Innate immune responses and antioxidant/oxidant imbalance are major determinants of human Chagas disease.

We investigated the pathological and diagnostic role of selected markers of inflammation, oxidant/antioxidant status, and cellular injury in human Chagas disease. METHODS: Seropositive/chagasic subjects characterized as clinically-symptomatic or clinically-asymptomatic (n = 116), seronegative/cardiac subjects (n = 102), and seronegative/healthy subjects (n = 45) were analyzed for peripheral blood biomarkers. RESULTS: Seropositive/chagasic subjects exhibited an increase in sera or plasma levels of myeloperoxidase (MPO, 2.8-fold), advanced oxidation protein products (AOPP, 56%), nitrite (5.7-fold), lipid peroxides (LPO, 12-17-fold) and malondialdehyde (MDA, 4-6-fold); and a decline in superoxide dismutase (SOD, 52%) and glutathione (GSH, 75%) contents. Correlation analysis identified a significant (p0.95). The MPO (r = 0.664) and LPO (r = 0.841) levels were also correlated with clinical disease state in chagasic subjects (p<0.001). Seronegative/cardiac subjects exhibited up to 77% decline in SOD, 3-5-fold increase in LPO and glutamate pyruvate transaminase (GPT) levels, and statistically insignificant change in MPO, AOPP, MDA, GPX, GSH, and creatine kinase (CK) levels. CONCLUSIONS: The interlinked effects of innate immune responses and antioxidant/oxidant imbalance are major determinants of human Chagas disease. The MPO, LPO and nitrite are excellent biomarkers for diagnosing seropositive/chagasic subjects, and MPO and LPO levels have potential utility in identifying clinical severity of Chagas diseaseFil: Dhiman, Monisha. University Of Texas Medical Branch. Department Of Microbiology & Immunology And Pathology; United State of America;Fil: Coronado, Yun A.. University Of Texas Medical Branch. Department Of Microbiology & Immunology And Pathology; United State of America;Fil: Vallejo, Cecilia K.. University Of Texas Medical Branch. Department Of Microbiology & Immunology And Pathology; United State of America;Fil: Petersen, John R.. University of Texas Medical Branch. Department of Pathology; United States of America;Fil: Ejilemele, Adetoum. University of Texas Medical Branch. Department of Pathology; United States of America;Fil: Nuñez, Sonia. Hospital Público de Gestión Descentralizada San Bernardo (HPGDSA); Argentina;Fil: Zago, María Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Salta. Instituto de Patologia Experimental; Argentina;Fil: Spratt, Heidi. Departments of Biochemistry and Molecular Biology and Preventive Medicine and Community Health. University of Texas Medical Branch; United States of America;Fil: Garg, Nisha Jain. University of Texas Medical Branch. Department of Pathology; United States of America

Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment

Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

BackgroundHistologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD.MethodsThis was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0–4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0–2 vs F3 vs F4; LSM: 2·67; NFS: 0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226.FindingsOf 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44–63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33–91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62–0·81) for histology, 0·76 (0·70–0·83) for LSM-VCTE, 0·74 (0·64–0·82) for FIB-4, and 0·70 (0·63–0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression.InterpretationSimple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases

Metabolic markers of tissue injury were not significantly altered in chagasic subjects.

<p>Shown are plasma levels of activities of the glutamate pyruvate transaminase (<b>A</b>) and creatine kinase (<b>B</b>), determined by spectrophotometry.</p

Correlation analysis.

<p>Plasma and sera samples from seronegative/healthy (SN/H, n = 45) and seropositive/chagasic (SP/C, n = 116) subjects were submitted to spectrophotometry analysis of various biomarkers of inflammation, oxidative stress, antioxidant status and cellular injury as described in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002364#s2" target="_blank">Materials and Methods</a>. Pearson's or Spearman's analysis was conducted to evaluate the strength of linear relationship between sera or plasma levels of biomarkers (among themselves) or with clinical disease category. Correlations coefficient (r) value of >0.8 was considered very strong and that of between 0.6–0.8 accepted as moderately strong <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002364#pntd.0002364-Chan1" target="_blank">[31]</a>. “-”indicates a significant correlation at p<0.01 was not present. ND: not determined.</p

SOD and GSH are indicators of compromised antioxidant status in chagasic subjects.

<p>Plasma <i>(</i><b><i>A, C, E</i></b><i>)</i> and sera <i>(</i><b><i>B, D, F</i></b><i>)</i> levels of activities of the superoxide dismutase (<b>A&B</b>) and glutathione peroxidase (<b>C&D</b>) were determined by spectrophotometry. The glutathione contents (<b>E&F</b>) were measured by GSSG-DTNB recycling assay.</p

LPO and MDA are biomarkers of increased oxidative stress in chagasic subjects.

<p>The plasma <i>(</i><b><i>A&C</i></b><i>)</i> and sera <i>(</i><b><i>B&D</i></b><i>)</i> levels of lipid hydroperoxides (<b>A&B</b>) and malondialdehyde (<b>C&D</b>) were measured by spectrophotometry.</p

Pair-wise correlation and modeling analysis.

<p>Pair-wise correlation analysis of (<b>A</b>) nitrite (µmol/mg protein) with LPO (µmol/ml) and (<b>B</b>) glutathione peroxidase (units/mg protein) with AOPP (µmol/ml) utilizing data from plasma analysis of seropositive/chagasic and seronegative/healthy subjects is shown. (<b>C&D</b>) MARS analysis was performed using 80% of the data for various biomarkers from seronegative/healthy and seropositive/chagasic subjects as training dataset (blue curve) and 20% of the remaining data as test dataset to assess the performance of the model (red curve). Shown in panel C is MARS analysis of plasma levels of the biomarkers that revealed model fits perfectly (AUC/ROC = 1) on the training data for LPO, nitrite and SOD (with AUC/ROC of 0.099955 with testing dataset). Shown in panel D is MARS analysis of sera levels of the biomarkers that revealed model fits perfectly (AUC/ROC = 1) on the training data for MPO, LPO, and nitrite (with AUC/ROC of 0.9589 with testing dataset). (<b>E&F</b>) Shown are pair-wise correlation analyses of MPO (E) and LPO (F) contents with clinical disease. Each dot represents an individual subject.</p