Search

Background: Emerging evidence suggests an association between impaired high-density lipoprotein (HDL) functionality and cardiovascular disease (CVD). HDL is essential for reverse cholesterol transport (RCT) and reduces inflammation and oxidative stress principally via paraoxonase-1 (PON1). RCT depends on HDL's capacity to accept cholesterol (cholesterol efflux capacity [CEC]) and active transport through ATP-binding cassette (ABC) A1, G1, and scavenger receptor-B1 (SR-B1). We have studied the impact of Roux-en-Y gastric bypass (RYGB) in morbidly obese subjects on RCT and HDL functionality., Methods: Biomarkers associated with increased CVD risk including tumour necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hsCRP), myeloperoxidase mass (MPO), PON1 activity, and CEC in vitro were measured in 44 patients before and 6 and 12 months after RYGB. Overweight but otherwise healthy (mean body mass index [BMI] 28 kg/m2) subjects acted as controls. Twelve participants also underwent gluteal subcutaneous adipose tissue biopsies before and 6 months after RYGB for targeted gene expression (ABCA1, ABCG1, SR-B1, TNF-α) and histological analysis (adipocyte size, macrophage density, TNF-α immunostaining)., Results: Significant (P < 0.05) improvements in BMI, HDL-cholesterol, hsCRP, TNF-α, MPO mass, PON1 activity, and CEC in vitro were observed after RYGB. ABCG1 (fold-change, 2.24; P = 0.005) and ABCA1 gene expression increased significantly (fold-change, 1.34; P = 0.05). Gluteal fat adipocyte size (P < 0.0001), macrophage density (P = 0.0067), and TNF-α immunostaining (P = 0.0425) were reduced after RYBG and ABCG1 expression correlated inversely with TNF-α immunostaining (r = -0.71; P = 0.03)., Conclusion: RYGB enhances HDL functionality in association with a reduction in adipose tissue and systemic inflammation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: NF-κB regulates genes that control inflammation, cell proliferation, differentiation and survival. Dysregulated NF-κB signalling alters normal skin physiology and deletion of cRel limits bleomycin-induced skin fibrosis. This study investigates the role of cRel in modulating fibroblast phenotype in the context of SSc., Methods: Fibrosis was assessed histologically in mice challenged with bleomycin to induce lung or skin fibrosis. RNA sequencing and pathway analysis was performed on wild type and Rel-/- murine lung and dermal fibroblasts. Functional assays examined fibroblast proliferation, migration and matrix production. cRel overexpression was investigated in human dermal fibroblasts. cRel immunostaining was performed on lung and skin tissue sections from SSc patients and non-fibrotic controls., Results: cRel expression was elevated in murine lung and skin fibrosis models. Rel-/- mice were protected from developing pulmonary fibrosis. Soluble collagen production was significantly decreased in fibroblasts lacking cRel while proliferation and migration of these cells was significantly increased. cRel regulates genes involved in extracellular structure and matrix organization. Positive cRel staining was observed in fibroblasts in human SSc skin and lung tissue. Overexpression of constitutively active cRel in human dermal fibroblasts increased expression of matrix genes. An NF-κB gene signature was identified in diffuse SSc skin and nuclear cRel expression was elevated in SSc skin fibroblasts., Conclusion: cRel regulates a pro-fibrogenic transcriptional programme in fibroblasts that may contribute to disease pathology. Targeting cRel signalling in fibroblasts of SSc patients could provide a novel therapeutic avenue to limit scar formation in this disease., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Diabetic peripheral neuropathy (DPN) can lead to foot ulceration and amputation. There are currently no disease-modifying therapies for DPN. The aim of this study was to determine if hypertension contributes to DPN in patients with type 1 diabetes mellitus (T1DM)., Methods: Subjects with T1DM (n = 70) and controls (n = 78) underwent a comprehensive assessment of DPN., Results: Hypertension was present in 40 of 70 T1DM subjects and 20 of 78 controls. Hypertension was associated with abnormal nerve conduction parameters (P = 0.03 to <0.001), increased vibration perception threshold (P = 0.01) and reduced corneal nerve fiber density and length (P = 0.02) in subjects with T1DM. However, after adjusting for confounding factors only tibial compound motor action potential and nerve conduction velocity were associated with hypertension (P = 0.03) and systolic blood pressure (P < 0.01 to <0.0001). Hypertension had no effect on neuropathy in subjects without diabetes., Conclusions: This study shows that hypertension is associated with impaired nerve conduction in T1DM. It supports previous small trials showing that angiotensin-converting enzyme inhibitors improve nerve conduction and advocates the need for larger clinical trials with blood pressure lowering agents in DPN., (© The Author(s) 2019. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

Context: Obstructive sleep apnea (OSA) complicates morbid obesity and is associated with increased cardiovascular disease incidence. An increase in the circulating markers of chronic inflammation and dysfunctional high-density lipoprotein (HDL) occur in severe obesity., Objective: The objective of the study was to establish whether the effects of obesity on inflammation and HDL dysfunction are more marked when complicated by OSA., Design and Patients: Morbidly obese patients (n = 41) were divided into those whose apnea-hypoapnea index (AHI) was more or less than the median value and on the presence of OSA [OSA and no OSA (nOSA) groups]. We studied the antioxidant function of HDL and measured serum paraoxonase 1 (PON1) activity, TNFα, and intercellular adhesion molecule 1 (ICAM-1) levels in these patients. In a subset of 19 patients, we immunostained gluteal sc adipose tissue (SAT) for TNFα, macrophages, and measured adipocyte size., Results: HDL lipid peroxide levels were higher and serum PON1 activity was lower in the high AHI group vs the low AHI group (P < .05 and P < .0001, respectively) and in the OSA group vs the nOSA group (P = .005 and P < .05, respectively). Serum TNFα and ICAM-1 levels and TNFα immunostaining in SAT increased with the severity of OSA. Serum PON1 activity was inversely correlated with AHI (r = -0.41, P < .03) in the OSA group. TNFα expression in SAT directly correlated with AHI (r = 0.53, P < .03) in the subset of 19 patients from whom a biopsy was obtained., Conclusion: Increased serum TNFα, ICAM-1, and TNFα expression in SAT provide a mechanistic basis for enhanced inflammation in patients with OSA. Decreased serum PON1 activity, impaired HDL antioxidant function, and increased adipose tissue inflammation in these patients could be a mechanism for HDL and endothelial dysfunction.

