Mechanistic and predictive studies on the oxidation of furans by cytochrome P450: A DFT study.

Furan-containing compounds distribute widely in food, herbal medicines, industrial synthetic products, and environmental media. These compounds can undergo oxidative metabolism catalyzed by cytochrome P450 enzymes (CYP450) within organisms, which may produce reactive products, possibly reacting with biomolecules to induce toxic effects. In this work, we performed DFT calculations to investigate the CYP450-mediated metabolic mechanism of furan-ring oxidation using 2-methylfuran as a model substrate, meanwhile, we studied the regioselective competition of another hydroxylation reaction involving methyl group of 2-methylfuran. As a result, we found the toxicological-relevant cis-enedione product can be produced from O-addition directly via a concerted manner without formation of an epoxide intermediate as traditionally believed. Moreover, our calculations demonstrate the kinetic and thermodynamic feasibility of both furan-ring oxidation and methyl hydroxylation pathways, although the former pathway is a bit more favorable. We then constructed a linear model to predict the rate-limiting activation energies (ΔE*) of O-addition with 11 diverse furan substates based on their adiabatic ionization potentials (AIPs) and condensation Fukui functions (CFFs). The results show a good predictive ability (R2=0.94, Q2CV=0.87). Therefore, AIP and CFF with clear physichem meanings relevant to the mechanism, emerge as pivotal molecular descriptors to enable the fast prediction of furan-ring oxidation reactivities for quick insight into the toxicological risk of furans, using just ground-state calculations.

Matrix Factorization-Based Dimensionality Reduction Algorithms─A Comparative Study on Spectroscopic Profiling Data.

Spectroscopic profiling data used in analytical chemistry can be very high-dimensional. Dimensionality reduction (DR) is an effective way to handle the potential "curse of dimensionality" problem. Among the existing DR algorithms, many can be categorized as a matrix factorization (MF) problem, which decomposes the original data matrix X into the product of a low-dimensional matrix W and a dictionary matrix H. First, this paper provides a theoretical reformulation of relevant DR algorithms under a unified MF perspective, including PCA (principal component analysis), NMF (non-negative matrix factorization), LAE (linear autoencoder), RP (random projection), SRP (sparse random projection), VQ (vector quantization), AA (archetypical analysis), and ICA (independent component analysis). From this perspective, an open-sourced toolkit has been developed to integrate all of the above algorithms with a unified API. Second, we made a comparative study on MF-based DR algorithms. In a case study of TOF (time-of-flight) mass spectra, the eight algorithms extracted three components from the original 27,619 features. The results are compared by a set of DR quality metrics, e.g., reconstruction error, pairwise distance/ranking property, computational cost, local and global structure preservations, etc. Finally, based on the case study result, we summarized guidelines for DR algorithm selection. (1) For reconstruction quality, choose ICA. In the case study, ICA, PCA, and NMF have high reconstruction qualities (reconstruction error < 2%), ICA being the best. (2) To keep the pairwise topological structure, choose PCA. PCA best preserves the pairwise distance/ranking property. (3) For edge computing and IoT scenarios, choose RP or SRP if reconstruction is not required and the JL-lemma condition is met. The RP family has the best computational performance in the experiment, almost 10-100 times faster than its peers.

Computational Investigation of the Bisphenolic Drug Metabolism by Cytochrome P450: What Factors Favor Intramolecular Phenol Coupling.

