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The multifaceted nature of multiple sclerosis requires quantitative biomarkers that can provide insights related to diverse physiological pathways. To this end, proteomic analysis of deeply-phenotyped serum samples, biological pathway modeling, and network analysis were performed to elucidate inflammatory and neurodegenerative processes, identifying sensitive biomarkers of multiple sclerosis disease activity. Here, we evaluated the concentrations of > 1400 serum proteins in 630 samples from three multiple sclerosis cohorts for association with clinical and radiographic new disease activity. Twenty proteins were associated with increased clinical and radiographic multiple sclerosis disease activity for inclusion in a custom assay panel. Serum neurofilament light chain showed the strongest univariate correlation with gadolinium lesion activity, clinical relapse status, and annualized relapse rate. Multivariate modeling outperformed univariate for all endpoints. A comprehensive biomarker panel including the twenty proteins identified in this study could serve to characterize disease activity for a patient with multiple sclerosis.

BACKGROUND: A better understanding of treatment progression and recovery in pulmonary tuberculosis (TB) infectious disease is crucial. This study analyzed longitudinal serum samples from pulmonary TB patients undergoing interventional treatment to identify surrogate markers for TB-related outcomes. METHODS: Serum that was collected at baseline and 8, 17, 26, and 52 weeks from 30 TB patients experiencing durable cure were evaluated and compared using a sensitive LC-MS/MS proteomic platform for the detection and quantification of differential host protein signatures relative to timepoint. The global proteome signature was analyzed for statistical differences across the time course and between disease severity and treatment groups. RESULTS: A total of 676 proteins showed differential expression in the serum over these timepoints relative to baseline. Comparisons to understand serum protein dynamics at 8 weeks, treatment endpoints at 17 and 26 weeks, and post-treatment at 52 weeks were performed. The largest protein abundance changes were observed at 8 weeks as the initial effects of antibiotic treatment strongly impacted inflammatory and immune modulated responses. However, the largest number of proteome changes was observed at the end of treatment time points 17 and 26 weeks respectively. Post-treatment 52-week results showed an abatement of differential proteome signatures from end of treatment, though interestingly those proteins uniquely significant at post-treatment were almost exclusively downregulated. Patients were additionally stratified based upon disease severity and compared across all timepoints, identifying 461 discriminating proteome signatures. These proteome signatures collapsed into discrete expression profiles with distinct pathways across immune activation and signaling, hemostasis, and metabolism annotations. Insulin-like growth factor (IGF) and Integrin signaling maintained a severity signature through 52 weeks, implying an intrinsic disease severity signature well into the post-treatment timeframe. CONCLUSION: Previous proteome studies have primarily focused on the 8-week timepoint in relation to culture conversion status. While this study confirms previous observations, it also highlights some differences. The inclusion of additional end of treatment and post-treatment time points offers a more comprehensive assessment of treatment progression within the serum proteome. Examining the expression dynamics at these later time periods will help in the investigation of relapse patients and has provided indicative markers of response and recovery.

The biuret method is currently recognized as a reference measurement procedure for serum/plasma total protein by the Joint Committee for Traceability in Laboratory Medicine (JCTLM). However, as the reaction involved in this method is highly time-dependent, to ensure identical measurement conditions for calibrator and samples for high accuracy, a fast and simple measurement procedure is critical to ensure the precision and trueness of this method. We measured serum/plasma total protein using a Cary 60 spectrophotometer coupled with a fiber optic probe, which was faster and simpler than the conventional cuvette method. The biuret method utilizing alkaline solutions of copper sulfate and potassium sodium tartrate was added to the sample and calibrator (NIST SRM 927e) incubated for 1 h before measurement. A panel of samples consisting of pooled human serum, single donor serum, and certified reference materials (CRMs) from three sources were measured for method validation. Sixteen native patient samples were measured using the newly developed biuret method and compared against clinical analyzers. Additionally, the results of three cycles of a local External Quality Assessment (EQA) Programme submitted by participating clinical laboratories were compared against the biuret method. Our biuret method using fiber optic probe demonstrated good precision with within-day relative standard deviation (RSD) of 0.04 to 0.23% and between-day RSD of 0.58%. The deviations between the obtained values and the certified values for all three CRMs ranged from −0.38 to 1.60%, indicating good method trueness. The routine methods using clinical analyzers were also found to agree well with the developed biuret method using fiber optic probe for EQA samples and native patient samples. The biuret method using a fiber optic probe represented a convenient and reliable way of measuring serum total protein. It also demonstrated excellent precision and trueness using CRMs and patient samples, which made the method a simpler candidate reference method for serum protein measurement. [ABSTRACT FROM AUTHOR]

Melatonin is produced in the pineal gland under very tight control through the influences of light and the suprachiasmatic nucleus. As such, melatonin circulates in the blood at levels <3 pg/ml during the day and is only actively secreted at night reaching levels of approximately 100 pg/ml. As a consequence of binding to plasma proteins, free melatonin appears in saliva at approximately one third the plasma concentration. Measurement of melatonin is technically challenging because of these very low concentrations and while a number of commercial immunoassay kits are available and mass spectrometry assay methods have been published, not all are fit for purpose and can lead to unreliable conclusions. In this review I discuss the aspects of pineal melatonin production that saliva melatonin reflects, the factors influencing melatonin production or metabolism, saliva collection and analysis methods. Examples are provided of the appropriate use of saliva melatonin measurements; Dim Light Melatonin Onset (DLMO) assessment, impact of light on melatonin and the monitoring of rhythms prior to specific treatments. Examples of inappropriate use of saliva melatonin measurements are also provided including the use of poorly validated assays, morning saliva collections, attempts to stimulate melatonin, and linking specific illnesses to saliva melatonin levels. [ABSTRACT FROM AUTHOR]

ABSTRACT Mesenchymal stem cells‐derived exosomes (MSCs‐EXs) applications have brought a key breakthrough in treating type 1 diabetes mellitus (T1DM) and its diabetic complications. However, various recent strategies aimed to construct prominent engineered EXs with greater precision and higher efficiency for diabetes syndrome were conducted. In this research, we seek to enhance the medicinal potentialities of MSCs‐EXs on type 1 diabetic rats' hepatic complications, via loading with either selenium (Se) or nano selenium (NSe) particles. For consecutive 4‐weeks, rats were divided into 8 groups as; control, EXs, EXs + Se, EXs + NSe, STZ‐diabetic (D), D + EXs, D + EXs + Se, and D + EXs + NSe groups. The three diabetic‐treated groups manifested a significant reduction in hepatic contents of oxidative stress (OS) (MDA, NO, and H2O2) inflammatory (IL‐6, TNF‐α, and TGF‐β), and apoptotic (P53, BAX, caspase‐3, and Bcl2) markers, with marked elevation in hepatic antioxidant levels (GSH, GPX, SOD, and CAT). Such results were supported by the marked diminish in serum total proteins, liver function enzymes (AST, ALT, and bilirubin), and both serum and liver lipid profile fractions. In addition, hepatic histological examination showed marked improvement in liver architecture of all treated diabetic rats' groups, compared to diabetic untreated rats. Significantly, diabetic rats with EXs loaded with NSe exhibited the most therapeutic superiority. [ABSTRACT FROM AUTHOR]

The article discusses a study on the bioactive mediator profile of patients with Eosinophilic Granulomatosis with Polyangiitis (EGPA) treated with mepolizumab. The research aimed to understand variations between patients with bronchial asthma (BA) and EGPA, as well as the mechanisms of action of glucocorticoid (GC) and mepolizumab therapy. The study found differences in protein levels between BA and EGPA, with specific proteins being elevated in EGPA cases. Additionally, the study highlighted the effects of GC treatment on EGPA and the additional changes induced by mepolizumab, suggesting a multifaceted role of IL-5 in the pathogenesis of EGPA. [Extracted from the article]

Background: Schizophrenia (SZ) is a severe mental disorder with complex origins. Observational studies suggested that inflammatory factors may play a role in the pathophysiology of SZ and we aim to investigate the potential genetic connection between them by examining the causal impact of circulating inflammatory proteins on SZ. Methods: We utilized Mendelian randomization (MR) analysis to assess the causal relationship between circulating inflammatory proteins and SZ and the GWAS summary datasets were sourced from public databases. The SZ dataset comprised 74,776 cases and 101,023 controls, while the summary results for 91 plasma proteins in 14,824 participants were obtained through the Olink Target platform. Moreover, to identify and evaluate potential drug targets, we searched the Drug-Gene Interaction Database (DGIdb). Results: The results of the MR study confirmed that nine inflammatory proteins had a causal effect on SZ. Among these proteins, IL1A (OR: 0.93), TNFB (OR: 0.94), TNFSF14 (OR: 0.96), and CD40 (OR: 0.95) exhibited protective effects against SZ. Conversely, CCL23 (OR: 1.04), CCL19 (OR: 1.04), 4EBP1 (OR: 1.06), TWEAK (OR: 1.08), and DNER (OR: 1.10) were associated with an increased risk of SZ. The MR-Egger and weighted median methods also supported the direction of these effects. According to the Gene-Drug analysis, LTA, IL1A, CD40, and 4EBP1 can serve as drug targets. Conclusions: Our study established causal relationships between circulating inflammatory proteins and SZ. It may be beneficial to personalize the treatment of SZ by incorporating inflammation management into the treatment regimen. [ABSTRACT FROM AUTHOR]

