Plasma Protein Concentration Research Articles

Brain endothelial permeability, transport, and flow assessed over 10 orders of magnitude using the in situ brain perfusion technique

BackgroundCerebral blood flow normally places a limit on the magnitude of brain vascular permeability (P) that can be measured in vivo. At normal cerebral blood flow, this limit falls at the lower end of lipophilicity for most FDA-approved CNS drugs. In this study, we report on two methods that can be used to overcome this limitation and measure brain vascular permeability values that are up to ~1000 times higher using the in situ brain perfusion technique.MethodsRat brain was perfused with physiological saline at increased flow rate and in the presence of various concentrations of plasma protein, serum albumin or alpha-acid glycoprotein. Plasma protein was added to the saline perfusion fluid to lower extraction into the measurable range using the Crone Renkin “diffusion-flow” equation to calculate brain PoS.ResultsCerebrovascular Po was determined for 125 solutes, of which 78 showed little or no evidence of active efflux transport. Fifty of the solutes were in the lipophilicity zone (Log Poct 1–5) of most FDA-approved CNS drugs. Care was taken to ensure the integrity of the brain vasculature during perfusion and to measure flow accurately using markers that had been verified for the flow rates. The results showed a linear relationship between Log Po and Log Poct over ~10 orders of magnitude with values for diazepam, estradiol, testosterone, and other agents that exceed prior published values by fivefold to 200-fold.ConclusionsThe results show that brain vascular permeability can be measured directly in vivo for highly lipophilic solutes and the PS values obtained match reasonably with that predicted by the Crone-Renkin flow diffusion equation with care taken to validate the accuracy for the component measurements and with no need to invoke “enhanced” or “induced” dissociation.

Misfolding of Transthyretin In Vivo is Controlled by the Redox Environment and Macromolecular Crowding

Transthyretin (TTR) amyloidosis is a progressive disorder characterized by peripheral neuropathy, autonomic dysfunction, and cardiomyopathy. The precise mechanism by which TTR misfolds and forms fibrils in vivo remains incompletely understood, posing challenges to the development of effective therapeutics. In this study, we reveal that the recently identified non-native pathological species (NNTTR), which is enriched in the plasma of ttr-val30met gene carriers, exhibits strong amyloidogenic properties, making it a promising therapeutic target. Notably, we demonstrate that NNTTR formation is dependent on an intermolecular disulfide bond and can be promoted by oxidative conditions while being effectively suppressed by reducing agents. The formation of this disulfide bond is incompatible with the native TTR fold, thereby necessitating structural flexibility. We further show that this required flexibility can be constrained using tetramer-stabilizing drugs, thereby suppressing NNTTR formation. Interestingly, the flexibility is also hindered by macromolecular crowding, and NNTTR formation is strongly suppressed by the high protein concentration in plasma. This suppression is released upon dilution, which thus promotes NNTTR formation in areas with lower protein content, highlighting a potential link to the interstitial space, brain, and vitreous body of the eye, where TTR-amyloid is frequently observed. In summary, we demonstrate that NNTTR displays strong amyloidogenic features, underscoring its potential as a therapeutic target. We identify the redox environment and macromolecular crowding as key modulatory factors. Our findings propose a mechanistic explanation for TTR misfolding and suggest a novel therapeutic approach.

Plasma proteomic signatures of liver steatosis and fibrosis in people living with HIV: a cross-sectional study

