Unethical pro-supervisor behavior and employees' family satisfaction: The roles of workplace ostracism and work-home segmentation preference.

The present study proposes a moderated mediation model that examines how and when unethical pro-supervisor behavior is related to employees' family satisfaction. The two-wave study design consisted of 207 full-time employees in China. The study results indicate that unethical pro-supervisor behavior is negatively related to family satisfaction, and that workplace ostracism mediates the influence of unethical pro-supervisor behavior on family satisfaction. In addition, the relationship between workplace ostracism and family satisfaction as well as the indirect influence of unethical pro-supervisor behavior on family satisfaction through workplace ostracism, are moderated by employees' work-home segmentation preference. The study findings not only enrich the literature on unethical pro-supervisor behavior, but also have important practical implications for organizational managers.

Human bone marrow mesenchymal stem cell-derived extracellular vesicles impede the progression of cervical cancer via the miR-144-3p/CEP55 pathway.

Cervical cancer is the most common gynaecological malignancy, with a high incidence rate and mortality rate in middle-aged women. Human bone marrow mesenchymal stem cells (hBMSCs) have been implicated in the initiation and subsequent development of cancer, along with the involvement of extracellular vesicles (EVs) mediating intracellular communication by delivering microRNAs (miRNAs or miRs). This study is aimed at investigating the physiological mechanisms by which EVs-encapsulated miR-144-3p derived from hBMSCs might mediate the progression of cervical cancer. The expression profiles of centrosomal protein, 55 Kd (CEP55) and miR-144-3p in cervical cancer cell lines and tissues, were quantified by RT-qPCR and Western blot analysis. The binding affinity between miR-144-3p and CEP55 was identified using in silico analysis and luciferase activity determination. Cervical cancer cells were co-cultured with EVs derived from hBMSCs that were treated with either miR-144-3p mimic or miR-144-3p inhibitor. Cervical cancer cell proliferation, invasion, migration and apoptosis were detected in vitro. The effects of hBMSCs-miR-144-3p on tumour growth were also investigated in vivo. miR-144-3p was down-regulated, whereas CEP55 was up-regulated in cervical cancer cell lines and tissues. CEP55 was targeted by miR-144-3p, which suppressed cervical cancer cell proliferation, invasion and migration and promoted apoptosis via CEP55. Furthermore, similar results were obtained by hBMSCs-derived EVs carrying miR-144-3p. In vivo assays confirmed the tumour-suppressive effects of miR-144-3p in hBMSCs-derived EVs on cervical cancer. Collectively, hBMSCs-derived EVs-loaded miR-144-3p impedes the development and progression of cervical cancer through target inhibition of CEP55, therefore providing us with a potential therapeutic target for treating cervical cancer.

A time-trend ecological study for identifying flood-sensitive infectious diseases in Guangxi, China from 2005 to 2012.

BACKGROUND: Flood-related damage can be very severe and include health effects. Among those health impacts, infectious diseases still represent a significant public health problem in China. However, there have been few studies on the identification of the spectrum of infectious diseases associated with floods in one area. This study aimed to quantitatively identify sensitive infectious diseases associated with floods in Guangxi, China. METHODS: A time-trend ecological design was conducted. A descriptive analysis was first performed to exclude infectious diseases with low incidence from 2005 to 2012 in ten study sites of Guangxi. The Wilcoxon rank-sum test was applied to examine the difference in the ten-day attack rate of infectious diseases between the exposure and control periods with different lagged effects. Negative binomial, zero-inflated Poisson and zero-inflated negative binomial models were used to examine the relationship and odd ratios (ORs) of the risk of floods on infectious diseases of preliminary screening. RESULTS: A total of 417,271 infectious diseases were notified. There were 11 infectious diseases associated with floods in the preliminary screening process for flood-sensitive infectious diseases. The strongest effect was shown with a 0-9 ten-day lag in different infectious diseases. Multivariate analysis showed that floods were significantly associated with an increased the risk of bacillary dysentery (odds ratio (OR) = 1.268, 95% confidence interval (CI): 1.072-1.500), acute haemorrhagic conjunctivitis (AHC, OR = 3.230, 95% CI: 1.976-5.280), influenza A (H1N1) (OR = 1.808, 95% CI: 1.721-1.901), tuberculosis (OR = 1.200, 95% CI: 1.036-1.391), influenza (OR = 2.614, 95% CI: 1.476-4.629), Japanese encephalitis (OR = 2.334, 95% CI: 1.119-4.865), and leptospirosis (OR = 1.138, 95% CI: 1.075-1.205), respectively. CONCLUSION: The spectrum of infectious diseases which are associated with floods are bacillary dysentery, AHC, influenza A (H1N1), tuberculosis, influenza, Japanese encephalitis and leptospirosis in Guangxi. Floods can result in differently increased risk of these diseases, and public health action should be taken to control a potential risk of these diseases after floods.