Intramolecular phenol coupling reactions of alkaloids can lead to active metabolites catalyzed by the mammalian cytochrome P450 enzyme (P450); however, the mechanistic knowledge of such an "unusual" process is lacking. This work performs density functional theory computations to reveal the P450-mediated metabolic pathway leading from R-reticuline to the morphine precursor salutaridine by exploring possible intramolecular phenol coupling mechanisms involving diradical coupling, radical addition, and electron transfer. The computed results show that the outer-sphere electron transfer with a high barrier (>20.0 kcal/mol) is unlikely to happen. However, for inter-sphere intramolecular phenol coupling, it reveals that intramolecular phenol coupling of R-reticuline proceeds via the diradical mechanism consecutively by compound I and protonated compound II of P450 rather than the radical addition mechanism. The existence of a much higher radical rebound barrier than that of H-abstraction in the quartet high-spin state can endow the R-reticuline phenoxy radical with a sufficient lifetime to enable intramolecular phenol coupling, while the H-abstraction/radical rebound mode with a negligible rebound barrier leading to phenol hydroxylation can only happen in the doublet low-spin state. Therefore, the ratio [coupling]/[hydroxylation] can be approximately reflected by the relative yield of the high-spin and low-spin H-abstraction by P450, which thus can provide a theoretical ratio of 16:1 for R-reticuline, which is in accordance with previous experimental results. Especially, the high rebound barrier of the phenoxy radical derived from the weak electron-donating ability of the phenoxy radical is revealed as an intrinsic nature. Therefore, the revealed intramolecular phenol coupling mechanism can be potentially extended to several other bisphenolic drugs to infer groups of unexpected metabolites in organisms.

Using Physical Organic Chemistry Knowledge to Predict Unusual Metabolites of Synthetic Phenolic Antioxidants by Cytochrome P450.

Biotransformation, especially by human CYP450 enzymes, plays a crucial role in regulating the toxicity of organic compounds in organisms, but is poorly understood for most emerging pollutants, as their numerous "unusual" biotransformation reactions cannot retrieve examples from the textbooks. Therefore, in order to predict the unknown metabolites with altering toxicological profiles, there is a realistic need to develop efficient methods to reveal the "unusual" metabolic mechanism of emerging pollutants. Combining experimental work with computational predictions has been widely accepted as an effective approach in studying complex metabolic reactions; however, the full quantum chemical computations may not be easily accessible for most environmentalists. Alternatively, this work practiced using the concepts from physical organic chemistry for studying the interrelationships between structure and reactivity of organic molecules, to reveal the "unusual" metabolic mechanism of synthetic phenolic antioxidants catalyzed by CYP450, for which the simple pencil-and-paper and property-computation methods based on physical organic chemistry were performed. The phenol-coupling product of butylated hydroxyanisole (BHA) (based on spin aromatic delocalization) and ipso-addition quinol metabolite of butylated hydroxytoluene (BHT) (based on hyperconjugative effect) were predicted as two "unusual" metabolites, which were further confirmed by our in vitro analysis. We hope this easily handled approach will promote environmentalists to attach importance to physical organic chemistry, with an eye to being able to use the knowledge gained to efficiently predict the fates of substantial unknown synthesized organic compounds in the future.

In Silico simulation of Cytochrome P450-Mediated metabolism of aromatic amines: A case study of N-Hydroxylation.

Aromatic amines, the widely used raw materials in industry, cause long-term exposure to human bodies. They can be metabolized by cytochrome P450 enzymes to form active electrophilic compounds, which will potentially react with nucleophilic DNA to exert carcinogenesis. The short lifetime and versatility of the oxidant (a high-valent iron (IV)-oxo species, compound I) of P450 enzymes prompts us to use theoretical methods to investigate the metabolism of aromatic amines. In this work, the density functional theory (DFT) has been employed to simulate the hydroxylation metabolism through H-abstraction and to calculate the activation energy of this reaction for 28 aromatic amines. The results indicate that the steric effects, inductive effects and conjugative effects greatly contribute to the metabolism activity of the chemicals. The further correlation reveals that the dissociation energy of -NH2 (BDEN-H) can successfully predict the time-consuming calculated activation energy (R2 for aromatic and heteroaromatic amines are 0.93 and 0.86, respectively), so BDEN-H can be taken as a key parameter to characterize the relative stability of aromatic amines in P450 enzymes and further to quickly assess their potential toxicity. The validation results prove such relationship has good statistical performance (qcv2 for aromatic and heteroaromatic amines are 0.95 and 0.90, respectively) and can be used to other aromatic amines in the application domain, greatly reducing computational cost and providing useful support for experimental research.

scTPA: a web tool for single-cell transcriptome analysis of pathway activation signatures.

