The effect of histo-blood group ABO system transferase (BGAT) on pregnancy related outcomes：A Mendelian randomization study.

Protein level of Histo-Blood Group ABO System Transferase (BGAT) has been reported to be associated with cardiometabolic diseases. But its effect on pregnancy related outcomes still remains unclear. Here we conducted a two-sample Mendelian randomization (MR) study to ascertain the putative causal roles of protein levels of BGAT in pregnancy related outcomes. Cis-acting protein quantitative trait loci (pQTLs) robustly associated with protein level of BGAT (P < 5 ×10-8) were used as instruments to proxy the BGAT protein level (N = 35,559, data from deCODE), with two additional pQTL datasets from Fenland (N = 10,708) and INTERVAL (N = 3301) used as validation exposures. Ten pregnancy related diseases and complications were selected as outcomes. We observed that a higher protein level of BGAT showed a putative causal effect on venous complications and haemorrhoids in pregnancy (VH) (odds ratio [OR]=1.19, 95% confidence interval [95% CI]=1.12-1.27, colocalization probability=91%), which was validated by using pQTLs from Fenland and INTERVAL. The Mendelian randomization results further showed effects of the BGAT protein on gestational hypertension (GH) (OR=0.97, 95% CI=0.96-0.99), despite little colocalization evidence to support it. Sensitivity analyses, including proteome-wide Mendelian randomization of the cis-acting BGAT pQTLs, showed little evidence of horizontal pleiotropy. Correctively, our study prioritised BGAT as a putative causal protein for venous complications and haemorrhoids in pregnancy. Future epidemiology and clinical studies are needed to investigate whether BGAT can be considered as a drug target to prevent adverse pregnancy outcomes.

A novel starch-active lytic polysaccharide monooxygenase discovered with bioinformatics screening and its application in textile desizing.

BACKGROUND: Lytic polysaccharide monooxygenases (LPMOs) catalyzing the oxidative cleavage of different types of polysaccharides have potential to be used in various industries. However, AA13 family LPMOs which specifically catalyze starch substrates have relatively less members than AA9 and AA10 families to limit their application range. Amylase has been used in enzymatic desizing treatment of cotton fabric for semicentury which urgently need for new assistant enzymes to improve reaction efficiency and reduce cost so as to promote their application in the textile industry. RESULTS: A total of 380 unannotated new genes which probably encode AA13 family LPMOs were discovered by the Hidden Markov model scanning in this study. Ten of them have been successfully heterologous overexpressed. AlLPMO13 with the highest activity has been purified and determined its optimum pH and temperature as pH 5.0 and 50 °C. It also showed various oxidative activities on different substrates (modified corn starch > amylose > amylopectin > corn starch). The results of enzymatic textile desizing application showed that the best combination of amylase (5 g/L), AlLPMO13 (5 mg/L), and H2O2 (3 g/L) made the desizing level and the capillary effects increased by 3 grades and more than 20%, respectively, compared with the results treated by only amylase. CONCLUSION: The Hidden Markov model constructed basing on 34 AA13 family LPMOs was proved to be a valid bioinformatics tool for discovering novel starch-active LPMOs. The novel enzyme AlLPMO13 has strong development potential in the enzymatic textile industry both concerning on economy and on application effect.

Versatile Design of Organic Polymeric Nanoparticles for Photodynamic Therapy of Prostate Cancer.

Radical prostatectomy is a primary treatment option for localized prostate cancer (PCa), although high rates of recurrence are commonly observed postsurgery. Photodynamic therapy (PDT) has demonstrated efficacy in treating nonmetastatic localized PCa with a low incidence of adverse events. However, its limited efficacy remains a concern. To address these issues, various organic polymeric nanoparticles (OPNPs) loaded with photosensitizers (PSs) that target prostate cancer have been developed. However, further optimization of the OPNP design is necessary to maximize the effectiveness of PDT and improve its clinical applicability. This Review provides an overview of the design, preparation, methodology, and oncological aspects of OPNP-based PDT for the treatment of PCa.