Self-Assembly of Polyoxometalate-Peptide Hybrids in Solution: Elucidating the Contributions of Multiple Possible Driving Forces.

Incorporating the building blocks of nature (e.g., peptides and DNA) into inorganic polyoxometalate (POM) clusters is a promising approach to improve the compatibilities of POMs in biological fields. To extend their biological applications, it is necessary to understand the importance of different non-covalent interactions during self-organization. A series of Anderson POM-peptide hybrids have been used as a simple model to demonstrate the role of different interactions in POM-peptide (biomolecules) systems. Regardless of peptide chain length, these hybrids follow similar solution behaviors, forming hollow, spherical supramolecular structures in acetonitrile/water mixed solvents. The incorporation of peptide tails introduces interesting stimuli-responsive properties to temperature, hybrid concentration, solvent polarity and ionic strength. Unlike the typical bilayer amphiphilic vesicles, they are found to follow the blackberry-type assemblies of hydrophilic macroions, which are regulated by electrostatic interaction and hydrogen bonding. The formation of electrostatic assemblies before the supramolecular formation is confirmed by ion-mobility mass spectrometry (IMS-MS).

Thymosin-ß4 Mediates Hepatic Stellate Cell Activation by Interfering with CircRNA-0067835/miR-155/FoxO3 Signaling Pathway.

BACKGROUND/AIMS: Hepatic stellate cells (HSCs) are the primary cell type responsible for liver fibrosis. Our study proved that thymosin beta 4 (Tß4) has anti-fibrogenic effects in HSCs through PI3K/AKT pathway. However, the underlying mechanisms are not fully elucidated. Circular RNAs (circRNAs) play important roles in fine-tuning gene expression and are often deregulated in cancers. However, the expression profile and clinical significance of in liver fibrosis is still unknown. Therefore, we hypothesize that Tß4 influences circRNAs in liver fibrosis. METHODS: Circular RNA microarray was conducted to identify Tß4-related circRNAs. Pathway analysis and miRNA response elements analysis was conducted to predict the potential roles of differentially expressed circRNAs in liver fibrosis. CCK8 assays and flow cytometric assays were conducted to clarify the role of circRNA in liver fibrosis. Bioinformatics analysis and in vitro experiments were conducted to clarify the mechanism of circRNA-mediated gene regulation in liver fibrosis. RESULTS: A total of 644 differentially expressed circRNAs were identified between the Tß4-depleted LX-2 cells and the control LX2 cells. The expression of circRNA-0067835 was significantly increased in the Tß4-depleted LX-2 cells compared with control. Knockdown of circRNA-0067835 observably decreased LX-2 cell proliferation by causing G1 arrest and promoting apoptosis. Bioinformatics online programs predicted that circRNA-0067835 acted as miR-155 sponge to regulate FOXO3a expression, which was validated using luciferase reporter assay. CONCLUSION: Our experiments showed that circRNA-0067835 regulated liver fibrosis progression by acting as a sponge of miR-155 to promote FOXO3a expression, indicating that circRNA-0067835 may serve as a potential therapeutic target for patients with liver fibrosis.