MOTIVATION: At present, a fundamental challenge in single-cell RNA-sequencing data analysis is functional interpretation and annotation of cell clusters. Biological pathways in distinct cell types have different activation patterns, which facilitates the understanding of cell functions using single-cell transcriptomics. However, no effective web tool has been implemented for single-cell transcriptome data analysis based on prior biological pathway knowledge. RESULTS: Here, we present scTPA, a web-based platform for pathway-based analysis of single-cell RNA-seq data in human and mouse. scTPA incorporates four widely-used gene set enrichment methods to estimate the pathway activation scores of single cells based on a collection of available biological pathways with different functional and taxonomic classifications. The clustering analysis and cell-type-specific activation pathway identification were provided for the functional interpretation of cell types from a pathway-oriented perspective. An intuitive interface allows users to conveniently visualize and download single-cell pathway signatures. Overall, scTPA is a comprehensive tool for the identification of pathway activation signatures for the analysis of single cell heterogeneity. AVAILABILITY AND IMPLEMENTATION: http://sctpa.bio-data.cn/sctpa. CONTACT: sujz@wmu.edu.cn or yufulong421@gmail.com or zgj@zjut.edu.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Computational Biotransformation Profile of Emerging Phenolic Pollutants by Cytochromes P450: Phenol-Coupling Mechanism.

Phenols are ubiquitous environmental pollutants, whose biotransformation involving phenol coupling catalyzed by cytochromes P450 may produce more lipophilic and toxic metabolites. Density functional theory (DFT) computations were performed to explore the debated phenol-coupling mechanisms, taking triclosan as a model substrate. We find that a diradical pathway facilitated by compound I and protonated compound II of P450 is favored vs alternative radical addition or electron-transfer mechanisms. The identified diradical coupling resembles a "two-state reactivity" from compound I characterized by significantly high rebound barriers of the phenoxy radicals, which can be formulated into three equations for calculating the ratio [coupling]/[hydroxylation]. A higher barrier for rebound than for H-abstraction in high-spin triclosan can facilitate the phenoxy radical dissociation and thus enable phenol coupling, while H-abstraction/radical rebound causing phenol hydroxylation via minor rebound barriers mostly occurs via the low-spin state. Therefore, oxidation of triclosan by P450 fits the first equation with a ratio [coupling]/[hydroxylation] of 1:4, consistent with experimental data indicating different extents of triclosan coupling (6-40%). The high rebound barrier of phenoxy radicals, as a key for the mechanistic identification of phenol coupling vs hydroxylation, originates from their weak electron donor ability due to spin aromatic delocalization. We envision that the revealed mechanism can be extended to the cross-coupling reactions between different phenolic pollutants, and the coupling reactions of several other aromatic pollutants, to infer unknown metabolites.

Congener-Specific Mother-Fetus Distribution, Placental Retention, and Transport of C10-13 and C14-17 Chlorinated Paraffins in Pregnant Women.

Short-chain chlorinated paraffins (SCCPs) and medium-chain chlorinated paraffins (MCCPs) are high-production-volume persistent and toxic industrial chemicals found ubiquitously in various environmental matrices. However, information is scarce regarding human internal exposure. The congener-specific SCCP and MCCP levels in matched maternal serum (n = 31), umbilical cord serum (n = 31), and placenta (n = 31) were studied to investigate the maternal-placenta-fetus distribution and the placental transport mechanisms of SCCPs and MCCPs. The results indicated that lower chlorinated and shorter carbon chain CPs were efficiently transported across placenta compared to highly chlorinated and longer carbon chain CPs. Meanwhile, ∑MCCP concentration followed the order of maternal sera > placentas > cord sera. The cord/maternal concentration fraction ratios (RCM) of CPs exhibited similar values from C10 to C14, and then from C15, a decreasing trend was observed with increasing carbon chain length. The log-normalized maternal SCCP concentrations were positively correlated (P < 0.01) with that in the cord, suggesting fetus exposure to SCCPs during pregnancy. Furthermore, the placenta/maternal concentration fraction ratio (RPM) values for MCCPs were relatively higher than those for SCCPs, demonstrating that MCCPs were not efficiently transported and effectively retained in placenta tissues. These findings provide a better understanding of the maternal-fetal transmission and neonatal exposure to CPs.

Multicenter biomonitoring of polybrominated diphenyl ethers (PBDEs) in colostrum from China: Body burden profile and risk assessment.

