ARRB1 downregulates acetaminophen-induced hepatoxicity through binding to p-eIF2α to inhibit ER stress signaling.

Acetaminophen (APAP) stands as the predominant contributor to drug-induced liver injury (DILI), and limited options are available. ß-Arrestin1 (ARRB1) is involved in numerous liver diseases. However, the role of ARRB1 in APAP-induced liver injury remained uncertain. Wild-type (WT) and ARRB1 knockout (KO) mice were injected with APAP and sacrificed at the indicated times. The histological changes, inflammation, endoplasmic reticulum (ER) stress, and apoptosis were then evaluated. Hepatic cell lines AML-12 and primary hepatocytes were used for in vitro analyses. Systemic ARRB1-KO mice were susceptible to APAP-induced hepatotoxicity, as indicated by larger areas of centrilobular necrosis area and higher levels of ALT, AST, and inflammation level. Moreover, ARRB1-KO mice exhibited increased ER stress (indicated by phosphorylated α subunit of eukaryotic initiation factor 2 (p-eIF2α)-activating transcription factor 4 (ATF4)-CCAAT-enhancer-binding protein homologous protein (CHOP)) and apoptosis (indicated by cleaved caspase 3). Further rescue experiments demonstrated that the induction of apoptosis was partially mediated by ER stress. Overexpression of ARRB1 alleviated APAP-induced ER stress and apoptosis. Moreover, co-IP analysis revealed that ARRB1 directly bound to p-eIF2α and eIF2α. ARRB1 protected against APAP-induced hepatoxicity through targeting ER stress and apoptosis. ARRB1 is a prospective target for treating APAP-induced DILI.

Outcomes of pregnancies complicated by cirrhosis: a retrospective cohort study.

BACKGROUND: Although pregnancy complicated by liver cirrhosis is rare, women with cirrhosis experience increased adverse pregnancy outcomes. This study aimed to evaluate pregnancy outcomes in women with liver cirrhosis and develop a predictive model using maternal factors for preterm birth in such pregnancies. METHODS: A retrospective analysis was conducted on pregnancy outcomes of a cirrhosis group (n = 43) and a non-cirrhosis group (n = 172) in a university hospital between 2010 and 2022. Logistic regression evaluated pregnancy outcomes, and a forward stepwise logistic regression model was designed to predict preterm birth in pregnant women with cirrhosis. The model's predictive performance was evaluated using the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC). RESULTS: The incidence of cirrhosis during pregnancy was 0.06% (50/81,554). Pregnant women with cirrhosis faced increased risks of cesarean section, preterm birth, intrahepatic cholestasis of pregnancy, thrombocytopenia, and postpartum hemorrhage. In pregnant women with cirrhosis, preterm birth risk significantly increased at an incidence rate of 46.51% (20/43). According to the prediction model, the key predictors of preterm birth in pregnant women with cirrhosis were intrahepatic cholestasis of pregnancy and total bilirubin. The model demonstrated accurate prediction, with an AUC of 0.847, yielding a model accuracy of 81.4%. CONCLUSIONS: Pregnant women with cirrhosis face a heightened risk of adverse obstetric outcomes, particularly an increased incidence of preterm birth. The preliminary evidence shows that the regression model established in our study can use the identified key predictors to predict preterm birth in pregnant women with cirrhosis, with high accuracy.

The effect of intrahepatic cholestasis in pregnancy combined with different stages of hepatitis B virus infection on pregnancy outcomes: a retrospective study.