Protective effects and possible molecular mechanism of Hovenia dulcis Thunb. extract on acetaminophen-induced hepatotoxicity.

Hovenia dulcis Thunb. is a traditional hepatoprotective Chinese medicine, and in research, much effort has been focused on the protection against alcoholic liver injury. In this study, the protective effects of a fruit ethanol extract of Hovenia dulcis (FE) against APAP-induced acute hepatotoxicity in mice and the possibly involved molecular mechanisms were investigated. Hepatoprotective activity of FE is clearly indicated by histopathological and biochemical examination. Treatment with FE resulted in inhibition of CYP2E1 activity involved in the transformation of APAP in vivo. Expressions of the altered bile acid metabolism and transport-related genes and relative proteins of apoptosis were normalized by preconditioning with FE before APAP treatment. These results suggested FE to alleviate APAP-induced liver injury in a dose-dependent manner by inhibition of cytochrome P450 activity, hepatocyte apoptosis and regulation of bile acid homeostasis imbalance.

Cation Translocation around Single Polyoxometalate-Organic Hybrid Cluster Regulated by Electrostatic and Cation-π Interactions.

We report herein an interesting dynamic translocation process of countercations around one polyoxometalate(POM)-organic hybrid anionic cluster at various concentrations and temperatures. It was found that both electrostatic interactions and cation-π interactions regulate the position of small countercations around single clusters. The dynamic geometry and the symmetry of the hybrid macroions are largely affected by the type of counterions, as shown by nuclear magnetic resonance (NMR) spectroscopy studies and all-atom molecular dynamics simulation. It is also shown that electrostatic interactions dominate over cation-π interactions in determining the locations of the counterions in the current system.

Self-Assembly of Polyoxovanadate-Containing Fluorosurfactants.

Two novel polyoxovanadate (POV)-containing fluorosurfactants, each with two hydrophobic fluorinated "tails" and one nanosized, hydrophilic, rigid POV "head group", are synthesized for the first time. They self-assemble into spherical, bilayer vesicles in acetonitrile/water mixed solvents, as evidenced by systemic studies using laser light scattering (LLS) and electron microscopy techniques. The vesicle sizes demonstrate dynamic change over different solvent compositions mainly as a result of the solvent swelling of the fluorocarbon chains, although the charge number on the POVs changes over the solvent polarity as well.

Changes of uterocervical angle and cervical length in early and mid-pregnancy and their value in predicting spontaneous preterm birth.

Objective: To explore the feasibility of transvaginal ultrasound measurement of uterocervical angle (UCA) and cervical length (CL) in early and mid-pregnancy and evaluate their combined prediction of spontaneous preterm birth (sPTB) in singleton pregnancies. Patients and Methods: This retrospective study comprised 274 pregnant women who underwent transvaginal ultrasound measurement of CL in mid-pregnancy (15-23+6 weeks); in 75 among them, CL also had been measured in early-pregnancy (<14 weeks). These 274 pregnant women were further divided into a preterm group (n = 149, <37 weeks gestation) and a control group (n = 125, >37 weeks gestation) according to delivery before or after 37 weeks, respectively. In the preterm group, 35 patients delivered before 34 weeks and the remaining 114 delivered between 34 and 37 weeks. Results: The optimal threshold of CL to predict preterm birth risk in women with <37 weeks gestation was 3.38 cm, and the optimal threshold of the UCA to predict preterm birth risk in the same group of women was 96°. The optimal threshold of CL to predict preterm birth risk in women with <34 weeks gestation was 2.54 cm, while that of the UCA in the same group of patients was 106°. The area under the curve for predicting preterm birth by combining the UCA and CL measurements was greater than that by using the UCA or CL alone (p < 0.01). The sensitivity and specificity for predicting preterm birth at <34 weeks gestation was 71.7% and 86.4%, respectively; and the sensitivity and specificity for predicting preterm birth at <37 weeks gestation was 87.6% and 80.6%, respectively. The difference between the two groups in CL and UCA were not significant in early pregnancy (p > 0.01), but only in mid-pregnancy (p < 0.01). There was a negative correlation between UCA and gestational week at delivery (r = -0.361, p < 0.001) and a positive correlation between CL and gestational week at delivery (r = 0.346, p < 0.001) in mid-pregnancy. The proportion of deliveries at <34 weeks was highest when the UCA was >105°, and the proportion of deliveries between 35 and 37 weeks was highest when the UCA was between 95° and 105°. The proportion of deliveries at <34 weeks was highest when the CL was <2.5 cm. Conclusion: The combination of UCA and CL has a better ability to predict preterm birth than either measurement alone. A more obtuse UCA or a shorter CL is associated with an earlier spontaneous preterm birth. The UCA increases from early to mid-pregnancy, while the CL decreases from early to mid-pregnancy.