Polybrominated diphenyl ethers (PBDEs) were listed in the Stockholm Convention due to their persistent and toxic nature. In utero exposure to PBDEs might affect fetal development as it is sensitive when exposed to even low dose of xenobiotic substances during the pregnancy. In this study, a multi-centre human biomonitoring study of tri-to hexa-BDEs was conducted in three Chinese cities using 60 colostrum samples from local residents. The patterns and influencing factors, correlation with the birth outcome, and potential health risks during the breastfeeding of tri-to hexa-BDEs in the colostrum samples were assessed. The median concentration of tri-to hexa-BDEs was 9.1 (Interquartile range: 3.1-19.5) ng g-1 lipid weight, and BDE-153 contributed 68% of the detected PBDEs. The PBDE levels were mostly associated with maternal age and drinking water sources, while correlations with other factors including weight gain, BMI, parity and the number of aborted pregnancies was not significant. The level of BDE-28 was positively correlated with the birth weight, while the BDE-99 was positively correlated with the head circumference, using multilinear regression. For the total hazard quotients, 60% of the infants have an estimated value higher than 1, showed potential chronic hazard for future development and possible adverse health effects to the babies from the exposure to PBDE congeners. Alternative food source seems to have a lower risk for neonates than the colostrum, but the advantages of breastfeeding undoubtedly outweigh the risks and potential adverse health effects caused by environmental PBDEs and other xenobiotic chemical exposure.

Enantioseparation of chiral perfluorooctane sulfonate (PFOS) by supercritical fluid chromatography (SFC): Effects of the chromatographic conditions and separation mechanism.

Perfluorooctane sulfonate (PFOS) is one of the most frequently detected perfluoroalkyl substances in environmental and human samples. Previous studies have shown that nonracemic PFOS in biological samples can be used as a marker of PFOS exposure sources. In recent years, supercritical fluid chromatography (SFC) has emerged as a powerful method to separate chiral compounds. In this study, a method of perfluoro-1-methylheptane sulfonate (1 m-PFOS) enantioseparation by SFC was established. The optimal separation was obtained using a Chiralpak QN-AX column with CO2 /2-propanol (70/30, v/v) as the mobile phase with a flow rate of 1 mL/min, column temperature was 32°C, and BPR pressure was 1800 psi. The resolution (Rs) and retention time were 0.88 and 130 minutes, respectively. This method is more economic and greener than HPLC. Modifier pH and column temperature were determined to be significant factors of SFC chiral separation. Modifier pH is negatively correlated with the retention factors and Rs. Adsorption thermodynamics were used to explain the influence of temperature change, and it was concluded that the transfer of two enantiomers from the mobile phase to the stationary phase is enthalpy-driven. Enantioseparation of 1 m-PFOS by SFC follows the same rules of ion exchange as those for the chiral separation by HPLC.

Enantioseparation of napropamide by supercritical fluid chromatography: Effects of the chromatographic conditions and separation mechanism.

Supercritical fluid chromatography (SFC) is already used for enantioseparation in the pharmaceutical industry, but it is rarely used for the separation of chiral pesticides. Comparing with high performence liquid chromatography, SFC uses much more environmnetal friendly and economic mobile phase, supercritical CO2 . In our work, the enantioseparation of an amide herbicide, napropamide, using three different polysaccharide-type chiral stationary phases (CSPs) in SFC was investigated. By studying the effect of different CSPs, organic modifiers, temperature, back-pressure regulator pressures, and flow rates for the enantioseparation of napropamide, we established a rapid and green method for enantioseparation that takes less than 2 minutes: The column was CEL2, the mobile phase was CO2 with 20% 2-propanol, and the flow rate was 2.0 mL/min. We found that CEL2 demonstrated the strongest resolution capability. Acetonitrile was favored over alcoholic solvents when the CSP was amylose and 2-propanol was the best choice when using cellulose. When the concentration of the modifiers or the flow rate was decreased, resolutions and analysis times increased concurrently. The temperature and back-pressure regulator pressure exhibited only minor influences on the resolution and analysis time of the napropamide enantioseparations with these chiral columns. The molecular docking analysis provided a deeper insight into the interactions between the enantiomers and the CSPs at the atomic level and partly explained the reason for the different elution orders using the different chiral columns.