Reduced atmospheric sulfate enhances fine particulate nitrate formation in eastern China.

Nitrate (NO3-) is a major component of atmospheric fine particles. Recent studies in eastern China have shown the increasing trend of NO3- in contrast to the ongoing control of nitrogen oxide (NOx). Here, we elucidate the effects of reduced sulfur dioxide (SO2) on the enhancement of NO3- formation based on field measurements at the summit of Mt. Tai (1534 m a.s.l.) and present detailed modelling analyses. From 2007 to 2018, the measured springtime concentrations of various primary pollutants and fine sulfate (SO42-) decreased sharply (-16.4 % to -89.7 %), whereas fine NO3- concentration increased by 22.8 %. The elevated NO3- levels cannot be explained by the changes in meteorological conditions or other related parameters but were primarily attributed to the considerable reduction in SO42- concentrations (-73.4 %). Results from a multi-phase chemical box model indicated that the reduced SO42- levels decreased the aerosol acidity and prompted the partitioning of HNO3 into the aerosol phase. WRF-Chem model analyses suggest that such a negative effect is a regional phenomenon throughout the planetary boundary layer over eastern China in spring. This study provides new insights into the worsening situation of NO3- aerosol pollution and has important implications for controlling haze pollution in China.

STAT3 regulates antiviral immunity by suppressing excessive interferon signaling.

This study identifies interleukin-6 (IL-6)-independent phosphorylation of STAT3 Y705 at the early stage of infection with several viruses, including influenza A virus (IAV). Such activation of STAT3 is dependent on the retinoic acid-induced gene I/mitochondrial antiviral-signaling protein/spleen tyrosine kinase (RIG-I/MAVS/Syk) axis and critical for antiviral immunity. We generate STAT3Y705F/+ knockin mice that display a remarkably suppressed antiviral response to IAV infection, as evidenced by impaired expression of several antiviral genes, severe lung tissue injury, and poor survival compared with wild-type animals. Mechanistically, STAT3 Y705 phosphorylation restrains IAV pathogenesis by repressing excessive production of interferons (IFNs). Blocking phosphorylation significantly augments the expression of type I and III IFNs, potentiating the virulence of IAV in mice. Importantly, knockout of IFNAR1 or IFNLR1 in STAT3Y705F/+ mice protects the animals from lung injury and reduces viral load. The results indicate that activation of STAT3 by Y705 phosphorylation is vital for establishment of effective antiviral immunity by suppressing excessive IFN signaling induced by viral infection.

The prognostic value and economic benefits of coronary angiography-derived fractional flow reserve-guided strategy in patients with coronary artery disease.

Objective: This study aims to investigate the prognostic value and economic benefit of coronary angiography-derived fractional flow reserve (caFFR) guided percutaneous coronary intervention (PCI) in patients with coronary artery disease. Methods: All patients with coronary artery disease (CAD) who underwent coronary angiography in our center between April 2021 and November 2021 were retrospectively enrolled and divided into the caFFR guidance group (n = 160) and angiography guidance group (n = 211). A threshold of caFFR≤0.8 was used for revascularization. Otherwise, delayed PCI was preferred. The patients were prospectively followed up by telephone or outpatient service at six months for major adverse cardiovascular events (MACE) of all-cause death, myocardial infarction or target vessel revascularization, stent thrombosis, and stroke. All in-hospital expenses were recorded, including initial hospitalization and re-hospitalization related to MACE. Results: There was no significant difference in the baseline characteristics between the two groups. There were 2 (1.2%) patients in the caFFR guidance group and 5 (2.4%) patients in the angiography guidance group with MACE events during the following six months. Compared with angiography guidance, caFFR guidance reduced the revascularization rate (63.7% vs. 84.4%, p = 0.000), the average length of stents implanted (0.52 ± 0.88 vs. 1.1 ± 1.4, P < 0.001). The cost of consumables in the caFFR guidance group was significantly lower than that in the angiography guidance group (33257 ± 19595 CNY vs. 38341 ± 16485 CNY, P < 0.05). Conclusion: Compared with coronary angiography guidance, caFFR guidance is of great significance in reducing revascularization and cost, which has significant health and economic benefits.