No causal relationship between serum vitamin D levels and alcoholic liver disease: a two-sample bidirectional Mendelian randomization study.

Background: Numerous observational studies have presented an association between Vitamin D (VD) and Alcoholic Liver Disease (ALD). However, sufficient evidence from Randomized Controlled Trials (RCTs) substantiating this correlation is scarce, thus leaving the causality of this relationship ambiguous. To overcome the shortcomings of traditional observational studies, we performed a two-sample bidirectional Mendelian randomization (MR) analysis to ascertain the causal relationship between VD and ALD. Methods: We utilized summary statistics datasets from Genome-Wide Association Studies (GWAS) for VD and ALD. We selected genetic instruments that measure circulating VD levels (n = 64,979), and retrieved ALD statistics from GWASs, inclusive of 1,416 cases and 217,376 healthy controls, while excluding chronic liver diseases such as nonalcoholic fatty liver disease, toxic liver disease, and viral hepatitis. Subsequent, MR analyses were performed to obtain effect estimates using inverse variance weighted (IVW) random effect models. Cochran's Q statistic and MR-Egger regression intercept analyses were used to assess pleiotropy. Sensitivity analyses using the MR Egger, weighted median, simple mode, and weighted mode methods were also performed. Leave-one-out analysis was used to identify SNPs with potential effect. Reverse MR analysis was also performed. Results: In IVW, our MR analysis incorporated 21 independent SNPs, circulating VD levels had no causal effect on ALD [OR = 0.624 (0.336-1.160), p = 0.136] and ALD had no causal effect on circulating VD [OR = 0.997 (0.986-1.008), p = 0.555]. No heterogeneity or pleiotropy was observed (p > 0.05). Other MR methods also agreed with IVW results. Conclusion: This study provides the causal relationship between genetically predicted circulating Vitamin D levels and ALD and provides new insights into the genetics of ALD.

[Effects of blueberry on the expression of PPARγ and PDGF-B in rat hepatic fibrosis].

OBJECTIVE: To explore the effects of blueberry on the expressions of peroxisome proliferator-activated receptor γ (PPARγ) and platelet-derived growth factor B (PDGF-B) in rat hepatic fibrosis. METHODS: A total of 45 male Sprague-Dawley rats were randomly divided into control group, CCl4-induced hepatic fibrosis (model group), blueberry prevention (BB group), DSHX prevention (DSHX group) and blueberry+DSHX prevention (BB+DSHX group) (n = 9 each). Fibrous liver models of rats were induced by subcutaneous injection of CCl4 and high-lipid/low-protein diet for 8 weeks except for control group. Then the expressions of collagen I (ColI), PPARγ and PDGF-B were determined by real-time polymerase chain reaction (RT-PCR), immunohistochemistry and Western blot respectively. RESULTS: Compared with the control group, the expression of PPARγ decreased and those of ColI and PDGF-B were elevated in model group (P < 0.05). The expression of PPARγ increased and ColI and PDGF-B decreased in BB, DSHX and BB+DSHX groups as compared to model group (P < 0.05). CONCLUSION: The inhibitory effects of blueberry in CCl4-induced liver fibrosis may be correlated with the activation of PPARγ, the inhibited expression of PDGF-B and the reduced synthesis of extracellular matrix.

