Explore the vast range of titles available.

Severe acute malnutrition (SAM) remains a global health concern. Studies on the impact of ready-to-use therapeutic foods (RUTFs) on micronutrient status during SAM treatment are almost nonexistent. The objective was to investigate the impact of RUTFs on the iron and vitamin A status of 6–59-month-old children receiving SAM treatment. Biomarkers of vitamin A status (retinol-binding protein, RBP), iron status (ferritin and soluble transferrin receptor, sTfR), and inflammation (C-reactive protein, CRP, and alpha-1 acid glycoprotein, AGP) were collected at admission and discharge (week 8) during an RUTF effectiveness trial. Vitamin A deficiency was defined as RBP <0.70 µmol/L, low body iron as body iron (BI) <0 mg/kg and deficient iron stores as ferritin <12 µg/L. Data were available for 110 and 75 children at admission and discharge, respectively. There was no significant difference in haemoglobin, ferritin, sTfR, BI or RBP concentrations between admission and discharge. At discharge, BI was 0.2 mg/kg lower, and there was a tendency towards a slightly lower RBP concentration, but the prevalence of vitamin A deficiency was low at admission and discharge (6% and 3%, respectively). The small impact of both RUTFs on improving vitamin A and iron status during SAM treatment calls for further research on the bioavailability of micronutrients to enhance the effectiveness of SAM treatment on micronutrient status.

Altered glycosylation patterns of plasma proteins are associated with autoimmune disorders and pathogenesis of various cancers. Elucidating glycoprotein microheterogeneity and relating subtle changes in the glycan structural repertoire to changes in protein–protein, or protein–small molecule interactions, remains a significant challenge in glycobiology. Here, we apply mass spectrometry-based approaches to elucidate the global and site-specific microheterogeneity of two plasma proteins: α1-acid glycoprotein (AGP) and haptoglobin (Hp). We then determine the dissociation constants of the anticoagulant warfarin to different AGP glycoforms and reveal how subtle N-glycan differences, namely, increased antennae branching and terminal fucosylation, reduce drug-binding affinity. Conversely, similar analysis of the haptoglobin–hemoglobin (Hp–Hb) complex reveals the contrary effects of fucosylation and N-glycan branching on Hp–Hb interactions. Taken together, our results not only elucidate how glycoprotein microheterogeneity regulates protein–drug/protein interactions but also inform the pharmacokinetics of plasma proteins, many of which are drug targets, and whose glycosylation status changes in various disease states.

Orosomucoid (ORM), or alpha-1-acid glycoprotein (AGP), is one of the acute-phase proteins. It has a molecular weight of 37–54 kDa, low pI of 2.8–3.8, and is heavily glycosylated (45 %). It is mainly synthesized by the liver, but many extrahepatic tissues have also been reported to produce ORM under myriad physiological and pathological conditions. Expression of the ORM gene is mainly controlled by a combination of the major regulatory mediators, such as glucocorticoids, interleukin (IL)-1, TNF-α, and IL-6. ORM has many activities including, but not limited to, acting as an acute-phase reactant and disease marker, modulating immunity, binding and carrying drugs, maintaining the barrier function of capillary, and mediating the sphingolipid metabolism. Its related receptor has been preliminarily explored in macrophages, neutrophils, and liver parenchymal cells, involving the membrane receptor CCR5, Siglect-5, and HBB, respectively. Additional activities of ORM such as regulating metabolism are currently being explored. Because of its regulation in liver diseases, cancer, and HIV, future ORM research is warranted.

According to the free drug hypothesis only the unbound drug is available to act at physiological sites of action, and as such the importance of plasma protein binding primarily resides in its impact on pharmacokinetics and pharmacodynamics. Of the major plasma proteins, alpha-1-acid glycoprotein (AAG) represents an intriguing one primarily due to the high affinity, low capacity properties of this protein. In addition, there are marked species and age differences in protein expression, homology and drug binding affinity. As such, a thorough understanding of drug binding to AAG can help aid and improve the translation of pharmacokinetic/pharmacodynamic (PK/PD) relationships from preclinical species to human as well as adults to neonates. This review provides a comprehensive overview of our current understanding of the biochemistry of AAG; endogenous function, impact of disease, utility as a biomarker, and impact on PK/PD. Experimental considerations are discussed as well as recommendations for understanding the potential impact of AAG on PK through drug discovery and early development.

