, did not affect the prognosis of GC patients, and a neutrophil immunosuppressive function was not observed. These results suggest that peripheral monocytes in the peri-operative period in GC patients are a useful marker for the prognosis of GC patients, and a subset of increased post-operative monocytes may be characterized as M-MDSCs. 10.1007/s00262-019-02366-0
    Decline of serum CA724 as a probable predictive factor for tumor response during chemotherapy of advanced gastric carcinoma. Zou Li,Qian Jun Chinese journal of cancer research = Chung-kuo yen cheng yen chiu OBJECTIVE:To evaluate the predictive value of decline in the serum level of carbohydrate antigen 724 (CA724) on tumor response during the chemotherapy in patients with advanced gastric carcinoma (GC). METHODS:The serum CA724 level was determined by electrochemiluminescence immunoassay, while the objective response rate (ORR) was assessed according to response evaluation criteria in solid tumors (RECIST). The association of the changes of serum concentration of CA724 with ORR was analyzed. RESULTS:The ORR in CA724 (pretreatment serum level) high and low groups was 32.3% (20/62) and 52.8% (19/36), respectively (P=0.045). The relationship between the reduction of CA724 and the ORR was statistically significant (P=0.044). Receiver operating characteristic (ROC) curve established the best cutoff value of the decrease ratio of CA724 as 20.5%. CONCLUSIONS:CA724 decline seems to indicate chemotherapy efficacy in patients with advanced GC, and an average drop of 20.5% in serum CA724 appears to predict the sensitivity to chemotherapy. 10.3978/j.issn.1000-9604.2014.07.02
    Bilirubin as a metabolic hormone: the physiological relevance of low levels. Creeden Justin F,Gordon Darren M,Stec David E,Hinds Terry D American journal of physiology. Endocrinology and metabolism Recent research on bilirubin, a historically well-known waste product of heme catabolism, suggests an entirely new function as a metabolic hormone that drives gene transcription by nuclear receptors. Studies are now revealing that low plasma bilirubin levels, defined as "hypobilirubinemia," are a possible new pathology analogous to the other end of the spectrum of extreme hyperbilirubinemia seen in patients with jaundice and liver dysfunction. Hypobilirubinemia is most commonly seen in patients with metabolic dysfunction, which may lead to cardiovascular complications and possibly stroke. We address the clinical significance of low bilirubin levels. A better understanding of bilirubin's hormonal function may explain why hypobilirubinemia might be deleterious. We present mechanisms by which bilirubin may be protective at mildly elevated levels and research directions that could generate treatment possibilities for patients with hypobilirubinemia, such as targeting of pathways that regulate its production or turnover or the newly designed bilirubin nanoparticles. Our review here calls for a shift in the perspective of an old molecule that could benefit millions of patients with hypobilirubinemia. 10.1152/ajpendo.00405.2020
    Anti-hepatic fibrosis effects of AD-2 affecting the Raf-MEK signaling pathway and inflammatory factors in thioacetamide-induced liver injury. Li Tao,Su GuangYue,Zhao YuQing Journal of food science 25-Hydroxylprotopanaxadiol-3β, 12β, 20-triol (25-OH-PPD or AD-2) belongs to dammarane ginsenoside, and is commonly obtained from the acidic hydrolysate of total ginsensides of Panax ginseng. This study investigated the potential mechanism of AD-2 toward improving thioacetamide (TAA)-induced hepatic fibrosis in mice. Mice were divided into seven groups: control group, TAA model group, TAA + AD-2 (5, 10, and 20 mg/kg) groups, TAA + silymarin (100 mg/kg) group, and TAA + Fu Fang Biejia (FFBj; 300 mg/kg) group. All mice were treated to intraperitoneal TAA injection to establish a hepatic fibrosis model, and drugs were administered orally. The mechanism and related pathways underlying the AD-2-mediated action against hepatic fibrosis were explored by Western blotting and immunohistochemical staining. After AD-2 treatment, the expression levels of Lipin-1, SREBP1, and F4/80 significantly decreased, meanwhile the protein expressions levels of IL1β, IL1R1, IL18, Bax, Bid, Bcl-2, and cFlips also decreased. Furthermore, AD-2 inhibited RAF and MEK pathways. The results demonstrate that AD-2 can alleviate hepatic fibrosis. The mechanism is likely related to the regulation of lipid accumulation, inflammatory response, apoptosis pathway, and Raf-MEK signaling pathways, which provide a basis for clinical research for the treatment of hepatic fibrosis. PRACTICAL APPLICATION: Ginsenoside is one of the main active ingredients of ginseng, and can alleviate the symptoms of various diseases, for example, hepatic fibrosis. This paper mainly used Western blotting to explore its possible mechanism of action. The goal was to provide a reference for the development of traditional Chinese medicines for hepatic fibrosis. 10.1111/1750-3841.15731
    Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial. Dai Qi,Zhu Xiangzhu,Manson JoAnn E,Song Yiqing,Li Xingnan,Franke Adrian A,Costello Rebecca B,Rosanoff Andrea,Nian Hui,Fan Lei,Murff Harvey,Ness Reid M,Seidner Douglas L,Yu Chang,Shrubsole Martha J The American journal of clinical nutrition Background:Previous in vitro and in vivo studies indicate that enzymes that synthesize and metabolize vitamin D are magnesium dependent. Recent observational studies found that magnesium intake significantly interacted with vitamin D in relation to vitamin D status and risk of mortality. According to NHANES, 79% of US adults do not meet their Recommended Dietary Allowance of magnesium. Objectives:The aim of this study was to test the hypothesis that magnesium supplementation differentially affects vitamin D metabolism dependent on baseline 25-hydroxyvitamin D [25(OH)D] concentration. Methods:The study included 180 participants aged 40-85 y and is a National Cancer Institute independently funded ancillary study, nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), which enrolled 250 participants. The PPCCT is a double-blind 2 × 2 factorial randomized controlled trial conducted in the Vanderbilt University Medical Center. Doses for both magnesium and placebo were customized based on baseline dietary intakes. Subjects were randomly assigned to treatments using a permuted-block randomization algorithm. Changes in plasma 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2 [25(OH)D2], 1,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D2, and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] were measured by liquid chromatography-mass spectrometry. Results:The relations between magnesium treatment and plasma concentrations of 25(OH)D3, 25(OH)D2, and 24,25(OH)2D3 were significantly different dependent on the baseline concentrations of 25(OH)D, and significant interactions persisted after Bonferroni corrections. Magnesium supplementation increased the 25(OH)D3 concentration when baseline 25(OH)D concentrations were close to 30 ng/mL, but decreased it when baseline 25(OH)D was higher (from ∼30 to 50 ng/mL). Magnesium treatment significantly affected 24,25(OH)2D3 concentration when baseline 25(OH)D concentration was 50 ng/mL but not 30 ng/mL. On the other hand, magnesium treatment increased 25(OH)D2 as baseline 25(OH)D increased. Conclusion:Our findings suggest that optimal magnesium status may be important for optimizing 25(OH)D status. This trial was registered at clinicaltrials.gov as NCT03265483. 10.1093/ajcn/nqy274
    Antifibrotic effects of hypocalcemic vitamin D analogs in murine and human hepatic stellate cells and in the CCl mouse model. Laboratory investigation; a journal of technical methods and pathology Liver cirrhosis is a life-threatening consequence of liver fibrosis. The aim of this study was to investigate the antifibrotic potential of clinically available vitamin D analogs compared to that of calcitriol in vitro and in vivo. Murine hepatic stellate cells, Kupffer cells, and human LX-2 cells were treated with vitamin D analogs, and the profibrotic behavior of these cells was studied. In vivo liver fibrosis was induced using CCl until measurable fibrosis was established. Animals were then treated with calcitriol and paricalcitol. Vitamin D and its analogs showed antifibrotic effects in vitro. Treatment with active vitamin D (calcitriol, CAL) and its analogs reduced the protein expression of α-smooth muscle actin (α-SMA) in mHSC. In human LX-2 cells alfacalcidol reduced transforming growth factor-β (TGF-β) induced platelet-derived growth factor receptor-β protein expression and contractility while paricalcitol (PCT), in its equipotent dose to CAL, reduced TGF-β induced α-SMA protein expression, and ACTA2 and TGF-β mRNA expression. No effects of a treatment with vitamin D and its analogs were observed in Kupffer cells. In vivo, PCT-treated mice had significantly lower calcium levels than CAL-treated mice. CAL and PCT reduced the hepatic infiltration of CD11b-positive cells and alanine transaminase levels, while PCT but not CAL significantly inhibited fibrosis progression, with a favorable side effect profile in the CCl model. We conclude that hypocalcemic vitamin D analogs should be considered in future studies investigating vitamin D for the treatment of liver fibrosis. 10.1038/s41374-019-0310-1
