Search Results (25)

Sepsis is a major medical emergency, characterized by a dysfunctional immune response to infection, which often progresses to multiple organ failure and death. Early diagnosis and prognostic evaluation present significant challenges due to limitations in the specificity and sensitivity of traditional biomarkers. This narrative review summarizes recent evidence on the potential of circulating microRNAs (miRNAs) such as miR-150, miR-146a, miR-223, miR-155, miR-122, and miR-4772-5p and plasma gelsolin (pGSN) as diagnostic and prognostic markers in sepsis. We discuss mechanisms involved and their potential for integration with artificial intelligence (AI) in personalized medicine. PubMed, Embase, and Web of Science databases were searched for relevant literature. Original research, systematic reviews, and meta-analyses focused on the diagnostic or prognostic value of circulating miRNAs or pGSN in sepsis were included; opinion papers and case reports were excluded. Altered expression of certain circulating microRNAs correlates with disease severity and mortality. Among circulating microRNAs (miRNAs), miR-122 and miR-150 have become the most consistently validated biomarkers in clinical studies, associated with sepsis severity and death rates. Additionally, other miRNAs such as miR-146a, miR-155, and miR-223 play roles in modulating immune and endothelial responses, highlighting the complex regulation of sepsis pathophysiology. Low pGSN concentrations at admission are associated with severe sepsis and acute respiratory distress syndrome, and serve as an independent predictor of mortality. Preclinical studies suggest that supplementation with exogenous pGSN could increase survival. AI algorithms show promising results for early sepsis detection and optimization of therapeutic decisions. However, combining circulating miRNAs and plasma gelsolin (pGSN) into AI-based models is still an exploratory idea that needs prospective validation, assay standardization, and multicenter studies before it can be used clinically. Full article

The goal of this study was to evaluate inflammatory and oxidative stress responses in human subjects (9 females and 15 males) (age [29.6 ± 11.5 years old (mean ± SD)], height [172.0 ± 10.05 cm], and weight [67.8 ± 12.4 kg]) exposed to 1.45 ATA of helium (He) or nitrogen (N₂) without concurrent hyperoxia. We hypothesized that elevated gas pressures would elicit an inflammatory response concurrent with oxidative stress. Consistent with ex vivo studies, both gasses elicited neutrophil activation, small elevations in microparticles (MPs) and increases in intra-MP interleukin (IL)-1β and inflammatory nitric oxide synthase, and an increase in urinary IL-6 concurrent with a marked reduction in plasma gelsolin. Mixed responses indictive of oxidative stress, with some biomarker elevations but little change in others and a decrease in some, were observed. Overall, these results demonstrate that exposure to typical diving gasses at a mildly elevated partial pressure will initiate inflammatory responses, which may play a significant role in decompression sickness (DCS). The complex pattern of oxidative stress responses may be indicative of competing systemic reactions and sampling different body fluids. Full article

(Background). Canine mammary tumors (CMTs) have emerged as an important model for understanding pathophysiological aspects of human disease. Liquid biopsy (LB), which relies on blood-borne biomarkers and offers minimal invasiveness, holds promise for reflecting the disease status of patients. Small extracellular vesicles (SEVs) and their protein cargo have recently gained attention as potential tools for disease screening and monitoring. (Objectives). This study aimed to isolate SEVs from canine patients and analyze their proteomic profile to assess their diagnostic and prognostic potential. (Methods). Plasma samples were collected from female dogs grouped into CMT (malignant and benign), healthy controls, relapse, and remission groups. SEVs were isolated and characterized using ultracentrifugation (UC), nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Proteomic analysis of circulating SEVs was conducted using liquid chromatography–mass spectrometry (LC–MS). (Results). While no significant differences were observed in the concentration and size of exosomes among the studied groups, proteomic profiling revealed important variations. Mass spectrometry identified exclusive proteins that could serve as potential biomarkers for mammary cancer. These included Inter-alpha-trypsin inhibitor heavy chain (ITIH2 and ITI4), phosphopyruvate hydratase or alpha enolase (ENO1), eukaryotic translation elongation factor 2 (eEF2), actin (ACTB), transthyretin (TTR), beta-2-glycoprotein 1 (APOH) and gelsolin (GSN) found in female dogs with malignant tumors. Additionally, vitamin D-binding protein (VDBP), also known as group-specific component (GC), was identified as a protein present during remission. (Conclusions). The results underscore the potential of proteins found in SEVs as valuable biomarkers in CMTs. Despite the lack of differences in vesicle concentration and size between the groups, the analysis of protein content revealed promising markers with potential applications in CMT diagnosis and monitoring. These findings suggest a novel approach in the development of more precise and effective diagnostic tools for this challenging clinical condition. Full article