Insights into the mechanisms driving metabolic dysfunction-associated steatotic liver disease (MASLD) in people living with HIV (PLHIV) remain limited. Plasma proteomics holds promise for biomarker discovery and the elucidation of biological mechanisms. We performed cross-sectional analyses on data from 1036 virally suppressed PLHIV using antiretroviral treatment (ART) from the Dutch multi-centre 2000HIV cohort. Participants underwent transient elastography to assess liver steatosis (controlled attenuation parameter (CAP)≥263dB/m) and -fibrosis (liver stiffness measurement (LSM)≥7.0kPa). Plasma protein concentrations (n=2367) (Olink® Explore Panel) were compared between PLHIV with vs. without liver steatosis and PLHIV with vs. without fibrosis. Enriched pathways (using GO, KEGG and Reactome libraries) and correlations with clinical characteristics wereassessed, and analyses were stratified by BMI category. In addition, concentrations of 242 proteins werecompared between individuals ("controls") with and without liver steatosis (ratio of methylene:methylene and water >5.6% on magnetic resonance spectroscopy) from a separate cohort (300-OB), all having a BMI >26kg/m2. Steatosis and fibrosis were associated with 67/2367 (2.2%) and 17/2367 (0.7%) differentially expressed proteins (DEP), respectively, enriched in mostly metabolic pathways. Immunoglobulin superfamily member 9 (IGSF9) was amongst the top DEP associated with both steatosis and fibrosis. Stratifying by BMI revealed 8/2367 DEP associated with steatosis in lean- and 12/2367 DEP in overweight/obese individuals, with two shared DEP (IGSF9 and GHR). Conversely, protein signatures of overweight/obese PLHIV (32/242 DEP) and overweight/obese HIV-uninfected individuals (32/242 DEP) exhibited substantial overlap with 16 shared DEP. Notably, DEP correlated with HIV characteristics in lean individuals but not in overweight/obese PLHIV. Lean and overweight/obese PLHIV exhibit distinct proteomic signatures associated with liver steatosis, with the former being more strongly correlated with HIV-specific factors and ART. In addition, we identified a protein, IGSF9, strongly related to liver fibrosis and steatosis across BMI categories. The 2000HIV study is funded by ViiV Healthcare.

In vitro Effect of Low-level Lasers on Proteomic Concentration in Human Blood Plasma Using 375 nm and 650 nm Lasers

Abstract Background: As a continuation of earlier laboratory research and its findings, we are studying the effects of biostimulation and alteration on human blood plasma to improve blood circulation in blood vessels, treat some infections, and treat various diseases, including blood protein-related ones. Methods: Blood samples were collected through venipuncture into tubes containing, ethylenediaminetetraacidic as an anticoagulant from healthy adult donors, and plasma was separated from blood components. Blood plasma samples were irradiated for varying periods (5, 10, 15, and20) min. Before and after irradiation, total protein and albumin concentrations were calculated using 375 nm and 650 nm lasers. Using a spectrophotometer, the concentration of total protein and albumin was determined for each sample. Results: At the (375 and 650) nm laser wavelength and exposure durations of (5, 10, 15, and 20) min, it was observed that the total protein concentration had significant differences between pre- and postirradiation probate value (P = 0.05, P = 0.05, P = 0.05, and P = 0.05, respectively). It was observed that the total protein and albumin concentrations had significant differences between pre- and postirradiation. In addition, the results demonstrate that the concentration of total protein and albumin decreases more significantly at a laser wavelength of 650 nm compared to a laser wavelength of 375 nm at times of (5 and 10) min. Conclusions: Our results clearly indicate that low-level lasers with different wavelengths of ( 375 , 630) nm both affect the concentration of total protein and albumin in human blood plasma, which can contribute to the treatment of many pathological conditions in the future.

Proteomic and genomic evaluation of plasma protein biomarkers for atrial fibrillation

Abstract Background Atrial fibrillation (AF) is a common arrhythmia and an important cause of ischemic stroke. Several plasma proteins have been suggested as biomarkers for the risk of AF and subsequent stroke in previous studies, but validation in independent cohorts is needed. Large-scale integration of proteomics with genetic and clinical data holds potential for refinement of disease prediction and risk stratification. Purpose This study aimed to evaluate previously suggested plasma protein biomarkers of AF and ischemic stroke using plasma protein measurements in a large cohort. Methods Ten tentative protein biomarkers previously associated with AF or ischemic stroke in AF patients, were evaluated in a nested case-control study comprising 49,757 individuals from the UK biobank (UKB). Plasma proteins were measured by normalized protein expression on the Olink platform. Outcomes were incident AF and ischemic stroke. The proteins were evaluated in Cox regression models adjusted for sex, age, and clinical risk factors. To assess whether the proteins were independent predictors, they were evaluated in sensitivity analyses with additional adjustment for NT-proBNP levels. Polygenic risk scores were calculated for plasma protein concentrations using the PRS-CS-auto algorithm and tested for association with AF or ischemic stroke in an independent subset of the UKB cohort without plasma protein measurements (n=379,392). Results All ten plasma proteins were associated with incident AF in the primary model, and eight were associated with incident ischemic stroke (P-values < 0.0025 for all). Adjusted for NT-proBNP levels, the proteins interleukin-6, GDF15, angiopoietin 2, and Troponin-I remained independently associated with AF, and the proteins GDF15, Cystatin-C, interleukin-6, ADAMTS13, and FGF23 remained independently associated with ischemic stroke. Polygenic risk scores for NT-proBNP and angiopoietin 2 were associated with increased rates of AF. No polygenic scores were significantly associated with ischemic stroke. Conclusion Large-scale proteomic evaluation validated ten plasma proteins associated AF and found eight to be associated with ischemic stroke. Seven proteins were associated with AF or ischemic stroke independently of NT-proBNP levels. Additional genomic evaluation provided evidence of associations between incident AF and genetically predicted plasma levels of angiopoietin 2 and NT-proBNP. As proteomic analyses of the plasma proteome become cheaper and more readily available, these findings could contribute to future risk stratification and selection of individuals for AF screening programs.Proteins associated with AFProteins associated with ischemic stroke

