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BackgroundThe combination antimicrobial therapy consisting of amikacin, polymyxin-B, and sulbactam demonstrated in vitro synergy against multi-drug resistant Acinetobacter baumannii.ObjectivesThe objectives were to predict drug disposition and extrapolate their efficacy in the blood, lung, heart, muscle and skin tissues using a physiologically-based pharmacokinetic (PBPK) modeling approach and to evaluate achievement of target pharmacodynamic (PD) indices against A. baumannii.MethodsA PBPK model was initially developed for amikacin, polymyxin-B, and sulbactam in adult subjects, and then scaled to pediatrics, accounting for both renal and non-renal clearances. The simulated plasma and tissue drug exposures were compared to the observed data from humans and rats. Efficacy was inferred using joint probability of target attainment of target PD indices.ResultsThe simulated plasma drug exposures in adults and pediatrics were within the 0.5 to 2 boundary of the mean fold error for the ratio between simulated and observed means. Simulated drug exposures in blood, skin, lung, and heart were consistent with reported penetration ratio between tissue and plasma drug exposure. In a virtual pediatric population from 2 to

Abstract Background To analyze the association of serum Asprosin concentrations with heart failure (HF). Methods A total of 103 patients with HF were included in the HF group, and 103 patients with health checkups were included in the non-HF group. The serum Asprosin levels of the two groups were measured, and relevant clinical data were collected for statistical analysis. Results Compared with the non-HF group, the serum Asprosin concentration was significantly higher in the HF group, and the difference was statistically significant (P

Iron deficiency anemia (IDA) is the most common nutrient-related health problem in the world. There is still a lack of comprehensive comparative study on the efficacies of commonly used iron supplements such as polysaccharide iron complex (PIC), iron protein succinylate (IPS) and ferrous succinate (FS) for IDA. In this study, we compared the PIC, IPS and FS efficacies in IDA rats via intragastric administration. The results showed that the three iron supplements had similar efficacies. PIC/IPS/FS at a dose of 15 mg Fe/kg/d for 10 d increased the hematological and serum biochemical parameters to 2.15/2.12/2.18 (Hb), 1.71/1.67/1.69 (RBC), 2.10/2.11/2.12 (HCT), 1.26/1.22/1.22 (MCV), all 1.34 (MCH), 1.15/1.15/1.14 (MCHC), 1.94/1.82/1.91 (SF), 9.75/9.67/9.53 (SI), and 23.30/22.68/21.64 (TS) times, and reduced TIBC to 0.42/0.43/0.44 times, compared to untreated IDA rats. PIC performed slightly better than IPS and FS in restoring MCV level. Meanwhile, the heart, spleen and kidney coefficients reduced to 67%/74%/65% (heart), all 59% (spleen) and 87%/88%/88% (kidney), and the liver coefficient increased to 116%/115%/116%, compared to untreated IDA rats. The liver iron content was found to be more affected by IDA than the spleen iron content. PIC/IPS/FS at 15 mg Fe/kg/d increased organ iron contents to 4.20/3.97/4.03 times (liver) and 1.36/1.24/1.41 times (spleen) within 10 d compared to untreated IDA rats, and PIC-H and FS were slightly better than IPS in restoring spleen iron content. The results of this study can provide useful data information for the comparison of three iron supplements, PIC, IPS and FS.

ABSTRACT The use of combination antibiotics has been useful in the treatment of multidrug-resistant bacterial infections. The synergistic effect of amoxicillin/clavulanate and aztreonam combination against Escherichia coli carrying New Delhi metallo-β-lactamase (NDM) was primarily due to clavulanate inhibiting aztreonam degradation. In the present study, we employed metabolomic analysis to investigate the downstream changes in E. coli after treatment with aztreonam and clavulanate. E. coli metabolomes were compared at 1 and 24 h following treatments with clavulanate (4 µg/mL) and aztreonam (4 µg/mL) alone and in combination. Excluding false positives, 198 metabolites were identified to be affected by antibiotic treatment. Aztreonam/clavulanate combination inhibited cell wall synthesis more aggressively at 1 h and 24 h than aztreonam alone. The purine and pyrimidine metabolism, the central carbon metabolism, and the amino acid metabolism were also disrupted resulting in a prolonged bactericidal effect. This study reveals the synergistic killing mechanism of clavulanate and aztreonam combination against E. coli harboring NDM and provides a theoretical basis for the combined use of aztreonam/clavulanate in the treatment of multidrug-resistant E. coli infection.IMPORTANCEMultidrug-resistant Escherichia coli is a major threat to the health care system and is associated with poor outcomes in infected patients. The combined use of antibiotics has become an important treatment method for multidrug-resistant bacteria. However, the mechanism for their synergism has yet to be explored.

