The P2Y1 receptor in the colonic myenteric plexus of rats and its correlation with opioid-induced constipation.

This study was designed to explore the expression changes of P2Y1 receptors in the distal colonic myenteric layer of rats. An opioid induced constipation(OIC) rat model was generated by intraperitoneal (i.p) injection of loperamide. At 7 days post-treatment, the model rats were assessed by calculating the fecal water content and the gastrointestinal transit ratio. The immunofluorescence (IF)-based histochemical study was used to observe the distribution of P2Y1 receptors in the distal colonic myenteric plexus. Western blotting (WB) was performed to evaluate the expression changes of P2Y1 proteins in the myenteric layer, and the electrophysiological approaches were carried out to determine the regulatory roles of P2Y1 receptors on distal colonic motor function. IF showed that P2Y1 receptors are co-expressed MOR in the enteric nerve cells of the distal colonic myenteric plexus. Moreover, the WB revealed that the protein levels of P2Y1 were significantly decreased in the distal colonic myenteric layer of OIC rats. In vitro tension experiments exhibited that the P2Y1 receptor antagonist MRS2500 enhanced the spontaneous contraction amplitude, adding EM2 and ß-FNA did not have any effect on MRS2500. Therefore, P2Y1 receptor expression could be associated with the occurrence of OIC in this rat model and the regulation of colonic motility by MOR may be related to the release of purine neurotransmitters such as ATP in the colonic nervous system.

A Novel Glycolysis-Related Signature for Predicting the Prognosis and Immune Infiltration of Uveal Melanoma.

INTRODUCTION: As the most common aggressive intraocular cancer in adults, uveal melanoma (UVM) threatens the survival and vision of many people. Glycolysis is a novel hallmark of cancer, but the role of glycolysis-related genes in UVM prognosis remains unknown. The purpose of the study was to establish a glycolysis-related gene signature (GRGS) to predict UVM prognosis. METHODS: Raw data were obtained from TCGA-UVM and GSE22138 datasets. The GRGS was established by univariate, LASSO, and multivariate Cox regression analyses. Kaplan-Meier survival and time-dependent receiver operating characteristic curves were used to evaluate the predictive ability of the GRGS. The relationships of the GRGS with infiltrating immune cell levels and mutations were analyzed with CIBERSORT and maftools. RESULTS: A novel GRGS (risk score = 0.690861*ISG20 + 0.070991*MET - 0.227520*SDC2 + 0.690223*FBP1 + 0.048008*CLN6 - 0.128520*SDC3) was developed for predicting UVM prognosis. The GRGS had robust predictive stability in UVM. Enrichment annotation suggested that the high-risk group had stronger adaptive immune responses and that the low-risk group had more innate immune cell infiltration. Moreover, BAP1 mutation was related to high risk, and SF3B1 mutation was related to low risk. CONCLUSIONS: This study developed and validated a novel GRGS to predict UVM prognosis and immune infiltration. The signature revealed an association between glycolysis-related genes and the tumor microenvironment, providing new insights into the role of glycolysis in UVM.

Effect of breast milk with or without bacteria on infant gut microbiota.