Objectives: Our aim was to establish which tissue components express advanced glycation/lipoperoxidation end products (AGEs) and their receptor (RAGE) in skin from patients with SSc, and how their expression relates to the disease subtypes and various clinical parameters., Methods: Skin punch biopsies were taken from the forearms of 61 SSc patients with lcSSc; 32 with calcinosis (lcSScCal) and 29 without lcSSc, 36 with the dcSSc subtype and 22 healthy control subjects. Immunohistochemical localization of AGE-CML [N(epsilon)-(carboxymethyl) lysine] and RAGE was assessed semi-quantitatively on the microvascular endothelium, dermal fibroblasts and the cutaneous extracellular matrix (ECM). The Kruskal-Wallis one-way ANOVA was used to compare data between groups., Results: AGE-CML expression on the papillary dermis ECM of lcSScCal was greater than in the control group (P = 0.016). The reticular dermis of lcSScCal showed increased AGE-N(epsilon)-(carboxymethyl) lysine (CML) expression compared with controls (P = 0.002), dcSSc (P = 0.024) and lcSSc (P = 0.025). Increased immunostaining for RAGE was seen on the reticular dermis ECM of the lcSScCal group compared with controls (P = 0.007). The lcSScCal subgroup showed statistically significant correlations for AGE-CML, and to a lesser extent for RAGE, with increased RP duration. There was no consistent evidence that the expression of AGE-CML or RAGE related to autoantibody status, clinical or histological skin score or patient age., Conclusions: Our results indicate the possible contribution of AGE-CML deposition on the ECM in the dermis of the lcSScCal subgroup to the pathogenesis of formation of calcinotic deposits.

Objectives: Our aim was to evaluate (i) whether the bone matrix proteins osteonectin and matrix gamma-carboxyglutamic acid protein (MGP) are up-regulated in skin biopsies from patients with systemic sclerosis (SSc) and (ii) whether there is differential expression between patients with and without dermal calcinosis, a distressing and debilitating complication of SSc., Methods: Skin punch biopsies were taken from the forearms of 38 SSc patients with the limited cutaneous subtype of SSc [17 without calcinosis (lcSSc) and 21 with calcinosis (lcSScCal)] and from 11 healthy control subjects. Immunohistochemistry was performed with antibodies to osteonectin and MGP. Staining was assessed semiquantitatively in the microvascular endothelium and in dermal fibroblasts. The Kruskal-Wallis one-way ANOVA was used to compare the data between patient groups., Results: Both lcSSc and lcSScCal groups showed a statistically significant increase in the percentage of microvessels with osteonectin-positive endothelial cells (EC) (especially the lcSScCal group), whereas lcSScCal alone showed an increase in the percentage of microvessels with MGP-positive EC when compared with controls. In both SSc groups, the percentage of osteonectin and MGP-stained fibroblasts was increased in the reticular dermis (for osteonectin this was more marked in the lcSScCal group). In the papillary dermis, the percentage of osteonectin-stained fibroblasts was increased in both SSc groups but the lcSScCal group alone had a higher percentage of MGP-stained fibroblasts., Conclusions: When compared with controls, protein expression of osteonectin and MGP was greater in SSc patients generally, and osteonectin expression was significantly higher in EC and fibroblasts of the lcSScCal patients than the lcSSc patients without calcinosis.

Tryptase and chymase immunolocalization techniques have been used to examine the distribution, activation, and tryptase/chymase phenotype of mast cells (MCs) in 107 endometrial specimens that represented every day of the human menstrual cycle. MCs were identified in the endometrium in all stages of the menstrual cycle; similar MC numbers were observed for the functionalis, basalis, and muscularis. Extensive MC activation/degranulation, as judged by extracellular tryptase, was a common feature of the functionalis in specimens sampled just prior to and during menstruation. MC activation was also prominent in the functionalis at times coincident with recognized stromal edema. MCs of the functionalis did not contain chymase; all stained for tryptase and represent the MCT phenotype. By contrast, the basalis and muscularis showed a proportion of MCs containing both tryptase and chymase, MCTC. One important function for extracellular MC tryptase and chymase is their ability to activate precursor forms of the matrix metalloproteinases, enzymes recognized as instrumental in stromal degradation. Quantitative analysis of MC numbers, expressed relative to stromal cell numbers/mm2, indicated no major changes during the menstrual cycle, although changes in MC morphology, granule content, and activation/degranulation were recognized for specific stages. Eosinophils, detected with monoclonal antibodies EG1 and EG2, were absent from extravascular sites between Days 5 and 26 but showed local accumulations just prior to and during menstruation. Since MCs and eosinophils between them contain a variety of potent mediators, it seems likely that both cell types assume important functional roles in relation to tissue and vascular remodeling associated with endometrial physiology.