Abstract N6-methyladenosine(m6A) is one of the most abundant modifications of mammalian cellular RNAs. m6A regulates various biological functions in epitranscriptomic ways, including RNA stability, decay, splicing, translation and nuclear export. Recent studies have indicated the growing importance of m6A modification in precancerous disease, influencing viral replication, immune escape, and carcinogenesis. Here, we review the role of m6A modification in HBV/HCV infection, NAFLD and liver fibrosis, and its function in liver disease pathogenesis. Our review will provide a new sight for the innovative treatment strategy for precancerous liver disease.

IntroductionThe emergence of multidrug-resistant (MDR) Acinetobacter baumannii prompts clinicians to consider treating these infections with polymyxin combination.MethodsMetabolomic analysis was applied to investigate the synergistic effects of polymyxin-B, amikacin and sulbactam combination therapy against MDR A. baumannii harboring OXA-23 and other drug resistant genes. The drug concentrations tested were based on their clinical breakpoints: polymyxin-B (2 mg/L), amikacin (16 mg/L), polymyxin-B/amikacin (2/16 mg/L), and polymyxin-B/amikacin/sulbactam (2/16/4 mg/L).ResultsThe triple antibiotic combination significantly disrupted levels of metabolites involved in cell outer membrane structure including fatty acids, glycerophospholipids, nucleotides, amino acids and peptides as early as 15 min after administration. Amikacin and polymyxin-B alone perturbed a large number of metabolites at 15 min and 1 h, respectively, but the changes in metabolites were short-lived lasting for less than 4 h. In contrast, the combination treatment disrupted a large amount of metabolites beyond 4 h. Compared to the double-combination, the addition of sulbactam to polymyxin-B/amikacin combination produce a greater disorder in A. baumannii metabolome that further confer susceptibility of bacteria to the antibiotics.ConclusionThe metabolomic analysis identified mechanisms responsible for the synergistic activities of polymyxin-B/amikacin/sulbactam against MDR A. baumannii.

As a crucial enzyme for cellulose degradation, β-glucosidase finds extensive applications in food, feed, and bioethanol production; however, its potential is often limited by inadequate thermal stability and glucose tolerance. In this study, a functional gene (lq-bg5) for a GH1 family β-glucosidase was obtained from the metagenomic DNA of a hot spring sediment sample and heterologously expressed in E. coli and the recombinant enzyme was purified and characterized. The optimal temperature and pH of LQ-BG5 were 55 °C and 4.6, respectively. The relative residual activity of LQ-BG5 exceeded 90% at 55 °C for 9 h and 60 °C for 6 h and remained above 100% after incubation at pH 5.0–10.0 for 12 h. More importantly, LQ-BG5 demonstrated exceptional glucose tolerance with more than 40% activity remaining even at high glucose concentrations of 3000 mM. Thus, LQ-BG5 represents a thermophilic β-glucosidase exhibiting excellent thermal stability and remarkable glucose tolerance, making it highly promising for lignocellulose development and utilization.