    Vitamin D/VDR attenuate cisplatin-induced AKI by down-regulating NLRP3/Caspase-1/GSDMD pyroptosis pathway. Jiang Siqing,Zhang Hao,Li Xin,Yi Bin,Huang Lihua,Hu Zhaoxin,Li Aimei,Du Jie,Li Yanchun,Zhang Wei The Journal of steroid biochemistry and molecular biology Vitamin D/Vitamin D receptor (VDR) has been shown to inhibit the NF-κB-mediated inflammatory effects. Up-regulation of the NLRP3(Recombinant NLR Family, Pyrin Domain Containing Protein 3)/Caspase-1/GSDMD (Gasdermin D) pathway through NF-κb is one of the key mechanisms leading to pyroptosis. This study aims to explore the effects of vitamin D/VDR on the pyroptosis pathway in cisplatin induced acute kidney injury (AKI) models. Our results showed that in wide type mice, renal function loss, tissue injury and cell death induced by cisplatin were alleviated by pretreatment of high-dose paricalcitol(a VDR agonist) accompanied with up-regulated VDR and decreased expression of NLRP3, GSDMD-N, Cleaved-Caspase-1 and mature Interleukin- 1β (features of pyroptosis). While, in VDR knock out mice, cisplatin induced more severer renal injury and further increased pyroptosis related protein than the wild type mice and the effect of paricalcitol were also eliminated. In tubular cell specific VDR-over expressing mice, those renal injury index as well as pyroptosis phenotype were significantly reduced by low-dose paricalcitol pretreatment with upregulated VDR expression compared with WT mice. In vitro data using gain and lose function experiments in Human tubular epithelial cell (HK-2) were consistent with the observation as in vivo work. Our further experiments in both animal and cell culture work has found that the level of IκBα(Inhibitor of NF-κB) were decreased and the nuclear level of NF-κB p65 of renal tubular cells were increased after cisplatin injury while VDR activation by paricalcitol could reverse up-regulation of nuclear NF-κB p65 with reduced cell pyroptosis. These data suggested that vitamin D/VDR could alleviate cisplatin-induced acute renal injury partly by inhibiting NF-κB-mediated NLRP3/Caspase-1/GSDMD pyroptosis. 10.1016/j.jsbmb.2020.105789
    Free vitamin D levels in steroid-sensitive nephrotic syndrome and healthy controls. Banerjee Sushmita,Basu Surupa,Akhtar Shakil,Sinha Rajiv,Sen Ananda,Sengupta Jayati Pediatric nephrology (Berlin, Germany) INTRODUCTION:Body stores of vitamin D are measured as "total" serum 25-hydroxy vitamin D (25(OH)D). Its largest component is protein bound and lost in urine in nephrotic syndrome (NS). Our study investigates whether "free" 25(OH)D levels are a better guide to bone health and need for vitamin D supplementation in patients with steroid-sensitive NS (SSNS). METHODS:A cross-sectional study was performed in children with SSNS and healthy controls. Blood was tested for albumin, creatinine, calcium, phosphate, ALP, total and free (by direct ELISA) 25(OH)D, iPTH, and urine for protein-creatinine ratio. RESULTS:Seventy-nine NS patients (48 in relapse, 31 in remission) and 60 healthy controls were included. The levels of total 25(OH)D were significantly different (lowest in NS relapse and highest in controls) (p < 0.001). Corrected calcium and phosphate levels were normal, and there were no differences in free 25(OH)D, ALP, or iPTH levels between groups. Only total and not free 25(OH)D correlated significantly and negatively with urinary protein creatinine ratios (r = - 0.42 vs. 0.04). Free 25(OH)D values of 3.75 and 2.85 pg/ml corresponded to total 25(OH)D levels of 20 and 12 ng/ml, respectively, in healthy controls. CONCLUSION:These results confirm that total 25(OH)D levels are low in NS and related to degree of proteinuria. However levels of free 25(OH)D, ALP, and iPTH did not change in relapse or remission in comparison with healthy controls. Our results suggest that in proteinuric renal diseases, free 25(OH)D rather than total 25(OH)D levels should be used to diagnose vitamin D deficiency and guide therapy. 10.1007/s00467-019-04433-1
    A Biological Circuit Involving Mef2c, Mef2d, and Hdac9 Controls the Immunosuppressive Functions of CD4+Foxp3+ T-Regulatory Cells. Di Giorgio Eros,Wang Liqing,Xiong Yan,Christensen Lanette M,Akimova Tatiana,Han Rongxiang,Samanta Arabinda,Trevisanut Matteo,Brancolini Claudio,Beier Ulf H,Hancock Wayne W Frontiers in immunology The Mads/Mef2 (Mef2a/b/c/d) family of transcription factors (TFs) regulates differentiation of muscle cells, neurons and hematopoietic cells. By functioning in physiological feedback loops, Mef2 TFs promote the transcription of their repressor, Hdac9, thereby providing temporal control of Mef2-driven differentiation. Disruption of this feedback is associated with the development of various pathologic states, including cancer. Beside their direct involvement in oncogenesis, Mef2 TFs indirectly control tumor progression by regulating