BACKGROUND: The breast milk microbiome could be a source of infant intestinal microbiota. Several studies have found that some breast milk is extremely low in bacteria or is even sterile. There are limited studies on the effect of milk without bacteria on the infant gut microbiota. The purpose of this study was to investigate the gut microbiota of infants fed with bacterial milk or sterile milk. Meanwhile, we attempted to find the cause of undetectable bacteria in milk. METHODS: A total of 17 healthy pregnant women and 17 infants were enrolled in this study. Fecal samples were collected from full-term pregnant women. Milk samples and infant fecal samples were collected on the 14th postnatal day. Breast milk and fecal samples were examined using 16S rRNA sequencing technology. Pregnant women and infants were grouped according to milk with or without bacteria. To compare the differences in gut microbiota and clinical characteristics between groups. RESULTS: Bacteria were detected in 11 breast milk samples, and the bacterial detection rate was 64.7%. Infants fed with bacterial milk showed higher Shannon index and Simpson index (P = 0.020, P = 0.048), and their relative abundance of Lachnospirales, Lachnospiraceae and Eggerthellaceae was markedly higher. In addition, there were more bacterial associations in the co-occurrence network of infants fed with bacterial milk. Pregnant women with sterile and bacterial breast milk showed no significant differences in their clinical characteristics, and microbial composition and diversity. CONCLUSIONS: Some breast milk from healthy postpartum women failed to be sequenced due to low microbial DNA quantities or is sterile. Research is needed to explore the reasons for this phenomenon. Infants fed with bacterial milk had higher Alpha diversity and more complex microbiota networks. These findings provide novel insight into milk microbiota and infant gut microbiota.

Differences in cognition, short-chain fatty acids and related metabolites in pregnant versus non-pregnant women: a cross-sectional study.

BACKGROUND: Pregnancy induces cognitive reorganization which can lead to mental disorders. The aim of this study is to determine differences in cognitive scores, short-chain fatty acids (SCFAs) and related metabolites between pregnant and non-pregnant participants. METHODS: This cross-sectional study included 67 full-term pregnant women and 31 non-pregnant women. We compared scores of mental state and cognitive assessment tests, as well as serum concentrations of SCFAs, hormones, inflammatory factors, and neurotransmitters between these groups. RESULTS: Scores for information processing speed, immediate visual memory, motor response speed and accuracy, execution ability and verbal use ability in the pregnant group were lower than those in the non-pregnant group (p < 0.05 for all tests). Total serum SCFAs in the pregnant group were significantly lower than those in the non-pregnant group (P = 0.031). Among them, acetate and propionate were significantly decreased (P = 0.013 and 0.037, respectively) whereas butyrate was significantly increased (P = 0.035). Serum peptide YY, glucagon-like peptide-1, γ-aminobutyric acid, and dopamine showed no differences between the two groups. However, cortisol, adrenocorticotropic hormone, and acetylcholine were significantly increased in the pregnant group as compared with the non-pregnant group (P = 0.039, 0.016, and 0.012, respectively). Tumor necrosis factor-α was increased and interleukin-10 significantly decreased in the pregnant group (P = 0.045 and 0.019, respectively). CONCLUSION: According to our study findings, cognitive reorganization in the third trimester of pregnancy showed that both the passive storage capacity of working memory and the executive function of online information processing were decreased to varying degrees. At the same time, the changes in total SCFAs, the proportions of SCFAs and related metabolites were also detected. These changes in the internal environment may be increasing the risk of perinatal mental illness.

Design, synthesis and biological evaluation of novel pyrrolidone-based derivatives as potent p53-MDM2 inhibitors.

Inhibition of the interactions of the tumor suppressor protein p53 with its negative regulators MDM2 in vitro and in vivo, representing a valuable therapeutic strategy for cancer treatment. The natural product chalcone exhibited moderate inhibitory activity against MDM2, thus based on the binding mode between chalcone and MDM2, a hit unsaturated pyrrolidone scaffold was obtained through virtual screening. Several unsaturated pyrrolidone derivatives were synthesized and biological evaluated. As a result, because the three critical hydrophobic pockets of MDM2 were occupied by the substituted-phenyl linked at the pyrrolidone fragment, compound 4 h demonstrated good binding affinity with the MDM2. Additionally, compound 4 h also showed excellent antitumor activity and selectivity, and no cytotoxicity against normal cells in vitro. The further antitumor mechanism studies were indicated that compound 4 h could successfully induce the activation of p53 and corresponding downstream p21 proteins, thus successfully causing HCT116 cell cycle arrest in the G1/M phase and apoptosis. Thus, the novel unsaturated pyrrolidone p53-MDM2 inhibitors could be developed as novel antitumor agents.