The objective of this study was to evaluate whether combinations of sulbactam, meropenem, and polymyxin-B could reduce or close the gap of mutant selection window (MSW) of individual antibiotics against Acinetobacter baumannii harboring OXA-23. MICs of three antimicrobials used alone and in combination (meropenem/polymyxin-B or meropenem/polymyxin-B/sulbactam) were obtained in 11 clinical isolates and mutant prevention concentrations were determined in 4 of the 11 isolates. All isolates were resistant to meropenem or polymyxin-B. Combining meropenem and polymyxin-B with or without sulbactam resulted in synergistic bactericidal activities. Pharmacokinetic (PK) simulations of drug concentrations in the blood and epithelial lining fluid coupled with pharmacodynamic (PD) evaluations revealed that the fractions of time over the 24-h in terms of free drug concentration within the MSW (fTMSW) and above the MPC (fT>MPC) were optimized by combination therapy. The resultant clinical regimens of meropenem, polymyxin-B, and sulbactam evaluated in the PK-PD analysis were 2 g q8h, 2.5 mg/kg loading dose followed by 1.5 mg/kg q12h, and 3 g q8h, respectively, in patients with normal renal function. Subsequent corresponding equivalent exposure regimens would depend on the extent of renal failure. The overall results indicate that combination antibiotics consisting of sulbactam/meropenem/polymyxin-B can confer potential efficacy against A. baumannii harboring OXA-23, and reduce the opportunity for bacteria to develop further resistance. This study provides a framework for pharmacodynamic evaluation of drug-resistant mutant suppression in an antimicrobial co-administration setting. The results thereby lay the groundwork for additional studies and future clinical confirmation is warranted.

Amikacin and polymyxins as monotherapies are ineffective against multidrug-resistant Acinetobacter baumannii at the clinical dose. When polymyxins, aminoglycosides, and sulbactam are co-administered, the combinations exhibit in vitro synergistic activities. The minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in 11 and 5 clinical resistant isolates of A. baumannii harboring OXA-23, respectively, in order to derive the fraction of time over the 24-h wherein the free drug concentration was within the mutant selection window (fTMSW) and the fraction of time that the free drug concentration was above the MPC (fT>MPC) from simulated pharmacokinetic profiles. The combination of these three antibiotics can confer susceptibility in multi-drug resistant A. baumannii and reduce the opportunity for bacteria to develop further resistance. Clinical intravenous dosing regimens of amikacin, polymyxin-B, and sulbactam were predicted to optimize fTMSW and fT>MPC from drug exposures in the blood. Mean fT>MPC were ≥ 60% and ≥ 80% for amikacin and polymyxin-B, whereas mean fTMSW was reduced to

Empirical therapies using polymyxins combined with other antibiotics are recommended in the treatment of Acinetobacter baumannii infections. In the present study, the synergistic activities of polymyxin-B, meropenem, and sulbactam as combination therapy were investigated using metabolomic analysis. The metabolome of A. baumannii was investigated after treatment with polymyxin-B alone (2 mg/l), meropenem (2 mg/l) alone, combination of polymyxin-B/meropenem at their clinical breakpoints, and triple-antibiotic combination of polymyxin-B/meropenem and 4 mg/l sulbactam. The triple-antibiotic combination significantly changed the metabolite levels involved in cell outer membrane and cell wall biosynthesis, including fatty acid, glycerophospholipid, lipopolysaccharide, peptidoglycan, and nucleotide within 15 min of administration. In contrast, significant changes in metabolome were observed after 1 h in sample treated with either meropenem or polymyxin-B alone. After 1 h of administration, the double and triple combination therapies significantly disrupted nucleotide and amino acid biosynthesis pathways as well as the central carbon metabolism, including pentose phosphate and glycolysis/gluconeogenesis pathways, and tricarboxylic acid cycle. The addition of sulbactam to polymyxin-B and meropenem combination appeared to be an early disruptor of A. baumannii metabolome, which paves the way for further antibiotic penetration into bacteria cells. Combination antibiotics consisting of sulbactam/meropenem/polymyxin-B can effectively confer susceptibility to A. baumannii harboring OXA-23 and other drug resistant genes. Metabolomic profiling reveals underlying mechanisms of synergistic effects of polymyxin-B combined with meropenem and sulbactam against multi-drug resistant A. baumannii.

