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

Editorial: Omics solutions for endocrine disorders

Multifactorial processes contribute to the development of endocrinological disorders such as diabetes, polycystic ovary syndrome (PCOS) and some carcinomas. Frequently, standard clinical tests are insufficient for proper diagnosis and treatment. Therefore, strategies providing further insight into endocrinological disorders that support the clinical pipeline are required. Recently, omics technologies such as genomics, transcriptomics, proteomics, metabolomics and lipidomics have been introduced into the field of complex disorders to improve diagnostics and treatment. This special edition highlights the use of omic technologies in endocrinological disorders, including diabetes and its comorbidities, as well as obesity and PCOS, further emphasizing their potential to be implemented into the clinical pipeline. What this special edition also emphasizes is the differing methodology available for each of the “omic” approaches that may not be directly comparable, one example being in proteomics where some groups use aptamer-based technology whilst others may use mass spectroscopy, and therefore the need for standardization. </p

Differing endometrial expression of calcium modulating transient receptor potential channels

Assisted reproductive techniques (ART) have increased the live birth success rate, but there is still a significant implantation failure rate. Epithelial cell calcium homeostasis is tightly regulated by mechanisms that include activation of the TRP channel superfamily of 9 families including TRPC (Canonical). TRPCs are located on the cell membrane and act as receptor-operated channels (ROC), whilst cytosolic localization of these channels indicates their role as store-operated channels (SOC): both ROCs and SOCs are key players in the regulation of intracellular calcium homeostasis. TRPC 1–4 and 6 expression in the bovine reproductive tract has been reported; these receptors exhibit hormone modulation and calcium dysregulation can lead to menstrual disturbances, suggesting that TRPC receptors may modulate calcium in the human endometrium and affect implantation and fertility.</p

Hypoglycemia impairs the heat shock protein response: a risk for heat shock in cattle?

Background: Heat stress (HS) in cattle is a major debilitating problem, affecting health and milk yield. Physiologically, HS has been shown to lower blood glucose levels to 2.5 mmol/l (45 mg/dl) and results in upregulation of heat shock proteins (HSPs), eliciting the heat shock response (HSR) of which HSP90, 70 and 27 have been shown to be protective. However, it is unclear if the HSP response is blunted by decreased glucose, thereby preventing adaptive mechanisms. To address this question, this exploratory reverse translational study on the effects of hypoglycemia on the HSP pathway was undertaken. Methods: A human prospective, study in healthy control individuals (n = 23) was undertaken. Subjects underwent hyperinsulinemic-induced hypoglycemia [≤2.0 mmol/L (36 mg/dl)] with blood sampling at baseline, at hypoglycemia and for a 24-h post-hypoglycemia follow-up period. Proteomic analysis of the heat shock-related protein pathway, the pathway associated with HS in cattle, was performed. Results: In response to hypoglycemia, HS pathway proteins were significantly decreased (p Conclusion: Heat stress in cattle reduces blood glucose that, in turn, may blunt the HS pathway protective response, including HSP 90, 70, 27 and the ubiquitin proteins, leading to adverse outcomes. Monitoring of blood glucose in susceptible cattle may allow for earlier intervention and may also identify those animals at greatest risk to ensure that milk yield is not compromised.</p

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 key upregulated genes involved in foam cell formation and the modulatory role of statin therapy

Background: We aimed to investigate the possible effect of statins on important genes/proteins involved in foam cell formation. Methods: The gene expression profile of the GSE9874, GSE54666, and GSE7138 from the Omnibus database were usedto identify genes involved in foam cell formation. The protein-protein interaction (PPI) network and MCODE analysis of the intersection of three databases were analyzed. We used molecular docking analysis to investigate the possible interaction of different statins with the overexpressed hub genes obtained from PPI analysis. Results: The intersection among the three datasets showed 54 upregulated and 26 down-regulated genes. The most critical overexpressed genes/proteins obtained as hub genes included: G6PD, NPC1, ABCA1, ABCG1, PGD, PLIN2, PPAP2B, and TXNRD1 based on PPI analysis. Functional enrichment analysis of 81 intersection DEGs at the biological process level focusing on the cholesterol metabolic process, secondary alcohol biosynthetic process and the cholesterol biosynthetic process. Under cellular components, the analysis confirmed that these 81 intersection DEGs were mainly applied in endoplasmic reticulum membrane, lysosome and lytic vacuole. The molecular functions were identified as sterol binding, oxidoreductase activity and NADP binding. The molecular docking showed that all statins appear to affect important protein targets overexpressed in foam cell formation. However, lipophilic statins, especially pitavastatin and lovastatin, had a greater effect than hydrophilic statins. The most significant protein target of all the overexpressed genes interacting with all statin types was ABCA1. Conclusion: The effect of lipophilic statins was shown for several critical proteins in foam cell formation.</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

Body appreciation around the world: measurement invariance of the Body Appreciation Scale-2 (BAS-2) across 65 nations, 40 languages, gender identities, and age

The Body Appreciation Scale-2 (BAS-2) is a widely used measure of a core facet of the positive body image construct. However, extant research concerning measurement invariance of the BAS-2 across a large number of nations remains limited. Here, we utilised the Body Image in Nature (BINS) dataset - with data collected between 2020 and 2022 - to assess measurement invariance of the BAS-2 across 65 nations, 40 languages, gender identities, and age groups. Multi-group confirmatory factor analysis indicated that full scalar invariance was upheld across all nations, languages, gender identities, and age groups, suggesting that the unidimensional BAS-2 model has widespread applicability. There were large differences across nations and languages in latent body appreciation, while differences across gender identities and age groups were negligible-to-small. Additionally, greater body appreciation was significantly associated with higher life satisfaction, being single (versus being married or in a committed relationship), and greater rurality (versus urbanicity). Across a subset of nations where nation-level data were available, greater body appreciation was also significantly associated with greater cultural distance from the United States and greater relative income inequality. These findings suggest that the BAS-2 likely captures a near-universal conceptualisation of the body appreciation construct, which should facilitate further cross-cultural research. </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