Deep Learning Radiomics Model of Dynamic Contrast-Enhanced MRI for Evaluating Vessels Encapsulating Tumor Clusters and Prognosis in Hepatocellular Carcinoma.

BACKGROUND: Vessels encapsulating tumor cluster (VETC) is a critical prognostic factor and therapeutic predictor of hepatocellular carcinoma (HCC). However, noninvasive evaluation of VETC remains challenging. PURPOSE: To develop and validate a deep learning radiomic (DLR) model of dynamic contrast-enhanced MRI (DCE-MRI) for the preoperative discrimination of VETC and prognosis of HCC. STUDY TYPE: Retrospective. POPULATION: A total of 221 patients with histologically confirmed HCC and stratified this cohort into training set (n = 154) and time-independent validation set (n = 67). FIELD STRENGTH/SEQUENCE: A 1.5 T and 3.0 T; DCE imaging with T1-weighted three-dimensional fast spoiled gradient echo. ASSESSMENT: Histological specimens were used to evaluate VETC status. VETC+ cases had a visible pattern (≥5% tumor area), while cases without any pattern were VETC-. The regions of intratumor and peritumor were segmented manually in the arterial, portal-venous and delayed phase (AP, PP, and DP, respectively) of DCE-MRI and reproducibility of segmentation was evaluated. Deep neural network and machine learning (ML) classifiers (logistic regression, decision tree, random forest, SVM, KNN, and Bayes) were used to develop nine DLR, 54 ML and clinical-radiological (CR) models based on AP, PP, and DP of DCE-MRI for evaluating VETC status and association with recurrence. STATISTICAL TESTS: The Fleiss kappa, intraclass correlation coefficient, receiver operating characteristic curve, area under the curve (AUC), Delong test and Kaplan-Meier survival analysis. P value <0.05 was considered as statistical significance. RESULTS: Pathological VETC+ were confirmed in 68 patients (training set: 46, validation set: 22). In the validation set, DLR model based on peritumor PP (peri-PP) phase had the best performance (AUC: 0.844) in comparison to CR (AUC: 0.591) and ML (AUC: 0.672) models. Significant differences in recurrence rates between peri-PP DLR model-predicted VETC+ and VETC- status were found. DATA CONCLUSIONS: The DLR model provides a noninvasive method to discriminate VETC status and prognosis of HCC patients preoperatively. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.

Carotenoids in maternal and cord blood, breast milk and their association with maternal dietary intake: a longitudinal study in Shanghai, China.

Carotenoids are important bioactive substances in breast milk, the profile of which is seldom studied. This study aimed to explore the profile of carotenoids in breast milk and maternal/cord plasma of healthy mother-neonate pairs in Shanghai, China, and their correlation with dietary intake. Maternal blood, umbilical cord blood and breast milk samples from five lactation stages (colostrum, transitional milk and early-, mid- and late-term mature milk) were collected. Carotenoid levels were analysed by HPLC. Carotenoid levels in breast milk changed as lactation progressed (P < 0·001). ß-Carotene was the primary carotenoid in colostrum. Lutein accounted for approximately 50 % of total carotenoids in transitional milk, mature milk and cord blood. Positive correlations were observed between five carotenoids in umbilical cord blood and maternal blood (P all < 0·001). ß-Carotene levels were also correlated between maternal plasma and three stages of breast milk (r = 0·605, P < 0·001; r = 0·456, P = 0·011, r = 0·446; P = 0·013, respectively). Dietary carotenoid intakes of lactating mothers also differed across lactation stages, although no correlation with breast milk concentrations was found. These findings suggest the importance of exploring the transport mechanism of carotenoids between mothers and infants and help guide the development of formulas for Chinese infants as well as the nutritional diets of lactating mothers.

Genotoxicity of bisphenol AF in rats: Detrimental to male reproductive system and probable stronger micronucleus induction potency than BPA.

