Plasma Gelsolin Research Articles

Recombinant Human Plasma Gelsolin Stimulates Phagocytosis while Diminishing Excessive Inflammatory Responses in Mice with Pseudomonas aeruginosa Sepsis.

Plasma gelsolin (pGSN) is a highly conserved abundant circulating protein, characterized by diverse immunomodulatory activities including macrophage activation and the ability to neutralize pro-inflammatory molecules produced by the host and pathogen. Using a murine model of Gram-negative sepsis initiated by the peritoneal instillation of Pseudomonas aeruginosa Xen 5, we observed a decrease in the tissue uptake of IRDye®800CW 2-deoxyglucose, an indicator of inflammation, and a decrease in bacterial growth from ascitic fluid in mice treated with intravenous recombinant human plasma gelsolin (pGSN) compared to the control vehicle. Pretreatment of the murine macrophage line RAW264.7 with pGSN, followed by addition of Pseudomonas aeruginosa Xen 5, resulted in a dose-dependent increase in the proportion of macrophages with internalized bacteria. This increased uptake was less pronounced when cells were pretreated with pGSN and then centrifuged to remove unbound pGSN before addition of bacteria to macrophages. These observations suggest that recombinant plasma gelsolin can modulate the inflammatory response while at the same time augmenting host antibacterial activity.

Delayed administration of recombinant plasma gelsolin improves survival in a murine model of severe influenza.

Background: Host-derived inflammatory responses contribute to the morbidity and mortality of severe influenza, suggesting that immunomodulatory therapy may improve outcomes. The normally circulating protein, human plasma gelsolin, is available in recombinant form (rhu-pGSN) and has beneficial effects in a variety of pre-clinical models of inflammation and injury. Methods: We evaluated delayed therapy with subcutaneous rhu-pGSN initiated 3 to 6 days after intra-nasal viral challenge in a mouse model of influenza A/PR/8/34. Results: Rhu-pGSN administered starting on day 3 or day 6 increased survival (12-day survival: 62 % vs 39 %, pGSN vs vehicle; p < 0.00001, summary of 18 trials), reduced morbidity, and decreased pro-inflammatory gene expression. Conclusions: Rhu-pGSN improves outcomes in a highly lethal influenza model when given after a clinically relevant delay.

Delayed administration of recombinant plasma gelsolin improves survival in a murine model of severe influenza

Background: Host-derived inflammatory responses contribute to the morbidity and mortality of severe influenza, suggesting that immunomodulatory therapy may improve outcomes. The normally circulating protein, human plasma gelsolin, is available in recombinant form (rhu-pGSN) and has beneficial effects in a variety of pre-clinical models of inflammation and injury. Methods: We evaluated delayed therapy with subcutaneous rhu-pGSN initiated 3 to 6 days after intra-nasal viral challenge in a mouse model of influenza A/PR/8/34. Results: Rhu-pGSN administered starting on day 3 or day 6 increased survival (12-day survival: 62 % vs 39 %, pGSN vs vehicle; p < 0.00001, summary of 18 trials), reduced morbidity, and decreased pro-inflammatory gene expression. Conclusions: Rhu-pGSN improves outcomes in a highly lethal influenza model when given after a clinically relevant delay.

Antioxidant and Wound Healing Property of Gelsolin in 3T3-L1 Cells.

Delineation of factors which affect wound healing would be of immense value to enable on-time or early healing and reduce comorbidities associated with infections or biochemical stress like diabetes. Plasma gelsolin has been identified earlier to significantly enable injury recovery compared to placebo. This study evaluates the role of rhuGSN for its antioxidant and wound healing properties in murine fibroblasts (3T3-L1 cell line). Total antioxidant capacity of rhuGSN increased in a concentration-dependent manner (0.75-200 μg/mL). Cells pretreated with 0.375 and 0.75 μg/mL rhuGSN for 24 h exhibited a significant increase in viability in a MTT assay. Preincubation of cells with rhuGSN for 24 h followed by oxidative stress induced by exposure to H2O2 for 3 h showed cytoprotective effect. rhuGSN at 12.5 and 25 μg/mL concentration showed an enhanced cell migration after 20 h of injury in a scratch wound healing assay. The proinflammatory cytokine IL-6 levels were elevated in the culture supernatant. These results establish an effective role of rhuGSN against oxidative stress induced by H2O2 and in wound healing of 3T3-L1 fibroblast cells.