A variant rs6214 within IGF-1 confers risk for ulcerative colitis in Chinese Han populations.

Insulin growth factor-1 (IGF-1) has been found to correlate with various diseases such as cancer and cardiovascular diseases including ulcerative colitis (UC). The present study aimed to investigate the plausible association of rs6214 (C > T) within IGF-1 and UC susceptibility in Chinese Han populations. A total of 977 UC patients and 1029 healthy controls were enrolled, and rs6214 was genotyped with PCR and direct sequencing on the ABI 3730XL DNA analyzer platform. Logistic regression analysis was applied for the correlation of rs6214 and UC susceptibility via calculation of odds ratio (OR) with a 95% confidence interval (95% CI) adjusted for age and sex under different genetic models. The difference of clinical parameters between genotypes was measured by one-way analysis of variance (ANOVA). Additional functional assays were conducted to establish the probable relationship. The results indicated that the T allele of rs6214 showed roughly 37% greater risk for UC risk in the additive model (OR = 1.37, 95% CI = 1.21-1.55, P < 0.000001) when compared with C allele carriers, and the pattern was similar in other three genetic models. Further stratified analysis suggested that the association was particularly noteworthy in UC patients with extensive colitis and severe condition. Moreover, the blood level of IGF-1 was downregulated in UC patients, and the mRNA level was lower in T allele carriers in rectal tissues of UC cases. Additional luciferase assay demonstrated that rs6214 regulates IGF-1 expression via promoting miR-2053. Collectively, rs6214 increased UC susceptibility and suppresses IGF-1 expression by enhancing miR-2053 binding. The current findings provided evidence that rs6214 is a promising biomarker for UC prediction and prognosis.

Copper-Modified Double-Emission Carbon Dots for Rapid Detection of Thiophanate Methyl in Food.

The detection of food safety and quality is very significant throughout the food supply. Stable dual-emission copper-modified fluorescent carbon dots (Cu-CDs) were successfully synthesized by a simple and environment-friendly hydrothermal, which was used for the real-time detection of pesticide residues in agricultural products. By optimizing the reaction conditions, Cu-CDs showed two emission peaks, with the highest fluorescence intensities at 375 and 450 nm. The structure, chemical composition and optical properties of Cu-CDs were investigated by XRD, TEM and IR. The results showed that thiophanate methyl (TM) could induce fluorescence quenching of Cu-CDs with no other ligands by the electron transfer through π-π stacking. The synchronous response of the dual-emission sensor enhanced the specificity of TM, which showed remarkable anti-interference capability. The fluorescence quenching degree of Cu-CDs had a good linear relationship with the TM concentration; the low detection limit for a pear was 0.75 µM, and for an apple, 0.78 µM. The recoveries in the fruit samples were 79.70-91.15% and 81.20-93.55%, respectively, and the relative standard deviations (RSDs) were less than 4.23% for the pear and less than 3.78% for the apple. Thus, our results indicate the feasibility and reliability of our methods in detecting pesticide residues in agricultural products.

Benzyne Polyfunctionalization via a Tandem C-C σ-Bond Insertion and Photo-Nazarov Cyclization.

A tandem benzyne C-C σ-bond insertion reaction and photo-Nazarov cyclization protocol was developed, leading to the formation of three C-C bonds at consecutive positions of a benzene ring with concomitant assembly of a 6-5-6 tricyclic ring system. When 3-silylbenzyne precursors were employed, a tandem process involving a benzyne C-C σ-bond insertion, a photo-Nazarov cyclization, and a 1,3-silyl group migration was observed, which could produce 1,2,3,5-tetrasubstituted benzenes.

Particulate organic nitrates at Mount Tai in winter and spring: Variation characteristics and effects of mountain-valley breezes and elevated emission sources.