Proteomic analysis of plasma-derived extracellular vesicles: pre- and postprandial comparisons

Extracellular vesicles (EVs) are key in intercellular communication, carrying biomolecules like nucleic acids, lipids, and proteins. This study investigated postprandial characteristics and proteomic profiles of blood-derived EVs in healthy individuals. Twelve participants fasted overnight before baseline assessments. After consuming a controlled isocaloric meal, EVs were isolated for proteomic and flow cytometric analysis. Plasma triacylglyceride levels confirmed fasting completion, while protein concentrations in plasma and EVs were monitored for postprandial stability. Proteomic analysis identified upregulated proteins related to transport mechanisms and epithelial/endothelial functions postprandially, indicating potential roles in physiological responses to nutritional intake. Enrichment analyses revealed vesicle-related pathways and immune system processes. Flow cytometry showed increased expression of CD324 on CD9+CD63+CD81+ large extracellular vesicles postprandially, suggesting an epithelial origin. These findings offer valuable insights into postprandial EV dynamics and their potential physiological significance, highlighting the need for stringent fasting guidelines in EV studies to account for postprandial effects on EV composition and function.

Sub-chronic Toxicological Evaluation of Drinking Water from Internally Displaced Persons (IDP) Camp in Wassa, Federal Capital Territory, Abuja, Nigeria

The number of Internally Displaced Persons (IDPs) camps has increased recently in Nigeria due to insurgency and natural disasters such as floods. This study aimed to evaluate the sub-chronic toxicological effects of the source of the drinking water in Wassa camp, Abuja, Nigeria. Forty-eight (48) mice were randomized into four (4) groups of twelve (12) mice each and orally administered different concentrations (5, 10, and 20 mL/kg body weight respectively) of the water sample from Wassa IDP for fourteen (14) days. The alteration was noticed in the liver and kidney indices of mice by a significant increase (p<0.05) in kidney-body weight ratio, kidney, liver and plasma protein concentrations, and a considerable decrease (p<0.05) in albumin, creatinine, uric acid and total bilirubin concentrations, 14-days post-treatment, particularly at a higher dose. Gamma-glutamyl transaminase in the liver and aspartate transaminase in both liver and kidney significantly (p<0.05) increased in mice with a resultant significant decrease (p<0.05) in the serum, 14 days post-treatment at 20 mL/kg bwt. There was no significant difference (p>0.05) observed in serum triglycerides, very-low-density-lipoprotein cholesterol concentrations at all doses 14-days post-treatment compared with the control but the concentrations of serum low-density-lipoprotein cholesterol and total cholesterol significantly reduced (p<0.05) at 20 mL/kg bwt 14-days post-treatment. The drinking water altered some liver-function indices while the cardiac-function indices were less affected. Therefore, prolonged consumption of the water may not be relatively safe. The provision of clean drinking water for the Wassa IDP camp will prevent adverse biochemical reaction reactions from prolonged water consumption.

The measurement of plasma fructosamine as a diagnostic tool to improve the interpretation of plasma glucose and proteins in alpacas (Vicugna pacos).