antitumor immunity. We recently reported that in CD4+CD25+Foxp3+ T-regulatory (Treg) cells, Mef2d is required for the acquisition of an effector Treg (eTreg) phenotype and for the activation of an epigenetic program that suppresses the anti-tumor immune responses of conventional T and B cells. We now report that as with Mef2d, the deletion of Mef2c in Tregs switches off the expression of and and leads to enhanced antitumor immunity in syngeneic models of lung cancer. Mechanistically, Mef2c does not directly bind the regulatory elements of and , but its loss-of-function in Tregs induces the expression of the transcriptional repressor, Hdac9. As a consequence, Mef2d, the more abundant member of the Mef2 family, is converted by Hdac9 into a transcriptional repressor on these loci. This leads to the impairment of Treg suppressive properties and to enhanced anti-cancer immunity. These data further highlight the central role played by the Mef2/Hdac9 axis in the regulation of CD4+Foxp3+ Treg function and adds a new level of complexity to the analysis and study of Treg biology. 10.3389/fimmu.2021.703632
    Overexpression and biological function of MEF2D in human pancreatic cancer. Song Zhiwang,Feng Chan,Lu Yonglin,Gao Yong,Lin Yun,Dong Chunyan American journal of translational research To explore the expression, clinical significance, biological function, and potential mechanism of MEF2D in pancreatic cancer, the expression of MEF2D in human pancreatic cancer tissues and corresponding adjacent normal tissues was analyzed through immunohistochemical staining. The association between MEF2D expression, clinicopathological parameters, overall survival, and disease-free survival was evaluated. Human pancreatic cancer cell lines BxPC-1 and SW1990 were selected to investigate the effect of MEF2D knockdown on cell proliferation, migration, and invasion. Western blot analysis was used to assess the effect of MEF2D expression on the Akt/GSK pathway, as well as the protein expression of cyclin B1, cyclin D1, matrix metalloprotein (MMP)-2, and MMP-9. Our results revealed that the expression of MEF2D was increased in pancreatic cancer tissues compared to adjacent normal tissues and the increased expression of MEF2D was associated with tumor size, histological differentiation, and TNM stage of pancreatic cancer patients. Moreover, the expression of MEF2D was an independent prognostic indicator for pancreatic cancer patients. In addition, knockdown of MEF2D in pancreatic cancer cells inhibited cell proliferation, migration, and invasion by down-regulating the protein expression of cyclin B1, cyclin D1, MMP-2, and MMP-9. Knockdown of MEF2D reduced the levels of phosphorylated Akt and GSK-3β. Our data indicated that MEF2D expression was increased in pancreatic cancer and was an independent molecular prognostic factor for pancreatic cancer patients. Furthermore, we showed that MEF2D controlled cell proliferation, migration, and invasion abilities in pancreatic cancer via the Akt/GSK-3β signaling pathway.
    MEF2D sustains activation of effector Foxp3+ Tregs during transplant survival and anticancer immunity. Di Giorgio Eros,Wang Liqing,Xiong Yan,Akimova Tatiana,Christensen Lanette M,Han Rongxiang,Samanta Arabinda,Trevisanut Matteo,Bhatti Tricia R,Beier Ulf H,Hancock Wayne W The Journal of clinical investigation The transcription factor MEF2D is important in the regulation of differentiation and adaptive responses in many cell types. We found that among T cells, MEF2D gained new functions in Foxp3+ T regulatory (Treg) cells due to its interactions with the transcription factor Foxp3 and its release from canonical partners, like histone/protein deacetylases. Though not necessary for the generation and maintenance of Tregs, MEF2D was required for the expression of IL-10, CTLA4, and Icos, and for the acquisition of an effector Treg phenotype. At these loci, MEF2D acted both synergistically and additively to Foxp3, and downstream of Blimp1. Mice with the conditional deletion in Tregs of the gene encoding MEF2D were unable to maintain long-term allograft survival despite costimulation blockade, had enhanced antitumor immunity in syngeneic models, but displayed only minor evidence of autoimmunity when maintained under normal conditions. The role played by MEF2D in sustaining effector Foxp3+ Treg functions without abrogating their basal actions suggests its suitability for drug discovery efforts in cancer therapy. 10.1172/JCI135486