Plasma gelsolin (pGSN) overexpression in ovarian cancer (OVCA) disarms immune function, contributing to chemoresistance. The aim of this study was to investigate the immunoregulatory effects of pGSN expression on natural killer (NK) cell function in OVCA. OVCA tissues from primary surgeries underwent immunofluorescent staining of pGSN and the activated NK cell marker natural cytotoxicity triggering receptor 1 to analyze the prognostic impact of pGSN expression and activated NK cell infiltration. The immunoregulatory effects of pGSN on NK cells were assessed using apoptosis assay, cytokine secretion, immune checkpoint-receptor expression, and phosphorylation of STAT3. In OVCA tissue analyses, activated NK cell infiltration provided survival advantages to patients. However, high pGSN expression attenuated the survival benefits of activated NK cell infiltration. In the in vitro experiment, pGSN in OVCA cells induced NK cell death through cell-to-cell contact. pGSN increased T-cell immunoglobulin and mucin-domain-containing-3 expression (TIM-3) on activated NK cells. Further, it decreased interferon-γ production in activated TIM-3+ NK cells, attenuating their anti-tumor effects. Thus, increased pGSN expression suppresses the anti-tumor functions of NK cells. The study provides insights into why immunotherapy is rarely effective in patients with OVCA and suggests novel treatment strategies. Full article

Intrauterine growth restriction (IUGR) remains a significant concern in modern obstetrics, linked to high neonatal health problems and even death, as well as childhood disability, affecting adult quality of life. The role of maternal and fetus adaptation during adverse pregnancy is still not completely understood. This study aimed to investigate the disturbance in biological processes associated with isolated IUGR via blood plasma proteomics. The levels of 125 maternal plasma proteins were quantified by liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM MS) with corresponding stable isotope-labeled peptide standards (SIS). Thirteen potential markers of IUGR (Gelsolin, Alpha-2-macroglobulin, Apolipoprotein A-IV, Apolipoprotein B-100, Apolipoprotein(a), Adiponectin, Complement C5, Apolipoprotein D, Alpha-1B-glycoprotein, Serum albumin, Fibronectin, Glutathione peroxidase 3, Lipopolysaccharide-binding protein) were found to be inter-connected in a protein–protein network. These proteins are involved in plasma lipoprotein assembly, remodeling, and clearance; lipid metabolism, especially cholesterol and phospholipids; hemostasis, including platelet degranulation; and immune system regulation. Additionally, 18 proteins were specific to a particular type of IUGR (early or late). Distinct patterns in the coagulation and fibrinolysis systems were observed between isolated early- and late-onset IUGR. Our findings highlight the complex interplay of immune and coagulation factors in IUGR and the differences between early- and late-onset IUGR and other placenta-related conditions like PE. Understanding these mechanisms is crucial for developing targeted interventions and improving outcomes for pregnancies affected by IUGR. Full article

Background: Ovarian cancer (OVCA) is the most fatal gynecological cancer with late diagnosis and plasma gelsolin (pGSN)-mediated chemoresistance representing the main obstacles to treatment success. Since there is no reliable approach to diagnosing patients at an early stage as well as predicting chemoresponsiveness, there is an urgent need to develop a diagnostic platform for such purposes. Small extracellular vesicles (sEVs) are attractive biomarkers given their potential accuracy for targeting tumor sites. Methods: We have developed a novel biosensor which utilizes cysteine-functionalized gold nanoparticles that simultaneously bind to cisplatin (CDDP) and plasma/cell-derived EVs, affording us the advantage of predicting OVCA chemoresponsiveness, and early diagnosis using surface-enhanced Raman spectroscopy. Results: We found that pGSN regulates cortactin (CTTN) content resulting in the formation of nuclear- and cytoplasmic-dense granules facilitating the secretion of sEVs carrying CDDP; a strategy used by resistant cells to survive CDDP action. The clinical utility of the biosensor was tested and subsequently revealed that the sEV/CA125 ratio outperformed CA125 and sEV individually in predicting early stage, chemoresistance, residual disease, tumor recurrence, and patient survival. Conclusion: These findings highlight pGSN as a potential therapeutic target and provide a potential diagnostic platform to detect OVCA earlier and predict chemoresistance; an intervention that will positively impact patient-survival outcomes. Full article