This study assesses the use of fructosamine as a diagnostic tool for hyperglycemia in alpacas in view of their sensitivity to stress and susceptibility to conditions like lipid mobilization syndrome. Plasma fructosamine, like in diagnosing diabetes in cats and dogs, can reveal long-term blood glucose trends, differentiating stress-induced spikes from persistent diabetic hyperglycemia. In 125 alpacas presented as patients of a veterinary clinic, plasma glucose and fructosamine concentrations were compared for correlations with findings of the general clinical examination, laboratory parameters, demographic data, and a behavioral stress assessment processed by using principal component analysis. Hyperglycemia was observed on admission of 71% (89/125) of the animals. This was significantly associated with a higher concentration of serum cortisol and a higher behavioral stress scoring. Fructosamine above the reference limit was detected in only 15% (13/89) of the hyperglycemic individuals. In addition to a positive correlation of fructosamine to glucose concentration, positive relationships with different plasma proteins were detected. A relationship to stress parameters was not observed. These findings underscore stress as a significant trigger for hyperglycemia in alpacas and suggest fructosamine as a valuable parameter for distinguishing between stress-induced and diabetic hyperglycemia. However, the dependence of fructosamine formation on total plasma protein concentration should be considered to avoid misinterpretation.

Methylglyoxal mediates the association between 2-hour plasma glucose and HbA1c with inflammation: The Maastricht Study.

Glucose excursions in persons with diabetes may drive chronic inflammation. Methylglyoxal (MGO) is formed from glucose, is elevated in persons with diabetes, and is a potent glycating agent linked with inflammation. We investigated whether glucose excursions are associated with low-grade inflammation and whether MGO mediates this association. We used data from The Maastricht Study, an extensive phenotyping study into the etiology of type 2 diabetes and its complications. Data of 3017 participants, who underwent an oral glucose tolerance test and where data on MGO levels and inflammation were available, were used. Linear regression analyses, adjusted for potential confounders, evaluated associations between fasting plasma glucose (FPG), 2-hours plasma glucose (2h-PG) and HbA1c and low-grade inflammation (stdβ, [95% confidence interval]), calculated from plasma concentrations of C-reactive protein, serum amyloid A, interleukin-6, interleukin-8, tumor necrosis factor and soluble intercellular adhesion molecule-1. Mediation analyses investigated whether MGO mediated these associations. 2h-PG (0.172 [0.110; 0.234]) and HbA1c (0.148 [0.101; 0.196]), but not FPG (0.049 [-0.002; 0.100]), were associated with low-grade inflammation. 2h-PG and HbA1c were also associated with 2h-MGO (0.471 [0.407; 0.534], and 0.244 [0.195; 0.294], respectively). Furthermore, 2h-MGO was independently and positively associated with low-grade inflammation (0.078 [0.037, 0.120]). 2h-MGO mediated 23% of the association between 2h-PG and inflammation, and 16% of the association between HbA1c and inflammation. MGO mediates the association between post-load glucose excursions and HbA1c with inflammation, providing evidence for a role of postprandial MGO formation to hyperglycemia-induced low-grade inflammation.

An overview of interpretability of two models of unbound fraction that are used in combination with the well-stirred model for predicting hepatic clearance of drugs

Hypothetical and experimental models of unbound fraction have been proposed to facilitate predicting the hepatic clearance (CLH) of drugs from values of intrinsic clearance for the unbound drug (CLint-in vitro-unbound) and the well-stirred model (WSM). The hypothetical model (fu-adjusted) is adjusting the unbound fractions determined in plasma in vitro to estimate the maximum unbound fractions at the hepatocytes if each drug-protein complex in plasma becomes fully dissociated at the membrane by any albumin (ALB)-facilitated hepatic uptake mechanism. The model of fu-adjusted is also adjusting the unbound fraction for a pH gradient effect across the membrane. Alternatively, the new experimental model (fu-dynamic) measures the unbound fractions resulting to the dynamic dissociation kinetics from proteins in the presence of plasma and a liver enzyme in an in vitro assay. The objective of this study was to conduct an in-depth analysis of previous CLH predictions made with these unbound fractions in a companion manuscript. Furthermore, a new dataset on transporter substrates was also included in this study. Finally, the physiological basis of fu-adjusted has been redefined to extend its applicability with more drugs. In this case, there are lower concentrations of binding proteins in liver versus plasma that could also explain the higher unbound fractions for that organ. The outcomes associated to additional analyses pointed out that fu-adjusted, again, generally provided the most accurate predictions of CLH because fu-dynamic has generated superior biases of underpredictions or overpredictions. For slowly metabolized drugs bound to ALB, fu-dynamic was definitively less accurate than fu-adjusted. For other drug properties, fu-dynamic fared better but it was still not generally more accurate than fu-adjusted. Furthermore, experimental values of fu-dynamic were sometimes incoherent. For example, drugs bound to alpha-acid glycoprotein (AGP) did not follow the principle of fu-dynamic (i.e., values of fu-dynamic did not correlate with values of CLint-in vitro-unbound) by contrast to those drugs bound to ALB. Therefore, the current experimental setting for fu-dynamic might be unsuitable in some circumstances. Overall, this study confirmed that calculated values of fu-adjusted were as accurate as experimental values of fu-dynamic and can even be more accurate. A guidance on which unbound fraction to use in the WSM is also provided.