    Abnormal acetylation of FOXP3 regulated by SIRT-1 induces Treg functional deficiency in patients with abdominal aortic aneurysms. Jiang Han,Xin Shijie,Yan Yumeng,Lun Yu,Yang Xiao,Zhang Jian Atherosclerosis BACKGROUND AND AIMS:Acetylation levels of FOXP3 could influence its expression level and SIRT1 is a deacetylase, which could regulate the acetylation level of FOXP3. We aimed to investigate the mechanism of Treg dysfunction, which might be caused by abnormal acetylation of FOXP3 regulated by SIRT1 in abdominal aortic aneurysm (AAA) patients. METHODS:Peripheral CD4 T cells from AAA patients, abdominal aortic atherosclerotic occlusive disease (AOD) patients, and healthy donors (HC) were analyzed by flow cytometry to determine the percentage of CD4CD25 Tregs and CD4CD25FOXP3 T cells in CD4 T cells. Expression of FOXP3 and SIRT1 was analyzed by Western Blot. Cultured CD4 T cells were treated with SIRT1 specific inhibitor EX-527 or left untreated. Acetylation expression of FOXP3 in CD4 T cells was analyzed by immunoprecipitation and Western Blot. The suppressive function of Treg was analyzed by CFSE-assay. RESULTS:AAA patients had significantly lower CD4CD25FOXP3 T cells. Western blot results showed that AAA CD4 T cells had significantly less FOXP3 expression but significantly higher SIRT1 expression. After EX-527 treatment, CD4CD25FOXP3 T cells and FOXP3 expression in the AAA group were significantly increased. FOXP3 acetylation level in the AAA group was lower than in control groups. After EX-527 treatment, it was significantly increased. AAA Tregs exhibited less suppressive activity, EX-527 treatment significantly increased the suppressive activity of AAA Tregs. CONCLUSIONS:Our data demonstrate that reduced FOXP3 expression and Treg function in AAA patients are regulated by SIRT1-induced FOXP3 deacetylation. EX-527 could up-regulate FOXP3 acetylation and increase number and suppressive function of Treg in AAA patients. 10.1016/j.atherosclerosis.2018.02.001
    Paeoniflorin ameliorates murine lupus nephritis by increasing CD4Foxp3 Treg cells via enhancing mTNFα-TNFR2 pathway. Liang Chun-Ling,Lu Weihui,Qiu Feifei,Li Dan,Liu Huazhen,Zheng Fang,Zhang Qunfang,Chen Yuchao,Lu Chuanjian,Li Bin,Dai Zhenhua Biochemical pharmacology Treg cells are essential for re-establishing self-tolerance in lupus. However, given that direct Treg therapies may be inadequate to control autoimmunity and inflammation, a strategy of inducing or expanding endogenous Treg cells in vivo may be a good option. Macrophages are main tissue-infiltrating cells and play a role in promoting Treg differentiation while paeoniflorin (PF), a monoterpene glycoside, exhibits anti-inflammatory and immunoregulatory effects. Here, we studied the effects of PF on CD4FoxP3 Treg frequency and the potential mechanisms involving M2 macrophages. We demonstrated that PF ameliorated lupus nephritis in lupus-prone B6/gld mice by reducing urinary protein, serum creatinine and anti-dsDNA levels, diminishing renal cellular infiltration, improving renal immunopathology and downregulating renal gene and protein expressions of key cytokines, including IFN-γ, IL-6, IL-12 and IL-23. PF also lowered the percentage of CD44CD62L effector T cells while augmenting CD4FoxP3 Treg frequency in B6/gld mice. Importantly, PF increased TNFR2 expression on CD4FoxP3 Tregs, but not CD4FoxP3 T cells, in vivo and in vitro. Furthermore, we found that CD206 subset of F4/80CD11b macrophages expressed a higher level of mTNF-α than their CD206 counterparts while PF increased mTNF-α expression on CD206 macrophages in vitro and in vivo. In vitro studies showed that mTNF-α M2 macrophages were more potent in inducing Treg differentiation and proliferation than their mTNF-α counterparts, whereas the effects of mTNF-α M2 macrophages were largely reversed by separation of M2 macrophages using a transwell or TNFR2-blocking Ab in the culture. Finally, PF also promoted in vitro Treg generation induced by M2 macrophages. Thus, we demonstrated that mTNFα-TNFR2 interaction is a new mechanism responsible for Treg differentiation mediated by M2 macrophages. We provided the first evidence that PF may be used to treat lupus nephritis. 10.1016/j.bcp.2021.114434
    Taraxacum mongolicum extract inhibited malignant phenotype of triple-negative breast cancer cells in tumor-associated macrophages microenvironment through suppressing IL-10 / STAT3 / PD-L1 signaling pathways. Deng Xin-Xin,Jiao Yan-Na,Hao Hui-Feng,Xue Dong,Bai Chang-Cai,Han Shu-Yan Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Triple-negative breast cancer (TNBC) is the most aggressive and the worst prognosis breast cancer with limited treatment options. Taraxacum mongolicum (also called dandelion) is a traditional Chinese medicine has been used to treat mastitis, breast abscess, and hyperplasia of mammary glands since ancient times. In modern pharmacological research, dandelion has been proven with anti-breast cancer activities. We previously reported that dandelion extract could induce apoptosis in