The effect of probiotic supplementation during pregnancy on the interaction network of vaginal microbiome.

AIM: To evaluate the effect of probiotic supplementation on the vaginal microbiome and provide the effective evidences for clinical management of pregnant women. METHODS: A total of 28 healthy pregnant women at 32 weeks of gestation were enrolled. The women were divided randomly to the probiotic group where they were prescribed with 2 g combined probiotics daily (13 cases) during the third trimester of pregnancy or to the control group (15 cases) on a voluntary basis. Their vaginal samples were taken for analyzing microbiome with the 16S rDNA amplicon sequencing of V4 region. RESULTS: There was no significant difference on the clinical characteristics between the probiotic and control groups. The complexity of vaginal microbial network increased from 32 weeks of gestation to antepartum. Lactobacillus was the dominant microbiota. The probiotic supplementation had no obvious influence on the structure of the vaginal microbiome, whereas the relationships of some pivotal vaginal microbiota at the genus level changed in the probiotic group. CONCLUSION: The vaginal microbiome varied during the third trimester of pregnancy. The features of the vaginal microbiota after probiotic supplementation had shifted and the interaction network had the tendency to be loose. The probiotic supplementation may be useful in regulating the interaction network of vaginal microbiome.

Density functional theory study on adsorption of L-cysteine by Y, Zr, Nb, Mo-doped graphenes.

The adsorption properties of l-cysteine (L-cys) on [Kr] 4d1-4 (Y-Mo) doped graphenes with single and double vacancies are studied using density functional theory calculations with dispersion correction. The results showed that Y, Zr, Nb and Mo doped single-vacancy and double-vacancy graphenes show chemical adsorption characteristics towards L-cys. For the respective S, O and N-end adsorption, the binding strengths of L-cys on XSVs decrease from Y to Nb, and then increase. The binding strengths of L-cys on XDVs have no regular trend. Nb-doped graphene exhibits the most stable adsorption characteristics in the [Kr] 4d1-4 element series, which is independent of the vacancy type. Zr-doped single and double vacancy graphene sensors have higher sensitivity than Y, Nb, Mo.

Effects of normal pregnancy on maternal EEG, TCD, and cerebral cortical volume.

OBJECTIVE: Pregnancy causes many changes in our body and some of them may affect our ability of learning and memory. We examined the cerebral cortical volume of brain during pregnancy and measured changes in the brain electrical activity and cerebral blood flow. METHOD: 35 women (20 normal full-term primigravida and 15 non-pregnant women) received the Electroencephalography (EEG) and Transcranial Doppler ultrasonography (TCD). 8 non-pregnant women and 9 primigravida after vaginal delivery underwent brain magnetic resonance imaging (MRI) voluntarily within 24 h. RESULTS: Compared with the non-pregnant, changes were shown by EEG through electrodes of T5, Pz, Cz, T6, F3 and F8. The results displayed increased activity in the central parietal area of pregnant women, while that in the temporoparietal junction decreased. The result of TCD revealed that pulsation index (PI) values of left and right internal and external carotid arteries were asymmetrical, but they all decreased in pregnancy. Atrophy of cortical volume had been found in many brain functional areas of pregnant women. The percentage of atrophy varied between 6.76% and 13.17%. CONCLUSION: Atrophy of cerebral cortex, changes in cerebral blood flow and neuron electrophysiology may be the physiological basis of the emotional, cognitive changes in pregnant women.