Case report: A rare case of pyruvate kinase deficiency and Crigler-Najjar syndrome type II with a novel pathogenic variant of PKLR and UGT1A1 mutation.

Pyruvate Kinase Deficiency (PKD) and Crigler-Najjar syndrome are rare autosomal recessive liver diseases. PKD is caused by homozygous or compound heterozygous mutations in the PKLR gene, leading to non-spherocytic hereditary hemolytic anemia. On the other hand, Crigler-Najjar syndrome (CNS-II) is characterized by the loss or reduced activity of UDP-glucuronosyltransferase, resulting in elevated levels of unconjugated bilirubin, which is the primary cause of disease manifestation. To date, there have been no reported cases of patients with both conditions. In this case report, we present the unique clinical course of a 15-year-old Chinese patient with both PKD and CNS-II. The patient was admitted for evaluation of hyperbilirubinemia and exhibited yellowish skin color, icteric sclera, and splenomegaly upon physical examination. Extensive laboratory examinations ruled out viral, hemolytic, autoimmune, and inborn or acquired metabolic etiologies of liver injury. Histopathological findings indicated benign recurrent intrahepatic cholestasis (BRIC) and hemosiderosis. Surprisingly, targeted next-generation sequencing (NGS) of the patient's blood did not reveal any mutation sites associated with BRIC. Instead, it identified a novel homozygous pathogenic variant of the PKLR gene [c.1276C>T (p.Arg426Trp)] and a rare heterozygous variant of UGT1A1 gene [c.-55_-54insAT, c.1091C>T (p.Pro364Leu)]. These findings strongly suggest a diagnosis of PKD and CNS-II in the patient. Treatment with 500 mg/day of ursodeoxycholic acid proved to be effective, rapidly reducing the patient's total bilirubin levels and shortening the symptomatic period. This case highlights the importance of genetic diagnosis in accurately identifying the underlying cause of hyperbilirubinemia, especially in patients with rare hereditary diseases. Furthermore, NGS can provide valuable insights into the genotype-phenotype correlation of PKD and CNS-II.

Insights into the characteristics of primary radioresistant cervical cancer using single-cell transcriptomics.

Radioresistance is a major cause of radiotherapy failure among patients with cervical cancer (CC), the fourth most common cause of cancer mortality in women worldwide. Traditional CC cell lines lose intra-tumoral heterogeneity, posing a challenge for radioresistance research. Meanwhile, conditional reprogramming (CR) maintains intra-tumoral heterogeneity and complexity, as well as the genomic and clinical characteristics of original cells and tissues. Three radioresistant and two radiosensitive primary CC cell lines were developed under CR conditions from patient specimens, and their characteristics were verified via immunofluorescence, growth kinetics, clone forming assay, xenografting, and immunohistochemistry. The CR cell lines had homogenous characteristics with original tumor tissues and maintained radiosensitivity in vitro and in vivo, while also maintaining intra-tumoral heterogeneity according to single-cell RNA sequencing analysis. Upon further investigation, 20.83% of cells in radioresistant CR cell lines aggregated in the G2/M cell cycle phase, which is sensitive to radiation, compared to 38.1% of cells in radiosensitive CR cell lines. This study established three radioresistant and two radiosensitive CC cell lines through CR, which will benefit further research investigating radiosensitivity in CC. Our present study may provide an ideal model for research on development of radioresistance and potential therapeutic targets in CC.

Cancer-Associated Fibroblasts Exposed to High-Dose Ionizing Radiation Promote M2 Polarization of Macrophages, Which Induce Radiosensitivity in Cervical Cancer.