Particulate organic nitrates, among the major components of secondary organic aerosols and fine particles, play important roles in regional nitrogen cycle, ozone budget, and cloud condensation nuclei formation. However, the pollution characteristics of particulate organic nitrates at mountain areas and the effects of anthropogenic pollutant transport remain poorly understood. In this study, field sampling and measurements were conducted at a high-elevation mountain site over North China Plain in winter and spring. Total five kinds of particulate organic nitrates in fine particles were determined by ultra-high performance liquid chromatography-electrospray mass spectrometry. The average total concentrations of particulate organic nitrates were 330 ± 121 ng m-3 and 247 ± 63 ng m-3 in winter and spring. The monoterpene-derived organic nitrates were the dominant components in both seasons with their contribution higher than 70%, accounting for 1.2 ± 0.8% and 2.0 ± 1.0% in organic aerosols in winter and spring, respectively. The significantly higher levels of particulate organic nitrates in winter than spring was ascribed to the strong effects of mountain-valley breezes and coal combustion plumes. The increasing concentrations of NOx and particulate matters brought by the valley breeze at daytime facilitated the formation of MHN215, OAKN359, and OAHN361, while the rising SO2 abundance and the sulfate aerosols transported by elevated emission sources affected the formation of MDCN247 at nighttime.

Nitrous acid in the polluted coastal atmosphere of the South China Sea: Ship emissions, budgets, and impacts.

Nitrous acid (HONO) can significantly contribute to hydroxyl radicals (OH) and thus regulate atmospheric oxidation chemistry; however, ambient HONO sources are not well quantified and vary in different environments. In this study, we conducted comprehensive field observations at a coastal site in the South China Sea and performed chemical box modelling to demonstrate contrasting budgets and impacts of diurnal atmospheric HONO derived from the sea, coastline and continent. The ship emission ratio of HONO/nitrogen oxides (NOx) (1.21 ± 0.99%) was calculated from hundreds of night-time fresh plume measurements. Offshore marine air was frequently influenced by ship exhausts, and the sea acted as an HONO sink. Heterogeneous conversions of nitrogen dioxide (NO2) on underlying surfaces and photolysis of adsorbed nitric acid (HNO3(ads)) were the major HONO sources in coastal air, when heterogeneous NO2 conversions on the ground surface and the homogeneous NO + OH reaction dominated HONO formation in continental air. HONO photolysis was a significant source of reactive radicals (ROx = OH + HO2 + RO2) in these air masses. Atmospheric box model including only homogeneous HONO source of the NO + OH reactions significantly underpredicted the OH concentration and atmospheric oxidising capacity in coastal and continental air. This study provides new insights into the complex sources and significant impacts of HONO in the polluted coastal boundary layer.

Investigating the sources of atmospheric nitrous acid (HONO) in the megacity of Beijing, China.

Nitrous acid (HONO) can powerfully influence atmospheric photochemistry by producing hydroxyl radical (OH), which is a crucial oxidant that controls the fate of atmospheric trace species. To deduce HONO formation mechanisms in polluted regions, two field observations were conducted in urban Beijing during the early summer of 2017 and the winter of 2018. These two seasons bore distinguishing pollution characteristics with a higher degree of ageing and heavier aerosol loading in the early summer and more abundant NOx (NOx = NO + NO2) in the winter. Elevated concentrations of HONO were observed during these two seasons, with the mean ± standard deviation (maximum) concentrations of 1.25 ± 0.94 (6.69) ppbv and 1.04 ± 1.27 (9.55) ppbv in early summer and winter, respectively. The observed daytime (08:00-17:00 h, local time) HONO production rate was several times higher in early summer than in winter (4.44 ± 1.93 ppbv h-1 vs. 0.88 ± 0.49 ppbv h-1). Budget analysis revealed distinct daytime HONO formation mechanisms during these two seasons. Photo-induced heterogeneous conversion of NO2 on the ground surface dominated in early summer, and homogeneous reaction of NO + OH was dominant in winter. Photolysis of HONO was the major source of primary OH in both seasons, and thus, played a key role in the regulation of atmospheric oxidising capacity. This study demonstrates the significant seasonal variations in HONO budget and underlines the predominant role of HONO in primary OH production in Beijing. Our findings will be helpful to gain an understanding of the chemical mechanisms underlying the formation of secondary pollution in metropolitan areas.