IntroductionCommunity-acquired pneumonia (CAP) is an important cause of hospitalization and death in patients with mental disorders. It is critical to understand the risk factors of CAP and determine prevention strategies to reduce CAP. The aim of this study is to explore the characteristics of inpatients with mental disorders who have CAP and analyze the risk factors.MethodsThis retrospective study included 16,934 inpatients with mental disorders who were admitted for the first time to a tertiary general hospital between January 2017 and July 2021 (excluding January 2020–May 2020). Risk factors for CAP were identified by logistic regression analysis after propensity score matching (PSM, 1:4) for age, gender, and BMI.ResultsThe CAP rate of inpatients with mental disorders was 1.78%. Inpatients who had CAP had a significantly prolonged hospital stay, and were more often admitted to a closed ward or the ICU. After PSM, the multivariable analysis revealed that clozapine use (OR = 3.212, 95% CI = 1.744–5.915, P < 0.001), schizophrenia spectrum disorder (OR = 2.785, 95% CI = 1.684–4.607, P < 0.001), alcohol consumption (OR = 2.549, 95% CI = 1.586–4.096, P < 0.001), cardiovascular disease (OR = 2.299, 95% CI = 1.362–3.879, P = 0.002), Charlson comorbidity index (CCI) ≥ 3 (OR = 2.092, 95% CI = 1.342–3.260, P = 0.001), organic mental disorder (OR = 1.941, 95% CI = 1.194–3.156, P = 0.007), antipsychotic drug use (OR = 1.886, 95% CI = 1.312–2.711, P = 0.001), unmarried status (OR = 1.720, 95% CI = 1.164–2.541, P = 0.006) and junior high school education (OR = 1.591, 95%CI = 1.010–2.508, P = 0.045) were independent risk factors for CAP in inpatients with mental disorders.ConclusionCAP was common in inpatients with mental disorders. Patients with mental disorders have unique risk factors for CAP. Further research is required to explore the relationship and mechanism between different mental disorders, antipsychotic drugs and CAP.

Abstract Background The SARS-CoV-2 RNA was detected positive again after discharged from hospital in some COVID-19 patients, with or without clinical symptoms such as fever or dry cough. Methods 1008 severe COVID-19 patients, with SARS-CoV-2 RNA positive detected with the mixed specimen of nasopharyngeal swab and oropharyngeal swab by real-time fluorescence quantitative PCR (RT-qPCR), were selected to monitor SARS-CoV-2 RNA with the 12 types of specimens by RT-qPCR during hospitalization. All of 20 discharged cases with COVID-19 were selected to detect SARS-CoV-2 RNA in isolation period with 7 types of specimens by RT-qPCR before releasing the isolation period. Results Of the enrolled 1008 severe patients, the nasopharyngeal swab specimens showed the highest positive rate of SARS-CoV-2 RNA (71.06%), followed by alveolar lavage fluid (66.67%), oropharyngeal swab (30.77%), sputum (28.53%), urine (16.30%), blood (12.5%), stool (12.21%), anal swab (11.22%) and corneal secretion (2.99%), and SARS-CoV-2 RNA couldn’t be detected in other types of specimen in this study. Of the 20 discharged cases during the isolation period, the positive rate of SARS-CoV-2 RNA was 30% (6/20): 2 cases were positive in sputum at the eighth and ninth day after discharge, respectively, 1 case was positive in nasopharynx swab at the sixth day after discharge, 1 case was positive in anal swab at the eighth day after discharge, and 1 case was positive in 3 specimens (nasopharynx swab, oropharynx swab and sputum) simultaneously at the fourth day after discharge, and no positive SARS-CoV-2 RNA was detected in other specimens including stool, urine and blood at the discharged patients. Conclusions SARS-CoV-2 RNA should be detected in multiple specimens, such as nasopharynx swab, oropharynx swab, sputum, and if necessary, stool and anal swab specimens should be performed simultaneously at discharge when the patients were considered for clinical cure and before releasing the isolation period.