Radiotherapy, including brachytherapy, is a major therapeutic regimen for cervical cancer. Radioresistance is a decisive factor in radiation treatment failure. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor microenvironment are critical factors in the curative effects of cancer therapies. However, the interactions between TAMs and CAFs in the context of ionizing radiation are not fully understood. This study was undertaken to investigate whether M2 macrophages induce radioresistance in cervical cancer and to explore the TAMs' phenotypic transformation after IR and its underlying mechanisms. The radioresistance of cervical cancer cells was enhanced after being co-cultured with M2 macrophages. TAMs tended to undergo M2 polarization after high-dose irradiation, which was strongly associated with CAFs in both mouse models and patients with cervical cancer. Additionally, cytokine and chemokine analysis was performed to find that high-dose irradiated CAFs promoted macrophage polarization towards the M2 phenotype through chemokine (C-C motif) ligand 2. Collectively, our results highlight the crucial role that high-dose irradiated CAFs play in the regulation of M2 phenotype polarization, which ultimately induces radioresistance in cervical cancer.

Causal association between constipation and risk of colorectal cancer: a bidirectional two-sample Mendelian randomization study.

Background: Colorectal cancer (CRC) is a globally significant health concern, necessitating effective preventive strategies through identifying modifiable risk factors. Constipation, characterized by infrequent bowel movements or difficulty passing stools, has been proposed as a potential CRC risk factor. However, establishing causal links between constipation and CRC remains challenging due to observational study limitations. Methods: Mendelian randomization (MR) utilizes genetic variants as instrumental variables, capitalizing on genetically determined variation to assess causal relationships. In this dual-sample bidirectional MR study, we extracted genetic data from independent cohorts with CRC (Include colon cancer and rectal cancer) and constipation cases. Genome-wide association studies (GWAS) identified constipation and CRC-associated genetic variants used as instruments to infer causality. The bidirectional MR analysis evaluated constipation's impact on CRC risk and the possibility of reverse causation. Results: Employing bidirectional MR, we explored the causal relationship between constipation and CRC using publicly available GWAS data. Analysis of constipation's effect on CRC identified 26 significant SNPs, all with strong instrumental validity. IVW-random effect analysis suggested a potential causal link [OR = 1.002(1.000, 1.004); P = 0.023], although alternative MR approaches were inconclusive. Investigating CRC's impact on constipation, 28 significant SNPs were identified, yet IVW analyses found no causal effect [OR = 0.137(0.007, 2.824); P = 0.198]. Other MR methods also yielded no significant causal association. We analyzed constipation separately from colon and rectal cancer using the same methodology in both directions, and no causal relationship was obtained. Conclusion: Our bidirectional MR study suggests a potential constipation-CRC link, with mixed MR approach outcomes. Limited evidence supports constipation causing CRC. Reliable instruments, minimal heterogeneity, and robust analyses bolster these findings, enriching understanding. Future research should explore additional factors to enhance comprehension and clinical implications.

Controllable self-assembly of organic-inorganic amphiphiles containing Dawson polyoxometalate clusters.

An organic-inorganic molecular hybrid containing the Dawson polyoxometalate, ((C(4)H(9))(4)N)(5)H[P(2)V(3)W(15)O(59)(OCH(2))(3)CNHCOC(15)H(31)], was synthesized and its surfactant-like amphiphilic properties, represented by the formation of bilayer vesicles, were studied in polar solvents. The vesicle size decreases with both decreasing hybrid concentration and with increasing polarity of the solvent, independently. The self-assembly behavior of this hybrid can be controlled by introducing different counterions into the acetonitrile solutions. The addition of ZnCl(2) and NaI can cause a gradual decrease and increase of vesicular sizes, respectively. Tetraalkylammonium bromide is found to disassemble the vesicle assemblies. Moreover, the original counterions of the hybrid can be replaced with protons, resulting in pH-dependent formation of vesicles in aqueous solutions. The hybrid surfactant can further form micro-needle structures in aqueous solutions upon addition of Ca(2+) ions.

Hepatitis B virus genotype is an independent prognostic factor of telbivudine and tenofovir treatment in hepatitis B surface antigen-positive pregnant women.