Introduction: Data overlapping of different biological conditions prevents personalized medical decision-making. For example, when the neutrophil percentages of surviving septic patients overlap with those of non-survivors, no individualized assessment is possible. To ameliorate this problem, an immunological method was explored in the context of sepsis. Methods: Blood leukocyte counts and relative percentages as well as the serum concentration of several proteins were investigated with 4072 longitudinal samples collected from 331 hospitalized patients classified as septic (n=286), non-septic (n=43), or not assigned (n=2). Two methodological approaches were evaluated: (i) a reductionist alternative, which analyzed variables in isolation; and (ii) a non-reductionist version, which examined interactions among six (leukocyte-, bacterial-, temporal-, personalized-, population-, and outcome-related) dimensions. Results: The reductionist approach did not distinguish outcomes: the leukocyte and serum protein data of survivors and non-survivors overlapped. In contrast, the non-reductionist alternative differentiated several data groups, of which at least one was only composed of survivors (a finding observable since hospitalization day 1). Hence, the non-reductionist approach promoted personalized medical practices: every patient classified within a subset associated with 100% survival subset was likely to survive. The non-reductionist method also revealed five inflammatory or disease-related stages (provisionally named 'early inflammation, early immunocompetence, intermediary immuno-suppression, late immuno-suppression, or other'). Mortality data validated these labels: both 'suppression' subsets revealed 100% mortality, the 'immunocompetence' group exhibited 100% survival, while the remaining sets reported two-digit mortality percentages. While the 'intermediary' suppression expressed an impaired monocyte-related function, the 'late' suppression displayed renal-related dysfunctions, as indicated by high concentrations of urea and creatinine. Discussion: The data-driven differentiation of five data groups may foster early and non-overlapping biomedical decision-making, both upon admission and throughout their hospitalization. This approach could evaluate therapies, at personalized level, earlier. To ascertain repeatability and investigate the dynamics of the 'other' group, additional studies are recommended. [ABSTRACT FROM AUTHOR]

Background: Membranous nephropathy (MN) and IgA nephropathy (IgAN) pose challenges in clinical treatment with existing therapies primarily focusing on symptom relief and often yielding unsatisfactory outcomes. The search for novel drug targets remains crucial to address the shortcomings in managing both kidney diseases. Methods: Utilizing GWAS data for MN (ncase = 2150, ncontrol = 5829) and IgAN (ncase = 15587, ncontrol = 462197), instrumental variables for plasma proteins were derived from recent GWAS. Sensitivity analysis involved bidirectional Mendelian randomization analysis, MR Steiger, Bayesian co-localization, and Phenotype scanning. The SMR analysis using eQTL data from the eQTLGen Consortium was conducted to assess the availability of selected protein targets. The PPI network was constructed to reveal potential associations with existing drug treatment targets. Results: The study, subjected to the stringent Bonferroni correction, revealed significant associations: four proteins with MN and three proteins with IgAN. In plasma protein cis-pQTL data from two cohorts, an increase in one standard deviation in PLA2R1 (OR = 2.01, 95%CI = 1.83–2.21), AIF1 (OR = 9.04, 95%CI = 4.69–17.41), MLN (OR = 3.79, 95%CI = 2.12–6.78), and NFKB1 (OR = 29.43, 95%CI = 7.73–112.0) was associated with an increased risk of MN. Additionally, in plasma protein cis-pQTL data, a standard deviation increase in FCGR3B (OR = 1.15, 95%CI = 1.09–1.22) and BTN3A1 (OR = 4.05, 95%CI = 2.65–6.19) correlated with elevated IgAN risk, while AIF1 (OR = 0.58, 95%CI = 0.46–0.73) exhibited IgAN protection. Bayesian co-localization indicated that PLA2R1 (coloc.abf-PPH4 = 0.695), NFKB1 (coloc.abf-PPH4 = 0.949), FCGR3B (coloc.abf-PPH4 = 0.909), and BTN3A1 (coloc.abf-PPH4 = 0.685) share the same variants associated with MN and IgAN. The SMR analysis indicated a causal link between NFKB1 and BTN3A1 plasma protein eQTL in both conditions, and BTN3A1 was validated externally. Conclusion: Genetically influenced plasma levels of PLA2R1 and NFKB1 impact MN risk, while FCGR3B and BTN3A1 levels are causally linked to IgAN risk, suggesting potential drug targets for further clinical exploration, notably BTN3A1 for IgAN. [ABSTRACT FROM AUTHOR]

Introduction: The role of the complement inhibitory proteins CD46 and CD59 in the immune response to an acute coronary syndrome (ACS) is unknown. We investigated the relationships between the shedding of CD46 and CD59 into the circulation, reflected by plasma levels of soluble CD46 and CD59, and the risk for post-ACS complications. Methods: We measured plasma sCD46 and sCD59 in a cohort of 546 ACS patients within 24 h after hospital admission, and after 6-weeks in a subgroup of 114 patients. Study outcomes were incident heart failure (HF), major adverse cardiovascular events (MACE) and mortality during a median follow-up period of up to 3.3 years. Echocardiography at 1-year was performed in the follow-up subgroup. Results: Elevated sCD46 and sCD59 were correlated with increased levels of inflammatory mediators and metalloproteinases in plasma, and were associated with increased risk for MACE in Cox proportional hazard models adjusted for cardiovascular risk factors and revascularization [HR 95% CI 1.24 (1.02–1.52), p = 0.034 for sCD46 and 1.18 (1.00–1.38), p = 0.049 for sCD59]. Elevated sCD59 was also associated with higher incidence of HF [HR 95% CI 1.41 (1.15–1.74), p = 0.001], and with lower left ventricular ejection fraction at 1-year post-ACS (Spearman r = − 0.234, p = 0.020). We found no associations between plasma levels of the proteins at 6 weeks and outcomes. Conclusions: Shedding of the complement regulators CD46 and CD59 in plasma in the acute phase of ACS is associated with a negative prognosis. Plasma sCD46 and sCD59 could reflect the degree of local immune activation and serve as prognostic biomarkers in ACS patients. [ABSTRACT FROM AUTHOR]

A 60-day feeding trial was conducted to evaluate the effects of dietary Anabaena blue-green algae (ABGA) meal on the growth performance, digestibility, and physio-metabolic responses of Catla catla fingerlings (initial average weight 9.45 ± 0.15 g). Six iso-nitrogenous (30% crude protein) and iso-caloric (378.09 Kcal. digestible energy/100 g) diets were formulated: a control diet (A0, 0% ABGA) and five experimental diets with varying ABGA inclusion levels (A3: 3%, A6: 6%, A9: 9%, A12: 12%, A15: 15%). The results demonstrated that there were no significant differences (P > 0.05) in percentage weight gain (PWG), specific growth rate (SGR), protein efficiency ratio (PER), and feed conversion ratio (FCR) among the experimental groups. Additionally, dietary ABGA did not significantly affect (P > 0.05) body carcass composition among different groups. However, amylase activity significantly decreased (P < 0.05) in the A12 and A15 fed groups, whereas lipase and protease activities remained insignificant (P > 0.05) across all groups. Notably, oxidative stress responses (SOD; superoxide dismutase and CAT; catalase), carbohydrate metabolic enzymes (LDH; lactate dehydrogenase and MDH; malate dehydrogenase), and serum glucose levels increased significantly (P < 0.05) with higher ABGA inclusion. Conversely, serum albumin content significantly decreased (P < 0.05) in the ABGA-fed groups. There were no significant differences (P > 0.05) observed in serum total protein, albumin/globulin (A/G) ratio, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) activities among the experimental groups. Hematological parameters revealed that RBC (red blood cell) count, hemoglobin (Hb) concentration, and packed cell volume (PCV) significantly decreased (P < 0.05), while WBC (white blood cell) count significantly (P < 0.05) increased with higher dietary ABGA inclusion. In conclusion, the inclusion of dietary ABGA up to 15% did not impair nutrient utilization and supported normal growth performance in C. catla fingerlings. However, higher inclusion levels may have a detrimental effect on their growth, nutrient utilization, and physio-metabolic responses. [ABSTRACT FROM AUTHOR]

AbstractBackgroundsObjectivesMaterial and MethodsResultsConclusionsOtolin-1 and otoconin-90, the main otoconia matrix protein, can pass through the labyrinth-blood barrier and are detectable in the peripheral blood. Previous studies have shown that serum levels of these proteins well reflect otolith status, but none of concerning Meniere’s disease (MD).This study aimed to evaluate the serum levels of otolin-1 and otoconin-90 in patients with MD.Patients with MD confirmed during an acute episode, and age- and sex-matched controls were recruited. Their demographic and clinical data were recorded. The serum levels of otolin-1 and otoconin-90 were measured and compared.A total of 33 patients with MD and 176 healthy controls were recruited. In patients with MD, the median otolin-1 level was 284.96 pg/mL (interquartile range [IQR] 208.65–331.49 pg/mL) and the median otoconin-90 level was 60.50 ng/mL (IQR 40.61–85.62 ng/mL), which were significantly higher than those in the control group (p < 0.0001 and p = 0.005, respectively). Among patients with MD, serum otoconin-90 levels were correlated with the MD clinical grade (ρ = 0.487, p = 0.04), whereas serum otoconin-1 levels were not (ρ = 0.327, p = 0.063).Serum levels of otolin-1 and otoconin-90 may serve as biomarkers of otolith lesions in patients with MD. [ABSTRACT FROM AUTHOR]

Background: With increasing age, the social and economic burdens of postmenopausal osteoporosis are steadily increasing. This study aimed to investigate the factors that influence the development of postmenopausal osteoporosis. Methods: Postmenopausal women at the Affiliated Hospital of Jiangnan University from January 2023 to December 2023 were recruited for BMD examination. The patients were divided into a normal group, an osteopenia group and an osteoporosis group according to their T value. Questionnaires, including the Gastrointestinal Symptom Rating Scale and Short Form 12, were administered through face-to-face interviews. Bone turnover markers and serum protein levels of Fasting venous blood were detected. Results: A total of 222 postmenopausal women met the inclusion criteria were recruited. Univariate analysis revealed statistically significant differences in age, education, BMI, supplementation with soy products, supplementation with dairy products, supplementation with other nutritional supplements, exercise frequency, gastrointestinal symptom score, quality of life, 25(OH)D, total protein, albumin and prealbumin among the three groups (P < 0.05). Pearson correlation analysis revealed that gastrointestinal symptoms (r = -0.518, P < 0.01) was negatively correlated with BMD in postmenopausal women, while PCS (r = 0.194, P = 0.004), MCS (r = 0.305, P < 0.01), 25(OH)D (r = 0.531, P < 0.01), total protein (r = 0.324, P < 0.01), albumin (r = 0.341, P < 0.01) and prealbumin (r = 0.259, P < 0.01) were positively correlated with BMD. Logistic regression analysis revealed that both the gastrointestinal symptom score and serum 25(OH)D level were found to have a significant association with BMD (both P < 0.01). This association remained significant even after adjusting for age, BMI, education level, dietary habits, and exercise frequency. Conclusion: Gastrointestinal symptoms and serum 25(OH)D elevel are associated with increased risk of osteoporosis in postmenopausal women and may be useful in predicting osteoporosis in postmenopausal women. [ABSTRACT FROM AUTHOR]