The role of protein corona in advancing plasma proteomics.

The protein corona, a layer of biomolecules forming around nanoparticles in biological environments, critically influences nanoparticle interactions with biosystems, affecting pharmacokinetics and biological outcomes. Initially, the protein corona presented challenges for nanomedicine and nanotoxicology, such as nutrient depletion in cell cultures and masking of nanoparticle-targeting species. However, recent advancements have highlighted its potential in environmental toxicity, proteomics, and immunology. This viewpoint focuses on leveraging the protein corona to enhance the depth of plasma proteome analysis, addressing challenges posed by the high dynamic range of protein concentrations in plasma. The protein corona simplifies sample preparation, enriches low-abundance proteins, and improves proteome coverage. Innovations include using diverse nanoparticles and spiking small molecules to increase the number of quantified proteins. Reproducibility issues across core facilities necessitate standardized protocols. Moreover, top-down proteomics enables proteoform-specific measurements, providing deeper insights into protein corona composition. Future research should aim at improving top-down proteomics techniques and integrating protein corona studies and proteomics for personalized medicine and advanced diagnostics.

Extracellular glypican-1 affects tumor progression and prognosis in esophageal cancer.

Cells are covered with a glycan surface layer that is referred to as the glycocalyx (GCX). It has been reported that the formation of the GCX is promoted on cancer cells and is associated with tumor growth and metastasis. Heparan sulfate proteoglycan glypican-1 (GPC1) is a core protein of the GCX that is overexpressed in esophageal squamous cell carcinoma (ESCC) and is involved in the development and progression of cancer cells. The purpose of the present study is to analyze the utility of GPC1 as a new biomarker ralated to glycocalyx that reflects therapeutic effect and prognosis of ESCC. We measured the concentration of GPC1 protein in preoperative plasma from advanced esophageal cancer patients and examined its relationships with clinicopathological factors and therapeutic efficacy, and the effects of extracellular GPC1 were investigated. The following clinical factors were significantly correlated with the preoperative high GPC1 concentration: male, tumor size ≥30 mm, venous invasion, pT factor ≥2, pStage ≥3, residual tumor, and distant metastatic recurrence. Both overall and recurrence-free survival were significantly worse in the high GPC1 group. Extracellular GPC1 protein concentration reflected intracellular GPC1 expression. Furthermore, we examined the effects of extracellular recombinant human (rh)GPC1 on ESCC cells, and found that extracellular rhGPC1 affects cell motility, including migration and invasion. These results demonstrated the utility of extracellular GPC1 as a biomarker, which can be assayed from a less invasive blood sample-based liquid biopsy. Extracellular GPC1 protein plays a role in both tumor cell motility and cancer progression. Thus, plasma GPC1 is a useful biomarker for esophageal cancer progression and may be a potential candidate of therapeutic target.