Penindolone (PND) is a novel broad-spectrum anti-Influenza A Virus (IAV) agent blocking hemagglutinin-mediated adsorption and membrane fusion. The goal of this work was to reveal the metabolic route of PND in rats. Ultra-high-performance liquid chromatography tandem high-resolution mass spectrometry (UHPLC–HRMS) was used for metabolite identification in rat bile, feces and urine after administration of PND. A total of 25 metabolites, including 9 phase I metabolites and 16 phase II metabolites, were characterized. The metabolic pathways were proposed, and metabolites were visualized via Global Natural Product Social Molecular Networking (GNPS). It was found that 65.24–80.44% of the PND presented in the formation of glucuronide conjugate products in bile, and more than 51% of prototype was excreted through feces. In in vitro metabolism of PND by rat, mouse and human liver microsomes (LMs) system, PND was discovered to be eliminated in LMs to different extents with significant species differences. The effects of chemical inhibitors of isozymes on the metabolism of PND in vitro indicated that CYP2E1/2C9/3A4 and UGT1A1/1A6/1A9 were the metabolic enzymes responsible for PND metabolism. PND metabolism in vivo could be blocked by UGTs inhibitor (ibrutinib) to a certain extent. These findings provided a basis for further research and development of PND.

This study aimed to examine specific niches and usage for the aztreonam/amoxicillin/clavulanate combination and to use population pharmacokinetic simulations of clinical dosing regimens to predict the impact of this combination on restricting mutant selection. The in vitro susceptibility of 19 New-Delhi metallo-β-lactamase (NDM)-producing clinical isolates to amoxicillin/clavulanate and aztreonam alone and in co-administration was determined based on the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC). The fractions of a 24-h duration that the free drug concentration was within the mutant selection window (fTMSW) and above the MPC (fT>MPC) in both plasma and epithelial lining fluid were determined from simulations of 10,000 subject profiles based on regimens by renal function categories. This combination reduced the MIC of aztreonam and amoxicillin/clavulanate to values below their clinical breakpoint in 7/9 K. pneumoniae and 8/9 E. coli, depending on the β-lactamase genes detected in the isolate. In the majority of the tested isolates, the combination resulted in fT>MPC > 90% and fTMSW < 10% for both aztreonam and amoxicillin/clavulanate. Clinical dosing regimens of aztreonam and amoxicillin/clavulanate were sufficient to provide mutant restriction coverage for MPC and MIC ≤ 4 mg/L. This combination has limited coverage against NDM- and extended-spectrum β-lactamase co-producing E. coli and K. pneumoniae and is not effective against isolates carrying plasmid-mediated AmpC and KPC-2. This study offers a potential scope and limitations as to where the aztreonam/amoxicillin/clavulanate combination may succeed or fail.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in most parts of the world. Although there is no first-line drug approved for the treatment of NAFLD, polyene phosphatidylcholine (PPC) is used by clinicians to treat NAFLD patients. This study aimed to evaluate the efficacy of PPC on a mice model of NAFLD, and to study the PPC’s mechanism of action. The mice were fed a choline-deficient, L-amino acid-defined (CDAA) diet to induce NAFLD and were subsequently treated with PPC. The treatment effects were evaluated by the liver index, histopathological examination, and routine blood chemistry analyses. Lipidomics and metabolomics analyses of 54 samples were carried out using ultraperformance liquid chromatography (UPLC) coupled to a mass spectrometer to select for changes in metabolites associated with CDAA diet-induced NAFLD and the effects of PPC treatment. The intestinal flora of mice were extracted for gene sequencing to find differences before and after the induction of NAFLD and PPC treatment. PPC significantly improved the CDAA diet-induced NAFLD condition in mice. A total of 19 metabolites including 5 polar metabolites and 14 lipids showed marked changes. In addition, significant differences in the abundance of Lactobacillus were associated with NAFLD. We inferred that the protective therapeutic effect of PPC on the liver was related to the supplement of phosphatidylcholine, lysophosphatidylcholine, and sphingomyelin (PC, LPC, and SM, resectively) and acylcarnitine metabolism. This study developed a methodology for exploring the pathogenesis of NAFLD and can be extended to other therapeutic agents for treating NAFLD.