To explore diagnostic and prognostic biomarkers in the progression of oral squamous cell carcinoma (OSCC) and to reveal their regulatory mechanisms in key pathways. A RayBiotech protein chip was used to screen differentially expressed serum proteins in OSCC, oral leukoplakia (OLK), and healthy participants. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to determine the pathways enriched by characteristic differential proteins. Immunohistochemical analysis and western blotting were used to verify the expression of characteristic differential proteins and key regulatory factors in human tissues and in a nude mouse model. Fibroblast growth factor 6 (FGF6) was identified as a key differential protein and was weakly expressed in OSCC tissues. The mitogen-activated protein kinases (MAPK) and PI3K-AKT pathways were identified as key signaling pathways. The results showed that pERK, Cyclin D1, pAKT, and BCL2 were highly expressed in OSCC, Caspase9 was lowly expressed in OSCC. With an increase in FGF6 expression in nude mice, the expression of FGFR4, pERK, Cyclin D1, pAKT, BCL2, GPX4, and ACSL4 increased, and the expression of Caspase9 decreased. FGF6 may change the expression of apoptosis-related proteins and proliferation factors by binding to FGFR4 in the PI3K-AKT/MAPK pathway and may inhibit the ferroptosis of OSCC, thereby possibly participating in the process of inhibiting OSCC. [ABSTRACT FROM AUTHOR]

Summary Insomnia has been suggested as a potential modulator of systemic inflammation. However, few studies have examined the longitudinal association between insomnia and inflammation as well as the role of sex differences, despite accumulating evidence of the vulnerability of women to immune consequences of disturbed sleep. In this study, we tested the association between self‐reported insomnia symptoms and serum C‐reactive protein, a marker of systemic inflammation, at 1‐year follow‐up, in 54 outpatients with inflammatory bowel disease (52.81 ± 16.09, 40.7% women). Insomnia symptoms were measured using the Insomnia Severity Index. After controlling for baseline inflammation and health variables, longitudinal moderated regression analysis showed that baseline insomnia symptoms predicted C‐reactive protein levels at follow‐up in women (β = 0.416, p = 0.014), but not in men (β = −0.179, p = 0.212). Results were not influenced by sex differences in insomnia severity or C‐reactive protein levels. This study suggests insomnia symptoms may partially influence systemic inflammation in women with inflammatory bowel disease. Sex‐specific psychological, immune and neuroendocrine pathways linking sleep to inflammation should be further elucidated. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion This prospective pilot study evaluated urinary interferon‐γ‐induced protein‐10 (IP‐10)/creatinine and tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL)/creatinine ratios as non‐invasive biomarkers for distinguishing bacterial from viral infections and assessing disease severity in febrile children.The study involved 85 febrile children and 29 healthy controls, measuring urinary IP‐10/creatinine and TRAIL/creatinine ratios to determine their diagnostic utility.Both ratios were significantly elevated in infected patients compared to controls. The IP‐10/creatinine ratio effectively assessed disease severity in the overall cohort and subgroups (AUC: 0.7324, 0.7192, 0.7277; p < 0.05). Serum C‐reactive protein showed limited discriminatory ability in viral infections (AUC = 0.5385, p = 0.7257). Differentiation between bacterial and viral infections using IP‐10/creatinine approached significance (p = 0.082). No significant differences in biomarker levels were observed across pathogens.The urinary IP‐10/creatinine ratio shows promise as a biomarker for assessing paediatric infection severity, particularly when traditional markers are less effective. Larger studies are needed to validate these results and improve its discriminatory accuracy in clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: Lefamulin is the first pleuromutilin antibiotic approved for the treatment of community-acquired bacterial pneumonia (CABP). However, the pharmacokinetic/pharmacodynamic (PK/PD) characteristics in Chinese CABP patients are not fully understood. This study aimed to evaluate its microbiological efficacy against Streptococcus pneumoniae and Staphylococcus aureus via PK/PD analysis. Methods: The population PK (PopPK) model, established with foreign data was validated using data from Chinese CABP patients. PK/PD analysis was conducted for the intravenous administration of 150 mg q12 h for 1-h, 1.5-h and extended 2-h infusion. Oral administrations of 600 mg q12 h were assessed, considering original and higher plasma protein binding. Results: Lefamulin displayed similar PK characteristics in both Chinese and Western populations. The PopPK model effectively predicted lefamulin concentrations in Chinese CABP patients. Under the dosage regimen of 150 mg q12 h via intravenous infusion for 1/1.5/2 h, the probability of target attainments reached 98% at the minimum inhibitory concentration for both 90% S. pneumoniae and S. aureus, considering both original and higher protein binding rates. It is advisable to extend the infusion duration from 1/1.5 h–2 h to minimize the risk of adverse effects at the infusion site. Regardless of fasted or fed conditions, the PTAs for 600 mg q12 h lefamulin via oral administration proved comparable to those for intravenous administration. Conclusion: This study proved that intravenous and oral administrations of lefamulin can reach preclinical PK/PD targets of S. pneumoniae and S. aureus. These findings support the optimal use of lefamulin for the safe and effective treatment of Chinese CABP patients. [ABSTRACT FROM AUTHOR]

Introduction: Ascaris lumbricoides infection is one of the most common soil-transmitted helminthiasis and IgE response to this helminth may increase the risk of asthma, bronchial hyperreactivity and atopy. There is not enough evidence showing the role of group-2 innate lymphoid cells (ILC2) in the pathogenesis of helminth infections in humans. Here, we aimed to investigate and characterize the influence of Ascaris lumbricoides infection on circulating ILCs in endemically exposed subjects. Methods: Non-infected (NI; n=16) and Ascaris-infected (AI; n=16) subjects from an endemic area were included. Two consecutive stool samples from each subject were examined by Kato-Katz to define parasite infection. Antibodies to the ABA-1 antigen of Ascaris and Ascaris extract were measured by ELISA. ILC subsets and their activation markers (CD25, CD69, thymic stromal lymphopoietin receptor (TSLPR) were evaluated in its PBMC by flow cytometry. Proximity extension assay (PEA) was performed to explore plasma proteins associated to infection. Results: No significant differences in the relative or absolute frequencies of total ILCs, ILC1, ILC2 and ILC3 cells were observed regarding the infection status. However, within AI group, IgE-sensitized subjects to ABA-1 had higher frequencies and counts of ILC2 (p<0.05). Frequencies of CD25+, CD69+ and TSLPR+ ILC2 were higher in AI compared to the NI (p<0.01). Additionally, egg burden was positively correlated with CD69+ ILC2 frequencies (r=0.67; p=0.005). Tryptase alpha/beta 1 (TPSAB1), GP6 and several plasma proteins associated with cell growth and granulocyte chemotaxis were highly expressed in the AI group (p<0.05). Interestingly, TPSAB1 levels were positively correlated with ILC2 expressing activation markers frequencies, egg burden and IgE levels against Ascaris. Discussion: Ascaris infection is associated with increased expression of ILC2 activation markers and TPSAB1, which may contribute to the type-2 response. [ABSTRACT FROM AUTHOR]

The protein corona formed on nanoparticles (NPs) has potential as a valuable diagnostic tool for improving plasma proteome coverage. Here, we show that spiking small molecules, including metabolites, lipids, vitamins, and nutrients into plasma can induce diverse protein corona patterns on otherwise identical NPs, significantly enhancing the depth of plasma proteome profiling. The protein coronas on polystyrene NPs when exposed to plasma treated with an array of small molecules allows for the detection of 1793 proteins marking an 8.25-fold increase in the number of quantified proteins compared to plasma alone (218 proteins) and a 2.63-fold increase relative to the untreated protein corona (681 proteins). Furthermore, we discovered that adding 1000 µg/ml phosphatidylcholine could singularly enable the detection of 897 proteins. At this specific concentration, phosphatidylcholine selectively depletes the four most abundant plasma proteins, including albumin, thus reducing the dynamic range of plasma proteome and enabling the detection of proteins with lower abundance. Employing an optimized data-independent acquisition approach, the inclusion of phosphatidylcholine leads to the detection of 1436 proteins in a single plasma sample. Our molecular dynamics results reveal that phosphatidylcholine interacts with albumin via hydrophobic interactions, H-bonds, and water bridges. The addition of phosphatidylcholine also enables the detection of 337 additional proteoforms compared to untreated protein corona using a top-down proteomics approach. Given the critical role of plasma proteomics in biomarker discovery and disease monitoring, we anticipate the widespread adoption of this methodology for the identification and clinical translation of biomarkers. The protein corona on nanoparticles has potential for application in protein diagnostics. Here, the authors report on the use of small molecules to change the protein and proteoform patterns of protein corona on otherwise identical nanoparticles, which can be leveraged to significantly enhance the depth of plasma proteome profiling. [ABSTRACT FROM AUTHOR]

Objectives: Colorectal cancer (CRC) is a major global health concern, ranking as the third most common cancer and the fourth leading cause of cancer-related deaths worldwide. Currently, the diagnostic accuracy of Lymph node metastasis (LNM) is currently unsatisfactory. Therefore, there is an urgent need to develop a reliable tool that can accurately predict lymph node metastasis (LNM) in patients diagnosed with CRC. Methods: We conducted an extensive proteomics investigation aimed at examining lymph node metastasis (LNM) in individuals diagnosed with colorectal cancer (CRC). In the discovery stage, employing a mass spectrometry-based proteomic approach, we analyzed a cohort of 60 colorectal cancer patients (NM=30, LNM=30), identifying distinct molecular profiles that differentiate patients with and without lymph node metastasis (LNM). Subsequently, we validated the protein classifier associated with lymph node metastasis. Results: We elucidated a combinatorial predictive protein biomarker that can distinguish patients with and without lymph node metastasis by LC-MS/MS. The classifier achieved an area under the curve (AUC) of 0.892 (95% CI, 0.842-0.941), while in the testing cohort, it attained an AUC of 0.929 (95% CI, 0.824-1.000). Furthermore, the four protein markers demonstrated an AUC of 0.84 (95% CI, 0.783–0.890) in the validation cohort. Additionally, we categorized patients into three types based on immunophenotyping. Type 1 primarily consisted of patients with negative lymph node metastasis (NM), characterized by immune cells such as NK cells, CD4 T effector memory cells, and memory B cells. Type 2 mainly included patients with positive lymph node metastasis (LNM), characterized by immune cells such as mesangial cells, epithelial cells, and mononuclear cells. In Type 1, a prominent upregulation observed in immune inflammation, as well as in glucose and lipid metabolism. In Type 2, significant upregulation was evident in pathways such as pyrimidine metabolism and cell cycle regulation. The findings of this study suggest that immune mechanisms may exert a pivotal role in the process of lymph node metastasis in CRC. Conclusions: Here, we present plasma protein signatures associated with lymph node metastasis in colorectal cancer (CRC). However, further validation across multiple centers is necessary to generalize these findings. [ABSTRACT FROM AUTHOR]

