UNASSIGNED: Cerebral cavernous malformations (CCMs) are pathologic lesions comprised of clusters of thin-walled capillaries characterized by abnormal proliferation, angiogenesis, and bleeding secondary to somatic or germline mutations in endothelial cells. CCMs can cause headaches, seizures and/or neurological defects. There is a clinical need to develop better tools to detect CCMs and follow their progression in conjunction with the current use of neuroimaging techniques. Here we present data supporting the utility of LOX-1 (lectin-type oxidized LDL receptor 1), a 50 kDa transmembrane protein implicated in endothelial cell dysfunction and ischemia, as a putative biomarker for CCM.
UNASSIGNED: CCM urine samples (n = 23) were collected from pediatric CCM patients. Matched healthy controls (n = 24) were collected from pediatric patients with either Chiari I malformation or fatty filum terminale, and otherwise normal findings. All samples were collected with patient/family consent and institutional review board approval.Samples were analyzed with Olink Proteomic Proximity Extension Assay (PEA). Differences in expression for 2,925 unique proteins were quantified between healthy control urine samples and CCM urine samples. The results were normalized, validated, and analyzed for demographic bias. In addition to urine samples, CCM tissue from patients was harvested and used to create primary cell lines for in vitro analysis of LOX-1 expression, in addition to immunofluorescence of lesional tissue excised at surgery.
UNASSIGNED: ANOVA analysis of the CCM urine samples showed a statistically significant increase in LOX-1 compared to the control samples, with CCM patients exhibiting a > 5-fold increase in urinary expression. Corroborating these elevated levels of circulating marker, analysis of source tissue from surgically resected CCMs revealed that LOX-1 is increased in both CCM patient cavernoma primary cell lines and operative specimens.
UNASSIGNED: LOX-1 is involved with pathways implicated in CCM pathogenesis and our data here reveals that LOX-1 expression is significantly elevated in CCM patients as compared to matched healthy control individuals, including both source tissue from surgically excised CCMs and in analysis of samples collected from outside of the central nervous system, particularly urine. This proof-of-principle data suggests that LOX-1 may have potential utility as a target for CCM treatment and supports further investigation related to its potential mechanistic impact on CCM pathogenesis.

BACKGROUND: Cognitive impairment is a core symptom of schizophrenia. Metabolic abnormalities impact cognition, and although the influence of blood lipids on cognition has been documented, it remains unclear. We conducted a small cross-sectional study to investigate the relationship between blood lipids and cognition in patients with stable-phase schizophrenia. Using Olink proteomics, we explored the potential mechanisms through which blood lipids might affect cognition from an inflammatory perspective.
METHODS: A total of 107 patients with stable-phase schizophrenia and cognitive impairment were strictly included. Comprehensive data collection included basic patient information, blood glucose, blood lipids, and body mass index. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and the MATRICS Consensus Cognitive Battery (MCCB). After controlling for confounding factors, we identified differential metabolic indicators between patients with mild and severe cognitive impairment and conducted correlation and regression analyses. Furthermore, we matched two small sample groups of patients with lipid metabolism abnormalities and used Olink proteomics to analyze inflammation-related differential proteins, aiming to further explore the association between lipid metabolism abnormalities and cognition.
RESULTS: The proportion of patients with severe cognitive impairment (SCI) was 34.58%. Compared to patients with mild cognitive impairment (MCI), those with SCI performed worse in the Attention/Alertness (t = 2.668, p = 0.009) and Working Memory (t = 2.496, p = 0.014) cognitive dimensions. Blood lipid metabolism indicators were correlated with cognitive function, specifically showing that higher levels of TG (r = -0.447, p < 0.001), TC (r = -0.307, p = 0.002), and LDL-C (r = -0.607, p < 0.001) were associated with poorer overall cognitive function. Further regression analysis indicated that TG (OR = 5.578, P = 0.003) and LDL-C (OR = 5.425, P = 0.001) may be risk factors for exacerbating cognitive impairment in individuals with stable-phase schizophrenia. Proteomics analysis revealed that, compared to individuals with stable-phase schizophrenia and normal lipid metabolism, those with hyperlipidemia had elevated levels of 10 inflammatory proteins and decreased levels of 2 inflammatory proteins in plasma, with these changes correlating with cognitive function. The differential proteins were primarily involved in pathways such as cytokine-cytokine receptor interaction, chemokine signaling pathway, and IL-17 signaling pathway.
CONCLUSIONS: Blood lipids are associated with cognitive function in individuals with stable-phase schizophrenia, with higher levels of TG, TC, and LDL-C correlating with poorer overall cognitive performance. TG and LDL-C may be risk factors for exacerbating cognitive impairment in these patients. From an inflammatory perspective, lipid metabolism abnormalities might influence cognition by activating or downregulating related proteins, or through pathways such as cytokine-cytokine receptor interaction, chemokine signaling pathway, and IL-17 signaling pathway.

