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PubMed1995

Cell swelling and depolarization in hemorrhagic shock.

Although an increase in intracellular water volume (IWV) in hemorrhagic shock has been inferred from measured changes in transmembrane potential, it has not been measured directly. We have described the presence of a circulating protein that appears in hemorrhagic shock [circulating shock protein (CSP) 70] that depolarizes numerous cell types. To determine if this substance produced a concurrent increase in intracellular water, cells were incubated with CSP 70. Then we measured IWV as the difference between the 3H water space and the [14C]mannitol space. CSP 70 increased IWV 9% in rat red blood cells (RBCs) (n = 8, p < 0.05), 22% in rat H9c2 cells (n = 7, p < 0.05), 11% in dog RBCs (n = 10, p < 0.005), and 31% in dog white blood cells (n = 8, p < 0.005). The results indicate that a protein that circulates in hemorrhagic shock depolarizes cells and increases intracellular water. This suggests that the changes in transmembrane potential observed in hemorrhagic shock are accompanied by movement of extracellular fluid into cells and may account for the inability to restore blood volume after large hemorrhage.

Animals↗
PubMed1988

Polycythemia and hydration: effects on thermoregulation and blood volume during exercise-heat stress.

We studied the effects of autologous erythrocyte infusion on thermoregulation and blood volume during exercise in the heat. Specifically, we wanted to determine whether heat-acclimated subjects, as well as hypohydrated subjects, would have a thermoregulatory advantage from acute polycythemia during exercise in the heat. Five heat-acclimated males attempted four heat stress tests (HSTs): two pre- and two postinfusion. Autologous erythrocyte infusion was accomplished with 500 ml of a NaCl-glucose-phosphate solution containing approximately 60% hematocrit. One HST, both pre- and postinfusion, was done while subjects were euhydrated, and one HST was done while subjects were hypohydrated (-5% of body wt). After 30 min of rest in a 20 degrees C antechamber, the HST consisted of a 120-min exposure (2 repeats of 15 min rest and 45 min walking) in a hot (35 degrees C, 45% relative humidity) environment. The findings concerning acute polycythemia in heat-acclimated subjects are summarized: 1) polycythemia increased (P less than 0.05) sweating rate and reduced (P less than 0.01) core temperature during exercise-heat stress for both euhydrated and hypohydrated subjects; 2) the erythrocyte infusion caused an increased (P less than 0.05) plasma volume and increased (P less than 0.01) blood volume; 3) the increased plasma volume was associated with an increased (P less than 0.05) total circulating protein mass; 4) the increased total circulating protein mass tended to better maintain plasma volume when hypohydrated; and 5) heat acclimation may increase extravascular protein mass. Therefore, it is concluded that erythrocyte infusion provides a thermoregulatory advantage during exercise in the heat for heat acclimated subjects when both euhydrated and hypohydrated.

Acclimatization↗
PubMed2005

CD36 is not involved in scavenger receptor-mediated endocytic uptake of glycolaldehyde- and methylglyoxal-modified proteins by liver endothelial cells.

Circulating proteins modified by advanced glycation end-products (AGE) are mainly taken up by liver endothelial cells (LECs) via scavenger receptor-mediated endocytosis. Endocytic uptake of chemically modified proteins by macrophages and macrophage-derived cells is mediated by class A scavenger receptor (SR-A) and CD36. In a previous study using SR-A knockout mice, we demonstrated that SR-A is not involved in endocytic uptake of AGE proteins by LECs [Matsumoto et al. (2000) Biochem. J. 352, 233-240]. The present study was conducted to determine the contribution of CD36 to this process. Glycolaldehyde-modified BSA (GA-BSA) and methylglyoxal-modified BSA (MG-BSA) were used as AGE proteins. 125I-GA-BSA and 125I-MG-BSA underwent endocytic degradation by these cells at 37 degrees C, and this process was inhibited by several ligands for the scavenger receptors. However, this endocytic uptake of 125I-GA-BSA by LECs was not inhibited by a neutralizing anti-CD36 antibody. Similarly, hepatic uptake of (111)In-GA-BSA after its intravenous injection was not significantly attenuated by co-administration of the anti-CD36 antibody. These results clarify that CD36 does not play a significant role in elimination of GA-BSA and MG-BSA from the circulation, suggesting that the receptor involved in endocytic uptake of circulating AGE proteins by LEC is not SR-A or CD36.