Blood-borne extracellular vesicles and inflammatory mediators were evaluated in divers using a closed circuit rebreathing apparatus and custom-mixed gases to diminish some diving risks. “Deep” divers (n = 8) dove once to mean (±SD) 102.5 ± 1.2 m of sea water (msw) for 167.3 ± 11.5 min. “Shallow” divers (n = 6) dove 3 times on day 1, and then repetitively over 7 days to 16.4 ± 3.7 msw, for 49.9 ± 11.9 min. There were statistically significant elevations of microparticles (MPs) in deep divers (day 1) and shallow divers at day 7 that expressed proteins specific to microglia, neutrophils, platelets, and endothelial cells, as well as thrombospondin (TSP)-1 and filamentous (F-) actin. Intra-MP IL-1β increased by 7.5-fold (p < 0.001) after day 1 and 41-fold (p = 0.003) at day 7. Intra-MP nitric oxide synthase-2 (NOS2) increased 17-fold (p < 0.001) after day 1 and 19-fold (p = 0.002) at day 7. Plasma gelsolin (pGSN) levels decreased by 73% (p < 0.001) in deep divers (day 1) and 37% in shallow divers by day 7. Plasma samples containing exosomes and other lipophilic particles increased from 186% to 490% among the divers but contained no IL-1β or NOS2. We conclude that diving triggers inflammatory events, even when controlling for hyperoxia, and many are not proportional to the depth of diving. Full article

A meta-analysis of the results of targeted quantitative screening of human blood plasma was performed to generate a reference standard kit that can be used for health analytics. The panel included 53 of the 296 proteins that form a “stable” part of the proteome of a healthy individual; these proteins were found in at least 70% of samples and were characterized by an interindividual coefficient of variation <40%. The concentration range of the selected proteins was 10⁻¹⁰–10⁻³ M and enrichment analysis revealed their association with rare familial diseases. The concentration of ceruloplasmin was reduced by approximately three orders of magnitude in patients with neurological disorders compared to healthy volunteers, and those of gelsolin isoform 1 and complement factor H were abruptly reduced in patients with lung adenocarcinoma. Absolute quantitative data of the individual proteome of a healthy and diseased individual can be used as the basis for personalized medicine and health monitoring. Storage over time allows us to identify individual biomarkers in the molecular landscape and prevent pathological conditions. Full article

Ovarian Cancer (OVCA) is the most fatal gynecologic cancer and has a 5-year survival rate less than 45%. This is mainly due to late diagnosis and drug resistance. Overexpression of plasma gelsolin (pGSN) is key contributing factor to OVCA chemoresistance and immunosuppression. Gelsolin (GSN) is a multifunctional protein that regulates the activity of actin filaments by cleavage, capping, and nucleation. Generally, it plays an important role in cytoskeletal remodeling. GSN has three isoforms: cytosolic GSN, plasma GSN (pGSN), and gelsolin-3. Exosomes containing pGSN are released and contribute to the progression of OVCA. This review describes how pGSN overexpression inhibits chemotherapy-induced apoptosis and triggers positive feedback loops of pGSN expression. It also describes the mechanisms by which exosomal pGSN promotes apoptosis and dysfunction in tumor-killing immune cells. A discussion on the potential of pGSN as a prognostic, diagnostic, and therapeutic marker is also presented herein. Full article