To determine whether a multimodal assay combining serum microRNA with protein biomarkers and metadata improves triage assessment of an adnexal mass. Serum samples from 468 training subjects (191 cancer cases and 277 benign adnexal mass controls or healthy controls) were analyzed for seven protein biomarkers and 180 miRNA. Circulating analyte data were combined with age and menopausal status (metadata) into a neural network model to classify samples as cases or controls. Forward regression with ten-fold cross-validation minimized the dimensionality of the model while maximizing linear separation between cases and controls. Model validation proceeded using both internal (44 cases and 56 controls) and external validation sets (51 cases and 59 controls). The total study population comprised 678 subjects, including 286 cases and 392 controls. Overall, 290 (43%) of the subjects were premenopausal. A panel of 10 miRNA delivered optimal performance when combined with protein and metadata features. The combined model improved the Receiver Operator Characteristic Area Under the Curve (ROC AUC) on the internal (AUC = 0.9; 95% CI 0.81–0.95) and external validation sets (AUC = 0.95; 95% CI 0.90–0.98) compared to miRNA alone or proteins plus metadata (without miRNA). On external validation, the combined model offered 92% sensitivity at 80% specificity overall, with 80% and 100% sensitivity for early and late-stage cancers, respectively, including 78% sensitivity for early-stage, serous ovarian cancers and 82% sensitivity for early-stage, non-serous cancers. A multimodal assay combining miRNA with protein biomarkers, age, and menopausal status improves surgical triage of an adnexal mass. • Serum miRNA and protein biomarkers are complementary in estimating the risk of malignancy of an ovarian mass. • An integrated model with proteins, miRNA, and metadata offers the most accurate classification performance. • The addition of miRNA improves sensitivity and specificity for identification of early-stage ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Allergy immunotherapy (AIT), a treatment approach for allergic rhinitis (AR), is recognized for its potential to modify the disease course beyond mere symptom relief. Interleukin‐36γ (IL‐36γ), a key player in immune responses, has been implicated in promoting eosinophilic inflammation in AR by activating eosinophils. We aimed to investigate the effect of IL‐36γ on group II lymphoid cell (ILC2) in AR patients who underwent sublingual immunotherapy (SLIT). Methods: Twenty‐four AR patients were enrolled and administered with SLIT. Serum proteins of IL‐36γ, interleukin‐5 (IL‐5), and interleukin‐13 (IL‐13) during SLIT were quantitatively assessed using enzyme‐linked immunosorbent assay (ELISA). The proportion of ILC2 was determined by flow cytometry. Sorted ILC2s were stimulated by IL‐36γ and ILC2 cell differentiation, and type II cytokines expression were examined. Results: SLIT treatment decreased the serum protein levels of IL‐36γ, IL‐5, IL‐13, and the proportion of ILC2 significantly. IL‐36γ suppressed the proliferation of ILC2 by inhibiting the levels of ILC2 transcription factor. IL‐36γ also inhibited IL‐5 and IL‐13 expression from ILC2. Conclusion: The changes of IL‐36γ during SLIT were related to the inhibited function of ILC2, implying that IL‐36γ may be used as a new biomarker for monitoring the efficacy of SLIT in AR. [ABSTRACT FROM AUTHOR]

A 30‐day research was carried out to examine the impacts of dietary taurine (Tau) on ovaries maturation and physiological responses of Penaeus vannamei female brooders (29.4 ± 0.2 g). A basal diet (497 g kg−1 protein and 140 g kg−1 lipid) was administered with graded levels of Tau ranging from 0 (control) to 2, 4, 6, 8, and 10 g kg−1. A total of 180 shrimp brooders were stocked into 18 250 L black circular polyethylene tanks. Female (n = 5) and male (n = 5) shrimps were stocked in each tank and supplied with seawater (35.2 ± 3.1 g L−1 salinity, 28.9 ± 1.4°C) and the experimental feeds were offered to shrimp twice a day at 5% of their biomass. Supplementing diet with 4–8 g Tau kg−1 reduced latency period after eye stalk ablation to spawning (5–6 days) that was associated with higher hepatopancreatic and gonadosomatic (except for 8 g Tau kg−1 diet) indices (p < 0.05). With 10 g Tau kg−1 diet hepatopancreas glutathione peroxidase activity and total antioxidant capacity increased and catalase activity increased by 6 g Tau kg−1 diet. Supplementing diet with Tau‐enhanced bile‐salt dependent lipase activity in the gut. Docosahexaenoic acid and Tau levels were elevated in the ovaries with the increment of dietary Tau level (p < 0.05). Plasma total protein, calcium, cholesterol, and high‐density lipoprotein increased with inclusion of 6–10 g Tau kg−1 diet. The transcription levels of vitellogenin, insulin-like growth factor II, superoxide dismutase, prophenoloxidase, and lysozyme genes transcription levels were upregulated in the hepatopancreas of shrimp brooders fed 6–10 g Tau kg−1 diet (p < 0.05). It seems that Tau at 4–8 g kg−1 diet by modulating lipid metabolism, antioxidant capacity, and immunocompetence can improve maturation and health status of P. vannamei brooders. [ABSTRACT FROM AUTHOR]

AbstractWe investigated serum concentrations of specific inflammatory parameters in patients with significant carotid artery stenosis (CAS) of 50–99%, with an additional focus on patients with moderate stenosis (50–69%), in terms of both symptomatic status and plaque morphology, to determine whether there are certain parameters that can be associated with plaque instability before the progression of CAS to a high degree. The study included 119 CAS patients, 29 of whom had moderate stenosis, and 46 controls. Ultrasonography of the carotid arteries was performed using color flow Doppler and B-mode duplex ultrasound, and serum inflammatory parameters were measured using commercially available enzyme immunoassays. When comparing patients with 50–99% stenosis, only serum amyloid A (SAA) was higher in symptomatic patients, while in the group of patients with 50–69% stenosis, myeloperoxidase (MPO) was higher and pentraxin-3 (PTX-3) was lower in symptomatic compared to asymptomatic patients, and soluble urokinase plasminogen activator receptor (suPAR) was higher in patients with carotid plaque of unstable compared to stable morphology. Our results suggest that the importance of different inflammatory parameters in patients with moderate CAS is not the same as in CAS patients in general, and therefore their separate investigation in patients with high and moderate stenosis may be beneficial. SAA has the potential to be further considered in research to predict CAS symptom risk. There is a possibility that MPO and PTX-3 play a role in the development of CAS symptoms originating from less stenotic plaques and that suPAR is involved in the destabilisation of such plaques. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have investigated the molecular properties that contribute to the symptoms of COVID-19, such as the virus's genetic makeup, its replication mechanisms, and how it interacts with host cells. However, identifying the immunopathological properties, such as the immune system's response, cytokine levels, and the presence of specific biomarkers, that are associated with the severity of the infection remains crucial for developing effective treatments and preventions. Methods: We analyzed blood protein factor profiles from 420 individuals to identify features differentiating between test-negative healthy, asymptomatic, and symptomatic individuals using statistical comparison and the least absolute shrinkage and selection operator (i.e., LASSO) algorithm. Additionally, we examined single-cell RNA sequencing data from 141 individuals to identify specific cell types associated with the COVID-19 symptoms. Results: Healthy individuals who tested negative had distinct blood protein factor levels compared to asymptomatic individuals. We identified two key protein factors, Serpin A10 and Complement C9, that differentiate between asymptomatic and symptomatic patients. Symptomatic patients showed lower levels of CD4+ T naïve, CD4+ T effector & memory, and CD8+ T naïve cells, along with higher levels of CD14+ classical monocytes compared to asymptomatic patients. Additionally, CD16+ non-classical monocytes, major producers of C1QA/B/C, appeared to contribute to the observed Complement C9 levels. Conclusions: These findings advance our understanding of the immunopathological mechanisms underlying COVID-19 and may inform the development of targeted therapies and preventative measures. Future research should focus on further elucidating these mechanisms and exploring their potential clinical applications in managing COVID-19 severity. [ABSTRACT FROM AUTHOR]

Objectives Background Methods/Materials Results Conclusion Fast thawing for emergency situations and reduction of plasma wastage.Evaluation of plasma units, pooled and pathogen reduced (PR) in “maxi‐pools” with amotosalen and UVA light, and fast thawing.Per replicate, 10 WB‐derived leukocyte depleted plasma units were frozen within 24 h at ≤ −25°C and stored for 7 days. After thawing, a maxi‐pool was constituted from the 10 units. After splitting into 4 sub‐pools of 650 mL, the sub‐pools were PR treated then split into 3 units resulting in 12 PR plasma units at 200 mL. Hundred and twenty PR plasma units were produced in total. The units were frozen at ≤ −25°C for 1 week, then thawed either in a fast plasma thawer for 5 min or in other control devices (17 to 23 min). FVIII:C, Fibrinogen, albumin, IgG, protein S and VWF were measured in plasma units, maxi‐pools and plasmas after PR treatment and thawing.There was a statistically significant (p < 0.001) but still clinically acceptable (over the recommended levels of ≥0.5 IU/mL and ≥2 g/L) reduction of FVIII:C and Fibrinogen after PR with 69% and 87% recovery, respectively. Other proteins were not significantly affected by the processes.Pooling 10 plasma units before the PR treatment standardises volume and protein content of plasma units. Besides the economic value of generating 12 products for transfusion, this procedure combined with a thawing time of about 5 min is of value in emergency situations and may reduce plasma wastage. [ABSTRACT FROM AUTHOR]