Combined plasma protein and memory T cell profiling discern IBD-patient-immunotypes related to intestinal disease and treatment outcomes

Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-naïve pediatric IBD (Crohn’s disease, CD: n = 62; ulcerative colitis, UC: n = 20; age-matched controls n = 43), and after 10–12 weeks’ induction therapy. At diagnosis, plasma protein profiles unveiled two UC and three CD clusters with distinct disease courses. UC patients displayed unchanged circulating Tmem, while CD exhibited increased frequencies of gut-homing ex-Th17, known for high IFN-γ production. UC#2 had elevated Th17/neutrophil-pathway-related proteins and severe disease, with higher endoscopic and histological damage and Th17/neutrophil infiltration. Although both UC#1 and UC#2 responded to therapy, UC#2 required earlier immunomodulation. CD#3 had lower plasma protein concentrations, especially IFN-γ pathway proteins, fewer gut-homing ex-Th17 and clinically milder disease, confirmed by intestinal gene expression. CD#1 and CD#2 had comparably high Th1-related immune profiles, but CD#1 exhibited higher concentrations of proteins previously associated with poorer prognosis. Both CD clusters responded to induction therapy, with similar one-year outcomes. This study highlights feasibility of discriminating patient-specific immunotypes in IBD, advancing our understanding of immune pathogenesis, needed for tailored treatment strategies.

The diabetic myocardial transcriptome reveals Erbb3 and Hspa2 as a novel biomarkers of incident heart failure.

Diabetes mellitus (DM) increases heart failure incidence and worsens prognosis, but its molecular basis is poorly defined in humans. We aimed to define the diabetic myocardial transcriptome and validate hits in their circulating protein form to define disease mechanisms and biomarkers. RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project was used to define differentially expressed genes (DEGs) in right atrial (RA) and left ventricular (LV) myocardium from people with versus without DM (type 1 or 2). DEGs were validated as plasma proteins in the UK Biobank cohort, searching for directionally concordant differential expression. Validated plasma proteins were characterized in UK Biobank participants, irrespective of diabetes status, using cardiac magnetic resonance imaging, incident heart failure and cardiovascular mortality.We found 32 and 32 DEGs associated with DM in the RA and LV, respectively, with no overlap between these. Plasma proteomic data was available for 12, with ERBB3, NRXN3 and HSPA2 (all LV hits) exhibiting directional concordance. Irrespective of DM status, lower circulating ERBB3 and higher HSPA2 were associated with impaired left ventricular contractility and higher LV mass. Participants in the lowest quartile of circulating ERBB3 or highest quartile of circulating HSPA2 had increased incident heart failure and cardiovascular death vs. all other quartiles. DM is characterized by lower Erbb3 and higher Hspa2 expression in the myocardium, with directionally concordant differences in their plasma protein concentration. These are associated with left ventricular dysfunction, incident heart failure and cardiovascular mortality.

Beat-to-beat blood pressure variability, hippocampal atrophy, and memory impairment in older adults.

Visit-to-visit blood pressure variability (BPV) predicts age-related hippocampal atrophy, neurodegeneration, and memory decline in older adults. Beat-to-beat BPV may represent a more reliable and efficient tool for prospective risk assessment, but it is unknown whether beat-to-beat BPV is similarly associated with hippocampal neurodegeneration, or with plasma markers of neuroaxonal/neuroglial injury. Independently living older adults without a history of dementia, stroke, or other major neurological disorders were recruited from the community (N = 104; age = 69.5 ± 6.7 (range 55-89); 63% female). Participants underwent continuous blood pressure monitoring, brain MRI, venipuncture, and cognitive testing over two visits. Hippocampal volumes, plasma neurofilament light, and glial fibrillary acidic protein levels were assessed. Beat-to-beat BPV was quantified as systolic blood pressure average real variability during 7-min of supine continuous blood pressure monitoring. The cross-sectional relationship between beat-to-beat BPV and hippocampal volumes, cognitive domain measures, and plasma biomarkers was assessed using multiple linear regression with adjustment for demographic covariates, vascular risk factors, and average systolic blood pressure. Elevated beat-to-beat BPV was associated with decreased left hippocampal volume (P = .008), increased plasma concentration of glial fibrillary acidic protein (P = .006), and decreased memory composite score (P = .02), independent of age, sex, average systolic blood pressure, total intracranial volume, and vascular risk factor burden. In summary,beat-to-beat BPV is independently associated with decreased left hippocampal volume, increased neuroglial injury, and worse memory ability. Findings are consistent with prior studies examining visit-to-visit BPV and suggest beat-to-beat BPV may be a useful marker of hemodynamic brain injury in older adults.