Enantioseparation and identification for the rationalization of the environmental impact of 4 polychlorinated biphenyls.

Polychlorinated biphenyls (PCBs) are harmful and persistent organic pollutants that have long been used in industrial manufacturing. Their persistence leads to accumulation in the food chain causing potential toxic effects. As 19 out of 78 of the chiral congeners have stable atropisomers at ambient temperature, we studied some typical enantiomers: PCB45, PCB95, PCB136, and PCB149. The chiral stationary phases OD-H and OJ-H were used for separation in analytic high-performance liquid chromatography (HPLC), as well as for collection in semi-preparative HPLC. The resolution was optimized with respect to n-hexane-based mobile phases, temperature, and flow rate. All pure enantiomers were recovered from semi-preparative HPLC within 15 minutes for practical purpose. Characterization of the absolute configurations were conducted with a combination of theoretical and experimental electronic circular dichroism measurements. The enantiomers of PCB45, PCB95, PCB136, and PCB149 proved to be eluted as R > S, S > R, R > S, and S > R, respectively. Molecular structures (eg, substituent groups) and properties (eg, bond lengths, bond angles, and dipole moments) were quantitatively analyzed to understand the toxicity effect of PCBs. In summary, we have developed a well-established methodology of collection and configuration identification for analogous PCB derivatives.

Alkylphenols disrupt estrogen homeostasis via diradical cross-coupling reactions: A novel pathway of endocrine disruption.

Estrogen, being an essential class of sex hormone, is an important target of endocrine disruption chemicals. It is well known that environmental disruptors could activate or inhibit estrogen receptors, acting as agonists or antagonists, and thus affect the circulating estrogen concentrations. Here, we report enzyme-mediated diradical cross-coupling reactions between alkylphenols (e.g., 2,4-di-tert-butylphenol [DBP], 4-nonylphenol [4-NP], and 4-tert-octylphenol [4-t-OP]) and estrogens (e.g., estradiol [E2]) that generate coupling metabolites and disrupt estrogen homeostasis. Among the phenolic xenobiotics, the screening of metabolic products revealed that alkylphenols had the highest reaction activities and generated coupling metabolites with high abundances (DBP-O-E2, 4-t-OP-O-E2, and 4-NP-O-E2). The coupling reactions were catalyzed by cytochrome P450 3A4 (CYP3A4) and verified by the detection of the coupling products in general populations. In vitro and in vivo exposures together with CYP3A4 inhibition demonstrated that cross-coupling reactions of phenols and E2 significantly reduced the normal levels of E2. We further established a unique spin-trapping-based high-throughput screening method to show the existence of diradicals in the coupling reaction. Density functional theory calculations revealed that spin aromatic delocalization was the fundamental cause of the high rebound barrier and sufficient lifetime of phenoxy radicals that enabled phenolic cross-coupling triggered by cytochrome P450. The identified mechanistic details for diradical cross-coupling reactions provide a novel pathway for phenolic chemicals to disrupt estrogen homeostasis.

Identification of Radix Bupleuri From Different Geographic Origins Using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry and Support Vector Machine Algorithm.

BACKGROUND: The geographic origin of Radix bupleuri is an important factor affecting its efficacy, which needs to be effectively identified. OBJECTIVE: The goal is to enrich and develop the intelligent recognition technology applicable to the identification of the origin of traditional Chinese medicine. METHOD: This article establishes an identification method of Radix bupleuri geographic origin based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and support vector machine (SVM) algorithm. The Euclidean distance method is used to measure the similarity between Radix bupleuri samples, and the quality control chart method is applied to quantitatively describe their quality fluctuation. RESULTS: It is found that the samples from the same origin are relatively similar and mainly fluctuate within the control limit, but the fluctuation range is large, and it is impossible to distinguish the samples from different origins. The SVM algorithm can effectively eliminate the impact of intensity fluctuations and huge data dimensions by combining the normalization of MALDI-TOF MS data and the dimensionality reduction of principal components, and finally achieve efficient identification of the origin of Radix bupleuri, with an average recognition rate of 98.5%. CONCLUSIONS: This newly established approach for identification of the geographic origin of Radix bupleuri has been realized, and it has the advantages of objectivity and intelligence, which can be used as a reference for other medical and food-related research. HIGHLIGHTS: A new intelligent recognition method of medicinal material origin based on MALDI-TOF MS and SVM has been established.