TNBC cells. However, its anti-tumor effects and mechanisms in the tumor microenvironment have not yet been elucidated. AIM OF THE STUDY:Tumor-associated macrophages (TAMs) play an important role in regulating the interaction between tumor cells and the immune system. The present study aimed to investigate the effects and mechanisms of dandelion extract on TNBC cells under the microenvironment of TAMs, as well as its influence on the polarization of M2 macrophages. MATERIALS AND METHODS:M2 macrophages were induced by phorbol-12-myristate 13-acetate (PMA) and interleukin 4 (IL-4), and verified by flow cytometry, quantitative RT-PCR (qRT-PCR), Western blotting, and ELISA. MDA-MB-231 and MDA-MB-468 TNBC cells were co-cultured with the supernatant of M2 macrophage which providing the TAMs microenvironment. The antitumor activity of dandelion extract in TNBC cells was evaluated by MTT assay. The invasive and migratory capacity of TNBC cells was measured by transwell assays. The expression of protein and gene was assessed by Western blotting and qRT-PCR, respectively. RESULTS:TAMs microenvironment promoted the proliferation, migration, and invasion of TNBC cells. However, dandelion extract inhibited the malignant property of MDA-MB-231 and MDA-MB-468 cells induced by TAMs. Both of TAMs and IL-10 caused STAT3 activation and PD-L1 higher expression, the immunosuppressive molecules in TNBC cells, and this effect can be attenuated by IL-10 neutralizing antibody. Dandelion extract exerted inhibition on STAT3 and PD-L1 in TNBC cells under TAMs microenvironment. Furthermore, in M2 macrophages, dandelion extract remarkably promoted the expression of M1-like marker TNF-α, IL-8, and iNOS, but reduced M2-like marker IL-10, CD206, Arginase-1, and TGF-β. CONCLUSION:Dandelion extract inhibited the proliferation, migration and invasion of TNBC cells in TAMs microenvironment through suppressing IL-10/STAT3/PD-L1 immunosuppressive signaling pathway. Furthermore, dandelion extract promoted the polarization of macrophages from M2 to M1 phenotype. Thus, our results indicated that dandelion may serve as a promising therapeutic strategy for TNBC by modulating tumor immune microenvironment. 10.1016/j.jep.2021.113978
    Unstable Foxp3+ regulatory T cells and altered dendritic cells are associated with lipopolysaccharide-induced fetal loss in pregnant interleukin 10-deficient mice. Prins Jelmer R,Zhang Bihong,Schjenken John E,Guerin Leigh R,Barry Simon C,Robertson Sarah A Biology of reproduction Maternal interleukin (IL) 10 deficiency elevates susceptibility to fetal loss induced by the model Toll-like receptor agonist lipopolysaccharide, but the mechanisms are not well elucidated. Here, we show that Il10 null mutant (Il10(-/-)) mice exhibit altered local T cell responses in pregnancy, exhibiting pronounced hyperplasia in para-aortic lymph nodes draining the uterus with >6-fold increased CD4(+) and CD8(+) T cells compared with wild-type controls. Among these CD4(+) cells, Foxp3(+) T regulatory (Treg) cells were substantially enriched, with 11-fold higher numbers at Day 9.5 postcoitum. Lymph node hypertrophy in Il10(-/-) mice was associated with more activated phenotypes in dendritic cells and macrophages, with elevated expression of MHCII, scavenger receptor, and CD80. Affymetrix microarray revealed an altered transcriptional profile in Treg cells from pregnant Il10(-/-) mice, with elevated expression of Ctse (cathepsin E), Il1r1, Il12rb2, and Ifng. In vitro, Il10(-/-) Treg cells showed reduced steady-state Foxp3 expression, and polyclonal stimulation caused greater loss of Foxp3 and reduced capacity to suppress IL17 in CD4(+)Foxp3(-) T cells. We conclude that despite a substantially expanded Treg cell pool, the diminished stability of Treg cells, increased numbers of effector T cells, and altered phenotypes in dendritic cells and macrophages in pregnancy all potentially confer vulnerability to inflammation-induced fetal loss in Il10(-/-) mice. These findings suggest that IL10 has a pivotal role in facilitating robust immune protection of the fetus from inflammatory challenge and that IL10 deficiency could contribute to human gestational disorders in which altered T cell responses are implicated. 10.1095/biolreprod.115.128694