Bisphenol AF (BPAF), as one of structural analogs of BPA, has been increasingly used in recent years. However, limited studies have suggested its adverse effects similar to or higher than BPA. In order to explore the general toxicity and genotoxicity of subacute exposure to BPAF, the novel 28-day multi-endpoint (Pig-a assay + micronucleus [MN] test + comet assay) genotoxicity evaluation platform was applied. Male rats were randomly distributed into seven main experimental groups and four satellite groups. The main experimental groups included BPAF-treated groups (0.5, 5, and 50 µg/kg·bw/d), BPA group (10 µg/kg·bw/d), two solvent control groups (PBS and 0.1% ethanol/99.9% oil), and one positive control group (N-ethyl-N-nitrosourea, 40 mg/kg bw). The satellite groups included BPAF high-dose recovery group (BPAF-HR), oil recovery group (oil-R), ENU recovery group (ENU-R), and PBS recovery group (PBS-R). All groups received the agents orally via gavage for 28 consecutive days, and satellite groups were given a recovery period of 35 days. Among all histopathologically examined organs, testis and epididymis damage was noticed, which was further manifested as blood-testis barrier (BTB) junction protein (Connexin 43 and Occludin) destruction. BPAF can induce micronucleus production and DNA damage, but the genotoxic injury can be repaired after the recovery period. The expression of DNA repair gene OGG1 was downregulated by BPAF. To summarize, under the design of this experiment, male reproductive toxicity of BPAF was noticed, which is similar to that of BPA, but its ability to induce micronucleus production may be stronger than that of BPA.

Mode of action exploration of reproductive toxicity induced by bisphenol S using human normal ovarian epithelial cells through ERß-MAPK signaling pathway.

BACKGROUND: In the plastics production sector, bisphenol S (BPS) has gained popularity as a replacement for bisphenol A (BPA). However, the mode of action (MOA) of female reproductive toxicity caused by BPS remains unclear and the safety of BPS is controversial. METHODS: Human normal ovarian epithelial cell line, IOSE80, were exposed to BPS at human-relevant levels for short-term exposure at 24 h or 48 h, or for long-term exposure at 28 days, either alone or together with five signaling pathway inhibitors: ICI 18,2780 (estrogen receptor [ER] antagonist), G15 (GPR30 specific inhibitor), U0126 (extracellular regulated protein kinase [ERK] 1/2 inhibitor), SP600125 (c-Jun N-terminal kinase [JNK] inhibitor) or SB203580 (p38 mitogen­activated protein kinase [p38MAPK] inhibitor). MOA through ERß-MAPK signaling pathway interruption was explored, and potential thresholds were estimated by the benchmark dose method. RESULTS: For short-term exposure, BPS exposure at human-relevant levels elevated the ESR2 and MAPK8 mRNA levels, along with the percentage of the G0/G1 phase. For long-term exposure, BPS raised the MAPK1 and EGFR mRNA levels, the ERß, p-ERK, and p-JNK protein levels, and the percentage of the G0/G1 phase, which was partly suppressed by U0126. The benchmark dose lower confidence limit (BMDL) of the percentage of the S phase after 24 h exposure was the lowest among all the BMDLs of a good fit, with BMDL5 of 9.55 µM. CONCLUSIONS: The MOA of female reproductive toxicity caused by BPS at human-relevant levels might involve: molecular initiating event (MIE)-BPS binding to ERß receptor, key event (KE)1-the interrupted expression of GnRH, KE2-the activation of JNK (for short-term exposure) and ERK pathway (for long-term exposure), KE3-cell cycle arrest (the increased percentage of the G0/G1 phase), and KE4-interruption of cell proliferation (only for short-term exposure). The BMDL of the percentage of the S phase after 24 h exposure was the lowest among all the BMDLs of a good fit, with BMDL5 of 9.55 µM.

Genotoxic mode of action and threshold exploration of 2-methyl furan under 120-day sub-chronic exposure in male Sprague-Dawley rats.