Environmental biotransformation mechanisms by flavin-dependent monooxygenase: A computational study.

The enzyme-catalyzed metabolic biotransformation of xenobiotics plays a significant role in toxicology evolution and subsequently environmental health risk assessment. Recent studies noted that the phase I human flavin-dependent monooxygenase (e.g., FMO3) can catalyze xenobiotics into more toxic metabolites. However, details of the metabolic mechanisms are insufficient. To fill the mechanism in the gaps, the systemic density functional theory calculations were performed to elucidate diverse FMO-catalyzed oxidation reactions toward environmental pollutants, including denitrification (e.g., nitrophenol), N-oxidation (e.g., nicotine), desulfurization (e.g., fonofos), and dehalogenation (e.g., pentachlorophenol). Similar to the active center compound 0 of cytochrome P450, FMO mainly catalyzed reactions with the structure of the tricyclic isoalloxazine C-4a-hydroperoxide (FADHOOH). As will be shown, FMO-catalyzed pathways are more favorable with a concerted than stepwise mechanism; Deprotonation is necessary to initiate the oxidation reactions for phenolic substrates; The regioselectivity of nicotine by FMO prefers the N-oxidation other than N-demethylation pathway; Formation of the P-S-O triangle ring is the key step for desulfurization of fonofos by FMO. We envision that these fundamental mechanisms catalyzed by FMO with a computational method can be extended to other xenobiotics of similar structures, which may aid the high-throughput screening and provide theoretical predictions in the future.

Exposure patterns, chemical structural signatures, and health risks of pesticides in breast milk: A multicenter study in China.

China is the world's largest pesticide user. These chemicals are bioaccumulative in the human body, and eventually could be transferred from the mother to the fetus/infant via placental and breastfeeding transport, which might pose developmental deficiency risks. In this study, human biomonitoring of legacy pesticides was conducted in three Chinese cities using 60 breast milk samples. The patterns, chemical structural signatures, and the estimated daily intake of pesticides were assessed. The median concentration of HCB (57.8 ng g-1 lw, Interquartile range: 28.5-76.9 ng g-1 lw) was the highest among all pesticides, whereas the HCHs, DDXs, TCVP, and heptachlor were also detected. A significantly different pattern of pesticides was found among three sampling cities: the Mianyang cases were mostly DDXs oriented while the Wuhan and Hangzhou cases were under HCB, HCHs, TCVP, and heptachlor influences. Maternal age and pre-pregnancy BMI were found to be the influencing factors for the pesticides in the breast milk, and dietary preferences were an important factor in the exposure scenario. Chemical structural signatures indicated that for HCHs and DDXs the exposure was mostly historical, while the lindane and dicofol exposure may exist among the volunteering mothers. The EF for chiral pesticides did not deviate significantly from the racemic value. The risk from breastfeeding was negligible according to the Chinese and UN standard, while some cases from Hangzhou and Wuhan exceeded the Canadian restrictions. Thus, the adverse health effects of chemical exposure by dietary intake for infants need to be closely monitored in future studies.

Potential health benefits of lowering gas production and bifidogenic effect of the blends of polydextrose with inulin in a human gut model.