To investigate whether HBV genotype influences the effect of tenofovir and telbivudine on HBV DNA and RNA levels in HBsAg-positive pregnant women. This was a retrospective study of 74 HBsAg-positive pregnant women in Guizhou of China. All patients were treated with telbivudine or tenofovir from 12 weeks of pregnancy and HBV infection to the date of delivery. Blood samples were collected at 12-24, 28-32, and 36-40 weeks of pregnancy for the measurement of genotype, HBsAg, hepatitis B e antigen (HBeAg), HBV DNA, HBV RNA, and liver function, including alanine transaminase, aspartate transaminase, total bilirubin, total bile acids, cholinesterase, alkaline phosphatase (ALP), and gamma-glutamyl transferase. All women with HBsAg were followed up. The HBV genotype was B in 64.9% and C in 35.1%. There were 37 patients of telbivudine and tenofovir group respectively. The telbivudine and tenofovir groups showed no differences in demographic and clinical characteristics, including liver function tests, HBsAg, HBeAg, log10(HBV DNA), and log10(HBV RNA). Compared with baseline (12-24 weeks), telbivudine group showed a significant increase in ALP and significant reductions in HBsAg, HBeAg, log10(HBV DNA), and log10(HBV RNA) at 36-40 weeks (p < .05). Tenofovir group exhibited a significant increase in ALP and significant reductions in HBeAg, log10(HBV DNA), and log10(HBV RNA) at 36-40 weeks, compared with baseline (p < .05). HBV genotype (B vs. C) was independently associated with HBV DNA change after therapy (p = .005). In telbivudine group, log10 (HBV DNA) increased from 3.38 (2.00-7.30) to 7.43 (4.68-8.70). In tenofovir group, log10 (HBV DNA) decreased from 7.52 (3.32-8.70) to 2.98 (2.00-5.01). HBV genotype was independently associated with HBV DNA change response to telbivudine or tenofovir in pregnant women with hepatitis B. These findings might be helpful for risk assessment regarding vertical transmission of HBV in HBeAg-positive mothers treated with nucleos(t)ide analogues.

Screening carbonic anhydrase IX inhibitors in traditional Chinese medicine based on electrophoretically mediated microanalysis.

An electrophoretically mediated microanalysis (EMMA) method for the screening of carbonic anhydrase IX inhibitors in traditional Chinese medicine (TCM) was developed. This method combines transverse diffusion of laminar flow profiles (TDLFP) and rapid polarity switching technology to achieve rapid mixing of different reactants. Different electromigration rates of different substances make it possible that incubation, separation and detection are carried out continuously in a same fused-silica capillary. In this experiment, p-nitrophenyl acetate (pNPA) was used as the substrate for the enzyme reaction, which solved the problem that capillary electrophoresis could not detect carbonate, carbon dioxide, etc., the conventional substrates of carbonic anhydrase IX. After optimizing the enzyme reaction and separation conditions, the separation of substrate and product can be finished by baseline within 4 min. The Michaelis constant of carbonic anhydrase IX was measured to be 1.2 mM. A known inhibitor acetazolamide was used to evaluate the feasibility of this method for screening carbonic anhydrase IX inhibitors, and the half-maximal inhibitory concentration (IC50) was calculated to be 1.26 µM. Finally, 4 natural compounds of 15 traditional Chinese medicine standards were discovered to exhibit enzyme inhibitory activity, including polydatin, matrine, dauricine and cepharanthine, proving that the EMMA method is an effective means for screening carbonic anhydrase IX inhibitors. The results were supported by molecular docking study.

MiR-571 affects the development and progression of liver fibrosis by regulating the Notch3 pathway.