Patchouli Oil Attenuates High Fat Diet-induced Non-alcoholic Hepatic Steatosis.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Nevertheless, no first-line therapy exists. Hepatic steatosis is the earliest stage of NAFLD, which is characterized by an accumulation of hepatic lipids. Patchouli oil (PO), which is isolated from the well-known Chinese herb named Pogostemon cablin (Blanco) Benth. (Lamiaceae), inhibits hepatic lipid accumulation effectively. However, its potential ability for the treatment of NAFLD had not been reported before. Thus, the objective of this study was to investigate the effectiveness of PO against hepatic steatosis and its underlying mechanisms. We used a high fat diet (HFD)-induced hepatic steatosis model of rats to estimate the effect of PO against NAFLD. Hematoxylin-eosin and oil red O staining were used to analyze the hepatic histopathological changes. ELISA, RT-qPCR, and Western blotting analysis were applied to evaluate the parameters for hepatic steatosis. Our results showed that PO significantly attenuated the lipid profiles and the serum enzymes, evidenced by quantitative and histopathological analyses. It also markedly down-regulated the expression of sterol regulatory element-binding protein 1 (SREPB-1c) with its downstream factors in de novo lipogenesis. And, likewise, in lipid export by very low-density lipoproteins (VLDL), related molecules were dramatically improved. Furthermore, PO observably normalized the aberrant peroxisome proliferator-activated receptor α (PPAR-α) signal in fatty acids oxidation. In conclusion, PO exerted a preventing effect against HFD-induced steatosis and might be due to decrease de novo lipogenesis, promote export of lipids, as well as owing to improve fatty acids oxidation.

Mortality Trends in Colorectal Cancer in China During 2000-2015: A Joinpoint Regression and Age-Period-Cohort Analysis.

INTRODUCTION: As lifestyles have increasingly become westernized in China, public health strategies have increasingly focused on cancer prevention. The objective of this study was to describe trends in colorectal cancer (CRC) mortality and the age, period, and cohort effects of CRC mortality in urban and rural China from 2000 to 2015. METHODS: We collected CRC mortality data from the China Health Statistics Yearbook. We used joinpoint regression analysis to estimate the slope of mortality trends. We then used the age-period-cohort (APC) model with intrinsic estimator to estimate the age, period, and cohort effects of CRC mortality. RESULTS: CRC mortality was higher in urban areas than in rural areas, and the average annual percentage change was also larger in urban areas (4.1%) than in rural areas (3.7%). CRC mortality risk was higher among older adults than among adults aged 20 to 24: the relative risk among adults aged 60 to 64 was 31.09 times higher in urban China and 11.46 times higher in rural China. CRC mortality risk increased with period: compared with period 2000, the relative risk was 1.01 in period 2005, 1.36 in period 2010, and 1.42 in period 2015 in urban China and 1.12 in period 2005, 1.24 in period 2010, and 1.69 in period 2015 in rural China. More recent cohorts had lower CRC mortality risk: compared with the cohort born during 1920-1924, the relative risk of cohort 1950-1954 was 0.70 in urban China and 0.69 in rural China. CONCLUSION: More interventions to reduce the burden of CRC should be conducted, and it is more necessary for older people and urban residents to adopt a healthy lifestyle in China.

Direct ChIP-bisulfite sequencing reveals a role of H3K27me3 mediating aberrant hypermethylation of promoter CpG islands in cancer cells.

The model describing that aberrant CpG island (CGI) methylation leads to repression of tumour suppressor genes in cancers has been influential, but it remains unclear how such aberrancy is induced. Recent studies provided clues indicating that promoter hypermethylation in cancers might be associated with PRC target genes. Here, we used ChIP-BS-seq to examine methylation of the DNA fragments precipitated by the antibodies to both H3K27me3 and H3K4me3 histone modifications. We showed that, for a set of genes highly enriched with H3K27me3 both in cancer and normal cells, CGI promoters were aberrantly hypermethylated only in cancer cells in comparison with normal cells. In contrast, such aberrant CGI hypermethylation in cancer promoters that were deficient of H3K27me3 was not notable. Furthermore, we confirmed that these genes were consistently hypermethylated in TCGA primary cancer cells. These works support the association between H3K27me3 and DNA methylation marks for specific cancer genes and will spur future work on combined histone and DNA methylation that could define cancer's epigenetic abnormalities.