Aryne 1,2,3,5-Tetrasubstitution Enabled by 3-Silylaryne and Allyl Sulfoxide via an Aromatic 1,3-Silyl Migration.

Although benzyne has been well-known to serve as a synthon that can conveniently prepare various 1,2-difunctionalized benzenes, the sites other than its formal triple bond remain silent in typical benzyne transformations. An unprecedented aryne 1,2,3,5-tetrasubstitution was realized from 3-silylbenzyne and aryl allyl sulfoxide, the mechanistic pathway of which includes a regioselective aryne insertion into the S═O bond, a [3,6]-sigmatropic rearrangement, and a thermal aromatic 1,3-silyl migration cascade.

Non-small cell lung cancer-targeted, redox-sensitive lipid-polymer hybrid nanoparticles for the delivery of a second-generation irreversible epidermal growth factor inhibitor-Afatinib: In vitro and in vivo evaluation.

Afatinib (Afa), a second-generation irreversible epidermal growth factor inhibitor for the development of non-small cell lung cancer, has low bioavailability and adverse reactions. Nanoscaled drug delivery systems offer promising alternatives to address these defects and improve therapeutic outcomes. In the present study, a Tf contained, redox-sensitive ligand was synthesized and used for the preparation of afatinib loaded, Tf modified redox-sensitive lipid-polymer hybrid nanoparticles (Tf-SS-Afa-LPNs). Subsequently, studies of biological experiments in vitro and in vivo were performed to investigate the therapeutic effect of the system in lung cancer. The results showed that Tf-SS-Afa-LPNs has particle size of 103.5 ± 4.1 nm and zeta potential of -21.2 ± 2.4 mV. Significantly higher drug release was observed in the presence of glutathione (GSH). The area under the plasma concentration - time curve (AUC), peak concentration (Cmax) and terminal half life (T1/2) of Tf-SS-Afa-LPNs were 866.56 mg/L.h, 25.62 ± 3.21 L/kg/h, and 43.25 ± 2.31 h. Tf-SS-Afa-LPNs exhibited the most remarkable in vivo anti-tumor efficiency efficacy, which inhibited the tumor volume from 919 mm3 to 212 mm3. Tf-SS-Afa-LPNs is a promising platform for the lung cancer treatment.

Emissions of fine particulate nitrated phenols from the burning of five common types of biomass.

Nitrated phenols are among the major constituents of brown carbon and affect both climates and ecosystems. However, emissions from biomass burning, which comprise one of the most important primary sources of atmospheric nitrated phenols, are not well understood. In this study, the concentrations and proportions of 10 nitrated phenols, including nitrophenols, nitrocatechols, nitrosalicylic acids, and dinitrophenol, in fine particles from biomass smoke were determined under three different burning conditions (flaming, weakly flaming, and smoldering) with five common types of biomass (leaves, branches, corncob, corn stalk, and wheat straw). The total abundances of fine nitrated phenols produced by biomass burning ranged from 2.0 to 99.5 µg m-3. The compositions of nitrated phenols varied with biomass types and burning conditions. 4-nitrocatechol and methyl nitrocatechols were generally most abundant, accounting for up to 88-95% of total nitrated phenols in flaming burning condition. The emission ratios of nitrated phenols to PM2.5 increased with the completeness of combustion and ranged from 7 to 45 ppmm and from 239 to 1081 ppmm for smoldering and flaming burning, respectively. The ratios of fine nitrated phenols to organic matter in biomass burning aerosols were comparable to or lower than those in ambient aerosols affected by biomass burning, indicating that secondary formation contributed to ambient levels of fine nitrated phenols. The emission factors of fine nitrated phenols from flaming biomass burning were estimated based on the measured mass fractions and the PM2.5 emission factors from literature and were approximately 0.75-11.1 mg kg-1. According to calculations based on corn and wheat production in 31 Chinese provinces in 2013, the total estimated emission of fine nitrated phenols from the burning of corncobs, corn stalks, and wheat straw was 670 t. This work highlights the apparent emission of methyl nitrocatechols from biomass burning and provides basic data for modeling studies.