Plasma Gelsolin Level as a diagnostic Biomarker in Early Onset Neonatal Sepsis at Zagazig University Hospitals

Plasma Gelsolin Level as a diagnostic Biomarker in Early Onset Neonatal Sepsis at Zagazig University Hospitals

Plasma gelsolin levels in patients with psoriatic arthritis: a possible novel marker.

Psoriatic arthritis (PsA) is an inflammatory disorder affecting the joints of psoriatic patients. Gelsolin regulated the actin assembly and disassembly. Reduction in plasma gelsolin levels was detected in tissue damages, including trauma, sepsis, and chronic inflammatory disorders. The study aims to investigate the potential role of gelsolin in PsA and to determine the association between gelsolin and the disease activity. Plasma gelsolin levels were measured in 76 PsA patients in comparison with 40 patients having psoriasis only and 40 age- and sex -matched healthy controls. Plasma gelsolin levels were decreased in PsA patients compared to controls and psoriasis-only patients (p˂0.0001). The optimal cutoff point of gelsolin was 172.5mg/L. Gelsolin showed 92.1% sensitivity and 95% specificity in detecting PsA. But, it had 92.1% sensitivity and 80% specificity in differentiating between psoriasis and PsA. Plasma gelsolin showed a significant negative correlation with inflammatory markers as C-reactive protein and erythrocyte sedimentation rate (p < 0.0001 and p = 0.039; respectively). A significant negative correlation between plasma gelsolin and PsA activity was detected (p < 0.0001). The PsA activity was defined by the Disease Activity for Psoriatic Arthritis Score and the Composite Psoriatic Disease Activity Index. The plasma gelsolin levels were decreased in PsA patients, suggesting that gelsolin may be implicated in the chronic joint inflammation process. Plasma gelsolin seems to be a useful predictive biomarker for diagnosing PsA and monitoring the disease activity.Key Points• This study introduces an unprecedented focus within which the relationship between the levels of plasma gelsolin and PsA is investigated• The study examines the potential role of gelsolin in PsA, and detects the association between gelsolin and the arthritis activity.• There were decreased plasma gelsolin levels in PsA patients. So, gelsolin can constitute a role in the chronic joint inflammation process.• Gelsolin may be a useful biomarker for diagnosing of PsA and monitoring the disease activity.

Research on the Correlation of Serum PCT and Plasma GSN Levels with the Prognosis of Urosepsis Patients.

Objective:To explore the correlation of procalcitonin (PCT) and gelsolin (GSN) with the prognosis of urosepsis patients.Method:The data of 71 urosepsis patients from March 2015 to April 2019 who were admitted to and treated in Affiliated Hospital of Hebei University were analyzed and compared with those of 92 healthy persons. Serum PCT and plasma GSN levels at different times after treatment were detected. According to prognosis, patients were classified into the good prognosis group or the poor prognosis group. The serum PCT and plasma GSN levels of both groups were compared.Result:The serum PCT level of the urosepsis group on the 1st, 3rd, 5th and 7th days was obviously higher than that of the control group (P<0.05). The plasma GSN levels of the urosepsis group on the 1st, 3rd, 5th and 7th days were obviously lower than those of the control group (P<0.05). The serum PCT level of the poor prognosis group on the 1st, 3rd, 5th and 7th days was obviously higher than that of the good prognosis group (P<0.05). The plasma GSN level of the poor prognosis group on the 1st, 3rd, 5th and 7th days was obviously lower than that of the good prognosis group (P<0.05). PCT was an independent risk factor influencing the prognosis of urosepsis patients and that GSN was a protective factor (P<0.05).Conclusion:The serum PCT and plasma GSN levels can accurately predict the severity and prognosis of urosepsis patients and reflect the disease state of early urosepsis patients. High PCT levels and low GSN levels indicate poor prognosis, and clinicians should consider these values.