Acetaldehyde↗
PubMed2002

Profile of monocyte chemoattractant protein-1 circulating levels in gastric cancer patients.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) has been shown to act as a chemokine in the recruitment of monocyte/macrophages during inflammation states. It acts as an important factor in the cytokine network, which regulates tumor proliferation, whereas the association between serum MCP-1 level and gastric cancer has not yet been clarified. METHODS: The serum concentration of MCP-1 in 76 gastric cancer patients and in 45 normal controls was determined using an immunoradiometric assay. The concentration of MCP-1 in the 47 cancer tissue samples was also determined. RESULTS: The serum concentration of MCP-1 in patients with advanced carcinoma was significantly lower than that in controls. The serum concentration of MCP-1 in patients with advanced carcinoma was significantly lower than that in patients with early carcinoma. The serum concentration of MCP-1 was associated with clinicopathological factors including lymph node metastasis, serosal invasion and histological differentiation of the tumor. In patients who underwent palliative surgery, the serum MCP-1 level significantly decreased postoperatively, whereas in patients who underwent curative surgery the serum MCP-1 level tended to increase. The 4-year survival rate in patients whose serum MCP-1 levels were lower than or equal to the median value was significantly lower than that in patients whose MCP-1 levels were higher than the median value. The tissue concentration of MCP-1 in the cancer tended to decrease in accordance with disease progression. CONCLUSIONS: The serum level of MCP-1 decreased in accord with disease progression, which reflects local consumption in gastric cancer. Serum MCP-1 may be a useful marker that reflects the host's local resistance to the tumor.

Adult↗
PubMed2006

Tissue and circulating immunoreactive protein for MMP-2 and TIMP-2 in head and neck squamous cell carcinoma--tissue immunoreactivity predicts aggressive clinical course.

Useful markers showing biological aggressiveness of head and neck squamous cell carcinoma (HNSCC) are needed to predict the outcome of the disease. MMP-2 is associated with aggressive behavior of several solid cancers. In this study, the clinical significance of tumor tissue and circulating immunoreactive proteins for MMP-2 and TIMP-2 was assessed in HNSCC. The study group consisted of 74 patients with HNSCC and 44 healthy controls. Expression of MMP-2 and TIMP-2 was examined in paraffin-embedded tumor sections by immunohistochemical methods using specific antibodies. The pretreatment serum levels of MMP-2, TIMP-2 and MMP-2:TIMP-2 complex were quantitatively measured by ELISA assay. The results were compared with the clinicopathological factors of the disease and the patients' outcome. Immunohistochemical overexpression of MMP-2 in tumor was found to be prognostic for shortened survival in HNSCC, the 5-year cumulative relapse-free survival being 42% in patients with high positivity for MMP-2 in tumor vs 61% in cases with a negative or only weakly MMP-2-positive tumor (P=0.045). Tissue MMP-2 positivity was also strongly connected with later lymph node or hematogenic relapses and associated to the cause-specific survival (P=0.055). Similarly, the 5-year cause-specific survival was significantly poorer in patients with extensive positive immunostaining for tumor TIMP-2 than in those with a TIMP-2-negative tumor (40 vs 64%, P=0.038). Patients with a TIMP-2-positive tumor also had an unfavorable 5-year relapse-free survival rate (43 vs 60%, respectively, P=0.071). Additionally, the overexpression of TIMP-2 was a powerful predictor of later lymph node or hematogenous metastases in HNSCC. Serum levels of MMP-2, TIMP-2 or MMP-2:TIMP-2 complex failed to associate with the clinical behavior of HNSCC in this material. The results of this study provide evidence that MMP-2 and TIMP-2 immunoreactive protein in tumor tissue of HNSCC patients, but not when assayed from preoperative serum samples, are prognostic in estimation of the aggressive clinical course of HNSCC.