Prevalence of and risk factors for intestinal colonisation by multidrug-resistant Gram-negative bacteria in patients with haematological malignancies: A systematic review and meta-analysis.

BACKGROUND: Patients with haematological malignancies (HM patients) are at high risk of infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB). MDR-GNB intestinal colonisation is associated with MDR-GNB infections. The aim of this systematic review and meta-analysis on HM patients was to pool the prevalence of and risk factors for intestinal colonisation by MDR-GNB, including carbapenem-resistant Enterobacterales (CRE) and extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales, reported in previous studies. METHODS: This study was conducted according to the protocol registered in PROSPERO (CRD42022374425). PubMed, Embase, Web of Science, Ovid MEDLINE(R) ALL and Cochrane Library were searched from inception to 25 October 2022. Observational studies reporting CRE and/or ESBL intestinal colonisation in HM patients were included. Subgroup analyses were conducted by study region. RESULTS: A total of 21 402 HM patients from 32 studies were analysed. The pooled CRE and ESBL colonisation rates were 21.7% [95% confidence interval (95%CI) 18.7-24.8] and 19.2% (95%CI 13.9-24.5), respectively. Prior exposure to tigecycline [odds ratio (OR) 3.99, 95%CI 2.08-7.68], carbapenem (OR 1.84, 95%CI 1.13-2.97) or penicillin (OR 1.72, 95%CI 1.05-2.83), as well as chemotherapy (OR 2.45, 95%CI 1.05-5.73), neutropenia (OR 1.88, 95%CI 1.08-3.26) and acute myeloid leukaemia (AML; OR 1.86, 95%CI 1.33-2.61), were risk factors for CRE colonisation in HM patients. Prior antibiotic exposure was a risk factor for ESBL colonisation in HM patients (OR 4.90, 95%CI 2.76-8.70). CONCLUSIONS: This study shows the high prevalence of MDR-GNB (CRE and ESBL) colonisation in HM patients and explains associated factors for the colonisation. The results provide evidence for MDR-GNB infection control in HM management.

Effect of probiotic administration during pregnancy on the functional diversity of the gut microbiota in healthy pregnant women.

Our study aims to investigate the impact of probiotic consumption during pregnancy on gut microbiota functional diversity in healthy pregnant women. Thirty-two pregnant women were randomly assigned to two groups. The probiotic group (PG) consisted of pregnant women who consumed triple viable Bifidobacterium longum, Lactobacillus delbrueckii bulgaricus, and Streptococcus thermophilus tablets from the 32nd week of pregnancy until delivery. The functional profiles of the gut microbiota were predicted through high-throughput 16S rRNA sequencing results using PICRUSt software and referencing the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. In the gut microbiota of the PG, the genera Blautia and Ruminococcus, as well as the species Subdoligranulum, showed significantly higher relative abundances compared to the control group (CG) (P < 0.05). At Level 1 of the KEGG signaling pathways, there was a significant reduction in the functional genes of the gut microbiota involved in Organismal Systems in the PG (P < 0.05). In Level 2 of the KEGG signaling pathways, there was a significant reduction in the functional genes of the gut microbiota involved in Infectious Disease in the PG (P < 0.05). In Level 3 of the KEGG signaling pathways, the PG exhibited a significant increase in the functional genes of the gut microbiota involved in ABC transporters, Oxidative phosphorylation, Folate biosynthesis, and Biotin metabolism (P < 0.05). The CG showed a significant increase in the functional genes related to Cysteine and methionine metabolism, Vitamin B6 metabolism, Tuberculosis, and Vibrio cholerae pathogenic cycle (P < 0.05). In conclusion, our findings suggest that probiotic supplementation during pregnancy has a significant impact on functional metabolism in healthy pregnant women. IMPORTANCE: Probiotics are considered beneficial to human health. There is limited understanding of how probiotic consumption during pregnancy affects the functional diversity of the gut microbiota. The aim of our study is to investigate the impact of probiotic consumption during pregnancy on the functional diversity of the gut microbiota. Our findings suggest that probiotic supplementation during pregnancy has a significant impact on functional metabolism. This could potentially open up new avenues for preventing various pregnancy-related complications. This also provides new insights into the effects of probiotic consumption during pregnancy on the gut microbiota and offers a convenient method for exploring the potential mechanisms underlying the impact of probiotics on the gut microbiota of pregnant women.