2-Methylfuran (2-MF) is an important member of the furan family generated during food thermal processing. An in-vivo multiple endpoint genotoxicity assessment system was applied to explore the genotoxic mode of action and threshold of 2-MF. Male Sprague-Dawley rats received 2-MF by oral gavage at doses of 0.16, 0.625, 2.5, and 10 mg/kg.bw/day for 120 days. An additional 15 days were granted for recovery. The Pig-a gene mutation frequency of RET and RBC showed significant increases among the 2-MF groups on day 120. After a 15-day recovery period, the Pig-a gene mutation frequency returned to levels similar to those in the vehicle control. The tail intensity (TI) values of peripheral blood cells at a dose of 10 mg/kg.bw/day significantly increased from day 4 and remained at a high level after the recovery period. No statistical difference was found in the micronucleus frequency of peripheral blood between any 2-MF dose group and the corn oil group at any timepoint. 2-MF may not induce the production of micronuclei, but it could cause DNA breakage. It could not be ruled out that 2-MF may accumulate in vivo and cause gene mutations. Hence, DNA, other than the spindle, may be directly targeted. The mode of action of 2-MF may be that it was metabolized by EPHX1 to more DNA-active metabolites, thus leading to oxidative and direct DNA damage. The point of departure (PoD) of 2-MF-induced genotoxicity was derived as 0.506 mg/kg bw/day.

[Toxicity of bisphenol S on human normal ovarian epithelial cells mediated by ERß-MAPK signaling pathway].

OBJECTIVE: To investigate the effects of long-term(7 days and 14 days) bisphenol S(BPS) exposure on the ERß-MAPK signaling pathway, hormone secretion phenotype and cell cycle in human normal ovarian epithelial cells IOSE 80 at actual human exposure level. METHODS: Physiologically based pharmacokinetic model combined with BPS levels in the serum of women along the Yangtze River in China was used to determine the dosing concentrations of BPS, and vehicle control and 17 ß-estradiol(E_2) control were used. Complete medium with corresponding concentrations(0, 6.79×10~(-6), 6.79×10~(-4), 6.79×10~(-2), 6.79 µmol/L BPS and 10 nmol/L E_2) was replaced every 2 days. mRNA expressions of estrogen receptor(ERß and GPR30), key genes in MAPK signaling pathway(P38/JNK/ERK signaling pathway) and gonadotropin-releasing hormone-related genes(GnRH-I, GnRH-II and GnRH-R) were measured by qPCR. The ERß-MAPK signaling pathway inhibitors were employed to detect the effect of long-term exposure to BPS on the cell cycle by flow cytometry. Dose-response relationship analysis was performed to calculate the benchmark does lower confidence limits. RESULTS: Compared to the vehicle control, after 7 days exposure to BPS, the ratio of G_2/M phase was significantly increased(P<0.05), and the mRNA expressions of GnRH-I, GnRH-II and GnRH-R were significantly decreased(P<0.05); after 14 days exposure to BPS, the mRNA expressions of ESR2, MAPK3, and MAPK9 were significantly increased(P<0.05), and the mRNA expressions of GnRH-II and GnRH-R were significantly decreased(P<0.05). The GnRH-II mRNA expression level of BPS treatment for 7 days; the G_0/G_1 phase ratio, MAPK3 and MAPK8 mRNA expression level of BPS exposure for 14 days; and the GnRH-I mRNA expression level after BPS treatment for 7 days and 14 days showed a good dose-response relationship but with poor fit. CONCLUSION: Long-term low-dose exposure to BPS may cause cell cycle arrest by activating the ERß-MAPK signaling pathway, and may lead to changes in the hormone secretion of IOSE 80 cells.

[Protective effects of galacto-oligosaccharide and polydextrose on Caco-2 intestinal cell barrier injury model].