Intracerebral hemorrhage (ICH) could trigger inflammatory responses. However, the specific role of inflammatory proteins in the pathological mechanism, complications, and prognosis of ICH remains unclear. In this study, we investigated the expression of 92 plasma inflammation-related proteins in patients with ICH (n = 55) and healthy controls (n = 20) using an Olink inflammation panel and discussed the relation to the severity of stroke, clinical complications, 30-day mortality, and 90-day outcomes. Our result showed that six proteins were upregulated in ICH patients compared with healthy controls, while seventy-four proteins were downregulated. In patients with ICH, seven proteins were increased in the severe stroke group compared with the moderate stroke group. In terms of complications, two proteins were downregulated in patients with pneumonia, while nine proteins were upregulated in patients with sepsis. Compared with the survival group, three proteins were upregulated, and one protein was downregulated in the death group. Compared with the good outcome group, eight proteins were upregulated, and four proteins were downregulated in the poor outcome group. In summary, an in-depth exploration of the differential inflammatory factors in the early stages of ICH could deepen our understanding of the pathogenesis of ICH, predict patient prognosis, and explore new treatment strategies.

UNASSIGNED: Physical activity has been associated with preventing the development of type 2 diabetes and atherosclerotic cardiovascular disease. However, our understanding of the precise molecular mechanisms underlying these effects remains incomplete and good biomarkers to objectively assess physical activity are lacking.
UNASSIGNED: We analyzed 3072 serum proteins in 26 men, normal weight or overweight, undergoing 12 weeks of a combined strength and endurance exercise intervention. We estimated insulin sensitivity with hyperinsulinemic euglycemic clamp, maximum oxygen uptake, muscle strength, and used MRI/MRS to evaluate body composition and organ fat depots. Muscle and subcutaneous adipose tissue biopsies were used for mRNA sequencing. Additional association analyses were performed in samples from up to 47,747 individuals in the UK Biobank, as well as using two-sample Mendelian randomization and mice models.
UNASSIGNED: Following 12 weeks of exercise intervention, we observed significant changes in 283 serum proteins. Notably, 66 of these proteins were elevated in overweight men and positively associated with liver fat before the exercise regimen, but were normalized after exercise. Furthermore, for 19.7 and 12.1% of the exercise-responsive proteins, corresponding changes in mRNA expression levels in muscle and fat, respectively, were shown. The protein CD300LG displayed consistent alterations in blood, muscle, and fat. Serum CD300LG exhibited positive associations with insulin sensitivity, and to angiogenesis-related gene expression in both muscle and fat. Furthermore, serum CD300LG was positively associated with physical activity and negatively associated with glucose levels in the UK Biobank. In this sample, the association between serum CD300LG and physical activity was significantly stronger in men than in women. Mendelian randomization analysis suggested potential causal relationships between levels of serum CD300LG and fasting glucose, 2 hr glucose after an oral glucose tolerance test, and HbA1c. Additionally, Cd300lg responded to exercise in a mouse model, and we observed signs of impaired glucose tolerance in male, but not female, Cd300lg knockout mice.
UNASSIGNED: Our study identified several novel proteins in serum whose levels change in response to prolonged exercise and were significantly associated with body composition, liver fat, and glucose homeostasis. Serum CD300LG increased with physical activity and is a potential causal link to improved glucose levels. CD300LG may be a promising exercise biomarker and a therapeutic target in type 2 diabetes.
UNASSIGNED: South-Eastern Norway Regional Health Authority, Simon Fougners Fund, Diabetesforbundet, Johan Selmer Kvanes\' legat til forskning og bekjempelse av sukkersyke. The UK Biobank resource reference 53641. Australian National Health and Medical Research Council Investigator Grant (APP2017942). Australian Research Council Discovery Early Career Award (DE220101226). Research Council of Norway (Project grant: 325640 and Mobility grant: 287198). The Medical Student Research Program at the University of Oslo. Novo Nordisk Fonden Excellence Emerging Grant in Endocrinology and Metabolism 2023 (NNF23OC0082123).
UNASSIGNED: clinicaltrials.gov: NCT01803568.