Evaluation of Plasma Gelsolin Level as a Diagnostic Biomarker in Pediatric Pneumonia

Evaluation of Plasma Gelsolin Level as a Diagnostic Biomarker in Pediatric Pneumonia

Matrine alleviates astrogliosis through sphingosine 1-phosphate signaling in experimental autoimmune encephalomyelitis

Expression of sphingosine/sphingosine 1-phosphate (SPH/S1P) in resident cells of the central nervous system plays an important role in the pathogenesis of multiple sclerosis (MS). Accumulated evidence has shown the protective effects of S1P receptor modulators on MS and its animal model, experimental autoimmune encephalomyelitis (EAE). However, effective therapies to regulate SPH/S1P molecules themselves have not been well addressed. Our previous studies showed that matrine (MAT), a natural alkaloid component extracted from the Sophora root, has beneficial effects in EAE through immunomodulation. Here we demonstrate that MAT alleviated astrogliosis in the CNS of EAE rats, and downregulated levels of SPH, S1P and S1P1 expression in CNS tissues and astrocytes. Expression of SPH kinases (SPHK) 1 and 2, which splice SPH into S1P, was also inhibited by MAT treatment. In vitro studies showed a direct inhibitory effect of MAT on S1P1 expression of activated astrocytes, suggesting that MAT could function as an S1PRs antagonist. Moreover, MAT upregulated the expression of plasma gelsolin, which combines with S1P to reduce its concentration. These findings indicate that MAT could alleviate astrogliosis in EAE through diminishing the SPH/SPHK/S1P1 pathway.

The exosome-mediated autocrine and paracrine actions of plasma gelsolin in ovarian cancer chemoresistance

Ovarian cancer (OVCA) is the most lethal gynecological cancer, due predominantly to late presentation, high recurrence rate and common chemoresistance development. The expression of the actin-associated protein cytosolic gelsolin (GSN) regulates the gynecological cancer cell fate resulting in dysregulation in chemosensitivity. In this study, we report that elevated expression of plasma gelsolin (pGSN), a secreted isoform of GSN and expressed from the same GSN gene, correlates with poorer overall survival and relapse-free survival in patients with OVCA. In addition, it is highly expressed and secreted in chemoresistant OVCA cells than its chemosensitive counterparts. pGSN, secreted and transported via exosomes (Ex-pGSN), upregulates HIF1α–mediated pGSN expression in chemoresistant OVCA cells in an autocrine manner as well as confers cisplatin resistance in otherwise chemosensitive OVCA cells. These findings support our hypothesis that exosomal pGSN promotes OVCA cell survival through both autocrine and paracrine mechanisms that transform chemosensitive cells to resistant counterparts. Specifically, pGSN transported via exosomes is a determinant of chemoresistance in OVCA.

Delayed administration of recombinant plasma gelsolin improves survival in a murine model of severe influenza.

Background: Host-derived inflammatory responses contribute to the morbidity and mortality of severe influenza, suggesting that immunomodulatory therapy may improve outcomes. The normally circulating protein, human plasma gelsolin, is available in recombinant form (rhu-pGSN) and has beneficial effects in a variety of pre-clinical models of inflammation and injury. Methods: We evaluated delayed therapy with subcutaneous rhu-pGSN initiated 3 to 6 days after intra-nasal viral challenge in a mouse model of influenza A/PR/8/34. Results: Rhu-pGSN administered starting on day 3 or day 6 increased survival (12-day survival: 62 % vs 39 %, pGSN vs vehicle; p < 0.00001, summary of 18 trials), reduced morbidity, and decreased pro-inflammatory gene expression. Conclusions: Rhu-pGSN improves outcomes in a highly lethal influenza model when given after a clinically relevant delay.