Aryne 1,2,3-Trifunctionalization with Aryl Allyl Sulfoxides.

An aryne 1,2,3-trisubstitution with aryl allyl sulfoxides is accomplished, featuring an incorporation of C-S, C-O, and C-C bonds on the consecutive positions of a benzene ring. The reaction condition is mild with broad substrate scope. Preliminary mechanistic study suggests a cascade formal [2 + 2] reaction of aryne with S═O bond, an allyl S → O migration, and a Claisen rearrangement.

Metabolomic approach to evaluating adriamycin pharmacodynamics and resistance in breast cancer cells.

Continuous exposure of breast cancer cells to adriamycin induces high expression of P-gp and multiple drug resistance. However, the biochemical process and the underlying mechanisms for the gradually induced resistance are not clear. To explore the underlying mechanism and evaluate the anti-tumor effect and resistance of adriamycin, the drug-sensitive MCF-7S and the drug-resistant MCF-7Adr breast cancer cells were used and treated with adriamycin, and the intracellular metabolites were profiled using gas chromatography mass spectrometry. Principal components analysis of the data revealed that the two cell lines showed distinctly different metabolic responses to adriamycin. Adriamycin exposure significantly altered metabolic pattern of MCF-7S cells, which gradually became similar to the pattern of MCF-7Adr, indicating that metabolic shifts were involved in adriamycin resistance. Many intracellular metabolites involved in various metabolic pathways were significantly modulated by adriamycin treatment in the drug-sensitive MCF-7S cells, but were much less affected in the drug-resistant MCF-7Adr cells. Adriamycin treatment markedly depressed the biosynthesis of proteins, purines, pyrimidines and glutathione, and glycolysis, while it enhanced glycerol metabolism of MCF-7S cells. The elevated glycerol metabolism and down-regulated glutathione biosynthesis suggested an increased reactive oxygen species (ROS) generation and a weakened ability to balance ROS, respectively. Further studies revealed that adriamycin increased ROS and up-regulated P-gp in MCF-7S cells, which could be reversed by N-acetylcysteine treatment. It is suggested that adriamycin resistance is involved in slowed metabolism and aggravated oxidative stress. Assessment of cellular metabolomics and metabolic markers may be used to evaluate anti-tumor effects and to screen for candidate anti-tumor agents.

Pharmacokinetic interactions between 20(S)-ginsenoside Rh2 and the HIV protease inhibitor ritonavir in vitro and in vivo.

AIM: 20(S)-Ginsenoside Rh2 (Rh2) has shown potent inhibition on P-glycoprotein (P-gp), while most HIV protease inhibitors are both substrates and inhibitors of P-gp and CYP3A4. The aim of this study was to investigate the potential pharmacokinetic interactions between Rh2 and the HIV protease inhibitor ritonavir. METHODS: The effects of Rh2 on the cellular accumulation and transepithelial transport of ritonavir were studied in Caco-2 and MDCK-MDR1 cells. Male rats were administered Rh2 (25 or 60 mg/kg, po) or Rh2 (5 mg/kg, iv), followed by ritonavir (25 mg/kg, po). The P-gp inhibitors verapamil (20 mg/kg, po) or GF120918 (5 mg/kg, po) were used as positive controls. The concentrations of ritonavir in plasma, bile, urine, feces and tissue homogenates were analyzed using LC-MS. RESULTS: Rh2 (10 µmol/L) significantly increased the accumulation and inhibited the efflux of ritonavir in Caco-2 and MDCK-MDR1 cells, as verapamil did. But Rh2 did not significantly alter ritonavir accumulation or transport in MDCK-WT cells. Intravenous Rh2 significantly increased the plasma exposure of ritonavir while reducing its excretion in the bile, and oral verapamil or GF120918 also increased plasma exposure of ritonavir but without changing its excretion in the bile. Interestingly, oral Rh2 at both doses did not significantly change the plasma profile of ritonavir. Moreover, oral Rh2 (25 mg/kg) significantly elevated the ritonavir concentration in the hepatic portal vein, and markedly increased its urinary excretion and tissue distribution, which might counteract the elevated absorption of ritonavir. CONCLUSION: Rh2 inhibits the efflux of ritonavir through P-gp in vitro. The effects of Rh2 on ritonavir exposure in vivo depend on the administration route of Rh2: intravenous, but not oral, administration of Rh2 significantly increased the plasma exposure of ritonavir.