A comprehensive study of the interactions of human serum albumin (HSA) and α-1-acid glycoprotein (AAG) with two isoquinoline alkaloids, i.e., allocryptopine (ACP) and protopine (PP), was performed. The UV-Vis spectroscopy, molecular docking, competitive binding assays, and circular dichroism (CD) spectroscopy were used for the investigations. The results showed that ACP and PP form spontaneous and stable complexes with HSA and AAG, with ACP displaying a stronger affinity towards both proteins. Molecular docking studies revealed the preferential binding of ACP and PP to specific sites within HSA, with site 2 (IIIA) being identified as the favored location for both alkaloids. This was supported by competitive binding assays using markers specific to HSA’s drug binding sites. Similarly, for AAG, a decrease in fluorescence intensity upon addition of the alkaloids to AAG/quinaldine red (QR) complexes indicated the replacement of the marker by the alkaloids, with ACP showing a greater extent of replacement than PP. CD spectroscopy showed that the proteins’ structures remained largely unchanged, suggesting that the formation of complexes did not significantly perturb the overall spatial configuration of these macromolecules. These findings are crucial for advancing the knowledge on the natural product–protein interactions and the future design of isoquinoline alkaloid-based therapeutics.

The enantioselective binding of three proton pump inhibitors (PPIs)—omeprazole, rabeprazole, and lansoprazole—to two key plasma proteins, α1-acid glycoprotein (AGP) and human serum albumin (HSA), was characterized. The interactions between PPI enantiomers and proteins were investigated using a multifaceted analytical approach, including high-performance liquid chromatography (HPLC), fluorescence and UV spectroscopy, as well as in silico molecular docking. HPLC analysis demonstrated that all three PPIs exhibited enantioseparation on an AGP-based chiral stationary phase, suggesting stereoselective binding to AGP, while only lansoprazole showed enantioselective binding on the HSA-based column. Quantitatively, the S-enantiomers of omeprazole and rabeprazole showed higher binding affinity to AGP, while the R-enantiomer of lansoprazole displayed greater affinity for AGP, with a reversal in the elution order observed between the two protein-based columns. Protein binding percentages, calculated via HPLC, were greater than 88% for each enantiomer across both transport proteins, with all enantiomers displaying higher affinity for AGP compared to HSA. Thermodynamic analysis indicated that on the HSA, the more common, enthalpy-controlled enantioseparation was found, while in contrast, on the AGP, entropy-controlled enantioseparation was observed. The study also identified limitations in using fluorescence titration due to the high native fluorescence of the compounds, whereas UV titration was effective for both proteins. The determined logK values were in the range of 4.47–4.83 for AGP and 4.02–4.66 for HSA. Molecular docking supported the experimental findings by revealing the atomic interactions driving the binding process, with the predicted enantiomer elution orders aligning with experimental data. The comprehensive use of these analytical methods provides detailed insights into the enantioselective binding properties of PPIs, contributing to the understanding of their pharmacokinetic differences and aiding in the development of more effective therapeutic strategies.

IntroductionUterine sarcoma (US) is a rare tumor characterized by high aggressiveness, a tendency for recurrence and distant metastasis, and an extremely poor prognosis. In this study, we evaluated the expression of Orosomucoid 1 (ORM1) in different subtypes of US and the relationship between survival rates and clinicopathological features.MethodA retrospective study was conducted on 50 cases diagnosed with US in our hospital from 2011 to 2023. Immunohistochemistry (IHC) was used to detect the expression levels of ORM1 in different subtypes of US.The chi-square test and Kaplan-Meier survival analysis were used to analyze the relationship between ORM1 expression and clinical parameters as well as prognosis. Cox analysis was employed to evaluate the relationships between prognosis and clinical parameters in US.ResultCompared to normal proliferative endometrial tissue (NPE), the expression of ORM1 was downregulated in low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and undifferentiated uterine sarcoma (UUS) (P < .001,P < .001,and P < .001, respectively). Compared to normal uterine smooth muscle tissue (UNSM), the expression of ORM1 was upregulated in leiomyosarcoma (LMS) (P = .006). High ORM1 expression levels in US patients were associated with poor overall survival (OS) and progression-free survival (PFS) (P = .027 and P = .005, respectively). Multivariate COX analysis revealed that tumor stage and ORM1 expression are independent prognostic factors for US patients.ConclusionORM1 is expressed at low levels in ESS and at high levels in LMS. ORM1 potentially serve as a novel biomarker for the diagnosis, classification, and prognosis of US.