Pre-operative Circulating Plasma Gelsolin Predicts Residual Disease and Detects Early Stage Ovarian Cancer

Ovarian cancer (OVCA) patients with suboptimal residual disease (RD) and advanced stages have poor survival. pGSN is an actin binding protein which protects OVCA cells from cisplatin-induced death. There is an urgent need to discover reliable biomarkers to optimize individualized treatment recommendations. 99 plasma samples with pre-determined CA125 were collected from OVCA patients and pGSN assayed using sandwich-based ELISA. Associations between CA125, pGSN and clinicopathological parameters were examined using Fisher’s exact test, T test and Kruskal Wallis Test. Univariate and multivariate Cox proportional hazard models were used to statistically analyze clinical outcomes. At 64 µg/ml, pGSN had sensitivity and specificity of 60% and 60% respectively, for the prediction of RD where as that of CA125 at 576.5 U/mL was 43.5% and 56.5% respectively. Patients with stage 1 tumor had increased levels of pre-operative pGSN compared to those with tumor stage >1 and healthy subjects (P = 0.005). At the value of 81 µg/mL, pGSN had a sensitivity and specificity of 75% and 78.4%, respectively for the detection of early stage OVCA. At the value of 0.133, the Indicator of Stage 1 OVCA (ISO1) provided a sensitivity of 100% at a specificity of 67% (AUC, 0.89; P < 0.001). In the multivariate Cox regression analysis, pGSN (HR, 2.00; CI, 0.99–4.05; P = 0.05) was an independent significant predictor of progression free survival (PFS) but not CA125 (HR, 0.68; CI, 0.41–1.13; P = 0.13). Pre-operative circulating pGSN is a favorable and independent biomarker for early disease detection, RD prediction and patients’ prognosis.

Gelsolin: a new biomarker of disease activity in SLE patients associated with HDL-c.

To identify potential biomarkers of disease activity analysing the proteome of high-density lipoprotein (HDL) particles from SLE patients in clinical remission and when they develop a flare compared with a healthy control group. Quantitative proteomic analyses of purified HDL were performed using Tandem Mass Tag isobaric tag-labelling and nanoLC-Orbitrap (nLC-MS/MS) from nine SLE patients in clinical remission when they developed a flare and from nine healthy controls (9-9-9). We verified the identified proteins by Western blot and ELISA in a cohort of 104 SLE women patients, 46 healthy women and 14 SLE patients when a flare developed. We found 17 proteins with a significant fold-change (>1.1) compared with the control group. In lupus patients experiencing a flare compared with those in remission, we identified four proteins with a significant fold-change (C4, Indian Hedgehog protein, S100A8 and gelsolin). Plasma gelsolin (pGSN) levels were decreased in the 104 SLE patients (176.02(74.9) mcg/l) compared with the control group (217.13(86.7) mcg/l); P=0.005 and when they developed a clinical flare (104.84(41.7) mcg/l); P=0.002). pGSN levels were associated with HDL cholesterol levels (r = 0.316, P<0.001). Antimalarial treated patients showed significant higher levels of pGSN (214.56(88.94) mcg/l regarding 170.35(66.36) mcg/l); P = 0.017. Decreased pGSN are associated with clinical disease activity in SLE patients. Antimalarial treatment and HDL cholesterol are associated with higher levels of pGSN.

Acute Lung Injury in Critically Ill Patients: Actin-Scavenger Gelsolin Signals Prolonged Respiratory Failure.

ABSTRACTBackground:Gelsolin is an actin-scavenger controlling the tissue damage from actin in the blood. Gelsolin levels in circulation drops when tissue damage and corresponding actin release is pronounced due to catabolic conditions. The purpose of this study was to determine if low plasma gelsolin independently predicts a reduced chance of weaning from ventilator-demanding respiratory failure in critically ill patients within 28 days from admission.Results:This cohort study included 746 critically ill patients with ventilator-demanding respiratory failure from the randomized clinical trial, “Procalcitonin And Survival Study (PASS).” Primary end point was successful weaning from mechanical ventilation within 28 days. We used multivariable Cox regression adjusted for age, sepsis, PaO2/FiO2 ratio and other known and suspected predictors of persistent respiratory failure. Follow-up was complete.For medical patients, baseline-gelsolin below the 25th percentile independently predicted a 40% lower chance of successful weaning within 28 days (HR 0.60, 95% CI 0.46–0.79, P = 0.0002); among surgical patients this end point was not predicted. Low gelsolin levels predicted chance of being “alive and out of intensive care at day 14” for both medical and surgical patients (HR 0.69, 95% CI 0.54–0.89, P = 0.004). Gelsolin levels did not predict 28 day mortality for surgical or medical patients.Conclusions:Low levels of serum gelsolin independently predict a decreased chance of successful weaning from ventilator within 28 days among medical intensive care patients. This finding has implications for identifying patients who need individualized intervention early in intensive care course to prevent unfavorable lung prognosis in acute respiratory failure.Trial registration:This is a substudy to the PASS, Clinicaltrials.gov ID: NCT00271752, first registered January 1, 2006.