    HDAC1-3 inhibitor MS-275 enhances IL10 expression in RAW264.7 macrophages and reduces cigarette smoke-induced airway inflammation in mice. Leus Niek G J,van den Bosch Thea,van der Wouden Petra E,Krist Kim,Ourailidou Maria E,Eleftheriadis Nikolaos,Kistemaker Loes E M,Bos Sophie,Gjaltema Rutger A F,Mekonnen Solomon A,Bischoff Rainer,Gosens Reinoud,Haisma Hidde J,Dekker Frank J Scientific reports Chronic obstructive pulmonary disease (COPD) constitutes a major health burden. Studying underlying molecular mechanisms could lead to new therapeutic targets. Macrophages are orchestrators of COPD, by releasing pro-inflammatory cytokines. This process relies on transcription factors such as NF-κB, among others. NF-κB is regulated by lysine acetylation; a post-translational modification installed by histone acetyltransferases and removed by histone deacetylases (HDACs). We hypothesized that small molecule HDAC inhibitors (HDACi) targeting class I HDACs members that can regulate NF-κB could attenuate inflammatory responses in COPD via modulation of the NF-κB signaling output. MS-275 is an isoform-selective inhibitor of HDAC1-3. In precision-cut lung slices and RAW264.7 macrophages, MS-275 upregulated the expression of both pro- and anti-inflammatory genes, implying mixed effects. Interestingly, anti-inflammatory IL10 expression was upregulated in these model systems. In the macrophages, this was associated with increased NF-κB activity, acetylation, nuclear translocation, and binding to the IL10 promoter. Importantly, in an in vivo model of cigarette smoke-exposed C57Bl/6 mice, MS-275 robustly attenuated inflammatory expression of KC and neutrophil influx in the lungs. This study highlights for the first time the potential of isoform-selective HDACi for the treatment of inflammatory lung diseases like COPD. 10.1038/srep45047
    Loss of MEF2D expression inhibits differentiation and contributes to oncogenesis in rhabdomyosarcoma cells. Zhang Meiling,Truscott Jamie,Davie Judith Molecular cancer BACKGROUND:Rhabdomyosarcoma (RMS) is a highly malignant pediatric cancer that is the most common form of soft tissue tumors in children. RMS cells have many features of skeletal muscle cells, yet do not differentiate. Thus, our studies have focused on the defects present in these cells that block myogenesis. METHODS:Protein and RNA analysis identified the loss of MEF2D in RMS cells. MEF2D was expressed in RD and RH30 cells by transient transfection and selection of stable cell lines, respectively, to demonstrate the rescue of muscle differentiation observed. A combination of techniques such as proliferation assays, scratch assays and soft agar assays were used with RH30 cells expressing MEF2D to demonstrate the loss of oncogenic growth in vitro and xenograft assays were used to confirm the loss of tumor growth in vivo. RESULTS:Here, we show that one member of the MEF2 family of proteins required for normal myogenesis, MEF2D, is largely absent in RMS cell lines representing both major subtypes of RMS as well as primary cells derived from an embryonal RMS model. We show that the down regulation of MEF2D is a major cause for the failure of RMS cells to differentiate. We find that MyoD and myogenin are bound with their dimerization partner, the E proteins, to the promoters of muscle specific genes in RMS cells. However, we cannot detect MEF2D binding at any promoter tested. We find that exogenous MEF2D expression can activate muscle specific luciferase constructs, up regulate p21 expression and increase muscle specific gene expression including the expression of myosin heavy chain, a marker for skeletal muscle differentiation. Restoring expression of MEF2D also inhibits proliferation, cell motility and anchorage independent growth in vitro. We have confirmed the inhibition of tumorigenicity by MEF2D in a tumor xenograft model, with a complete regression of tumor growth. CONCLUSIONS:Our data indicate that the oncogenic properties of RMS cells can be partially attributed to the loss of MEF2D expression and that restoration of MEF2D may represent a useful therapeutic strategy to decrease tumorigenicity. 10.1186/1476-4598-12-150
    MEF2D-NR4A1-FAM134B2-mediated reticulophagy contributes to amino acid homeostasis. Shiozaki Yuji,Miyazaki-Anzai Shinobu,Keenan Audrey L,Miyazaki Makoto Autophagy We recently identified FAM134B2, which is an N-terminal truncated reticulophagy receptor highly induced by starvation such as fasting of mice and treatment of mammalian cells with a starvation medium that does not contain amino acids, glucose and growth factors. However, which starvation signal mediates the induction of FAM134B2 is still obscure. In this study, we found that amino acid deficiency (AAD) could mimic the starvation condition to induce FAM134B2 expression. Unexpectedly, EIF2AK4/GCN2-mediated integrated signal response (ISR) and MTOR (mechanistic target of rapamycin kinase) signals, which constitute two major signaling pathways that respond to AAD, did not contribute to AAD-induced FAM134B2 induction. mRNA-seq and siRNA screenings identified two ISR-independent transcription factors, MEF2D (myocyte enhancer factor 2D) and NR4A1 (nuclear receptor subfamily 4 group A member 1), involved in AAD-induced FAM134B2 expression. AAD induces MEF2D, resulting in the induction of NR4A1, which in turn induces FAM134B2-mediated reticulophagy to maintain intracellular amino acid levels. In conclusion, the MEF2D-NR4A1-FAM134B2 cascade is a critical signal in amino acid homeostasis. 10.1080/15548627.2021.1968228