Multi-omics analysis reveals the associations between altered gut microbiota, metabolites, and cytokines during pregnancy.

For embryo implantation and fetal development, the maternal immune system undergoes dramatic changes. The mechanisms involved in inducing alterations of maternal immunity have not been fully clarified. Gut microbiome and metabolites were thought to influence the host immune response. During normal pregnancy, notable changes occur in the gut microbiota and metabolites. However, the relationship of these alterations to immune function during pregnancy remains unclear. In this study, we examined gut microbiota, fecal metabolites, plasma metabolites, and cytokines in pregnant women and non-pregnant women. Our findings revealed that, in comparison to non-pregnant women, pregnant women exhibit a significant increase in the relative abundance of Actinobacteriota and notable differences in metabolic pathways related to bile acid secretion. Furthermore, there was a marked reduction in pro-inflammatory cytokines levels in pregnant women. Correlation analyses indicated that these alterations in cytokines may be linked to specific gut bacteria and metabolites. Bacteria within the same microbial modules exhibited consistent effects on cytokines, suggesting that gut bacteria may function as functional groups. Mediation analysis further identified that certain bacteria might influence cytokines through metabolites, such as bile acids and arachidonic acid. Our findings propose potential biological connections between bacteria, metabolites, and immunity, which require further validation in future studies.IMPORTANCEA great number of studies have focused on diseases induced by intestinal microecological disorders and immune imbalances. However, the understanding of how intestinal microbiota interacts with immunity during normal pregnancy, which is fundamental to studying pathological pregnancies related to intestinal microbiota disturbances, has not been well elucidated. Our study employed multi-omics analysis to discover that changes in gut microbiota and metabolites during pregnancy can impact immune function. In addition, we identified several metabolites that may mediate the effect of gut microbes on plasma cytokines. Our study offered new insights into our understanding of the connections between the gut microbiome, metabolome, and the immune system during pregnancy.

Double restriction-enzyme digestion improves the coverage and accuracy of genome-wide CpG methylation profiling by reduced representation bisulfite sequencing.

BACKGROUND: Reduced representation bisulfite sequencing (RRBS) was developed to measure DNA methylation of high-CG regions at single base-pair resolution, and has been widely used because of its minimal DNA requirements and cost efficacy; however, the CpG coverage of genomic regions is restricted and important regions with low-CG will be ignored in DNA methylation profiling. This method could be improved to generate a more comprehensive representation. RESULTS: Based on in silico simulation of enzyme digestion of human and mouse genomes, we have optimized the current single-enzyme RRBS by applying double enzyme digestion in the library construction to interrogate more representative regions. CpG coverage of genomic regions was considerably increased in both high-CG and low-CG regions using the double-enzyme RRBS method, leading to more accurate detection of their average methylation levels and identification of differential methylation regions between samples. We also applied this double-enzyme RRBS method to comprehensively analyze the CpG methylation profiles of two colorectal cancer cell lines. CONCLUSION: The double-enzyme RRBS increases the CpG coverage of genomic regions considerably over the previous single-enzyme RRBS method, leading to more accurate detection of their average methylation levels. It will facilitate genome-wide DNA methylation studies in multiple and complex clinical samples.

Density functional theory study on the interactions of L-cysteine with graphene: adsorption stability and magnetism.