Nephrotoxicity is a major cause of intrinsic acute kidney injury (AKI). Because renal tissue damage may occur independently of a reduction in glomerular filtration rate and of elevations in plasma creatinine concentration, so-called injury biomarkers have been proposed to form part of diagnostic criteria as reflective of tubular damage independently of renal function status. We studied whether the urinary level of NGAL, KIM-1, GM2AP, t-gelsolin, and REGIIIb informed on the extent of tubular damage in rat models of nephrotoxicity, regardless of the etiology, moment of observation, and underlying pathophysiology. At a time of overt AKI, urinary biomarkers were measured by Western blot or ELISA, and tubular necrosis was scored from histological specimens stained with hematoxylin and eosin. Correlation and regression studies revealed that only weak relations existed between biomarkers and tubular damage. Due to high interindividual variability in the extent of damage for any given biomarker level, urinary injury biomarkers did not necessarily reflect the extent of the underlying tissue injury in individual rats. We contended, in this work, that further pathophysiological contextualization is necessary to understand the diagnostic significance of injury biomarkers before they can be used for renal tubular damage severity stratification in the context of nephrotoxic and, in general, intrinsic AKI. Full article

Ovarian cancer (OVCA) is the most lethal gynaecological cancer with a 5-year survival rate less than 50%. Despite new therapeutic strategies, such as immune checkpoint blockers (ICBs), tumor recurrence and drug resistance remain key obstacles in achieving long-term therapeutic success. Therefore, there is an urgent need to understand the cellular mechanisms of immune dysregulation in chemoresistant OVCA in order to harness the host’s immune system to improve survival. The over-expression of plasma gelsolin (pGSN) mRNA is associated with a poorer prognosis in OVCA patients; however, its immuno-modulatory role has not been elucidated. In this study, for the first time, we report pGSN as an inhibitor of M1 macrophage anti-tumor functions in OVCA chemoresistance. Increased epithelial pGSN expression was associated with the loss of chemoresponsiveness and poor survival. While patients with increased M1 macrophage infiltration exhibited better survival due to nitric-oxide-induced ROS accumulation in OVCA cells, cohorts with poor survival had a higher infiltration of M2 macrophages. Interestingly, increased epithelial pGSN expression was significantly associated with the reduced survival benefits of infiltrated M1 macrophages, through apoptosis via increased caspase-3 activation and reduced production of iNOS and TNFα. Additionally, epithelial pGSN expression was an independent prognostic marker in predicting progression-free survival. These findings support our hypothesis that pGSN is a modulator of inflammation and confers chemoresistance in OVCA, in part by resetting the relative abundance and function of macrophage subtypes in the ovarian tumor microenvironment. Our findings raise the possibility that pGSN may be a potential therapeutic target for immune-mediated chemoresistance in OVCA. Full article

Significant inter-individual variation in terms of susceptibility to several stress-related disorders, such as myocardial infarction and Alzheimer’s disease, and therapeutic response has been observed among healthy subjects. The molecular features responsible for this phenomenon have not been fully elucidated. Proteomics, in association with bioinformatics analysis, offer a comprehensive description of molecular phenotypes with clear links to human disease pathophysiology. The aim of this study was to conduct a comparative plasma proteomics analysis of glucocorticoid resistant and glucocorticoid sensitive healthy subjects and provide clues of the underlying physiological differences. For this purpose, 101 healthy volunteers were given a very low dose (0.25 mg) of dexamethasone at midnight, and were stratified into the 10% most glucocorticoid sensitive (S) (n = 11) and 10% most glucocorticoid resistant (R) (n = 11) according to the 08:00 h serum cortisol concentrations determined the following morning. One month following the very-low dose dexamethasone suppression test, DNA and plasma samples were collected from the 22 selected individuals. Sequencing analysis did not reveal any genetic defects in the human glucocorticoid receptor (NR3C1) gene. To investigate the proteomic profile of plasma samples, we used Liquid Chromatography–Mass Spectrometry (LC-MS/MS) and found 110 up-regulated and 66 down-regulated proteins in the S compared to the R group. The majority of the up-regulated proteins in the S group were implicated in platelet activation. To predict response to cortisol prior to administration, a random forest classifier was developed by using the proteomics data in order to distinguish S from R individuals. Apolipoprotein A4 (APOA4) and gelsolin (GSN) were the most important variables in the classification, and warrant further investigation. Our results indicate that a proteomics signature may differentiate the S from the R healthy subjects, and may be useful in clinical practice. In addition, it may provide clues of the underlying molecular mechanisms of the chronic stress-related diseases, including myocardial infarction and Alzheimer’s disease. Full article