Inflammatory Biomarkers in Patients With Type 2 Diabetes Mellitus and Heart Failure With Preserved Ejection Faction.

To verify the relationship between gene polymorphisms of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) with inflammation markers and codependent metabolic variables in patients with type 2 diabetes mellitus and chronic heart failure (CHF). This study included 154 patients (mean age, 69.1±3.2 years). The control group consisted of 47 patients with metabolic syndrome (MS) without CHF; the 2nd group included 56 patients with CHF with preserved ejection fraction (CHFpEF); and the 3rd group consisted of 51 patients with CHF with reduced ejection fraction (CHFrEF). The rs1800629 polymorphism of the TNF-α gene (TNF-α: G308A) was studied in real time by the polymerase chain reaction (PCR) method and the rs1800795 polymorphism of the IL-6 gene (IL-6: 174 G>C) was studied by PCR with the electrophoretic detection. The frequencies of polymorphic alleles were compared with the clinical blood test results, plasma concentrations of C-reactive protein (CRP), TNF-α, leptin, and fibrinogen. Differences between the groups were determined using the F test. Relationships between individual studied parameters were identified using the regression analysis. In most patients, the occurrence of gene polymorphisms was eident as increased plasma concentrations of biomarkers. An association was found between the TNF-α gene polymorphism (G308A) and an increase in plasma TNF-α and between the IL-6 gene polymorphism (174 C>G) and an increase in plasma CRP. In the CHFpEF group, the rs1800629 gene polymorphism was observed in 55% of patients, among whom 93% had increased TNF-α. The rs1800795 gene polymorphism was observed in 82% of CHFpEF patients, among whom 21% had increased CRP. In the CHFrEF group, the G308A transition in the TNF-α gene was observed in 53% of patients; an increase in the respective cytokine was noted in 67% of patients; the IL-6 gene polymorphism 174 C>G was found in 78%, however, only 14% of patients with this polymorphism had also increased CRP. In the control group, the TNF-α G308A gene polymorphism was found in 30% of patients, while an increase in free TNF-α was associated with this polymorphism in 50% of patients; the IL-6 174 C>G gene polymorphism was detected in 78%, while no increase in the CRP level was observed in this group. This demonstrates a high probability of the TNF-α G308A gene polymorphism occurrence in patients with CHF. Inflammatory markers are important predictors of CHF. The most significant predictor was the TNF-α G308A gene polymorphism, which was observed in more than 50% of patients, the majority of whom had an increase in plasma TNF-α.

Associations between genetically predicted concentrations of plasma proteins and the risk of prostate cancer

BackgroundProstate cancer (PCa) is a leading cause of cancer-related death in men. Understanding the proteomic landscape associated with PCa risk can provide insights into its molecular mechanisms and pave the way for potential therapeutic interventions.MethodsA proteome-wide Mendelian randomization (MR) analysis was employed to determine associations between genetically predicted protein concentrations in plasma and PCa risk. From an initial list of 4,364 proteins, significant associations were identified and validated. Multiple sensitivity analyses were also conducted to enhance the robustness of our findings.ResultsOf the 4,364 genetically predicted proteins, 308 exhibited preliminary associations with PCa risk. After rigorous statistical refinement, genetically predicted concentrations of 14 proteins showed positive associations with PCa risk, with odds ratios spanning from 1.55 (95% CI 1.28–1.87) for ATG4B to 2.67 (95% CI 1.94–3.67) for HCN1. In contrast, genetically predicted concentrations of ATG7, B2M, MSMB, and TMEM108 demonstrated inverse associations with PCa. The replication analysis further substantiated positive associations for MDH1 and LSM1, and a negative one for MSMB with PCa. A meta-analysis harmonizing primary and replication data mirrored these findings. Furthermore, the MVMR analysis pinpointed B2M and MSMB as having significant associations with PCa risk.ConclusionThe genetic evidence unveils a refined set of proteins associated with PCa risk. The findings underscore the potential of these proteins as molecular markers or therapeutic targets for PCa, calling for deeper mechanistic studies and exploration into their translational relevance.