Metabolic phenotype of rats exposed to heroin and potential markers of heroin abuse.

BACKGROUND: Metabolomics allows the high-throughput analysis of low molecular mass compounds in biofluids, which can reflect the metabolic response of the body to heroin exposure and potentially reveal biomarkers of heroin abuse. METHODS: Heroin was administered to Sprague-Dawley rats in increasing doses from 3 to 16.5 mg kg(-1)d(-1) (i.p.) for 10 days, then withdrawn and re-administered for 4 days. The analytes in serum and urine were profiled using gas chromatography-mass spectrometry, and metabolic patterns were evaluated based on the metabolomics data. RESULTS: Both the administration and withdrawal of heroin resulted in aberrant behaviour in the rats; however, the rats gradually became adapted to heroin. Metabolomics data showed that heroin administration caused deviations in the metabolic patterns, whereas heroin withdrawal restored the metabolic patterns towards baseline. Re-administration of heroin caused the metabolic patterns to deviate again. Analysis of the metabolites revealed that heroin induced an acceleration of the tricarboxylic acid cycle and the metabolism of free fatty acids that may contribute to the reduction in observed body weight in the heroin group. Heroin administration decreased tryptophan and 5-hydroxytryptamine levels in peripheral serum but increased urinary tryptophan and 5-hydroxyindoleacetate. Withdrawal of heroin for 4 days efficiently restored all metabolites to baseline, except serum myo-inositol-1-phosphate, threonate, and hydroxyproline in the urine. CONCLUSIONS: Heroin administration significantly perturbed metabolic pathways, elevated energy metabolism, whereas heroin withdrawal restored all but a few metabolites to baseline. These peripheral metabolites were indicated as the surrogates characterising the metabolic effect of heroin on central nervous system function.

Prediction of the pharmacokinetic parameters of triptolide in rats based on endogenous molecules in pre-dose baseline serum.

BACKGROUND: Individual variances usually affect drug metabolism and disposition, and hence result in either ineffectiveness or toxicity of a drug. In addition to genetic polymorphism, the multiple confounding factors of lifestyles, such as dietary preferences, contribute partially to individual variances. However, the difficulty of quantifying individual diversity greatly challenges the realization of individualized drug therapy. This study aims at quantitative evaluating the association between individual variances and the pharmacokinetics. METHODOLOGY/PRINCIPAL FINDINGS: Molecules in pre-dose baseline serum were profiled using gas chromatography mass spectrometry to represent the individual variances of the model rats provided with high fat diets (HFD), routine chows and calorie restricted (CR) chows. Triptolide and its metabolites were determined using high performance liquid chromatography mass spectrometry. Metabonomic and pharmacokinetic data revealed that rats treated with the varied diets had distinctly different metabolic patterns and showed differential C(max) values, AUC and drug metabolism after oral administration of triptolide. Rats with fatty chows had the lowest C(max) and AUC values and the highest percentage of triptolide metabolic transformation, while rats with CR chows had the highest C(max) and AUC values and the least percentage of triptolide transformation. Multivariate linear regression revealed that in baseline serum, the concentrations of creatinine and glutamic acid, which is the precursor of GSH, were linearly negatively correlated to C(max) and AUC values. The glutamic acid and creatinine in baseline serum were suggested as the potential markers to represent individual diversity and as predictors of the disposal and pharmacokinetics of triptolide. CONCLUSIONS/SIGNIFICANCE: These results highlight the robust potential of metabonomics in characterizing individual variances and identifying relevant markers that have the potential to facilitate individualized drug therapy.