Understanding the interactions between graphene and biomolecules is of fundamental relevance to the area of nanobiotechnology. Herein, we take l-cysteine as the probe biomolecule and investigate its adsorption on pristine graphene and B-, N-, Al-, Ni-, Ga-, Pd-doped graphene using density functional theory calculations. Three kinds of upright adsorption configurations, via unprotonated functional groups (-SH, -NH2, -COOH), are considered. The calculations reveal pristine graphene physically adsorbs l-cysteine. N-doped graphene shows physisorption towards the S-end and N-end l-cysteine, and chemisorption towards the O-end radical. Strong chemisorption, with site-specific preference, occurs on Al-, Ni-, Ga- and Pd-doped graphene, accompanied by severe structural changes. Spin polarization with an unusual mirror symmetry on Ni- and Pd-doped graphene is induced by chemisorption of unprotonated l-cysteine, except for O-end adsorption on Pd-doped graphene. The magnetization arises mainly from spin polarization of the C 2pz orbital, with a minor magnetism located on Ni or Pd. The influence of van der Waals forces is also evaluated. A thorough analysis of the adsorption stability and magnetism of these systems would be beneficial to facilitate applications in graphene-based biosensing, biomolecule immobilization, magnetic bio-separation and other fields in bionanotechnology.

Prognostic value of blood inflammatory parameters for predicting mortality in neonates with sepsis.

BACKGROUND: Neonatal sepsis is a major cause of morbidity and mortality in neonates. The diagnosis of neonatal sepsis has been widely explored using blood inflammatory parameters. However, few researches have focused on the predictive significance of blood inflammation parameters for predicting mortality. This study aimed to evaluate the prognostic value of blood inflammatory parameters, including white blood cell (WBC), neutrophil, lymphocyte, monocyte, platelet and C-reactive protein (CRP) for predicting mortality in neonates with sepsis. METHODS: Neonates with culture-proven sepsis were enrolled in this study. The clinical characteristics and levels of white blood cell, neutrophil, lymphocyte, monocyte, platelet and CRP were recorded. The receiver-operating characteristic (ROC) curve was applied to calculate the area under the curve (AUC) and determine the optimal cutoff values. Multivariable Cox regression model was used to evaluate the independent prognostic significance of variables. Kaplan-Meier curve was used to assess survival. RESULTS: A total of 188 neonates with culture-proven sepsis were included for analysis. The 7-day mortality rate was 11.2 % (21/188) and the 28-day mortality rate was 13.8 % (26/188). The levels of white blood cell, neutrophil, monocyte and platelet in non-survivors were lower than those in survivors (P < 0.05). Platelet yielded higher AUC values than other parameters for predicting mortality with the best cutoff value of 132 × 109/L, followed by WBC with the optimal cutoff value of 6.15 × 109/L. Multivariable Cox regression analysis showed platelet and WBC were independent prognostic factors for predicting mortality. Low platelet group showed lower survival according to Kaplan-Meier method. CONCLUSIONS: In conclusion, the levels of platelet and WBC on the day of sepsis onset are valuable indicators for predicting mortality in neonates with sepsis.

Association between gut microbiota, microbial network, and immunity in pregnancy with a focus on specific bacterial clusters.