ABSTRACT Mineral nutrient deficiencies and metal ion toxicities coexist on acid soils. Phosphorus (P) deficiency in plants is generally accompanied with significant levels of leaf manganese (Mn) accumulation. However, the molecular regulatory mechanisms underpinning remain unclear. The present study found that P‐deficient soybean plants accumulated more Mn compared to P‐sufficient ones on acid soils in both field and greenhouse experiments. Meanwhile, both P deficiency and Mn toxicity enhanced the expression of GmSTOP1‐3. Over‐expressing GmSTOP1‐3 enhanced Mn accumulation in transgenic soybean hairy roots, but RNA‐interference did not show obvious differences. Moreover, transgenic soybeans with GmSTOP1‐3‐overexpression showed enhanced root citrate exudation and augmented Mn accumulation. RNA‐sequence identified four downstream genes of GmSTOP1‐3, including multidrug and toxic compound extrusion (GmMATE2/13) and metal transporter genes (GmZIP6/GmIREG3), which encode plasma membrane proteins. GmSTOP1‐3 activated the transcription of these four genes by directly binding to their promoter regions. In addition, both GmZIP6 and GmIREG3 functioned in Mn uptake as manifested by the higher Mn concentration and decreased growth of soybean hairy roots with their overexpression. Taken together, it is suggested that upregulation of GmSTOP1‐3 by low P stress on acid soils activates transcripts of GmMATE2/13 and GmZIP6/GmIREG3, which consequently result in enhanced Mn accumulation in soybean. [ABSTRACT FROM AUTHOR]

Identifying the function and composition of the protein corona (i.e., the set of host proteins interacting with nanoparticles) is considered a crucial step in the development of nanoparticles for medical and pharmacological applications. Evidence suggests that host proteins can alter NP stability, biocompatibility, and pharmacokinetics features. Therefore, in this review, we provide an updated conceptual, methodological, and experimental guideline for the study of the NP protein corona. We surveyed recent literature (2009–2024) focusing on in vitro and in vivo studies. We show that several methods, including shot-gun proteomics, protein identification after in-gel digestion, and TMT proteomics, must be carefully applied and integrated to shed light on this complex phenomenon. Hence, we discuss in detail the relative protocols, highlighting the importance of the experimental conditions, ranging from the administration route to basic, but determinant, parameters like the kind of biological host fluids, the incubation times and the NP concentrations. Additionally, we propose a series of protocols that involve studying the protein corona using purified serum or plasma proteins, as well as sera depleted of specific complement proteins, to investigate the role of their deposition on the nanoparticle surface. We also explore how the role of the protein corona in inducing uptake by phagocytic cells can be examined; finally, we discuss several methodological approaches to study the effects of different coatings on the composition of the protein corona. Available data indicated that it is possible to characterize and punctually study the differential adsorption of specific proteins onto the nanoparticle surface. This allows designing NP chemical coatings features to actively guide the protein corona formation, thus improving nanotheranostic development. [ABSTRACT FROM AUTHOR]

Objective: Pyrotinb has been approved for the treatment of HER2-positive advanced or metastatic breast cancer in China. However, the plasma concentration of pyrotinb in different patients varies greatly, and in the course of treatment, if patients have intolerable adverse reactions, the drug dosage will be reduced or even stopped. This study set out to establish an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the determination of pyrotinb in human plasma, analyze the population pharmacokinetics (PPK) of pyrotinib and assess the influence of patient variables on PK of pyrotinib in patients with HER2 positive breast cancer. Method: An UPLC-MS/MS method was developed to measure pyrotinib in human plasma. Utilizing a gradient elution procedure and a Kinetex C18 column (2.1 mm × 100 mm, 1.7 μm), sample separation was accomplished in 5.5 min. Pyrotinb extraction via protein precipitation was used as a sample pre-treatment technique. In total, 50 patients provided 158 plasma samples, which were identified and used in the PPK investigation. The non-linear mixed-effects modeling (NONMEM) approach was used to assess the plasma concentrations and covariates information. For the final PPK model evaluation, external evaluation, non-parametric bootstrap, visual predictive check (VPC), and goodness-of-fit (GOF) were used. Results: The UPLC-MS/MS method for determining plasma concentration of pyrotinib in patients had good selectivity and linearity in the range of 1–1,000 ng/mL. Pyrotinib concentration profile in HER2-positive breast cancer patients was well described by a single-compartment PPK model with first-order absorption and elimination. The formulas for the final estimated values of overall parameters of CL/F and Vd/F and Ka are respectively: C L / F L / h = 88.8 × e TP / 67.2 × 0.376 , V / F L = 3940 , K A h − 1 = 0.357 F I X E D. No dosage adjustment was advised, despite the possibility that the total protein levels could have a substantial impact on the apparent distribution volume of pyrotinib with limited magnitude. Conclusion: In this study, an UPLC-MS/MS method was established to determine the concentration of pyrotinib in human plasma. A population pharmacokinetic model of pyrotinib in HER2 positive breast cancer patients suggested that low serum total protein reduced the clearance rate of pyrotinib in patients. Clinical medical staff should pay attention to the liver function of patients with abnormal serum total protein and be alert to the occurrence of adverse drug reactions. [ABSTRACT FROM AUTHOR]

Plasma membrane proteins play pivotal roles in receiving and transducing signals from other cells and from the environment and are vital for cellular functionality. Enzyme-based, proximity-dependent approaches, such as biotin identification (BioID), combined with mass spectrometry have begun to illuminate the landscape of proximal protein interactions within intracellular compartments. To extend the potential of these approaches to study the extracellular environment, we developed extracellular TurboID (ecTurboID), a method designed to profile the interactions between proteins on the surfaces of living cells over short timescales using the fast-acting biotin ligase TurboID. After optimizing our experimental and data analysis strategies to capture extracellular proximity interactions, we used ecTurboID to reveal the proximal interactomes of several plasma membrane proteins, including the epidermal growth factor receptor (EGFR). We found that EGF stimulation induced an association between EGFR and the low-density lipoprotein receptor (LDLR) and changed the interactome of LDLR by increasing its proximity with proteins that regulate EGFR signaling. The identification of this interaction between two well-studied and clinically relevant receptors illustrates the utility of our modified proximity labeling methodology for identifying dynamic extracellular associations between plasma membrane proteins. Editor's summary: Proximity labeling using the biotin ligase TurboID enables the identification of proteins that interact directly or indirectly inside cells. To extend the reach of this method to the extracellular side of the plasma membrane, Al Mismar et al. developed a form of TurboID optimized for use on the cell surface. The authors used it to identify the extracellular interactomes of several transmembrane proteins and ligand-dependent changes in the interaction partners of the epidermal growth factor receptor (EGFR). EGF stimulation induced EGFR to associate with the low-density lipoprotein receptor, demonstrating the utility of the method for detecting previously unknown interactions. —Annalisa M. VanHook [ABSTRACT FROM AUTHOR]

This study aimed to determine the antimicrobial effects of ethanolic extracts of Ulva sp. and garlic (Allium sativum) powder ethanolic extracts against Vibrio harveyi in vitro. The stimulatory effects of Ulva sp. extract (UE) and garlic powder extract (GPE) on the growth performance and innate immune responses of white‐leg shrimp, Litopenaeus vannamei, and their challenge against V. harveyi infection were also investigated. A commercial shrimp diet (36.1% protein) was enriched with 0.5, 1.0 and 2.0 g UE/kg diet and 2, 4 and 6 g GPE/kg diet, whereas the control group was free of any supplement. Health juveniles of L. vannamei (average weight 2–3 g) were distributed in 21 fiberglass reinforced plastic (FRP) tanks (500‐L capacity) at a stocking density of 300 animals/tank to represent each treatment in triplicate. The animals were fed ad libitum on the experimental diets up to satiety four times daily for 60 days. The phytochemical analysis of ethanolic extracts of Ulva sp. and garlic powder evoked their richness of several bioactive compounds showing significant antibacterial activity against V. harveyi. The GPE exhibited a higher inhibition zone than that of the UE. The supplemented diets did not significantly affect weight gain %, final weight, feed conversion ratio, specific growth rate and survival rates of white shrimp compared to those fed on the control diet. Significant increases were observed in total haemocyte count, phagocytosis and phagocytic index of all treatments compared with the control group. There were significant increases in serum total protein, acid phosphatase activity, alkaline phosphatase, lysosomal enzyme activity, phenoloxidase activity and superoxide dismutase activity with offered diets with increasing the levels of ethanolic extracts of Ulva sp. and garlic powder up to 2.0 g UE/kg diet and 6 g GPE/kg diet, respectively. The ethanolic extraction of Ulva sp. and garlic powder‐supplemented diet groups, particularly at treatments of 2.0 and 6 g GPE/kg diet, respectively, significantly reduced the shrimp mortality induced by V. harveyi infection when compared with the control group. The net results evoked that ethanolic extraction of Ulva sp. (2.0 g UE/kg) and garlic powder (6 g GPE/kg diet) enhanced the immune response and disease resistance of the white‐leg shrimp, L. vannamei. It is also noted that the GPE is more efficient than the UE in vitro and in vivo investigations. [ABSTRACT FROM AUTHOR]

Background: Understanding and finding the correlation between morphometric measurements and horse blood parameters is crucial for predicting equine metabolic issues. Objective: This study aims to analyse morphometric measurements and blood samples in horses with varying adiposity levels. Study design: Cross‐sectional observational. Methods: A total of 50 horses were included in the study and categorized into groups based on their body condition score (BCS) and cresty neck score (CNS). Results: The insulin concentration was significantly higher in overweight horses (p = 0.022). Female horses exhibited higher cortisol concentrations (p = 0.025) and girth circumference at the withers (p = 0.004) compared to males. Lactating mares exhibited higher concentrations of serum total protein (p = 0.012) and globulin (p = 0.003). A positive correlation was observed between BCS and insulin concentrations (r = 0.290, p = 0.041). Negative correlations were found between neck circumference to height at withers and glucose (r = −0.309, p = 0.029), CNS and glucose (r = −0.315, p = 0.026) as well as between crest diameter and cortisol (r = −0.360, p = 0.01). Main limitations: Increasing the sample size and conducting longitudinal studies would enhance the study's validity and reliability. Conclusion: Although insulin, glucose and cortisol concentrations have predictive capabilities based on signs and certain morphometric measurements, their correlations are not always strong. Therefore, this study challenges the notion that all overweight horses are unhealthy, as overweight horses can still have good metabolic health. Conversely, lean horses may also experience metabolic issues. Hence, relying solely on visual cues is insufficient to diagnose the metabolic status of horses. Other factors must also be considered to assess their health status accurately. [ABSTRACT FROM AUTHOR]

