Metabolic consequences of obesity on the hypercoagulable state of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) women have a hypercoagulable state; however, whether this is intrinsically due to PCOS or, alternatively, a consequence of its metabolic complications is unclear. We determined plasma coagulation pathway protein levels in PCOS (n = 146) and control (n = 97) women recruited to a PCOS biobank. Circulating levels of a panel of 18 clotting pathway proteins were determined by Slow Off-rate Modified Aptamer-scan plasma protein measurement. Cohorts were age matched, though PCOS had elevated body mass index (p < 0.001), insulin (p < 0.001) and C-reactive protein (CRP) (p < 0.0001). Eight pro-coagulation proteins were elevated in PCOS: plasminogen activator inhibitor-1 (p < 0.0001), fibrinogen (p < 0.01), fibrinogen gamma chain (p < 0.0001), fibronectin (p < 0.01), von Willebrand factor (p < 0.05), D-dimer (p < 0.0001), P-selectin (p < 0.05), and plasma kallikrein (p < 0.001). However, two anticoagulant proteins, vitamin K-dependent protein-S (p < 0.0001) and heparin cofactor-II (p < 0.001) were elevated and prothrombin was decreased (p < 0.05). CRP, as a marker of inflammation, and insulin resistance (HOMA-IR) correlated with 11 and 6 of the clotting proteins, respectively (p < 0.05). When matched for BMI < 25 (16 PCOS, 53 controls) HOMA-IR remained elevated (p < 0.05) and heparin cofactor-II was increased (p < 0.05). In a multivariate analysis accounting for inflammation, insulin resistance and BMI, there was no correlation of PCOS with any of the coagulation proteins. The hypercoagulable state in PCOS is not intrinsic to the disease as it can be fully accounted for by BMI, inflammation and insulin resistance

Oxidative stress markers and heat shock proteins in non-obese women with polycystic ovary syndrome are not elevated and show no correlation with vitamin D

Introduction: Oxidative stress (OS) is recognized in the pathophysiology of polycystic ovary syndrome (PCOS). OS results in intracellular reactive oxygen species generation, causing oxidative protein damage that is protected by heat shock proteins (HSPs). Vitamin D is thought to reduce and protect against OS; therefore, OS, HSP, and vitamin D levels may be associated with PCOS. However, their expression in PCOS without underlying inflammation is unknown. Methods: In this exploratory study, the plasma levels of 7 OS proteins and 10 HSPs that are affected by the OS process were measured using Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurements in non-obese, non-insulin resistant women with PCOS (n = 24) without systemic inflammation and control (n = 24) women; the cohorts were matched for weight and age. The OS proteins and HSPs were correlated with 25-hydroxy vitamin D3 (25(OH)D3) and the active form, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), as measured by isotope-dilution liquid chromatography tandem mass spectrometry. Results: The PCOS women versus the controls had comparable insulin resistance and systemic inflammation (C-reactive protein 2.0 mg/L vs. 2.3 mg/L, p > 0.05), but higher free androgen index and anti-mullerian hormone levels. Among the OS proteins, only esterase D (ESD; p Conclusions: In a PCOS population that was non-obese and without insulin resistance and systemic inflammation, only ESD was elevated in PCOS, whilst the other OS proteins and HSPs were not elevated. Further, none of the OS proteins or HSPs were correlated with either 25(OH)D3 or 1,25(OH)2D3 in either cohort of women or when both cohorts were combined, indicating that the OS and HSP responses were largely absent and not affected by vitamin D in a non-obese PCOS population.</p

Identification of difluorinated curcumin molecular targets linked to traumatic brain injury pathophysiology

Traumatic brain injury (TBI) affects approximately 50% of the world population at some point in their lifetime.  To date, there are no effective treatments as most of the damage occurs due to secondary effects through a variety  of pathophysiological pathways. The phytoceutical curcumin has been traditionally used as a natural remedy for  numerous conditions including diabetes, inflammatory diseases, and neurological and neurodegenerative dis?orders. We have carried out a system pharmacology study to identify potential targets of a difluorinated cur?cumin analogue (CDF) that overlap with those involved in the pathophysiological mechanisms of TBI. This  resulted in identification of 312 targets which are mostly involved in G protein-coupled receptor activity and  cellular signalling. These include adrenergic, serotonergic, opioid and cannabinoid receptor families, which have  been implicated in regulation of pain, inflammation, mood, learning and cognition pathways. We conclude that  further studies should be performed to validate curcumin as a potential novel treatment to ameliorate the effects  of TBI. </p