As a significant global health issue, frailty has important implications for clinical practice and public health. Systemic inflammation has been identified as an important mechanism influencing the development of frailty. However, the potential impact of the inflammatory marker alpha-1-acid glycoprotein (AGP) on frailty is unclear. The aim of this study was to investigate the relationship between AGP levels and frailty. The present study employed a cross-sectional design and included a sample of 3802 females aged 20–49 years, drawn from the 2015–2023 National Health and Nutrition Examination Survey (NHANES) database. A weighted multivariate logistic regression was employed to construct a series of adjustment models, comprising crude, partial and fully adjusted models, with the objective of testing the potential association between AGP and frailty. Smoothed curve fitting plots were used to test the nonlinear relationship between AGP and frailty. The diagnostic value of AGP and hsCRP for frailty was compared using receiver operating characteristic (ROC) curve analysis. Finally, subgroup analyses and interaction tests were conducted to explore the stability of the findings. After adjusting for all potential confounding variables, AGP was found to be significantly and positively associated with frailty, with a corresponding 2.42-fold increase in the incidence of frailty observed for each unit increase in AGP (OR = 3.42, 95%CI = 1.83–6.39, P  < 0.001). When AGP was analyzed as a tertile variable, individuals in the highest tertile had a higher risk of frailty compared to those in the lowest tertile after adjusting for all covariates (OR = 1.78, 95%CI = 1.21–2.59, p  = 0.003, P for trend = 0.002). The results of the multifactor-adjusted smoothed curve fitting plots and threshold effect analyses indicated a nonlinear relationship between AGP and frailty, with an inflection point of 1.05. In addition, ROC curve analysis showed that AGP (AUC = 0.664) had a greater diagnostic value for frailty than hsCRP (AUC = 0.656). Subgroup and interaction analyses demonstrated that none of the examined variables showed a statistically significant interaction with the association between AGP and frailty. The results of this cross-sectional study indicate a significant positive association between AGP and frailty in a population of females aged 20–49 years in the United States. However, these findings need to be further validated and extended in large-scale prospective studies.

The relationship between drug‐induced liver injury and liver metastasis of colorectal cancer and the underlying mechanisms are not well understood. In this study, we used carbon tetrachloride to construct a classic mouse liver injury model and injected CT26 colorectal cancer cells into the mouse spleen to simulate the natural route of colorectal cancer liver metastasis. Liver injury significantly increased the number of colorectal cancer liver metastases. Transcriptome sequencing and data‐independent acquisition protein quantification identified proteins that were significantly differentially expressed in injured livers, and orosomucoid (ORM) 2 was identified as a target protein for tumor liver metastasis. In vitro experiments showed that exogenous ORM2 protein increased the expression of EMT markers such as Twist, Zeb1, Vim, Snail1 and Snail2 and chemokine ligands to promote CT26 cell migration. In addition, liver‐specific overexpression of the ORM2 protein in the mouse model significantly promoted tumor cell liver metastasis without inducing liver injury. Our results indicate that drug‐induced liver injury can promote colorectal cancer liver metastasis and that ORM2 can promote cell migration by inducing EMT in tumor cells. We found that DILI promotes liver metastasis of colorectal cancer in a classic DILI mouse model. Further analysis using high‐throughput transcriptome sequencing and proteomics identified ORM2 as a key gene that promotes liver metastasis. ORM2 upregulation enhances tumor cell migration by promoting EMT of tumor cells and increasing the expression of chemokine ligands. Targeting ORM2 may be an effective therapeutic strategy for inhibiting malignant tumor metastasis.

There are a number of uncertainties regarding plasma protein binding and blood distribution of the active drugs favipiravir (FAVI), molnupiravir (MOLNU) and imatinib (IMA), which were recently proposed as therapeutics for the treatment of COVID-19 disease. Therefore, proton dissociation processes, solubility, lipophilicity, and serum protein binding of these three substances were investigated in detail. The drugs display various degrees of lipophilicity at gastric (pH 2.0) and blood pH (pH 7.4). The determined pKa values explain well the changes in lipophilic character of the respective compounds. The serum protein binding was studied by membrane ultrafiltration, frontal analysis capillary electrophoresis, steady-state fluorometry, and fluorescence anisotropy techniques. The studies revealed that the ester bond in MOLNU is hydrolyzed by protein constituents of blood serum. Molnupiravir and its hydrolyzed form do not bind considerably to blood proteins. Likewise, FAVI does not bind to human serum albumin (HSA) and α1-acid glycoprotein (AGP) and shows relatively weak binding to the protein fraction of whole blood serum. Imatinib binds to AGP with high affinity (logK′ = 5.8–6.0), while its binding to HSA is much weaker (logK′ ≤ 4.0). The computed constants were used to model the distribution of IMA in blood plasma under physiological and ‘acute-phase’ conditions as well.