The Asia‐Pacific Plasma Leaders' Network (APPLN) plays a crucial role in addressing the regional shortage of plasma‐derived medicinal products (PDMPs), particularly in low‐ and middle‐income countries (LMICs). It provides a platform for experts to share their expertise and drive multi‐stakeholder collaborations. While several PDMPs are acknowledged by the World Health Organization (WHO) as life‐saving therapeutics on the Model List of Essential Medicine for treating various chronic and acute life‐threatening diseases, there are still many inadequacies in the availability and affordability of PDMPs. These challenges arise from insufficient domestic supplies of plasma suitable for fractionation, as well as a lack of technical and financial capabilities to implement contract or domestic plasma fractionation programmes. At two separate dialogue forums organized by the APPLN in 2023, experts discussed the unmet needs of PDMPs for individuals living with haemophilia and immunodeficiencies in the region. They also highlighted the limited access to early diagnosis and patient‐centred care in several LMICs. To address these issues, there is an urgent need to increase the availability of high‐quality domestic plasma for fractionation. Adopting a stepwise approach to utilize unused recovered plasma and establishing contract fractionation programmes could be viable strategies to potentially enhance PDMP availability in LMICs. However, achieving this goal requires improving existing domestic infrastructures for blood collection, implementing adequate policy reforms and fostering competent local leadership. Ultimately, there is no 'one‐size‐fits‐all' strategy for securing safe plasma proteins for all patients in need. Collaborative efforts are essential for achieving progressive self‐sufficiency in PDMPs. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a chronic inflammatory disease often associated with serious cardiovascular comorbidities. The aim of this study was to investigate the systemic inflammatory burden in psoriasis by examining various inflammatory markers and to assess the relationship between these markers and the severity of the disease. Methods: This retrospective study was conducted on medical records of patients who visited the dermatology outpatient clinic between 1 January 2016 and 31 December 2022. The study included patients with psoriasis vulgaris and healthy volunteers. Demographic data, Psoriasis Area and Severity Index score, C‐reactive protein, monocyte‐high‐density lipoprotein cholesterol ratio, neutrophil‐to‐lymphocyte ratio, platelet‐to‐lymphocyte ratio, monocyte‐to‐lymphocyte ratio, systemic immune‐inflammation index, and Systemic Inflammation Response Index were analysed and compared. Results: A total of 278 psoriasis patients and 90 healthy volunteers were analysed. Compared to the control group, psoriasis patients showed significantly higher systemic immune‐inflammation index, Systemic Inflammation Response Index, neutrophil‐to‐lymphocyte ratio, monocyte‐high‐density lipoprotein cholesterol ratio, serum C‐reactive protein levels, neutrophil count, monocyte count, body mass index, and waist circumference (p < 0.001, p = 0.001, p < 0.001, p = 0.014, p < 0.001, p < 0.001, p = 0.046, p < 0.001, and p = 0.011, respectively). Among patients with severe psoriasis (Psoriasis Area and Severity Index >10), systemic immune‐inflammation index, neutrophil‐to‐lymphocyte ratio, platelet‐to‐lymphocyte ratio, and serum C‐reactive protein levels were significantly higher compared to patients with mild/moderate psoriasis (Psoriasis Area and Severity Index ≤10). In the ROC curve analysis, the optimal cut‐off (AUC, sensitivity, specificity) values for neutrophil‐to‐lymphocyte ratio, systemic immune‐inflammation index, and platelet‐to‐lymphocyte ratio were found to be 2.11 (0.592, 62%, 57%), 552.9 (0.579, 61%, 58%), and 111.9 (0.578, 64%, 46%), respectively. The inflammatory parameters that showed correlation with Psoriasis Area and Severity Index were systemic immune‐inflammation index, Systemic Inflammation Response Index, neutrophil‐to‐lymphocyte ratio, monocyte‐high‐density lipoprotein cholesterol ratio, monocyte‐to‐lymphocyte ratio, and C‐reactive protein. Conclusion: The findings of this study suggest that systemic immune‐inflammation index, Systemic Inflammation Response Index, neutrophil‐to‐lymphocyte ratio, monocyte‐high‐density lipoprotein cholesterol ratio, and C‐reactive protein values have the potential to serve as simple and cost‐effective markers for assessing the inflammatory burden in individuals with psoriasis. [ABSTRACT FROM AUTHOR]

Serum amyloid A (SAA) is a small protein consisting of 104 residues and, under physiological conditions, exists mainly in hexameric form. It belongs to the positive acute-phase proteins, which means that its plasma concentration increases rapidly in response to injury, inflammation, and infection. The accumulation of SAA molecules promotes the formation of amyloid aggregates, which deposit extracellularly in many organs, causing their dysfunction. In our previous work, we successfully designed a peptidomimetic that inhibited the aggregation of amyloidogenic SAA fragments. In the present paper, we show how the same inhibitor, named saa3Dip, affects the oligomerization and aggregation processes of MetSAA1.1 protein. The thioflavin T assay showed that saa3Dip inhibited its fibrillization. The measurement of the internal fluorophore fluorescence (Trp) showed differences that occurred in the tertiary structure of MetSAA1.1 in the presence of the inhibitor, which was also confirmed by CD spectra in the aromatic range. FTIR results suggested that saa3Dip could stabilize some fragments of the native structure of MetSAA1.1, which was confirmed by determining the melting temperature (Tm) of the protein–inhibitor complex. AFM images demonstrated that the presence of saa3Dip prevented the formation of large SAA aggregates. Our results suggest that saa3Dip stabilizes the native conformation of MetSAA1.1. [ABSTRACT FROM AUTHOR]

Clinical differentiation of progressive supranuclear palsy (PSP) from Parkinson's disease (PD) is challenging due to overlapping phenotypes and late onset of PSP specific symptoms, highlighting the need for easily assessable biomarkers. We used proximity elongation assay (PEA) to analyze 460 proteins in serum samples from 46 PD, 30 PSP patients, and 24 healthy controls. ANCOVA was used to identify the most promising proteins and machine learning (ML) XGBoost and random forest algorithms to assess their classification performance. Promising proteins were also quantified by ELISA. Moreover, correlations between serum biomarkers and biological and clinical features were investigated. We identified five proteins (TFF3, CPB1, OPG, CNTN1, TIMP4) showing different levels between PSP and PD, which achieved good performance (AUC: 0.892) when combined by ML. On the other hand, when the three most significant biomarkers (TFF3, CPB1 and OPG) were analyzed by ELISA, there was no difference between groups. Serum levels of TFF3 positively correlated with age in all subjects' groups, while for OPG and CPB1 such a correlation occurred in PSP patients only. Moreover, CPB1 positively correlated with disease severity in PD, while no correlations were observed in the PSP group. Overall, we identified CPB1 correlating with PD severity, which may support clinical staging of PD. In addition, our results showing discrepancy between PEA and ELISA technology suggest that caution should be used when translating proteomic findings into clinical practice. [ABSTRACT FROM AUTHOR]

The composition of the protein corona covering any nanoparticle (NP) when it enters a biological fluid determines the parameters of the NP's interaction with the body. To "control" these parameters, it is important to know the composition of the protein corona, the determination of which is a complex task associated with the two-layer organization of the corona (hard and soft coronas). In a previous publication, we reported obtaining lipid-coated NPs with a full protein corona, isolating them, and proving the presence of the corona on the surface of the NPs. This work reports on the preparation, isolation, and purification of lipid-coated NPs bearing a hard corona. The protein corona composition was determined by using the LC–MS/MS method. Thirty-seven serum proteins were identified with a high degree of reliability. The hard corona contained various apolipoproteins, including apolipoprotein E, which can potentially affect the penetration of NPs into the cell. [ABSTRACT FROM AUTHOR]

Background: ST-elevation myocardial infarction (STEMI) and Takotsubo syndrome (TS) are two distinct cardiac conditions that both result in sudden loss of cardiac dysfunction and that are difficult to distinguish clinically. This study compared plasma protein changes in 24 women with STEMI and 12 women with TS in the acute phase (days 0–3 post symptom onset) and the stabilization phase (days 7, 14, and 30) to examine the molecular differences between these conditions. Methods: Plasma proteins from STEMI and TS patients were extracted during the acute and stabilization phases and analyzed via quantitative proteomics. Differential expression and functional significance were assessed. Data are accessible on ProteomeXchange, ID PXD051367. Results: During the acute phase, STEMI patients showed higher levels of myocardial inflammation and tissue damage proteins compared to TS patients, along with reduced tissue repair and anti-inflammatory proteins. In the stabilization phase, STEMI patients exhibited ongoing inflammation and disrupted lipid metabolism. Notably, ADIPOQ was consistently downregulated in STEMI patients in both phases. When comparing the acute to the stabilization phase, STEMI patients showed increased inflammatory proteins and decreased structural proteins. Conversely, TS patients showed increased proteins involved in inflammation and the regulatory response to counter excessive inflammation. Consistent protein changes between the acute and stabilization phases in both conditions, such as SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE, suggest shared underlying pathophysiological mechanisms. Conclusions: This study presents protein changes in women with STEMI or TS and identifies ADIPOQ, SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE as candidates for further exploration in both therapeutic and diagnostic contexts. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with ovarian cancer have elevated platelet counts and an increased risk of dying from blood clots. It is logical that this increased blood clot risk is caused by the increased numbers of platelets. However, to develop prevention for thrombosis in patients with ovarian cancer, it is important to know if the platelets in patients with ovarian cancer are different from the platelets in healthy individuals. In this study, we demonstrated through carefully controlled experiments that increased platelet aggregation, which is necessary for clotting, is caused by both the elevated numbers and altered behavior of platelets in patients with ovarian cancer. Furthermore, we show that the platelets from patients with ovarian cancer have elevated levels of platelet activation markers compared to healthy patients. Future experiments will evaluate why platelets in patients with ovarian cancer are more prone to clotting and will study medications that could reduce the increased blood clot risk. Background: Patients with ovarian cancer have high platelet counts, which correlate with disease burden, incidence, and lethality of blood clots (thrombosis). We hypothesized that elevated aggregation is associated with both increased platelet number and altered behavior of platelets in patients with ovarian cancer. Methods: Healthy controls and patients with suspected or diagnosed ovarian cancer were evaluated for complete blood counts. To evaluate the effects of platelet count versus platelet behavior, equal platelet-rich plasma (PRP) volumes versus equal platelet numbers were used in platelet aggregation assays. Arachidonic acid, adenosine diphosphate, and collagen platelet agonists were used to induce aggregation. Volunteers were grouped into healthy controls (23), benign/borderline cases (7), and cancer cases (25 ovarian, 1 colorectal, and 2 endometrial). Results: The rate and amount of platelet aggregation were higher in patients compared to healthy controls regardless of whether the same platelet number or PRP volume was used. Compared to healthy controls, patients with untreated ovarian cancer exhibited high levels of platelet activation markers, P-selectin (27.06 vs. 31.06 ng/mL, p = 0.03), and beta-thromboglobulin (3.073 vs. 4.091 µg/mL, p = 0.02) in their plasma. The significance of the elevation and its correlations with platelet number or PRP volume varied depending on the agonist. Platelet (305.88 vs. 134.12, p < 0.0001) and white blood cell (8.459 vs. 5.395, p < 0.01) counts (×109/L) were elevated pre-chemotherapy and decreased post-chemotherapy, respectively. Conclusions: Elevated platelet aggregation is caused by both altered platelet number and behavior in patients with ovarian cancer. These results support the study of antiplatelet agents for thrombosis prevention in these patients. [ABSTRACT FROM AUTHOR]