A cross-sectional study of Alzheimer-related proteins in women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine condition in women of reproductive age, and several risk factors found in PCOS are associated with an increased risk of Alzheimer’s disease (AD). Proteins increased in AD have been reported to include fibronectin (FN) fragments 3 and 4 (FN1.3 and FN1.4, respectively) and ApoE. We hypothesized that Alzheimer-related proteins would be dysregulated in PCOS because of associated insulin resistance and obesity. In this comparative cross-sectional analysis, aptamer-based SomaScan proteomic analysis for the detection of plasma Alzheimer-related proteins was undertaken in a PCOS biobank of 143 women with PCOS and 97 control women. Amyloid precursor protein (APP) (p < 0.05) and amyloid P-component (APCS) (p < 0.001) were elevated in PCOS, while alpha-synuclein (SNCA) (p < 0.05) was reduced in PCOS. Associations with protective heat shock proteins (HSPs) showed that SNCA positively correlated with HSP90 (p < 0.0001) and HSP60 (p < 0.0001) in both the PCOS and control women. Correlations with markers of inflammation showed that APCS correlated with interleukin 6 (IL6) (p = 0.04), while Apolipoprotein (Apo) E3 correlated with TNF-alpha (p = 0.02). FN, FN1.3, FN1.4 and ApoE were all elevated significantly (p < 0.05). An AD-associated protein pattern with elevated FN, FN1.3, FN1.4 and ApoE was found in PCOS, in addition to elevated APP and reduced SNCA, which was the same as reported for type 2 diabetes (T2D) with, additionally, an elevation in APCS. With the AD biomarker pattern in PCOS being very similar to that in T2D, where there is an association between AD and T2D, this suggests that larger prospective cohort studies are needed in women with PCOS to determine if there is a causal association with AD

Coagulation factor dysregulation in polycystic ovary syndrome is an epiphenomenon of obesity

Objective: Obese women with polycystic ovary syndrome (PCOS) exhibit a hypercoagulable state, with the suggestion that this may be obesity-driven rather than an intrinsic facet of PCOS; however, this has not yet been definitively determined since body mass index (BMI) is so highly correlated with PCOS. Therefore, only a study design where obesity, insulin resistance and inflammation are matched can answer this question. Design: This was a cohort study. Patients Weight and aged-matched nonobese women with PCOS (n = 29) and control women (n = 29) were included. Measurements Plasma coagulation pathway protein levels were measured. Circulating levels of a panel of nine clotting proteins known to differ in obese women with PCOS were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. Results: Women with PCOS showed a higher free androgen index (FAI) and anti-Müllerian hormone, but measures of insulin resistance, and C reactive protein (as a marker of inflammation), did not differ between the nonobese women with PCOS and the control women. Seven pro-coagulation proteins (plasminogen activator inhibitor-1, fibrinogen, fibrinogen gamma chain, fibronectin, d-dimer, P-selectin and plasma kallikrein) and two anticoagulant proteins (vitamin K-dependent protein-S and heparin cofactor-II) known to be elevated in obese women with PCOS did not differ from controls in this cohort. Conclusions: This novel data show that clotting system abnormalities do not contribute to the intrinsic mechanisms underlying PCOS in this nonobese noninsulin resistant population of women with PCOS matched for age and BMI, and without evidence of underlying inflammation, but rather the clotting factor changes are an epiphenomenon coincident with obesity; therefore, increased coagulability is unlikely in these nonobese PCOS women.</p

Angiopoietin-1: an early biomarker of diabetic nephropathy?