UNASSIGNED: Postmenopausal osteoporosis (PMOP) can cause postmenopausal women to experience pain and interference. Identifying and exploring potential early diagnostic biomarkers of PMOP is of substantial clinical value and social significance. This study aimed to screen for potential novel diagnostic biomarkers of PMOP through a multiomics approach, providing new directions and ideas for the early prevention and treatment of this disease.
METHODS: Fifteen postmenopausal women with osteoporosis and 12 without were recruited. Clinical information was collected, and various clinical biochemical parameters were tested. Plasma and fecal samples were collected and analyzed using Olink proteomics and gut microbial metabolomics.
RESULTS: The functions of the differentially abundant metabolites were mainly related to autophagy and arginine and proline metabolism and were involved in immunoinflammatory metabolic processes. Olink showed significant differences in the expression of seven inflammation-related proteins between the two groups.
CONCLUSIONS: We demonstrated that metabolic differences between PMOP patients and healthy controls were associated with inflammatory responses and found seven proteins with significant differences. Among these proteins, CDCP1, IL10, and IL-1alpha combined with clinical indicators had high discriminant efficiency in identifying PMOP. This is also the first study to demonstrate noteworthy changes in CDCP1 levels in patients with PMOP.

The study of the cellular secretome using proteomic techniques continues to capture the attention of the research community across a broad range of topics in biomedical research. Due to their untargeted nature, independence from the model system employed, historically superior depth of analysis, as well as comparative affordability, mass spectrometry-based approaches traditionally dominate such analyses. More recently, however, affinity-based proteomic assays have massively gained in analytical depth, which together with their high sensitivity, dynamic range coverage as well as high throughput capabilities render them exquisitely suited to secretome analysis. In this review, we revisit the analytical challenges implied by secretomics and provide an overview of affinity-based proteomic platforms currently available for such analyses, using the study of the tumor secretome as an example for basic and translational research.

The objective is to characterize differentially expressed proteins (DEPs) in Guillain-Barré Syndrome (GBS) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) through high-throughput analysis. Sera from 11 healthy controls (HCs), 21 GBS and 19 CIDP patients were subjected to Olink Proteomics Analysis. In the comparison between CIDP and GBS groups, up-regulation of ITM2A and down-regulation of NTF4 were observed. Comparing GBS with HCs revealed 18 up-regulated and 4 down-regulated proteins. Comparing CIDP with the HCs identified 15 up-regulated and 4 down-regulated proteins. Additionally, the correlation between clinical characteristics and DEPs were uncovered. In conclusion, the DEPs have significant potential to advance our understanding of the pathogenesis in these debilitating neurological disorders.