Stromal interaction molecule 1 (STIM1) resides primarily in the sarco/endoplasmic reticulum, where it senses intraluminal Ca²⁺ levels and activates Orai channels on the plasma membrane to initiate Ca²⁺ influx. We have previously shown that STIM1 is involved in the dynamic remodeling of the actin cytoskeleton. However, the downstream effectors of STIM1 that lead to cytoskeletal remodeling are not known. The proximity-labeling technique (BioID) can capture weak and transient protein-protein interactions, including proteins that reside in the close vicinity of the bait, but that may not be direct binders. Hence, in the present study, we investigated the STIM1 interactome using the BioID technique. A promiscuous biotin ligase was fused to the cytoplasmic C-terminus of STIM1 and was stably expressed in a mouse embryonic fibroblast (MEF) cell line. Screening of biotinylated proteins identified several high confidence targets. Here, we report Gelsolin (GSN) as a new member of the STIM1 interactome. GSN is a Ca²⁺-dependent actin-severing protein that promotes actin filament assembly and disassembly. Results were validated using knockdown approaches and immunostaining. We tested our results in neonatal cardiomyocytes where STIM1 overexpression induced altered actin dynamics and cytoskeletal instability. This is the first time that BioID assay was used to investigate the STIM1 interactome. Our work highlights the role of STIM1/GSN in the structure and function of the cytoskeleton. Full article

Bariatric surgery restores glucose tolerance in many, but not all, severely obese subjects with type 2 diabetes (T2D). We aimed to evaluate the plasma protein profiles associated with the T2D remission after obesity surgery. We recruited seventeen women with severe obesity submitted to bariatric procedures, including six non-diabetic patients and eleven patients with T2D. After surgery, diabetes remitted in 7 of the 11 patients with T2D. Plasma protein profiles at baseline and 6 months after bariatric surgery were analyzed by two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight coupled to mass spectrometry (MALDI-TOF/TOF MS). Remission of T2D following bariatric procedures was associated with changes in alpha-1-antichymotrypsin (SERPINA 3, p < 0.05), alpha-2-macroglobulin (A2M, p < 0.005), ceruloplasmin (CP, p < 0.05), fibrinogen beta chain (FBG, p < 0.05), fibrinogen gamma chain (FGG, p < 0.05), gelsolin (GSN, p < 0.05), prothrombin (F2, p < 0.05), and serum amyloid p-component (APCS, p < 0.05). The resolution of diabetes after bariatric surgery is associated with specific changes in the plasma proteomic profiles of proteins involved in acute-phase response, fibrinolysis, platelet degranulation, and blood coagulation, providing a pathophysiological basis for the study of their potential use as biomarkers of the surgical remission of T2D in a larger series of severely obese patients. Full article

A high level of uric acid may cause hyperuricemia, which further develops into gout, eventually leading to chronic kidney disease. However, the pathogenic mechanism remains largely unknown. To investigate the cause and block the transformation of hyperuricemia to related diseases, it is important to discover the alterations in protein levels between gout patients and non-gout individuals. To date, human blood plasma is still the predominant matrices for clinical analysis. Due to the high abundance, the proteins of plasma samples have strong shielding effects on low abundance proteins, thus, the information on low abundance protein expression is always masked, while the low abundance proteins of human plasma are often of great significance for the diagnosis and treatment of diseases. Therefore, it is very important to separate and analyze the plasma proteins. High-performance liquid chromatography (LC) tandem mass spectrometry (MS)-based proteomics has been developed as a powerful tool to investigate changes in the human plasma proteome. Here, we used LC-MS/MS to detect the differential proteins in the plasmas from simple gout patients, gout with kidney damage patients, and non-gout individuals. We identified 32 obviously differential proteins between non-gout and gout subjects and 10 differential proteins between simple gout and gout with kidney damage patients. These differential proteins were further analyzed to characterize their localization and functions. Additionally, the correlation analysis showed multiple relationships between the abnormal plasma proteins and clinical biochemical indexes, particularly for the immune-inflammatory response proteins. Furthermore, inflammation factors gelsolin (GSN) were confirmed. Our results offer a view of plasma proteins for studying biomarkers of gout patients. Full article