Delayed Administration of Recombinant Plasma Gelsolin Improves Survival in a Murine Model of Penicillin-Susceptible and Penicillin-Resistant Pneumococcal Pneumonia.

Therapy to enhance host immune defenses may improve outcomes in serious infections, especially for antibiotic-resistant pathogens. Recombinant human plasma gelsolin (rhu-pGSN), a normally circulating protein, has beneficial effects in diverse preclinical models of inflammation and injury. We evaluated delayed therapy (24-48 hours after challenge) with rhu-pGSN in a mouse model of pneumococcal pneumonia. rhu-pGSN without antibiotics increased survival and reduced morbidity and weight loss after infection with either penicillin-susceptible or penicillin-resistant pneumococci (serotypes 3 and 14, respectively). rhu-pGSN improves outcomes in a highly lethal pneumococcal pneumonia model when given after a clinically relevant delay, even in the setting of antimicrobial resistance.

Protective effects of gelsolin in acute pulmonary thromboembolism and thrombosis in the carotid artery of mice.

The present study provides first evidence on the role of plasma gelsolin in protecting pulmonary thromboembolism and thrombosis in a mouse model. Gelsolin is the most abundant actin depolymerizing protein in plasma and its significantly depleted values have been reported in metabolic disorders including cardiovascular diseases and myocardial infarction. Though gelsolin replacement therapy (GRT) has been shown to be effective in some animal models, no such study has been reported for thrombotic diseases that are acutely in need of bio-therapeutics for immediate and lasting relief. Here, using mice model and recombinant human gelsolin (rhuGSN), we demonstrate the antithrombotic effect of gelsolin in ferric chloride induced thrombosis in carotid artery and thrombin induced acute pulmonary thromboembolism. In thrombosis model, arterial occlusion time was significantly enhanced upon subcutaneous (SC) treatment with 8 mg of gelsolin per mice viz. 15.83 minutes vs. 8 minutes in the placebo group. Pertinently, histopathological examination showed channel formation within the thrombi in the carotid artery following injection of gelsolin. Fluorescence molecular tomography imaging further confirmed that administration of gelsolin reduced thrombus formation following carotid artery injury. In thrombin-induced acute pulmonary thromboembolism, mice pretreated with aspirin or gelsolin showed 100 and 83.33% recovery, respectively. In contrast, complete mortality of mice was observed in vehicle treated group within 5 minutes of thrombin injection. Overall, our studies provide conclusive evidence on the thrombo-protective role of plasma gelsolin in mice model of pulmonary thromboembolism and thrombosis.

Hypogelsolinemia in Patients Diagnosed with Acute Myeloid Leukemia at Initial Stage of Sepsis.

BackgroundGelsolin (GSN) is an actin-binding and PIP2/Ca2+-regulated protein found in the cytoplasm and blood plasma. Hypogelsolinemia occurs in a wide range of traumatic injuries and inflammatory reactions. We hypothesize that blood GSN levels will be altered in patients diagnosed with acute myeloid leukemia (AML) that develop sepsis, and assessment of GSN concentration will be a useful marker to determine their clinical outcome. To achieve this task, we evaluated the plasma gelsolin concentration in blood samples collected from patients diagnosed with acute myeloid leukemia (AML) at initial stages of sepsis.Material/MethodsTo assess if AML patients might be at risk of sepsis, a SOFA score was determined. Plasma gelsolin concentration was evaluated using an immunoblotting technique.ResultsWe found that GSN concentration in the blood of the AML group with developing sepsis was significantly lower (32±41 μg/ml; p<0.05) compared to the AML group (65±35 μg/ml) and control group (176±37 μg/ml; p<0.001). Additionally, low gelsolin concentration in the blood of AML patients developing sepsis was associated with a high SOFA score. A decrease of GSN concentration in the blood of AML subjects with developing sepsis suggests that GSN level in blood reflects not only chronic inflammation stage associated with leukemia, but that GSN depletion also manifests the inflammation associated with sepsis development.ConclusionsThe results presented here suggest the possible utility of GSN evaluation for diagnostic purposes. Overall, these data support the that reversing plasma GSN deficiency might be a possible new strategy in sepsis treatment.