Polydextrose is a nutrient supplement, which is widely applied in the food industry. The use of polydextrose in combination with prebiotics and probiotics has recently increased, whereas the fermentation properties of its blend have not yet been fully revealed. We evaluated the metabolic profile of polydextrose, inulin, and their blends by a batch in vitro fermentation of fifteen human fecal inocula. After 24 h of fermentation, polydextrose increased the production of gas, ammonia, and several short chain fatty acids, including propionate and butyrate, when compared to its blends, inulin, and fructo-oligosaccharides. Furthermore, polydextrose had the slowest degradation rate of all the carbohydrates tested, consistent with its partial fermentation in the distal colon. The 16S rRNA gene sequencing analysis of the gut microbiome exhibited significantly increased relative abundance of Clostridium_XVIII, Megamonas, Mitsuokella, and Erysipelotrichaceae_incertae_sedis in polydextrose compared to other carbohydrates. On the other hand, the blends of polydextrose and inulin (1:1 or 2:1) showed reduced gas production and similar bifidogenicity to inulin alone. The blends not only had similar alpha-diversity and PCoA to inulin but also had a similar abundance of beneficial bacteria, such as Faecalibacterium and Roseburia, suggesting potential health benefits. Also their low gas production was likely due to the abundance of Faecalibacterium and Anaerostipes, which were negatively correlated with gas production. Additionally, our in vitro fermentation model shows advantages in the large-scale assessment of fermentation performance.

Progressive hemifacial atrophy in a Chinese patient: A case report.

BACKGROUND: Progressive hemifacial atrophy (PHA) is a rare and progressive condition of unknown etiology that is characterized by chronic progressive atrophy of the skin, subcutaneous tissue, muscle, and bone on 1 side of the face. However, its precise pathogenesis remains poorly understood. CASE PRESENTATION: Here, we report a case of PHA, which manifested as left-sided facial atrophy. Whole-exome sequencing of peripheral blood samples from the patient and his parents, together with bioinformatics analyses, led to the identification of mutations in ARHGAP4 and CFAP47. CONCLUSION: This report is the first to describe ARHGAP4 and CFAP47 mutations in a patient with PHA. These mutations may be related to the occurrence of hemifacial atrophy, although further studies are needed to clarify the role of ARHGAP4 and CFAP47 in the context of PHA pathogenesis.

Polychlorinated biphenyls (PCBs) in the colostrum samples from the Yangtze River Region: Exposure profile and risk assessment.

Polychlorinated biphenyls (PCBs) may transfer into the neonates through the placental transfer and via breastfeeding after the delivery, thus might be harmful to the infant. Sixty colostrum samples in the Yangtze River Region were collected to investigate the concentration, distribution pattern, and enantiomer characteristic of the PCB exposure. Among all samples, over 90% of pollutants were tetra-to hepta-chlorinated PCBs. The sum concentration of the PCB was 512 (IQR: 322-856) ng g-1 lipid weight. Enantiomer fraction (EF) of PCB 95 and PCB 149 was found lower than the racemic value, while EFs of PCB 45 and PCB 136 were found higher and near-racemic state, respectively. The concentration pattern and enantiomeric properties of the PCBs indicated that the mothers from Mianyang had a recent exposure to PCBs. Among all samples, similar exposure and metabolic pathways of the PCB congeners were observed. PCB exposure showed no significant correlation with the birth outcome of the infants, but 43.3% of the infants have potential health risks via breastfeeding.

Transplacental transfer mechanism of organochlorine pesticides: An in vitro transcellular transport study.

Recent studies show that, even after being banned for agricultural applications for over 30 years, organochlorine pesticides (OCPs), including hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethane (DDT) and its metabolites (DDXs), can still be found in various biological matrices and pose a potential hazard to the fetus in the womb. This study aimed to investigate the possible transplacental transfer mechanism of OCPs using an in vitro placental model. The results showed that for HCHs and DDXs, the placenta had a potential protection mechanism for the fetus by having higher efflux than intake active transport efficiency to transfer the xenobiotic out of the fetal circulation. No enantiomer-specific transport was observed for the chiral OCPs in vitro, hints simple diffusion played the major role in the transplacental transfer. Metabolic and transporter inhibitors were applied in the transepithelial transport experiment to evaluate the role that major transporting protein played in the active efflux process. The ATP production inhibitors were observed to have significant inhibition on transfer, proving the hypothesis that active transport participates in the transplacental transport of OCPs in humans. Multiple transporters contributed simultaneously in the active transport for the OCPs. In this study, we could confirm that the transplacental transfer of OCPs is a combination of simple diffusion and active transport. ATP-binding cassette (ABC) superfamily transporters on the placenta contribute in the active transport. These findings could improve the understanding of the mechanisms of transplacental transfer of the OCPs.