Diabetic kidney disease (DKD) with progression to end-stage renal disease (ESRD) is a much-feared diabetes complication. Early recognition is key to preventing decline in renal function and, hence, biomarkers to stratify risk of functional decline have been actively sought. In a recent publication, plasma proteomic analysis was performed using the SOMASCAN platform in two longitudinal exploratory studies of type 1 (T1D) and type 2 diabetes (T2D) patients with chronic kidney disease (CKD) stage-3 to identify candidate protective biomarkers against progressive renal function decline/progression to ESRD, findings validated in a T1D patient cohort with normal renal function. Their findings distilled down to three proteins that showed a strong, additive protective effect against decline in renal function: angiopoeitin-1 (ANGPT1), tumor necrosis factor receptor superfamily 12 (TNFRSF12) and fibroblast growth factor 20 (FGF20).</p

Pro-fibrotic M2 macrophage markers may increase the risk for COVID19 in type 2 diabetes with obesity

Diabetes and obesity are associated with severe COVID-19-associated disease including acute respiratory distress syndrome (ARDS). Alveolar macrophage-derived cytokines contribute to the inflammation underlying ARDS, resulting in pulmonary fibrosis and edema, central facets of acute lung injury. Post-mortem histopathological features in the lung tissue of patients who died of severe COVID-19 disease demonstrate an extensive inflammatory infiltrate dominated by macrophages in the alveolar lumina. Thus, infected alveolar macrophages might drive the “cytokine storm” and lead to multiple organ failure in COVID-19 infected patients. Moreover, systemic cytokine profiles resemble cytokine release syndromes, such as macrophage activation syndrome, in patients with severe COVID-19 disease.</p

Correction to: COVID-19 biomarkers for severity mapped to polycystic ovary syndrome

Following publication of the original article, the authors would like to correct the author group with regards to the equal contributions: Stephen L. Atkin and Alexandra E. Butler should be listed as joint senior authors. The author group has been updated above and the original article has been corrected

The relationship of soluble neuropilin-1 to severe COVID-19 risk factors in polycystic ovary syndrome

The SARS-CoV-2 coronavirus enters target cells via the angiotensin-converting enzyme 2 (ACE2) receptor; however, ACE2 expression does not match SARS-CoV-2 tissue load, suggesting additional co-factors are required for viral entry. Neuropilin-1 (NRP1) is such a co-factor that, when expressed alone shows minimal viral infectivity, but when co-expressed with ACE2 markedly increases viral infectivity. NRP1 is a transmembrane glycoprotein, which is expressed in endothelial cells, and serves as a receptor for vascular endothelial growth factor (VEGF), and both NRP1 and VEGF expression are increased in COVID-19 patients. SARS-CoV-2 uses the viral spike protein for cell entry, cleaving the protein that then attaches to NRP1. Therefore, tissues enriched for NRP1 have increased infectivity risk and subjects expressing increased NRP1 may have increased risk.</p

Complement dysregulation in obese versus nonobese polycystic ovary syndrome patients

Introduction: Upregulation of complement system factors are reported to be increased in polycystic ovary syndrome (PCOS) and may be due to obesity and insulin resistance rather than inherently due to PCOS. We directly compared complement factors from an obese, insulin-resistant PCOS population to a nonobese, non-insulin-resistant PCOS population in a proteomic analysis to investigate this. Methods: Plasma was collected from 234 women (137 with PCOS and 97 controls) from a biobank cohort and compared to a nonobese, non-insulin-resistant population (24 with PCOS and 24 controls). Slow off-rate modified aptamer (SOMA) scan plasma protein measurement was undertaken for the following complement system proteins: C1q, C1r, C2, C3, C3a, iC3b, C3b, C3d, C3adesArg, C4, C4a, C4b, C5, C5a, C5b-6 complex, C8, properdin, factor B, factor D, factor H, factor I, Mannose-binding protein C (MBL), complement decay-accelerating factor (DAF) and complement factor H-related protein 5 (CFHR5). Results: The alternative pathway of the complement system was overexpressed in both obese and nonobese PCOS, with increased C3 (p p p p p p p p Conclusion: The upregulation of the alternative complement pathway was seen in nonobese PCOS and was further exacerbated in obese PCOS, indicating that this is an inherent feature of the pathophysiology of PCOS that is worsened by obesity and is reflected in the differences between the nonobese and obese PCOS phenotypes. However, the increase in the complement proteins associated with activation was counterbalanced by upregulation of complement inhibitors; this was evident in both PCOS groups, suggesting that insults, such as a cardiovascular event or infection, that cause activation of complement pathways may be amplified in PCOS.</p