Adult↗
PubMed1998

Expression of adhesion molecules and G proteins in circulating neutrophils in chronic obstructive pulmonary disease.

We investigated the expression of adhesion molecules in circulating neutrophils (lymphocyte function-associated antigen-1 [LFA-1], Mac-1, and L-selectin) and endothelial cells (soluble intercellular adhesion molecule-1[sICAM-1]) in 23 patients with stable chronic obstructive pulmonary disease (COPD), 18 subjects with exacerbated COPD, and 23 healthy volunteers. Also, in these circulating neutrophils, we assessed the expression of two G protein subunits (Galphas and Galphai1/2). Compared with control subjects, patients with stable COPD showed increased expression of Mac-1 (p < 0.001) and lower levels of sICAM-1 (p = 0.002); LFA-1 and L-selectin expression was similar in patients and control subjects. During exacerbations, compared with stable patients, the expression of Mac-1 and LFA-1 was reduced (p < 0.001). Finally, the expression of Galphas (but not Galphai1/2) was also reduced (p < 0.001) in circulating neutrophils of patients with COPD, irrespective of the clinical condition of the patient. These results indicate that in patients with COPD: (1) the expression of some neutrophil adhesion molecules (Mac-1) is abnormal, and that this pattern changes during exacerbations; (2) there may be a form of endothelial dysfunction, as suggested by the low sICAM-1 levels; (3) the expression of G protein subunit (Galphas) in circulating neutrophils is downregulated, irrespective of their clinical conditions. Overall, these results indicate the presence of significant systemic abnormalities in COPD.

Analysis of Variance↗
PubMed2006

Plasmid-mediated muscle-targeted gene therapy for circulating therapeutic protein replacement: a tale of the tortoise and the hare?

There is now conclusive evidence that gene therapy can lead to real clinical benefit. Initial enthusiasm has been muted by set-backs related to viral vectors including retroviral oncogenesis and adenoviral inflammatory response. Plasmid-mediated muscle-targeted gene transfer offers the potential of a cost-effective pharmaceutical grade therapy delivered by simple intramuscular injection without the need for anaesthetic, cell culture, transplantation or immunosuppression. This approach is particularly appropriate for long-term circulating therapeutic protein replacement currently requiring repeated injection therapy. Wide-ranging clinical applications include haemophilia, chronic anaemia, growth hormone deficiency and diabetes. Inadequate transgene expression, unregulated protein delivery and immune response have been major limiting factors. Recent innovations including in situ electroporation enabling sustained systemic protein delivery within the therapeutic range are reviewed. Pharmacological and physiological approaches to regulation are discussed in addition to the role of innate and humoral immunity. Translation of advances in all of these areas to clinical success will enable muscle-targeted gene therapy to capitalise on its inherent strengths and realise its long-standing promise.

Animals↗
PubMed1994

A circulating shock protein depolarizes cells in hemorrhage and sepsis.