Inhibition of inflammatory response in human keratinocytes by magnetic nanoparticles functionalized with PBP10 peptide derived from the PIP2-binding site of human plasma gelsolin

BackgroundHuman plasma gelsolin (pGSN) is a multifunctional actin-binding protein involved in a variety of biological processes, including neutralization of pro-inflammatory molecules such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA) and modulation of host inflammatory response. It was found that PBP10, a synthetic rhodamine B-conjugated peptide, based on the phosphoinositide-binding site of pGSN, exerts bactericidal activity against Gram-positive and Gram-negative bacteria, interacts specifically with LPS and LTA, and limits microbial-induced inflammatory effects. The therapeutic efficiency of PBP10 when immobilized on the surface of iron oxide-based magnetic nanoparticles was not evaluated, to date.ResultsUsing the human keratinocyte cell line HaCaT stimulated by bacterially-derived LPS and LTA as an in vitro model of bacterial infection, we examined the anti-inflammatory effects of nanosystems consisting of iron oxide-based magnetic nanoparticles with aminosilane (MNP@NH2) or gold shells (MNP@Au) functionalized by a set of peptides, derived from the phosphatidylinositol 4,5-bisphosphate (PIP2)-binding site of the human plasma protein gelsolin, which also binds LPS and LTA. Our results indicate that these nanosystems can kill both Gram-positive and Gram-negative bacteria and limit the production of inflammatory mediators, including nitric oxide (NO), reactive oxygen species (ROS), and interleukin-8 (IL-8) in the response to heat-killed microbes or extracted bacterial cell wall components. The nanoparticles possess the potential to improve therapeutic efficacy and are characterized by lower toxicity and improved hemocompatibility when compared to free peptides. Atomic force microscopy (AFM) showed that these PBP10-based nanosystems prevented changes in nanomechanical properties of cells that were otherwise stimulated by LPS.ConclusionsNeutralization of endotoxemia-mediated cellular effects by gelsolin-derived peptides and PBP10-containing nanosystems might be considered as potent therapeutic agents in the improved therapy of bacterial infections and microbial-induced inflammation.

Nanobody interaction unveils structure, dynamics and proteotoxicity of the Finnish-type amyloidogenic gelsolin variant

AGel amyloidosis, formerly known as familial amyloidosis of the Finnish-type, is caused by pathological aggregation of proteolytic fragments of plasma gelsolin. So far, four mutations in the gelsolin gene have been reported as responsible for the disease. Although D187N is the first identified variant and the best characterized, its structure has been hitherto elusive. Exploiting a recently-developed nanobody targeting gelsolin, we were able to stabilize the G2 domain of the D187N protein and obtained, for the first time, its high-resolution crystal structure. In the nanobody-stabilized conformation, the main effect of the D187N substitution is the impairment of the calcium binding capability, leading to a destabilization of the C-terminal tail of G2. However, molecular dynamics simulations show that in the absence of the nanobody, D187N-mutated G2 further misfolds, ultimately exposing its hydrophobic core and the furin cleavage site. The nanobody's protective effect is based on the enhancement of the thermodynamic stability of different G2 mutants (D187N, G167R and N184K). In particular, the nanobody reduces the flexibility of dynamic stretches, and most notably decreases the conformational entropy of the C-terminal tail, otherwise stabilized by the presence of the Ca2+ ion. A Caenorhabditis elegans-based assay was also applied to quantify the proteotoxic potential of the mutants and determine whether nanobody stabilization translates into a biologically relevant effect. Successful protection from G2 toxicity in vivo points to the use of C. elegans as a tool for investigating the mechanisms underlying AGel amyloidosis and rapidly screen new therapeutics.

The use of atomic force microscopy to assess anti-inflammatory activity of magnetic nanosystems contatining PIP2-binding domain of plasma gelsolin

The use of atomic force microscopy to assess anti-inflammatory activity of magnetic nanosystems contatining PIP2-binding domain of plasma gelsolin