Prognostic value of laboratory markers in patients with acute pulmonary embolism

BackgroundAcute pulmonary embolism (APE) is a serious illness. Identifying prognostic factors for APE may help in the management of those patients. This study’s objective was to evaluate the prognostic value of laboratory markers in predicting right ventricular dysfunction (RVD) and 30-day mortality in pulmonary embolism patients.MethodsEighty patients with APE were enrolled and followed up for 30 days. Detailed echocardiography was done to evaluate RVD. All patients were subjected to arterial blood gas analysis, complete blood count (CBC), plasma concentration of C-reactive protein (CRP), serum D-dimer level, and serum troponin I level, and the following ratio were calculated: neutrophil-to-lymphocytic ratio (NLR), platelet to lymphocytic ratio (PLR), red cell distribution width (RDW), mean platelet volume (MPV), and alveolar to arterial gradient.ResultsOur results analysis revealed significantly elevated levels of median NLR, PLR, CRP, D-dimer, and troponin in both the RVD and non-survivor groups (P value < 0.001). The blood markers that showed the highest predictive ability for right ventricular dysfunction (RVD) and 30-day mortality, as determined by receiver operating characteristic (ROC) analysis and logistic regression, were A-a O2 gradient, serum troponin, CRP, D-dimer, NLR, and PLR (P value < 0.001).ConclusionEvaluation of different serum markers including NLR, PLR, RDW, CRP, D-dimer, troponin, and A-a O2 gradient is a simple and available marker for predicting right ventricular dysfunction (RVD) and 30-day mortality in patients with APE.Trial registrationClinicalTrials.gov ID: NCT04237974.

Plasma concentration of serum amyloid A and lipopolysaccharide binding protein in horses with laminitis resulted from hindgut acidosis

Many studies have shown a strong correlation between Hindgut Acidosis (HGA) and the occurrence of laminitis in horses; therefore, the early diagnosis of HGA is essential. In this study, we investigated changes in the plasma concentrations of lipopolysaccharide-binding protein (LBP) and serum amyloid A (SAA) as inflammatory markers in horses with laminitis. Sixteen healthy male Arabian horses that had cecal cannulation without visible laminitis or general symptoms were randomly divided into two groups. The horses were fed two different diets in a forage-to-concentrate ratio. Blood samples were collected on Days 1, 10, and 20. The primary objective of this study was to analyze plasma levels of LBP and SAA. Cecal specimens were obtained from each equine subject on three designated days: days 1, 10, and 20. The second objective was to assess the levels of pH and volatile fatty acids (VFA) in the samples. Throughout the study period, horses fed a high-concentrate diet exhibited a significantly elevated average lameness grade on days 10 and 20 compared to the initial stage (P < 0.001). On day 20, a significant increase in the concentration of SAA was observed in horses fed a high-concentrate diet, in contrast to the initial stage of the study. LBP levels in the plasma were significantly elevated on days 10 and 20 in horses fed a high-concentrate diet. Based on our findings, it is recommended that the evaluation of plasma LBP concentrations is more effective than SAA for the early identification of HGA in horses fed a high-grain diet.

Levels of circulating angiotensin-converting enzyme 2 are affected by acute exercise and correlate with markers of physical fitness in male athletes.

While under physiological conditions angiotensin-converting enzyme 2 (ACE2) is an antagonist of vasoconstrictive agents in the renin-angiotensin-aldosterone system (RAAS), in the context of SARS coronavirus 2 (SARS-CoV-2) ACE2 serves as the gateway into cells. Furthermore, RAAS has previously been shown to be influenced by exercise training and is suggested to be involved in skeletal muscle mass maintenance. Given this connection, the investigation of circulating ACE2 plasma protein concentration before and following acute and chronic endurance and resistance exercise could increase the understanding of the implications of the exposure of athletes to SARS-CoV-2. Therefore, this study investigated levels of circulating ACE2 in lifelong high-level trained endurance and resistance athletes and control subjects in response to either acute endurance or resistance exercise. Results show no baseline differences in absolute ACE2 concentration between groups, but a strong negative correlation with levels of fitness and positive correlation with BMI in control subjects. Furthermore, acute endurance exercise significantly increased ACE2 levels across all groups, but only in the strength group in response to resistance exercise. This indicates that circulating ACE2 plasma levels are influenced by levels of fitness and health, and that acute endurance exercise has a stronger effect on plasma ACE2 levels than resistance exercise.