OBJECTIVE: A study to determine if both septic and hemorrhagic shock lead to the appearance of a substance that depolarizes cells in plasma was performed. SUMMARY BACKGROUND DATA: Transmembrane potential decreases in skeletal muscle, hepatocytes, and red blood cells early in the development of both hemorrhagic and septic shock. The associated movement of ions and water into cells leads to extracellular fluid loss and exacerbates shock. METHODS: Adult male Sprague-Dawley rats with indwelling arterial and venous cannulae were bled 20 mL/kg or received intravenously 2 x 10(10) Escherichia coli suspended in 400 mL of 0.9% saline. Blood samples were taken after hemorrhage and induction of sepsis to determine the presence of a plasma factor that depolarized red blood cells. Control rats were not injected with E. coli or bled. Plasma from bled and septic rats was processed by sequential precipitation with ammonium sulfate and subjected to gel filtration. RESULTS: Depolarizing activity was highest 20 minutes after hemorrhage and 60 minutes after E. coli injection, decreasing to control levels by 2 (hemorrhage) and 4 (sepsis) hours. Control rats showed no significant change in depolarizing activity. Tryptic and chymotryptic digestion eliminated the depolarizing activity, indicating that the active substance is, at least in part, a protein. Depolarizing activity from bled and septic processed plasma was confined essentially to the 70% ammonium sulfate fraction and the activity migrated with an apparent molecular mass of 200 kD after gel filtration. Separation of the complex by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) produced an identical pattern of bands in both bled and septic animals. CONCLUSIONS: A circulating plasma protein complex of high molecular weight causes cellular depolarization in both hemorrhage and sepsis and may be responsible for the associated increases in cell sodium and water seen in both hemorrhagic and septic shock.

Ammonium Sulfate↗
PubMed2002

Circulating S100beta protein is increased in intrauterine growth-retarded fetuses.

To determine whether S100beta, an acidic calcium-binding protein previously demonstrated as a reliable indicator of a brain lesion, could be helpful in the detection of brain distress in intrauterine growth-retarded (IUGR) fetuses, we studied, by a case-control study, the correlation between S100B protein and the degree of fetoplacental blood flow impairment. Maternal and umbilical blood samples and placental tissue specimens were collected at delivery from IUGR pregnancies with normal (n = 10) or abnormal (n = 10) umbilical artery Doppler findings and from 40 uncomplicated pregnancies. S100beta protein levels were measured by means of a specific RIA, and flow velocimetry waveforms were recorded from uterine, umbilical, and fetal middle cerebral arteries. Overall mean S100beta proteins in umbilical plasma levels were higher (p < 0.05) in IUGR patients (121.8 +/- 70.4 fmol/mL) than in control patients (54.7 +/- 21.9 fmol/mL). IUGR fetuses with redistribution of blood flow showed the higher concentration of the protein (163.7 +/- 55.2 fmol/mL). Fetal S100beta concentrations correlated with middle cerebral artery pulsatility index (r = -0.536, p < 0.03) and with umbilical artery pulsatility index to middle cerebral artery pulsatility index ratio (r = 0.469, p < 0.03). No difference in the localization or intensity of S100beta staining in the placental tissues or cord between uncomplicated and IUGR pregnancies was found. This study provides evidence that circulating S100beta protein is increased in IUGR fetuses and correlates with cerebral hemodynamics, suggesting that it may represent an index of cerebral cell damage in the perinatal period.

Adult↗
PubMed2025

Integrative proteomic analysis provides novel therapeutic insights for etiological subtypes of diabetes.

AIMS: Type 2 diabetes (T2D) is a highly heterogeneous disease characterised by subtypes with variations in aetiology, disease progression, and risk of complications. However, potential drug targets for these subtypes have not been explored. This study aims to investigate potential drug targets by integrating proteomics. MATERIALS AND METHODS: Summary-level data of circulating proteins were extracted from the UK Biobank and the deCODE Health Study. Genetic associations with five diabetes subtypes were obtained from Swedish All New Diabetics in Scania and Malm&#xf6; Diet and Cancer cohort, including severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). The associations between circulating proteins and diabetes subtypes were assessed through Mendelian randomisation, followed by multiple sensitivity and colocalization analyses. Additionally, tissue-specific, pathway and functional enrichment analysis, assessment of protein druggability, and the protein-protein interaction (PPI) networks were used to further explore biological mechanisms and therapeutic potential. RESULTS: Genetically predicted levels of 2, 2, 9, 3, and 5 circulating proteins were associated with SIRD, SIDD, MARD, MOD, and SAID, respectively. Colocalization analyses further revealed links between GRN with MARD/SIRD, LILRB5 with SIDD/MARD, CR1 with MARD, TNFSF12 with MOD, and DAPK2 with SAID. Enrichment analysis suggested that these proteins were mainly enriched in blood and adipose tissues and involved in immune and inflammatory related pathways. PPI analysis revealed GRN, TNFSF12, and DAPK2 are associated with known T2D targets. CONCLUSIONS: Our study identified several potential drug targets for different subtypes of diabetes using an integrated genetic approach, yielding new insights for precision medicine of diabetes.