Exploring the expression of miR-571 in patients with liver fibrosis and its role in the progression of liver fibrosis. A total of 74 patients with liver fibrosis in our institution from September to December 2018 were collected for study, and the expression of miR-571, Notch3 and Jagged1 in patients with different progressions of liver fibrosis was determined by RT-PCR and Western blot analysis. Set up Notch3 up group and Notch3 down regulated group, RT-PCR and Western blot were used to determine the effect of Notch signaling on the expression of fibrogenic factors. CCK-8, cell scratch assays, Transwell assays, flow cytometry were used to determine the effect of miR-571 on LX-2 proliferation, migration, apoptosis in human stem stellate cells, and RT-PCR, Western blot assays were performed to determine the effect of miR-571 on the Notch3 signaling pathway and the expression of profibrogenic factors. miR-571, Notch3 and Jagged1 are up-regulated in patients with liver fibrosis and is associated with the progression of liver fibrosis. Notch3 signaling pathway can promote the expression of fibroblast in human hepatic stellate cells; miR-571 can inhibit the apoptosis of human hepatic stellate cells, promote cell proliferation and migration; up regulation of miR-571 can promote the expression of Notch3 and Jagged1, and up-regulation of miR-571 also promoted the expression of related fibroblasts. MiR-571 can promote the activation of human stem cell stellate cells and the expression of fibroblast related factors through Notch3 signaling pathway.

Transforming growth factor beta-1 upregulates glucose transporter 1 and glycolysis through canonical and noncanonical pathways in hepatic stellate cells.

BACKGROUND: Hepatic stellate cells (HSCs) are the key effector cells mediating the occurrence and development of liver fibrosis, while aerobic glycolysis is an important metabolic characteristic of HSC activation. Transforming growth factor-ß1 (TGF-ß1) induces aerobic glycolysis and is a driving factor for metabolic reprogramming. The occurrence of glycolysis depends on a high glucose uptake level. Glucose transporter 1 (GLUT1) is the most widely distributed glucose transporter in the body and mainly participates in the regulation of carbohydrate metabolism, thus affecting cell proliferation and growth. However, little is known about the relationship between TGF-ß1 and GLUT1 in the process of liver fibrosis and the molecular mechanism underlying the promotion of aerobic glycolysis in HSCs. AIM: To investigate the mechanisms of action of GLUT1, TGF-ß1 and aerobic glycolysis in the process of HSC activation during liver fibrosis. METHODS: Immunohistochemical staining and immunofluorescence assays were used to examine GLUT1 expression in fibrotic liver tissue. A Seahorse extracellular flux (XF) analyzer was used to examine changes in aerobic glycolytic flux, lactate production levels and glucose consumption levels in HSCs upon TGF-ß1 stimulation. The mechanism by which TGF-ß1 induces GLUT1 protein expression in HSCs was further explored by inhibiting/promoting the TGF-ß1/mothers-against-decapentaplegic-homolog 2/3 (Smad2/3) signaling pathway and inhibiting the p38 and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. In addition, GLUT1 expression was silenced to observe changes in the growth and proliferation of HSCs. Finally, a GLUT1 inhibitor was used to verify the in vivo effects of GLUT1 on a mouse model of liver fibrosis. RESULTS: GLUT1 protein expression was increased in both mouse and human fibrotic liver tissues. In addition, immunofluorescence staining revealed colocalization of GLUT1 and alpha-smooth muscle actin proteins, indicating that GLUT1 expression was related to the development of liver fibrosis. TGF-ß1 caused an increase in aerobic glycolysis in HSCs and induced GLUT1 expression in HSCs by activating the Smad, p38 MAPK and P13K/AKT signaling pathways. The p38 MAPK and Smad pathways synergistically affected the induction of GLUT1 expression. GLUT1 inhibition eliminated the effect of TGF-ß1 on HSC proliferation and migration. A GLUT1 inhibitor was administered in a mouse model of liver fibrosis, and GLUT1 inhibition reduced the degree of liver inflammation and liver fibrosis. CONCLUSION: TGF-ß1 induces GLUT1 expression in HSCs, a process related to liver fibrosis progression. In vitro experiments revealed that TGF-ß1-induced GLUT1 expression might be one of the mechanisms mediating the metabolic reprogramming of HSCs. In addition, in vivo experiments also indicated that the GLUT1 protein promotes the occurrence and development of liver fibrosis.