OBJECTIVE: To explore the protective effect of different ratios of galactose oligosaccharide(GOS) and polydextrose(PDX) on intestinal cell barrier damage model of Caco-2. METHODS: The same batch of Caco-2 cells were cultured to form a cell barrier model and randomly divided into damaged model group without calcium, calcium-containing blank control group(1.8 mmol/L Ca~(2+)), low-ratio/low-dose group(1.8 mmol/L Ca~(2+)+2 mg/mL GOS+2 mg/mL PDX) and low-ratio/medium-dose group(1.8 mmol/L Ca~(2+)+4 mg/mL GOS+4 mg/mL PDX), low-ratio/high-dose group(1.8 mmol/L Ca~(2+)+8 mg/mL GOS+8 mg/mL PDX) and high-ratio/low-dose group(1.8 mmol/L Ca~(2+)+0.8 mg/mL GOS+3.2mg/mL PDX), high-ratio/medium-dose group(1.8 mmol/L Ca~(2+)+1.6 mg/mL GOS+6.4 mg/mL PDX), high-ratio/high-dose group(1.8 mmol/L Ca~(2+)+3.2mg/mL GOS+12.8 mg/mL PDX), a total of 8 groups, three parallel groups were performed in each group. The Trans Epithelial Electrical Resistance value and apparent permeability coefficient value of each group were determined after 4 d culture, and the morphology of tight junction proteins ZO-1, Occludin and Claudin-1 were observed by immunofluorescence method, and the expression levels of inflammatory related factors in each group were determined by protein microarray method. RESULTS: Compared with damaged model group, TEER ratio in calcium-containing blank control group was significantly increased(P<0.05), while Papp value was significantly decreased(P<0.05);Compared with calcium-containing blank control group, TEER ratio in low-ratio/medium-dose group and high-ratio/high-dose group was significantly increased(P<0.05) while Papp value was significantly decreased(P<0.05), and they could significantly down-regulate some inflammatory response related cytokines. The cell barrier was intact in all groups except for the compact junction protein structure in the model group. CONCLUSION: Compared with Ca~(2+) alone, the combination of two prebiotics can enhance the density of Caco-2 cell barrier and reduced the permeability of cell bypass. And it can significantly reduce the expression level of some inflammatory cytokines and effectively protect the intestinal cell barrier.

Association between dietary intake of α-tocopherol and cadmium related osteoporosis in population ≥ 50 years.

INTRODUCTION: To analyze the association between α-tocopherol intake and cadmium (Cd) exposure and osteoporosis in population ≥ 50 years. MATERIALS AND METHODS: Sociodemographic data, physical examination, and laboratory indicators including serum Cd level and dietary α-tocopherol intake of 8459 participants were extracted from the National Health and Nutrition Examination Survey (NHANES) database in this cross-sectional study. The associations between α-tocopherol intake, serum Cd levels and osteoporosis were evaluated using univariate and multivariate logistic regression analyses, with the estimated value (ß), odds ratios (ORs) and 95% confidence intervals (CIs). We further explored the impact of α-tocopherol intake on Cd exposure and the bone mineral density (BMD) in total femur and femur neck. RESULTS: A total of 543 old adults suffered from osteoporosis. The serum Cd level (0.52 µg/L vs. 0.37 µg/L) and α-tocopherol intake (5.28 mg vs. 6.50 mg) were statistical different in osteoporosis group and non-osteoporosis group, respectively. High level of Cd exposure was related to the increased risk of osteoporosis [OR = 1.60, 95% CI (1.15-2.21)]. In the total femur, α-tocopherol intake may improve the loss of BMD that associated with Cd exposure [ß = - 0.047, P = 0.037]. Moreover, high α-tocopherol intake combined with low Cd exposure [OR = 0.54, 95% CI (0.36-0.81)] was linked to the decreased risk of osteoporosis comparing with low α-tocopherol intake combined with high Cd exposure. CONCLUSION: High α-tocopherol intake may improve the Cd-related osteoporosis and loss of BMD that could provide some dietary reference for prevention of osteoporosis in population ≥ 50 years old.

Pharmaceutical Cocrystal Discovery via 3D-SMINBR: A New Network Recommendation Tool Augmented by 3D Molecular Conformations.