Humans↗
PubMedDate not supplied

High levels of circulating cardiac proteins indicate cardiac impairment in African children with severe Plasmodium falciparum malaria.

A role of the heart in the pathophysiology of severe Plasmodium falciparum malaria has recently been suggested. The objective of the present study was to substantiate this finding in a large group of African children and to correlate results with metabolic conditions in these children. Furthermore, the impact of a potential cardiac impairment on outcome in severe cases was assessed. Results may have important implications on the currently ongoing debate on fluid management in severe malaria patients. Plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), heart-type fatty acid-binding protein (H-FABP), myoglobin and creatine kinase muscle-brain (CK-MB) were compared in 400 African children with severe and mild falciparum malaria. Plasma levels of these markers were correlated with lactate and glucose blood levels, indicators for hypovolemia, and with clinical outcome. Children suffering from severe malaria and children who died (n = 22) exhibited high to very high levels of cardiac markers, respectively. Cardiac factors themselves were not predictive of fatal outcome, while, in multivariate analysis, lactic acidosis was the most important biochemical predictor of death in the severe malaria group. Lactic acidosis and hypoglycemia, however, result in cardiac impairment as defined by elevated levels of circulating cardiac proteins. Our results point to hypovolemia as a major underlying cause of lactic acidosis and hypoglycemia in African children with severe falciparum malaria. These deleterious metabolic conditions contribute to myocardial affection which was evident but not predictive per se of fatal outcome.

Blood Glucose↗
PubMed2005

Reactive oxygen species (ROS) induce chemical and structural changes on human insulin in vitro, including alterations in its immunoreactivity.

Oxidative stress occurs when the production of reactive oxygen species (ROS) exceeds the endogenous antioxidant defense. Peroxidations induced by ROS are the key of chemical and structural modifications of biomolecules including circulating proteins. To elucidate the effect of ROS on circulating proteins and considering the presence of oxidative stress in Diabetes Mellitus, the effects of ROS, in vitro, on human insulin were studied. We utilized the Fenton reaction for free hydroxyl radical (HO*) generation in presence of human recombinant insulin measuring chemical changes on its molecular structure. The induced changes in insulin were: a) significant increase on absorbance (280 nm) due to phenylalanine hydroxylation (0.023 +/- 0.007 to 0.13 +/- 0.07). b) Peroxidation products formed on amino acids side branches (peroxyl and alcohoxyl group); measured as increased capacity of reduce nitroblue of tetrazolium (NBT) to formazan (0.007 +/- 0.007 to 0.06 +/- 0.02). c) Increased concentration of free carbonyl groups (8.8 +/- 8.7 to 45.6 +/- 20.2 pmoles dinitrophenylhidrazones/nmol insulin) with lost of secondary structure, and d) Modification of epithopes decreasing the insulin antigen-antibody reactivity measured as a decrease in insulin concentration by RIA. In conclusion, the radical hydroxyl in vitro is able to induce molecular modifications on insulin.

Carbon↗
PubMed1994

Origin and significance of the heterogeneity of protein hormones.

The heterogeneity of circulating protein hormone is the result of multiple steps including gene expression, mRNA maturation, post-translational processing and peripheral catabolism. As a consequence of these cumulative events, it seems difficult to evaluate the endocrine function by using specific radioimmunoassays for each circulating variant of a protein hormone. Moreover, the discovery of new molecular variants of protein hormones with unknown biological significance complicates the standardization and the clinical interpretation of immunoassays.

Blood Proteins↗
PubMedDate not supplied

Circulating activated protein C in subjects with heterozygous Gln506-factor V.