Glycosaminoglycan from Apostichopus japonicus (AHG) and its depolymerized fragments (DAHGs) are anticoagulant fucosylated chondroitin sulfate. The aim of this study was to further evaluate the anticoagulant and antithrombic activity of AHG and DAHGs, as well as reveal the dynamic relationship between exposure and effect in vivo. The results demonstrated that AHG100 (Mw~100 kDa), DAHG50 (Mw~50 kDa), and DAHG10 (Mw~10 kDa) exhibited potent anticoagulant activity by inhibiting intrinsic factor Xase complex (FXase) as well as antithrombin-dependent factor IIa (FIIa) and factor Xa (FXa). These glycosaminoglycans markedly prevented thrombosis formation and thrombin-induced platelet aggregation in a dose- and molecular weight-dependent manner in vitro and in vivo. The further bleeding time measurement indicated that DAHG10 exhibited obviously lower hemorrhage risks than native AHG100. Following oral administration, DAHG10 could be absorbed into blood, further dose-dependently prolonging activated partial thromboplastin time (APTT) and thrombin time (TT) as well as inhibiting FXa and FIIa partially through FXase. Anticoagulant activity was positively associated with plasma concentration following oral administration of DAHG10. Our study proposed a new point of view to understand the correlation between effects and exposure of fucosylated chondroitin sulfate as an effective and safe oral antithrombotic agent.

Abnormal tryptophan metabolism is linked to cancer and neurodegenerative diseases, and tryptophan metabolites have been reported as potential prostate cancer (PCa) biomarkers. However, little is known about the bioactivities of tryptophan metabolites on PCa cell growth. In this study, MTT and transwell assays were used to study the cytotoxicities of 13 major tryptophan metabolites on PCa and normal prostate epithelial cell lines. Ultraperformance liquid chromatography–high resolution mass spectrometry (UPLC–HRMS) was used to analyze metabolic changes in cells treated with tryptamine. Flow cytometry, confocal imaging, and Western blot were used to test the apoptosis induced by tryptamine. It was shown that tryptamine had obvious inhibitory effects on PCa cell lines PC-3 and LNCaP, stronger than those on the normal prostate cell line RWPE-1. Tryptamine was further shown to induce apoptosis and inhibit PC-3 cell migration. Metabolic changes including amino acid metabolism related to cell proliferation and metastasis were found in PC-3 cells treated with tryptamine. Furthermore, a PC-3 xenograft mouse model was used to study the effect of tryptamine in vivo. The intratumoral injection of tryptamine was demonstrated to significantly reduce the tumor growth and tumor sizes in vivo; however, intraperitoneal treatment resulted in increased tumor growth. Such dual effects in vivo advanced our understanding of the bioactivity of tryptamine in regulating prostate tumor development, in addition to its major role as a neuromodulator.

Calcium carbonate which is extracted from the Earth in combination with other mineral impurities, is largely used in preparations for pediatric supplements. Elemental impurities in drug products pose toxicological concerns without therapeutic benefits. Thus, it is very urgent to assess the safety of chronic exposure to elements that may be present in trace amounts. In the present study, we developed high throughput ICP-MS method for the quantitative determination of 62 elemental impurities in high matric calcium carbonate samples and validated according to USP 233. Calcium carbonate preparations which state clearly used for child (including neonates, infants, toddlers and children) from 9 manufactures and two types of raw materials (light calcium carbonate and ground calcium carbonate) were investigated in terms of the content and variability of 62 elemental impurities. According to the results, ground calcium carbonate was more suitable to be used in pediatric preparations concerning elemental impurities. Parts of elemental impurities in CaCO3 preparations which are derived from the raw materials and the preparation process, may cause potential risks for children. These results indicate that it is necessary to establish a modern instrumental analysis method to evaluate and control elemental impurities in CaCO3 raw materials and preparations.

Study region: The Baliqlu Chai Watershed is located in Iran in Ardabil province, with area of 1036 km2 and average rainfall of 280.9 mm. The area has been plagued with mismanagement of water resources. Due to the degradation of vegetation, runoff increases, that it can cause problems. Thus, forecasting runoff over the next few years can help manage water resources. Study focus: In this study, used of the SWAT and ANN models and an improved model of a metaheuristic employed for resolving the explained shortcoming. The method of optimization is based on a Mutated model of the Whale Optimization Algorithm (MWOA) that enhances the expected results by reducing the error in the ANN. First, the runoff estimated by the SWAT model, for this purpose, is used of 30 years of statistical data for the calibration and validation model. simulated runoff transmitted as input to the ANN and evaluated, and the MLP/MWOA algorithm used to improve the accuracy of the predicted runoff. New hydrological insights: The results show that according to the regression model, the points distribution in SWAT-MLP/MWOA model is less and has the best linear fit. The values obtained from statistical indices showed that the SWAT-ANN is better than the SWAT model because it has R2 = 0.80, RMSE = 1.61, NSE = 0.79, RE=-0.11. But SWAT-MLP/WOA model has R2 = 0.84, RMSE = 1.42, NSE = 0.81 and RE=-0.09, so SWAT-MLP/ MWOA model is presented as the best model for runoff prediction.