Cocrystals have significant potential in various fields such as chemistry, material, and medicine. For instance, pharmaceutical cocrystals have the ability to address issues associated with physicochemical and biopharmaceutical properties. However, it can be challenging to find proper coformers to form cocrystals with drugs of interest. Herein, a new in silico tool called 3D substructure-molecular-interaction network-based recommendation (3D-SMINBR) has been developed to address this problem. This tool first integrated 3D molecular conformations with a weighted network-based recommendation model to prioritize potential coformers for target drugs. In cross-validation, the performance of 3D-SMINBR surpassed the 2D substructure-based predictive model SMINBR in our previous study. Additionally, the generalization capability of 3D-SMINBR was confirmed by testing on unseen cocrystal data. The practicality of this tool was further demonstrated by case studies on cocrystal screening of armillarisin A (Arm) and isoimperatorin (iIM). The obtained Arm-piperazine and iIM-salicylamide cocrystals present improved solubility and dissolution rate compared to their parent drugs. Overall, 3D-SMINBR augmented by 3D molecular conformations would be a useful network-based tool for cocrystal discovery. A free web server for 3D-SMINBR can be freely accessed at http://lmmd.ecust.edu.cn/netcorecsys/.

Characterization of benzo[a]pyrene and colchicine based on an in vivo repeat-dosing multi-endpoint genotoxicity quantitative assessment platform.

Two prototypical genotoxicants, benzo[a]pyrene (B[a]P) and colchicine (COL), were selected as model compounds to deduce their quantitative genotoxic dose-response relationship at low doses in a multi-endpoint genotoxicity assessment platform. Male Sprague-Dawley rats were treated with B[a]P (2.5-80 mg/kg bw/day) and COL (0.125-2 mg/kg bw/day) daily for 28 days. The parameters included were as follows: comet assay in the peripheral blood and liver, Pig-a gene mutation assay in the peripheral blood, and micronucleus test in the peripheral blood and bone marrow. A significant increase was observed in Pig-a mutant frequency in peripheral blood for B[a]P (started at 40 mg/kg bw/day on Day 14, started at 20 mg/kg bw/day on Day 28), whereas no statistical difference for COL was observed. Micronucleus frequency in reticulocytes of the peripheral blood and bone marrow increased significantly for B[a]P (80 mg/kg bw/day on Day 4, started at 20 mg/kg bw/day on Days 14 and 28 in the blood; started at 20 mg/kg bw/day on Day 28 in the bone marrow) and COL (started at 2 mg/kg bw/day on Day 14, 1 mg/kg bw/day on Day 28 in the blood; started at 1 mg/kg bw/day on Day 28 in the bone marrow). No statistical variation was found in indexes of comet assay at all time points for B[a]P and COL in the peripheral blood and liver. The dose-response relationships of Pig-a and micronucleus test data were analyzed for possible point of departures using three quantitative approaches, i.e., the benchmark dose, breakpoint dose, and no observed genotoxic effect level. The practical thresholds of the genotoxicity of B[a]P and COL estimated in this study were 0.122 and 0.0431 mg/kg bw/day, respectively, and our results also provided distinct genotoxic mode of action of the two chemicals.

Heavy metals exposure is associated with early liver dysfunction among rural residents aged 40-75 years in southwest China.

Heavy metals exposure has been associated with liver dysfunction in recent reports, while the hepatoxicity of lead (Pb) and cadmium (Cd) has been well established. However, the combined effects of multi-metal in real-world scenario on liver dysfunction are still unclear. This cross-sectional study examined associations between 10 biomarkers of early liver injury and multiple heavy metals levels. The levels of heavy metals/metalloid (magnesium [Mg], calcium [Ca], iron [Fe], zinc [Zn], arsenic [As], Cd, copper [Cu], and Pb) were measured in blood and urinary sample collected from 725 participants in a Cd-polluted area and an unpolluted area in southwest China. The early liver dysfunction biomarkers included the liver enzymes (ALT, ALP, AST, and GGT), proteins (TP, ALB, and GLO), and bilirubin (TBIL, DBIL, and IBIL). Confounder-adjusted beta coefficients were determined using multiple linear regression model analysis for the group-classified and gender-classified samples. Our results showed that blood Fe, Cd, and Cu levels were found to be positively related to elevated ALT levels and blood Cu was positively associated with AST levels in the Cd-polluted area, while the highest blood Zn quartile in the polluted area and blood Mg quartile in the unpolluted area were associated with lower ALT levels. Our finding implies that industrial pollution results in heavy metals of Cd and Pb exposure and effects of Fe, Cd, Cu, and Pb in the Cd-polluted area may be the main contributors to increase the risk of liver dysfunction while Zn in the Cd-polluted area and Mg in the unpolluted area may be the protective factors.