Congenital resistance to activated protein C due to a point mutation in the factor V gene (Gln506-FV) is the most common genetic risk factor for familial venous thrombosis. Considering the central role of activated protein C as a physiological anticoagulant, the question of why the thrombotic risk associated with Gln506-FV was not more pronounced was asked. We hypothesized that in Gln506-FV heterozygotes, enhanced thrombin formation might preferentially activate protein C and thereby constitute a compensatory antithrombotic effect. We compared the circulatory level of activated protein C in twelve heterozygous carriers of Gln506-FV mutation with that in eighteen noncarriers in same families, and used prothrombin fragment 1+2 as a measure of thrombin generation. The circulating level of activated protein C was higher but not significantly different in heterozygotes compared with normal relatives. Activated protein C levels correlated strongly and positively with protein C antigen levels in both carriers (Spearman R 0.684, p < 0.05) and controls (Spearman R 0.642, p < 0.01). Correlation between activated protein C and prothrombin fragment 1+2 levels was of borderline significance (Spearman R 0.354, p = 0.055). In the current study, thrombin formation assessed by prothrombin fragment 1+2 levels was not significantly enhanced in subjects with heterozygous Gln506-FV compared with family members without the mutation. In conclusion, enhanced thrombin formation is not present in all healthy Gln506-FV heterozygotes in basal conditions. It seems that enhanced protein C activation by thrombin does not constitute a compensatory anticoagulant feedback loop in heterozygous carriers of Gln506-FV. However, the positive correlation between prothrombin fragment 1+2 and activated protein C suggests that, in healthy subjects and in basal conditions, thrombin upregulates the anticoagulant protein C pathway. Thus, it is questionable whether prothrombin fragment 1+2 can directly be used as an indicator of a hypercoagulable state.

Adolescent↗
PubMed1984

Mediterranean glucose 6-phosphate dehydrogenase (G6PD) deficiency--near normal decay of the mutant enzyme protein in circulating erythrocytes.

Complete removal of leucocytes and platelets from erythrocytes and the development of a sensitized procedure for the assay of G6PD activity allowed the biochemical mechanisms of the Mediterranean variety of G6PD deficiency to be re-evaluated. Activity in the young erythrocytes from 9 G6PD-deficient subjects averaged 0.1% of the levels observed in the corresponding erythrocyte fraction from normal individuals: moreover, the decline of activity during aging of the G6PD-deficient erythrocytes was comparable with that observed for the normal enzyme. Mutant G6PD purified from granulocytes of a G6PD-deficient subject and entrapped within the corresponding erythrocytes was remarkably stable. Exposure of native erythrocytes to an oxidative stress (divicine plus ascorbate) resulted in a decrease of G6PD activity that was significantly more rapid and extensive in control than in G6PD-deficient cells. These results seem to exclude enhanced intracellular breakdown of the mutant protein within the circulating erythrocytes.

Ascorbic Acid↗
PubMed1987

Plasmodium falciparum: elicitation by peptides and recombinant circumsporozoite proteins of circulating mouse antibodies inhibiting sporozoite invasion of hepatoma cells.

The immunodominant epitope region of the circumsporozoite protein of Plasmodium falciparum sporozoites contains 37 tandem repeats of the tetrapeptide Asn-Ala-Asn-Pro and 4 repeats of Asn-Val-Asp-Pro. Synthetic peptides and recombinant proteins of the repeat region were used to immunize mice using different doses and adjuvants. Antisera were tested for inhibition of sporozoite invasion of cultured human hepatoma cells. Synthetic peptides and recombinant proteins elicited high levels of antibodies that inhibited sporozoite invasion when emulsified with complete Freund's adjuvant. Since recombinant proteins with alum elicited a better antibody response to sporozoite invasion than they did without adjuvant, it may be that a recombinant protein containing 32 tandem copies of the tetrapeptide repeat combined with alum could be a candidate malarial vaccine suitable for human trials.

Animals↗