Background: The community characteristics of the gut microbiota are not well defined and are not as widely studied as the functions of individual bacteria. This study aims to investigate the community composition of intestinal flora in women of childbearing age by conducting cluster analysis of gut microbiota and analyzing the relationship between different clusters and immune status. Methods: A total of 45 women of childbearing age were recruited in the study, including 15 non-pregnant women and 30 women in late pregnancy, and stool samples were collected twice during the third trimester, specifically at 32 weeks and at full term. The gut microbiota data was analyzed using 16S rRNA amplicon sequencing. Partitioning Around Medoids algorithm was employed to assess microbial clustering patterns. Microbial network for each cluster was performed and plasm cytokines were measured to analyze the relationship between specific genera and immune state in clusters. Results: There were three distinct clusters of intestinal community composition in women of childbearing age. Cluster 1 (PAM_1) was characterized by a high abundance of Bacteroides, while cluster 2 (PAM_2) showed higher levels of Bifidobacterium and Blautia, along with a significantly increased Firmicutes to Bacteroidota ratio. Cluster 3 (PAM_3) displayed a high abundance of Escherichia-shigella. PAM_1 was the most dominant cluster in non-pregnant women, and this dominant cluster was also one of the main in late pregnancy. At full term, the majority of subjects retained the same cluster as at 32 weeks, while a few experienced a shift. The microbial correlation networks differed across the three clusters, with PAM_1 exhibiting higher modularity and fewer connections. Analysis of the correlation between genera and plasma cytokines showed significant differences in their associations with cytokines between pregnancy and nonpregnancy within the same cluster, and the same genera had different effects in different clusters. Conclusion: Women of childbearing age exhibit three distribution patterns of gut microbiota, and the intestinal clusters reshaped during late pregnancy in a small population. Different clusters may have diverse immunomodulatory effects in different physiological states. When studying the gut microbiome during pregnancy, it is crucial to consider the cluster differences within healthy women.

Curcumin Alleviates High-fat Diet-induced Nonalcoholic Steatohepatitis via Improving Hepatic Endothelial Function with Microbial Biotransformation in Rats.

Hepatic endothelial function is central to the development of nonalcoholic steatohepatitis (NASH). Curcumin (Cur) is reportedly hepatoprotective, however, it remains unknown whether Cur improves hepatic endothelial function in NASH. Additionally, the poor bioavailability of Cur renders it difficult to elucidate its hepatoprotective effect, hence, its biotransformation should be considered. Herein, we investigated the effects and mechanisms of Cur and its bioconversion on hepatic endothelial function against high-fat diet-induced NASH in rats. The results revealed that Cur improved hepatic lipid accumulation, inflammation, and endothelial dysfunction by inhibiting NF-κB and PI3K/Akt/HIF-1α pathways, however, these effects were weakened via antibiotic addition, which was closely related to reduced tetrahydrocurcumin (THC) produce in the liver and intestinal content. Moreover, THC exerted a better effect than Cur on restoring liver sinusoidal endothelial cells function to attenuate steatosis and injury in L02 cells. Thus, these findings indicate that the effect of Cur on NASH is closely related to hepatic endothelial function improvement with intestinal microbial biotransformation.

Structure-based discovery of novel α-aminoketone derivatives as dual p53-MDM2/MDMX inhibitors for the treatment of cancer.

The function of the p53 protein is impaired by the overexpression of its negative regulator murine double minute 2 protein (MDM2) and homologous protein MDMX. Disruption of the p53-MDM2/MDMX interaction to restore the transcriptional function of p53 is considered a promising strategy for cancer therapy. To design dual MDM2/MDMX inhibitors, the binding modes of MDM2 or MDMX with their inhibitors are elucidated. Several hot-spot residues of MDM2 or MDMX are identified by molecular dynamics simulations, alanine scanning and MM-GBSA calculations. Then, focusing on the interaction with hot-spot residues, two series of derivatives bearing 1,3-diketone and α-aminoketone scaffolds are designed and synthesized. Among these compounds, C16 is identified as the most potent compound with low micromolar binding affinities with MDM2 and MDMX. C16 also displays moderate antiproliferative activities against MDM2-overexpressing and MDMX-overexpressing cells, with IC50 values of 0.68 µM in HCT116 cells and 0.54 µM in SH-SY5Y cells. Furthermore, C16 inhibits cell migration and invasion, reactivates the function of p53, arrests the cell cycle and induces cellular apoptosis in HCT116 and SH-SY5Y cells. Collectively, C16 can be developed as a dual MDM2 and MDMX inhibitor for cancer therapy.