Dilated cardiomyopathy (DCM) is characterized by reduced left ventricular ejection fraction (LVEF) and left or biventricular dilatation. We evaluated sex-specific associations of circulating proteins and metabolites with structural and functional heart parameters in DCM. Plasma samples (297 men, 71 women) were analyzed for proteins using Olink assays (targeted analysis) or LC-MS/MS (untargeted analysis), and for metabolites using LC MS/MS (Biocrates AbsoluteIDQ p180 Kit). Associations of proteins (n = 571) or metabolites (n = 163) with LVEF, measured left ventricular end diastolic diameter (LVEDDmeasured), and the dilation percentage of LVEDD from the norm (LVEDDacc. to HENRY) were examined in combined and sex-specific regression models. To disclose protein-metabolite relations, correlation analyses were performed. Associations between proteins, metabolites and LVEF were restricted to men, while associations with LVEDD were absent in both sexes. Significant metabolites were validated in a second independent DCM cohort (93 men). Integrative analyses demonstrated close relations between altered proteins and metabolites involved in lipid metabolism, inflammation, and endothelial dysfunction with declining LVEF, with kynurenine as the most prominent finding. In DCM, the loss of cardiac function was reflected by circulating proteins and metabolites with sex-specific differences. Our integrative approach demonstrated that concurrently assessing specific proteins and metabolites might help us to gain insights into the alterations associated with DCM.

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful nodules, abscesses and purulent secretions in intertriginous regions. Intense pruritus frequently accompanies HS lesions, adding further discomfort for patients. While Th17 pathway activation is implicated in HS pathogenesis, disease mechanisms are still not fully understood, and therapeutics are lacking. Previous reports raise a potential role for eosinophils in HS, showing a strong association of eosinophil levels with disease severity. To investigate eosinophils in HS, we recruited patients and matched healthy controls and then performed flow-cytometry studies, eosinophil stimulation assays, and lesional skin staining for eosinophils. We found that HS patients reported similar levels of pain and itch. Compared to matched controls, HS blood exhibited decreased mature eosinophils and increased numbers of immature eosinophils, coupled with a significant increase in dermal eosinophilic infiltrates. Additionally, IL-17RA+ eosinophils were highly and significantly correlated with multiple HS-related clinical scores. In both stimulated and unstimulated conditions, HS eosinophils showed an inflammatory phenotype versus controls, including an increase in costimulatory T- and B-cell markers (e.g. CD5 and CD40) following all stimulations (TNFα/IL-17A/IL-17F). These findings highlight the significance of pruritus in HS and suggest a higher turnover of eosinophils in HS blood, potentially due to the consumption of eosinophils in skin lesions. Our data delineate the features and functions of eosinophils in HS and suggest that eosinophils participate in disease pathogenesis, advancing Th17-related inflammation. Further studies are needed to investigate eosinophils\' response to current HS treatments and their potential as a therapeutic target in the disease.

To investigate predictive biomarkers that could be used to identify patients\' response to treatment, plasma metabolomics and proteomics analyses were performed in Kashin-Beck disease (KBD) patients treated with Fufang Duzhong Jiangu Granules (FDJG). Plasma was collected from 12 KBD patients before treatment and 1 month after FDJG treatment. LC-MS and olink proteomics were employed for obtaining plasma metabolomics profiling and inflammatory protein profiles. Patients were classified into responders and non-responders based on drug efficacy. Enrichment analyses of differential metabolites and proteins of the responders at baseline and after treatment were conducted to study the mechanism of drug action. Differential metabolites and proteins between the two groups were screened as biomarkers to predict the drug efficacy. The receiver operating characteristic curve was used to evaluate the prediction accuracy of biomarkers. The changes in metabolites and inflammatory proteins in responders after treatment reflected the mechanism of FDJG treatment for KBD, which may act on glycerophospholipid metabolism, d-glutamine and d-glutamate metabolism, nitrogen metabolism and NF-kappa B signaling pathway. Three metabolites were identified as potential predictors: N-undecanoylglycine, β-aminopropionitrile and PC [18:3(6Z,9Z,12Z)/20:4(8Z,11Z,14Z,17Z)]. For inflammatory protein, interleukin-8 was identified as a predictive biomarker to detect responders. Combined use of these four biomarkers had high predictive ability (area under the curve = 0.972).