The objective of this randomized controlled trial was to assess the relative merits of offering unweaned calves 3 different types of diets to meet energy and water deficits that can occur during journeys. A total of 6 young unweaned male Holstein calves were randomly selected from within 2 body weight ranges (median 48 and 42 kg) from each of 29 loads (total n = 174 calves) transported from an auction market or a collection center to a calf sorting center before transport to a veal unit. The calves were then randomly allocated to one of 3 dietary treatments (n = 58 calves/dietary treatment). They were offered either a milk replacer diet (M), a glucose-electrolyte diet (G) or a whey-based diet with added electrolytes (W). The ability of these diets to provide sufficient nutrient energy to restore vigor, and avoid hypoglycemia and clinical signs of dehydration without increasing the risk of diarrhea was assessed. A clinical assessment of dehydration, health, and vigor was made, and the calves were blood sampled before feeding and at 2 h and 4 h after feeding. The plasma glucose concentration was increased 2 h and 4 h after feeding the M and W diets. The increases in plasma glucose concentration were greater 2 h and 4 h after (1) feeding the M than after the W diet and (2) feeding the M and W diets than after the G diet. Back-transformed means and 95% CI for the ratio of the plasma glucose concentration at 4 h compared with 0 h for the M, G, and W diets were 1.2 m M (CI = 1.21, 1.35), 0.95 m M (CI = 0.92, 0.97), and 1.09 m M (CI = 1.06, 1.14), respectively. We found no effect of diet on the change in serum total protein concentration between before feeding and 2 h and 4 h after feeding. The serum osmolality was lower 2 h after feeding the G diet. The fall in serum osmolality was greater 2 h after feeding the G diet than after feeding the M and W diets. The changes in the serum osmolality between before feeding and 2 h after feeding for the milk replacer, glucose-electrolytes and whey-based diets were −0.68 mOsmol (CI = −3.27, 1.91); −5.23 mOsmol (CI = −7.82, and −2.64); and −0.13 mOsmol (CI = −2.77, 2.51), respectively. The diet offered at the sorting center had no effect on subsequent growth on the veal-rearing farm between arrival and slaughter (milk replacer, 1.22 kg/d [CI = 1.17, 1.28]; glucose-electrolyte diet, 1.23 kg/d [CI = 1.18, 1.28]; whey-based diet 1.28 kg/d [CI = 1.23, 1.33]). The M diet provided the calves with nutrients and water to replace energy and water deficits that had accumulated before arrival at the sorting center, and these dietary benefits were still apparent 4 h after feeding. The benefits of the W diet were similar to those of the M diet, but the M diet was better able to assist the calves in maintaining their plasma glucose concentration 4 h after feeding than the W diet. The G diet had some short-term benefits in providing energy and assistance to the calves to recover from dehydration, as indicated by a decrease in serum osmolality. However, the G diet was clearly inferior to the M and W diets in providing sufficient energy to assist the calves in recovering from the effects of transport and fasting. During the 4 h after feeding, no adverse effects of offering the calves the M or W diets were observed. The benefits of the W diet in replacing energy and water deficits were similar to those of the M diet, but the M diet was better able to assist the calves in maintaining their blood glucose concentration 4 h after feeding than the W diet. The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. [Display omitted] [ABSTRACT FROM AUTHOR]

Background Cavernous nerve (CN) injury, which occurs in prostatectomy and diabetic cases, initiates penile remodeling, including smooth muscle apoptosis and increased collagen in the corpora cavernosa, which are underlying causes of erectile dysfunction. Sonic hedgehog (SHH) is a critical regulator of penile smooth muscle, and SHH treatment suppresses corpora cavernosa remodeling that occurs with CN injury. Aim We examine if SHH treatment by peptide amphiphile (PA) in the first week after CN injury is sufficient to prevent long-term penis remodeling and if apoptosis inhibitors also suppress penile remodeling. Methods Bilateral CN crush was performed on adult Sprague-Dawley rats (P115-120) that underwent 1 of 3 treatments with novel extended-release nanofiber PA hydrogels for delivery: SHH protein (n = 10), mouse serum albumin protein (control, n = 7), or caspase 3 inhibitor (AC-DEVD-CHO, n = 10). Rats were sacrificed after 18 to 24 days. Additional rats underwent CN injury (n = 6) or CN injury and SHH PA treatment for 2 and 4 days (n = 8) and included sham controls (n = 3) and nonsurgery controls (n = 3). Outcomes Trichrome stain, hydroxyproline assay, and Western analysis for α-actin (smooth muscle) and GAPDH were performed to examine smooth muscle retention and collagen abundance. Results Smooth muscle decreased with CN injury. Corpora cavernosa showed increased smooth muscle at 2, 4, and 24 days after CN injury with SHH PA treatment in comparison with mouse serum albumin treatment among CN-injured controls. Caspase 3–inhibited penis demonstrated little smooth muscle preservation. Collagen was decreased 23% with SHH PA treatment (P  < .001) at 18 to 24 days after CN injury. Collagen was unchanged with caspase 3 inhibitor treatment (P  > .99). Clinical Translation It is important to know that treatments given at the time of CN injury have a sustained effect on preserving penile architecture and thus erectile function, making them valuable for clinical translation. Strengths and Limitations SHH PA treatment preserves penile smooth muscle after CN injury. Time points past 24 days were not examined, although penile remodeling takes place acutely after CN injury. Measurement of erectile function was not examined. Conclusions SHH treatment by PA in the first week after CN injury is sufficient to suppress penile remodeling and to preserve penile smooth muscle over time, which is critical to prevent development of erectile dysfunction. There is a difference in the corpora cavernosa smooth muscle from proximal to distal in the penis of the Sprague-Dawley rat model. It is critical when examining therapy efficacy to ensure that comparable regions of the penis are analyzed. Statement of Significance In this study, we examine if suppression of apoptosis in penile smooth muscle in the first week after cavernous nerve injury is sufficient to preserve smooth muscle long-term. [ABSTRACT FROM AUTHOR]

Endometrial polyps and uterine leiomyomas are common gynecological conditions that significantly affect women's health. Recent studies have begun to explore potential biomarkers that could assist in the early diagnosis and understanding of the pathophysiology of these conditions. One such biomarker is Serum Sestrin 2 (SESN2), a protein involved in cellular stress response. This review aims to synthesize research findings on the relationship between serum SESN2 levels and the presence of endometrial polyps and uterine leiomyomas. It examines the potential of SESN2 as a diagnostic tool and its role in the underlying mechanisms of these conditions. Studies suggest that SESN2 levels are elevated in patients with these conditions compared to controls, indicating its involvement in their pathophysiology. Furthermore, the review discusses the implications of these findings for clinical practice, particularly in terms of early detection and targeted therapies. Future research directions and the need for large-scale studies to validate SESN2 as a clinical marker are also addressed. This review highlights the importance of biomarkers like SESN2 in enhancing our understanding and management of gynecological disorders. [ABSTRACT FROM AUTHOR]

Hypothetical and experimental models of unbound fraction have been proposed to facilitate predicting the hepatic clearance (CL H) of drugs from values of intrinsic clearance for the unbound drug (CL int-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 CL H 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 CL H 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 CL int-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. [ABSTRACT FROM AUTHOR]

Calcified areas in aortic valves often co-localize with amyloid fibrils that can promote calcification. Patient-derived amyloid fibrils contain arrays of acidic residues that can bind calcium and organize calcium phosphate nucleation clusters, while collagen fibrils guide crystal growth. This process is akin to functional biomineralization guided by Ca entrapment by acidic arrays in proteins, including amyloids. High shear stress and turbulent blood flow across the aortic valve, which are exacerbated in calcific aortic valve disease (CAVD), augment amyloid formation by plasma proteins. The main amyloid protein is probably apolipoprotein A-I (apoA-I), yet other proteins can also be involved. Lipoprotein(a) [Lp(a)], a genetic risk factor for CAVD, contributes to calcification. Enzymatic hydrolysis of oxidized phospholipids in Lp(a) helps generate orthophosphate, whereas apo(a) blocks collagen and amyloid fibril degradation by plasmin. Calcific aortic valve disease (CAVD) is a widely prevalent heart disorder in need of pharmacological interventions. Calcified areas in aortic valves often contain amyloid fibrils that promote calcification in vitro. This opinion paper suggests that amyloid contributes to CAVD development; amyloid-assisted nucleation can accelerate hydroxyapatite deposition onto collagen matrix. Notably, acidic arrays in amyloid match calcium–calcium spacing in the amorphous hydroxyapatite precursor, while oscillating hemodynamic perturbations promote amyloid deposition in the valve. Lipoprotein(a), a genetic risk factor for CAVD, augments calcification via several mechanisms, wherein hydrolysis of oxidized phospholipids (oxPLs) by Lp(a)-associated enzymes helps generate orthophosphate, and apolipoprotein(a) blocks plasmin-induced fibril degradation. Current studies of amyloid–calcium–collagen interactions in solution and in fibrillar complexes allow deeper insight into the role of amyloid in calcification. [ABSTRACT FROM AUTHOR]