General toxicity and genotoxicity of altertoxin I: A novel 28-day multiendpoint assessment in male Sprague-Dawley rats.

The mycotoxin altertoxin I (ATX-I) is one of secondary metabolites produced by Alternaria fungi and is frequently detected as food and feed contaminants. Little is known about the genotoxicity of the ATX-I. In order to evaluate potential genotoxicity and general toxicity of ATX-I, the novel 28-day multiendpoint (Pig-a assay + micronucleus [MN] test + comet assay) genotoxicity platform was applied. Male Sprague-Dawley (SD) rats were randomized to five groups (six rats per group), that is, a positive control group (N-ethyl-N-nitrosourea [ENU], 40 mg/kg.bw/d), two solvent control groups (PBS and corn oil), and two ATX-I-treated groups (low-dose group [1.10 µg/kg.bw/d] and high-dose group [5.51 µg/kg.bw/d]). Treatments were administered by oral gavage to male SD rats for 28 consecutive days. Histopathological damages in the liver, kidney, and spleen were observed, but without significant changes in hematological and serum biochemical parameters. Genotoxic endpoints indicated that ATX-I could cause DNA damage. To summarize, in a relatively low-dose range, ATX-I may not have direct genotoxicity in vivo but could induce liver, kidney, and spleen damage.

Developmental immunotoxicity and its potential gender differences of perinatal exposure to 4-nonylphenol on offspring rats: JAK-STAT signaling pathway involved.

The aim of our study was to explore the developmental immunotoxicity (DIT) and its potential gender differences of perinatal exposure to 4-nonylphenol (4-NP), which was significant for the risk assessment of 4-NP exposure to fetuses and infants. Wistar pregnant rats were given the National Institution of Health (NIH)- 31 modified feed containing 0, 10, 100 and 500 mg/kg 4-NP from the gestation day (GD) 6 to the postnatal day (PND) 21. At PND21, the offspring rats were randomly selected to detect developmental immunotoxicity related indicators. Results suggested that high-dose 4-NP perinatal exposure caused growth retardation in infancy of male offspring rats, which was not obvious in female offspring rats. Also, 4-NP perinatal exposure induced DIT (mainly manifested as immunosuppression) with potential gender differences, including decreased weight of immune organs, suppressed immune function, decreased ratio of transforming growth factor (TGF)-ß/interleukin (IL)- 17A, increased ratio of T helper (Th) 17/regulatory T (Treg) cells et al. In addition, exploration of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway showed that JAK-STAT pathway mediated the leftward of Th17/Treg cells balance. Furthermore, the DIT to female offspring rats was more sensitive than to the males, which may be related to the differences of biological processes involved and needed to be further explored.

Transcriptomics analysis and benchmark concentration estimating-based in vitro test with IOSE80 cells to unveil the mode of action for female reproductive toxicity of bisphenol A at human-relevant levels.