In this study, the immunomodulatory activities of Apostichopus japonicus glycosaminoglycan (AHG) on the nature killer (NK) cells, cytotoxic T lymphocytes (CTLs) and cyclophosphamide (CY)-treated mice were investigated. After stimulation with multiple concentrations of AHG (0–100 μg/mL), NK cells and CTLs displayed outperformance against YAC-1 and B16 cells, respectively. Furthermore, the mitogen-induced splenic lymphocyte proliferation in CY-induced immunosuppressed mice was significantly promoted by AHG. In addition, the administration of AHG dramatically increased the splenocytes Ca2+ concentration and the delayed-type hypersensitivity (DTH) reaction in a dose-dependent manner. Besides, AHG could strongly increase the total antioxidant capacity (T-AOC), the activities of superoxidase dismutase (SOD), catalase (CAT) as well as glutathione peroxidase (GSH-PX), and could decrease the malondialdehyde (MDA) level in the heart, kidney and liver. These findings indicated that AHG played an important role in the immune enhancement and protection against CY-induced immunosuppression and oxidative damage. Our findings provide experimental evidence for further research and possible immunostimulatory applications of AHG in clinical practice.

The present study is focused on the intestinal absorption of sea cucumber saponins. We determined the pharmacokinetic characteristics and bioavailability of Echinoside A and Holotoxin A1; the findings indicated that the bioavailability of Holotoxin A1 was lower than Echinoside A. We inferred that the differences in chemical structure between compounds was a factor that explained their different characteristics of transport across the intestine. In order to confirm the absorption characteristics of Echinoside A and Holotoxin A1, we examined their transport across Caco-2 cell monolayer and effective permeability by single-pass intestinal perfusion. The results of Caco-2 cell model indicate that Echinoside A is transported by passive diffusion, and not influenced by the exocytosis of P-glycoprotein (P-gp, expressed in the apical side of Caco-2 monolayers as the classic inhibitor). The intestinal perfusion also demonstrated well the absorption of Echinoside A and poor absorption of Holotoxin A1, which matched up with the result of the Caco-2 cell model. The results demonstrated our conjecture and provides fundamental information on the relationship between the chemical structure of these sea cucumber saponins and their absorption characteristics, and we believe that our findings build a foundation for the further metabolism study of sea cucumber saponins and contribute to the further clinical research of saponins.

Background: We aimed to assess whether the levels of FFAs (free fatty acids) in ACS (acute coronary syndrome) patients depend on the extent of myocardial ischemia during the subacute phase of ACS attack.Methods: A total of 892 consecutive CAD (coronary artery disease) subjects undergoing coronary angiography were enrolled. The FFAs contents were measured based on enzymatic assay. The relationship between FFAs and Gensini score and ACS susceptibility was assessed.Results: In the overall population, the upper FFAs quartile was accompanied with higher ischemia parameters and increased occurrence of ACS and STEMI (ST-segment elevation myocardial infarction) (P < 0.05). The FFAs concentrations were approximately 1.5-fold higher in ACS than in stable CAD patients, roughly 1.3-fold higher in STEMI than non-STEMI ACS patients and probably 1.3-fold higher in non-STEMI ACS than in stable CAD patients. After adjusted for traditional cardiovascular risk factors, the FFAs level remained a risk factor for a higher Gensini score with more than 40 (P < 0.001) and prevalent ACS (P < 0.001). After adjusted for traditional risk factors, FFAs levels after natural logarithm transformation were associated with hs-CRP and WBC counts in ACS patients. A multiplicative interaction was found between hs-CRP, WBC counts and FFAs in incident ACS and higher Gensini score (P < 0.001).Conclusions: Higher in-hospital levels of FFAs persist and may reflect the severity of ischemia and necrosis during the subacute phase of ACS attack. [ABSTRACT FROM AUTHOR]