The trail aimed to explore the effect of dietary supplementation of curcumin loaded olive oil nanoemulsion (CUR‐OLNE) on growth performance, feed utilization, blood biochemical, redox status, and immune response of Litopenaeus vannamei shrimp, considering the economic efficiency of supplementation. A total of 280 healthy shrimps (3.42 ± 0.02 g) were randomly distributed into five equal groups and were fed diets containing 0 (CUR‐OLNE0), 5(CUR‐OLNE5), 10(CUR‐OLNE10), 15(CUR‐OLNE15) and 20 (CUR‐OLNE20) mg CUR‐OLNE/kg diet, respectively for 16 weeks. Among CUR‐OLNE treated groups, CUR‐OLNE20 showed the highest growth performance and feed utilization traits, including final body weight, specific growth rate, feed conversion ratio, and protein efficiency ratio. Notably, the photomicrographs provided further compelling evidence regarding the potential effect of CUR‐OLNE supplementation on muscle structure and integrity. Compared to the control, the levels of blood protein significantly induced in CUR‐OLNE15 and CUR‐OLNE20 treated groups (p < 0.05). All CUR‐OLNE ‐supplemented groups possessed lower activities of liver enzymes as well as the levels of urea and creatinine compared to the control (p < 0.05). The addition of 20 mg CUR‐OLNE/kg diet decreased the concentrations of cortisol, glucose and triglycerides. The dietary treatment significantly improved the secretion of digestive enzymes, including amylase, lipase, and protease. The lowest levels of Malondialdehyde and the highest levels of total antioxidant capacity, super oxide dismutase, catalase, lysozyme and immunoglobulin M were detected in both of CUR‐OLNE15, and CUR‐OLNE20 treated groups compared to the control (p < 0.05). There were considerable significant effects of dietary supplementation of CUR‐OLNE on economic efficiency. In conclusion, the application of nanocarriers for the delivery of dietary immune stimulants such as CUR‐OLNE to Litopenaeus vannamei shrimp is a promising strategy for improving shrimp nutrition. The addition of 20 mg CUR‐OLNE/kg to the diets of can be recommended as an affective intervention to improve growth performance, feed utilization, and health status of shrimp. Implementing this intervention can maximize the economic efficiency of shrimp farming while promoting sustainable practices in the industry. [ABSTRACT FROM AUTHOR]

Anticoagulation treatment for patients with high bleeding risk during hemodialysis is challenging. Contact between the dialysis membrane and the blood leads to protein adsorption and activation of the coagulation cascade reaction. Activated coagulation Factor X (FXa) plays a central role in thrombogenesis, but anticoagulant modification of the dialysis membrane is rarely targeted at FXa. In this study, we constructed an anticoagulant membrane using the polydopamine coating method to graft FXa inhibitors (apixaban and rivaroxaban) on the membrane surface. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and atomic force microscopy (AFM) were used to characterize the membranes. The apixaban- and rivaroxaban-modified membranes showed lower water contact angles, decreased albumin protein adsorption, and suppressed platelet adhesion and activation compared to the unmodified PES membranes. Moreover, the modified membranes prolonged the blood clotting times in both the intrinsic and extrinsic coagulation pathways and inhibited FXa generation and complement activation, which suggested that the modified membrane enhanced biocompatibility and antithrombotic properties through the inhibition of FXa. Targeting FXa to design antithrombotic HD membranes or other blood contact materials might have great application potential. [ABSTRACT FROM AUTHOR]

Two trials were performed to evaluate the effect of renal and hepatic impairment on the pharmacokinetics of pritelivir and its metabolites. The renal impairment trial included subjects with mild, moderate, and severe impairment, while the hepatic impairment trial included subjects with moderate impairment. Both trials recruited a matched control group of healthy subjects. Following a single oral dose of 100 mg of pritelivir, mild and moderate renal impairment and moderate hepatic impairment did not have a clinically relevant effect on the pharmacokinetics of pritelivir. In subjects with severe renal impairment, pritelivir exposure (area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐inf) was 57% higher compared with controls. Pritelivir plasma protein binding was similar in subjects and controls with renal impairment, while the free fraction was higher in subjects with moderate hepatic impairment, increasing unbound pritelivir exposure by 23%. For the metabolites pyridinyl phenyl acetic acid (PPA), amino thiazole sulfonamide (ATS), and PPA‐acyl glucuronide, generally higher exposure was observed with increasing degree of renal impairment (ie, moderate to severe), but not with mild impairment. A modest effect of moderate hepatic impairment was observed for PPA and ATS. Pritelivir was safe and well tolerated in healthy subjects and subjects with renal or hepatic impairment. [ABSTRACT FROM AUTHOR]

Purpose: Recently, there has been significant focus on extracellular matrix proteolysis due to its importance in the pathological progression of intervertebral disc degeneration (IVDD). The present study investigates the circulating levels of extracellular matrix proteins in the plasma of IVDD and determines their potential relevance as biomarkers in disc degeneration. Methods: Global proteomic analysis was performed in the plasma samples of 10 healthy volunteers (HV) and 10 diseased subjects (DS) after depletion of highly abundant proteins such as albumin and IgG. Results: We identified 144 and 135 matrix-associated proteins in plasma samples from healthy volunteers (HV) and patients with disc degeneration (DS), respectively. Among these, 49 of the matrix-associated proteins were identical to the proteins found in intervertebral disc (IVD) tissues retrieved from the in-house library. Applying stringent parameters, we selected 28 proteins, with 26 present in DS and 21 in HV. 19 proteins were found common between the groups, two of which—aggrecan (ACAN) and fibulin 1 (FBLN1) - showed statistically significant differences. Specifically, ACAN was up-regulated and FBLN1 was down-regulated in the DS-plasma. In particular, DS-plasma exhibited specific expression of collagen type 2a1 (COL2A1), native to the nucleus pulposus. Conclusion: The distinct presence of collagen type 2a1 and the elevated expression of aggrecan in IVDD plasma may serve as the basis for the development of a potential biomarker for monitoring the progression of disc degeneration. [ABSTRACT FROM AUTHOR]

The prevalence of coronary heart disease (CHD) has increased significantly with the aging population worldwide. It is unclear whether ferroptosis occurs during CHD. Hence, we aimed to investigate the potential mechanisms associated with ferroptosis in CHD. Bioinformatics was used to characterize differentially expressed genes (DEGs) in CHD-related datasets (GSE21610 and GSE66360). There were 76 and 689 DEGs in the GSE21610 and GSE66360, respectively, and they predominantly associated with immune and inflammatory responses. DDX3Y, EIF1AY, KDM5D, RPS4Y1, SGK1, USP9Y, and NSG1 were intersecting DEGs of GSE21610 and GSE66360. Their expression pattern in circulating endothelial cells (ECs) derived from healthy individuals and CHD patients are consistent with the results of bioinformatics analysis, especially SGK1. In vitro , SGK1 knockdown alleviated the Erastin-induced downregulation of SLC7A11, GPX4, GSH, and GSSG, as well as the upregulation of lipid peroxidation, Fe accumulation, and mitochondrial damage in mouse aortic ECs (MAECs). Notably, SGK1 may interact with NEDD4L according to the String database. Moreover, SGK1 promoted NEDD4L and p-P65 expression in MAECs. Interestingly, the effect of SGK1 knockdown on ferroptosis in MAECs was rescued by overexpression of NEDD4L or PMA (NF-κB pathway activator). In vivo , SGK1 knockdown facilitated the recovery of body weight, blood lipids, and aortic tissue structure in CHD animal models. Furthermore, SGK1 knockdown alleviated Fe accumulation in the aorta and inactivated the NEDD4L-NF-κB pathway. In conclusion, SGK1 contributes to EC ferroptosis by regulating the NEDD4L-NF-κB pathway. SGK1 could be recognized as a therapeutic target related to ferroptosis in CHD. [Display omitted] • SGK1 is aberrantly high-expressed in CHD-derived circulating endothelial cells. • SGK1 contributes to endothelial cell ferroptosis in coronary heart disease. • SGK1 interacts with NEDD4L, and facilitates the expression of NEDD4L. • NEDD4L and NF-κB pathway are downstream of SGK1-mediated ferroptosis. [ABSTRACT FROM AUTHOR]

Background: Both anti-aging protein α-Klotho and the triglyceride-glucose (TyG) index hold predictive value for the incidence, progression, and outcomes of cardiovascular disease, diabetes and many other diseases. However, their relationship remains unclear. Methods: We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) 2007–2016. Weighted multivariate linear regression models and subgroup analysis were constructed to assess the association between TyG index and α-Klotho levels. Nonlinear correlations were explored using restricted cubic splines (RCS), generalized additive models (GAM) and smooth curve fitting. Segmented regression model was conducted to explore potential threshold effects and identify the inflection point. Results: A total of 2568 participants satisfied the predetermined criteria were enrolled in the final analysis. After fully adjusting for covariates, TyG index was shown to be markedly negatively correlated with α-Klotho [β=-74.07, 95%CI (-100.29,-47.85), p < 0.001]. Gender was significantly correlated with this negative connection according to subgroup analysis and interaction testing (p for interaction < 0.05).Additionally, we discovered a linear association between TyG index and α-Klotho in all participants (p for nonlinear = 0.761), while non-linear association in female (p for nonlinear = 0.016).The analysis of threshold effect in the female participants found that the inflection point of TyG index was 8.01, exceed which the level of α-Klotho decreased significantly with increasing TyG index[β=-151.72, 95%CI (-201.93, -101.50), p < 0.001]. Conclusion: Our findings demonstrate a negative association between TyG index and α-Klotho levels, with the effect being more pronounced in females. TyG index may serve as an early indicator of individuals with low α-Klotho levels, especially among females. These findings highlight the need for gender-specific considerations in clinical interventions to improve public health. Further research is needed to clarify the causal direction of this association. [ABSTRACT FROM AUTHOR]