Bisphenol A (BPA) is of great concern in public health, of which female reproductive toxicity is one major adverse health effect with the unclear mode of action (MOA) yet. Based on the principle of Toxicity Testing in the 21st Century, the purpose of this study is to explore the MOA for female reproductive toxicity using human normal ovarian epithelial cells IOSE80 at 28-day human-relevant-level exposure. A physiological based pharmacokinetic model was used to select the administration concentrations according to the BPA levels in female gonads at human actual exposure scenario. Enrichment KEGG pathways interrupted by BPA consisted of RNA transport, ribosome biogenesis in eukaryotes, cell cycle, cellular senescence, progesterone-mediated oocyte maturation, and oocyte meiosis. Increased relative mRNA and protein expressions of ERK and CDKN3, and proportion of S phase, as well as decreased proportion of G0/G1 phase were observed with increasing BPA concentrations, which could be partially inhibited by ERK inhibitor U0126. Among all the benchmark concentration lower confidence limits, mRNA expression of MAPK3 served as the lowest. In conclusion, the MOA of BPA induced female reproductive toxicity at human-relevant levels may include: key event (KE)1-ERK activation, KE2-increased expression of CDKN3, and KE3-cell cycle arrest. However, more in vivo studies may be needed to complete the MOA.

Low-dose florfenicol and copper combined exposure during early life induced health risks by affecting gut microbiota and metabolome in SD rats.

The potential health risks associated with simultaneous presence of residues of heavy metals and antibiotics in the environment and food have been of wide concern. However, the adverse health effects of combined heavy metal and antibiotic exposure at low doses remain unclear. In this study, the effects of combined exposure to florfenicol and copper at low doses during early life on toxicity, gut microbiota, drug resistance genes, and the fecal metabolome were investigated in Sprague-Dawley (SD) rats. The results showed that combined exposure induced inflammatory responses and visceral injury as well as faster weight gain compared with florfenicol or copper exposure alone. Alpha and beta diversity indices indicated that the composition of the gut microbiota and the abundance of bacteria related to energy intake and disease in the combined exposure group were significantly altered. The increase in resistance genes (floR, fexA) induced by florfenicol exposure was suppressed under combined exposure to florfenicol and copper. The fecal metabolome also demonstrated that metabolic pathways related to energy intake and liver injury were significantly affected in the combined exposure group. In conclusion, this study shows that combined exposure to florfenicol and copper during early life can pose a nonnegligible health risk even if the exposure concentration of florfenicol or copper is below the safe limit.

Rimonabant potentiates the antifungal activity of amphotericin B by increasing cellular oxidative stress and cell membrane permeability.

Amphotericin B (AmB) is a very effective antifungal agent, and resistance in clinical isolates is rare. However, clinical treatment with AmB is often associated with severe side effects. Reducing the administration dose of AmB by combining it with other agents is a promising strategy to minimize this toxicity. In this study, we screened a small compound library and observed that the anti-obesity drug rimonabant exhibited synergistic antifungal action with AmB against Candida species and Cryptococcus neoformans. Moreover, the combination of AmB and rimonabant exhibited synergistic or additive effects against Candida albicans biofilm formation and cell viability in preformed biofilms. The effects of this combination were further confirmed in vivo using a murine systemic infection model. Exploration of the mechanism of synergy revealed that rimonabant enhances the fungicidal activity of AmB by increasing cellular oxidative stress and cell membrane permeability. These findings provide a foundation for the possible development of AmB-rimonabant polytherapies for fungal infections.

Carotenoid profile in breast milk and maternal and cord plasma: a longitudinal study in Southwest China.

Carotenoids are increasingly being implicated to have an important role in brain and eye development. This study aimed to quantify the content and profile of carotenoids in human breast milk, maternal plasma and neonatal umbilical cord plasma in Chengdu, an urban area in Southwest China. In this study, fifty-four healthy mothers were enrolled. Maternal blood, umbilical cord blood, colostrum, transitional milk and mature milk were collected. Concentrations of carotenoids (lutein, zeaxanthin, ß-cryptoxanthin, ß-carotene and lycopene) were analysed by HPLC. We found that carotenoid concentrations decreased from colostrum to mature milk. Hydrocarbon carotenoids with weaker polarity decreased more than the polar carotenoids. Lycopene concentrations dropped by 99 %, ß-carotene by 92 %, ß-cryptoxanthin by 83 %, lutein by 32 % and zeaxanthin by 22 %. Lycopene and ß-carotene accounted for 70 % of the total carotenoids in colostrum, and lutein predominated amongst carotenoids in transitional milk and mature milk (51-55 %). Carotenoid concentrations in maternal plasma were much higher than that in cord plasma. Lutein predominated in cord plasma. The concentrations of all carotenoids in maternal plasma were correlated with those of cord plasma and human milk. These results are consistent with selective transport mechanisms in the mammary gland related to the polarity of carotenoids, and each carotenoid has its own implications, which may have different priorities in the early life development of infants. These findings may help guide dietary recommendations for carotenoid inclusion in infant formulas.