    Using data mining technology to explore homocysteine at low levels. Tseng Fei-Ching,Huang Tin-Chung Medicine ABSTRACT:A high homocysteine level is known to be an independent risk factor for cardiovascular diseases; however, whether or not low homocysteine level contributes to any damage to the body has not been extensively studied. Furthermore, acquiring healthy subject databases from domestic studies on homocysteine is not trivial. Therefore, we aimed to investigate the causality between serum homocysteine levels and health status and lifestyle factors, particularly with a focus on low serum homocysteine levels. Additionally, we discussed a systematic methodical platform for data collection and statistical analysis, using the descriptive analysis of the chi-square test, t test, multivariate analysis of variance, and logistic regression.This study was a cross-sectional analysis of 5864 subjects (i.e., clients of a health examination clinic) in Taipei, Taiwan during a general health check-up in 2017. The patients' personal information and associated links were excluded. A sample group was selected as per the health criteria defined for this research whose data were processed using SPSS for descriptive statistical analysis using chi-square test, t test, multivariate analysis of variance, and logistic regression analysis.Those working for >12 hours/day had a higher homocysteine level than those working for <12 hours/day (P < .001). The average serum homocysteine level was 7.9 and 8.6 mol/L for people with poor sleep quality and good sleep quality, respectively (P = .003). The homocysteine value of people known to have cancer was analyzed using the logistic regression analysis, revealing a Δodds value of 0.898. The percentage of subjects with a homocysteine value of ≤6.3 μmol/L, who perceived their health status as "not very good" or "very bad," was higher than those with a higher homocysteine level. The number of subjects who perceived their health as poor was higher than expected.The results suggest that the homocysteine level could be an effective health management indicator. We conclude that normal homocysteine level should not be ≤6.3 μmol/L. Moreover, homocysteine should not be considered as harmful and its fluctuations from the normal range could be utilized to infer a person's physical status for health management. 10.1097/MD.0000000000026893
    Associations of Homocysteine Metabolism With the Risk of Spinal Osteoarthritis Progression in Postmenopausal Women. Nakano Masaki,Nakamura Yukio,Urano Tomohiko,Miyazaki Akiko,Suzuki Takako,Watanabe Kazuki,Takahashi Jun,Shiraki Masataka The Journal of clinical endocrinology and metabolism CONTEXT:Although homocysteine accumulation is a reported risk factor for several age-related disorders, little is known about its relationship with osteoarthritis (OA). OBJECTIVE:We investigated for associations of homocysteine and C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR), which is involved in homocysteine clearance, with the development and progression of spinal OA through a combined cross-sectional and longitudinal cohort study. METHODS:A total of 1306 Japanese postmenopausal outpatients participating in the Nagano Cohort Study were followed for a mean 9.7-year period. Cross-sectional multiple logistic regression for spinal OA prevalence at registration by serum homocysteine level was performed with adjustment for confounders. In addition to Kaplan-Meier analysis, multivariate Cox regression was employed to examine the independent risk of MTHFR C677T variant for spinal OA progression. RESULTS:Multivariate regression analysis revealed a significant association between homocysteine and spinal OA prevalence (odds ratio 1.38; 95% CI 1.14-1.68). Kaplan-Meier curves showed a gene dosage effect of the T allele in MTHFR C677T polymorphism on the accelerated progression of spinal OA severity (P = 0.003). A statistically significant independent risk of the T allele for spinal OA advancement was validated by Cox regression analysis. Respective adjusted hazard ratios for the CT/TT and TT genotypes were 1.68 (95% CI, 1.16-2.42) and 1.67 (95% CI, 1.23-2.28). CONCLUSION:Circulating homocysteine and C677T variant in MTHFR are associated with the prevalence rate and ensuing progression, respectively, of spinal OA. These factors may represent potential interventional targets to prevent OA development and improve clinical outcomes. 10.1210/clinem/dgab591