Abstract: A simple method for the determination of glucosamine and lactose in milk-based formulae by high-performance liquid chromatography (HPLC) with refractive index detector was developed and validated. Samples were cleaned up just by protein precipitation before HPLC analysis. Separation was achieved with a Shodex Asahipak NH2P-50 column. The method showed good linearity, sensitivity, precision and recovery, and proved very simple and rapid for routine analysis since separation was completely achieved at 10min. [Copyright &y& Elsevier]

Purpose: Several novel genetic variants for type 2 diabetes mellitus (T2DM) have been identified through genome-wide association studies (GWAS). A case-controll study was performed to investigate the association of five new European or South Asian GWASderived susceptibility loci with T2DM in a Chinese population. Methods: Five single nucleotide polymorphisms (SNPs) were genotyped: rs3923113 near GRB14, rs16861329 in ST6GAL1, rs1802295 in VPS26A, rs7178572 in HMG20A, and rs231362 near KCNQ1, by high-resolution melting (HRM) of small amplicons. The association between T2DM and related quantitative traits in a total of 900 Chinese individuals, including 498 type 2 diabetic patients and 402 ethnically matched control subjects, were examined. Results: Afier adjusting for age and gender, rs1802295 (OR 5.724, P=0.03) and rs231362 (OR=5.683, P=0.016) were found to be associated with T2DM. Triglyceride levels were higher in TT and CT carriers for rs16861329 (1.05 (0.8-1.34) mmol/l) than in CC carriers (0.91 (0.73-1.23) mmol/l) with P=0.008 and that high-density lipoprotein cholesterol (HDL-C) was lower in TT and CT carriers (1.17 (1.02-1.33) mmol/l) than in CC carriers (1.21 (1.05-1.41) mmol/l), with P=0.034. For rs3923113, the HDL-C levels were lower in the GG carriers (1.08 (0.90-1.18) mmol/l) than in the GT+TT carriers (1.21 (1.04-1.38) mmol/l), with P=0.018. Ours is the first report of this association. Conclusion: rs231362-KCNQ1 and rs1802295-VPS26A are associated with T2DM in the Chinese population. The remaining three SNPs are associated with other aspects of lipid metabolism. [ABSTRACT FROM AUTHOR]

Background: PS916, chitosan derivative with shown activities in atherosclerotic and fatty liver, is being investigated as an anti-atherosclerotic agent in clinical trials in China., Methods: Fluorescein-labeled PS916 (PS916-FTC) was prepared by the reaction with fluorescein isothiocyanate. The pharmacokinetics and bio-disposition of PS916-FTC were studied in rats after oral or intravenous administration., Results: Analysis of the plasma, urine, fecal and tissue samples collected at intervals up to 72 h revealed that PS916-FTC exhibited moderate volume of distribution (Vss, 0.650~0.748 L/kg), and low clearance (60.9~107 mL/h/kg) after intravenous administration. The pharmacokinetics of PS916-FTC was characterized by low bioavailability (8.40%) after oral administration. The average accumulation ratio for PS916-FTC exposure after steady-state administration was 1.04. A two-compartmental pharmacokinetics model was employed. The urinary route was the major pathway (54.4%), and the fecal route was a minor pathway (6.29%) for PS916-FTC elimination after intravenous administration; the fecal route was the major pathway (79.0%) for PS916-FTC elimination after oral administration., Conclusion: PS916-FTC was widely distributed to most tissues in rats; relatively high levels of PS916-FTC in kidney and liver were observed after intravenous or oral administration. These findings supported the understanding of pharmacokinetics and bio-disposition of PS916 in rats and provide relevant information for future design of clinical studies., Highlights: 1) Fluorescein-labeled PS916 was successfully synthesized. 2) A rapid and sensitive analytical method of PS916-FTC was validated. 3) The pharmacokinetic of PS916-FTC in rats was investigated. 4) The bio-distribution of PS916-FTC in rats was investigated., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)