Precise and convenient size barcode on microfluidic chip for multiplex biomarker detection.

The existing multiplex biomarker detection methods are limited by the high demand for coding material and expensive detection equipment. This paper proposes a convenient and precise coding method based on a wedge-shaped microfluidic chip, which can be further applied in multiplex biomarker detection. The proposed microfluidic chip has a microchannel with continuously varying height, which can naturally separate and code microparticles of different sizes. Our data indicate that this method can be applied to code more than 5 or 7 kinds of microparticles, even when their size discrepancies are smaller than 1 µm. Based on these, multiplex biomarker detection can be implemented by using microparticles of different sizes, hence each kind of microparticle that coats one kind of antibody represents the species of targets. This method is simple and easy to operate, with no clogging or sophisticated coding design, showing its significant potential in the area of point-of-care tests (POCT).

Azole-triphenylphosphonium conjugates combat antifungal resistance and alleviate the development of drug-resistance.

Azole antifungals are commonly used to treat fungal infections but have resulted in the occurrence of drug resistance. Therefore, developing azole derivatives (AZDs) that can both combat established drug-resistant fungal strains and evade drug resistance is of great importance. In this study, we synthesized a series of AZDs with a fluconazole (FLC) skeleton conjugated with a mitochondria-targeting triphenylphosphonium cation (TPP+). These AZDs displayed potent activity against both azole-sensitive and azole-resistant Candida strains without eliciting obvious resistance. Moreover, two representative AZDs, 20 and 25, exerted synergistic antifungal activity with Hsp90 inhibitors against C. albicans strains resistant to the combination treatment of FLC and Hsp90 inhibitors. AZD 25, which had minimal cytotoxicity, was effective in preventing C. albicans biofilm formation. Mechanistic investigation revealed that AZD 25 inhibited the biosynthesis of the fungal membrane component ergosterol and interfered with mitochondrial function. Our findings provide an alternative approach to address fungal resistance problems.

Total and Sn-2 Fatty Acid Profile in Human Colostrum and Mature Breast Milk of Women Living in Inland and Coastal Areas of China.

INTRODUCTION: Although lipid is the major energy source and exerts beneficial effects on infant growth, research on the composition of fatty acid (FA) at the sn-2 position of human milk (HM) in China and abroad is limited. OBJECTIVES: This study aimed to investigate the FA positional distribution in colostrum and mature HM of women living in the inland and coastal areas of China and explore the potential influences of geographical region and lactation stage on the FA profile of Chinese women. METHODS: Colostrum milk (n = 61) and mature milk (n = 56) samples were obtained longitudinally from healthy lactating women in Guangzhou and Chengdu, China. Gas chromatography was used to determine the total and sn-2 FA composition. RESULTS: Significant differences were observed in the FA profile of HM between different regions and lactation stages, with differences in polyunsaturated FA levels being the most pronounced. Nearly 70% of sn-2 FAs were saturated FAs, of which C16:0 accounted for approximately 75%. C8:0, C10:0, C18:0, C20:0, C22:0, and all of the unsaturated FAs were mainly located at the sn-1 and sn-3 positions, while C14:0, C15:0, and C16:0 were mainly at the sn-2 position. The proportion of C12:0 and C17:0 at sn-2 was approximately equivalent to that at the sn-1, 3 positions. CONCLUSIONS: The results indicate the variability in the FA profile of HM between regions and lactation stages. The contents of polyunsaturated FAs and sn-2 FAs, especially palmitic acid, should be paid more attention when optimizing infant formula.