BACKGROUND AND AIMS: To investigate the impact of intrahepatic cholestasis of pregnancy (ICP) with hepatitis B virus (HBV) infection on pregnancy outcomes. METHODS: We selected 512 pregnant women, collected the data including maternal demographics, main adverse pregnancy outcomes and maternal HBV infected markers HBeAg and HBV-DNA loads status, then have a comparative analysis. RESULTS: There were 319 solitary ICP patients without HBV infection (Group I) and 193 ICP patients with HBV infection. Of the latter, there were 118 cases with abnormal liver function(Group II) and 80 cases with normal liver function(Group III). All HBV-infected pregnant women with ICP were divided into hepatitis Be antigen (HBeAg)-positive group (102 cases) and HBeAg-negative group (91 cases), according to the level of the serum HBeAg status; and into high viral load group (92 cases), moderate viral load group (46 cases) and low viral load group (55 cases) according to the maternal HBV-DNA level. Group II had a higher level of serum total bile acids, transaminase, bilirubin as well as a higher percentage of premature delivery, neonatal intensive care unit (NICU) admission and meconium-stained amniotic fluid (MSAF) compared with the other two groups(P < 0.05), but there were no significant differences in the above indicators between the Group I and Group III. Among the HBV-infected patients with ICP, HBeAg-positive group had a higher level of serum transaminase, bilirubin and bile acid as well as earlier gestational weeks of delivery, lower birth weight of new-borns and a higher rate of NICU admission than HBeAg-negative group (P < 0.05). Those with a high viral load (HBV-DNA > 106 IU/ml) had a higher level of transaminase, bilirubin, and bile acid as well as shorter gestational weeks of delivery, lower birth weight of new-borns and a higher rate of NICU admission compared with those with a low or moderate viral load (P < 0.05). CONCLUSION: HBV-infected pregnant women with ICP combined with abnormal liver function have more severe liver damage, a higher percentage of preterm birth and NICU admission. HBeAg-positive status and a high HBV-DNA load will increase the severity of conditions in HBV-infected pregnant women with ICP. HBV-infected patients with ICP who have abnormal liver function, HBeAg-positive or a high viral load should be treated more actively.

Generation of Slco1a4-CreERT2-tdTomato Knock-in Mice for Specific Cerebrovascular Endothelial Cell Targeting.

The cerebrovascular endothelial cells with distinct characteristics line cerebrovascular blood vessels and are the fundamental structure of the blood-brain barrier, which is important for the development and homeostatic maintenance of the central nervous system. Cre-LoxP system-based spatial gene manipulation in mice is critical for investigating the physiological functions of key factors or signaling pathways in cerebrovascular endothelial cells. However, there is a lack of Cre recombinase mouse lines that specifically target cerebrovascular endothelial cells. Here, using a publicly available single-cell RNAseq database, we screened the solute carrier organic anion transporter family member 1a4 (Slco1a4) as a candidate marker of cerebrovascular endothelial cells. Then, we generated an inducible Cre mouse line in which a CreERT2-T2A-tdTomato cassette was placed after the initiation codon ATG of the Slco1a4 locus. We found that tdTomato, which can indicate the endogenous Slco1a4 expression, was expressed in almost all cerebrovascular endothelial cells but not in any other non-endothelial cell types in the brain, including neurons, astrocytes, oligodendrocytes, pericytes, smooth muscle cells, and microglial cells, as well as in other organs. Consistently, when crossing the ROSA26LSL-EYFP Cre reporter mouse, EYFP also specifically labeled almost all cerebrovascular endothelial cells upon tamoxifen induction. Overall, we generated a new inducible Cre line that specifically targets cerebrovascular endothelial cells.

A pregnant woman with congenital hepatic fibrosis delivers a healthy neonate.

BACKGROUND AND AIMS: Congenital hepatic fibrosis (CHF) is a rare disease associated with polycystic kidney gene mutation and is characterized by liver fibrosis and portal hypertension. The pathology of CHF has common characteristics with hepatitis B cirrhosis. Currently, little is known about the clinical course of CHF during pregnancy or its effect on maternal and fetal outcomes. METHODS: Whole exome sequencing (WES), and laboratory and histopathological findings of the patient were documented. RESULTS: We report the case of a 30-year-old Chinese woman who had been diagnosed with hepatitis B cirrhosis 17 years before and whose diagnosis was revised to CHF based on confirmation by liver biopsy and WES. She conceived naturally and delivered a healthy live infant. CONCLUSIONS: The diagnostic methods for CHF are liver biopsy and WES. In pregnant patients with CHF, prenatal monitoring is mainly performed to monitor liver function, platelet and clotting function, portal hypertension and degree of esophageal and gastric varices. Precise guidelines for screening and management of patients with CHF need to be better defined.

Concise total synthesis of (+)-Zeylenone with antitumor activity and the structure-activity relationship of its derivatives.

Natural products--polyoxygenated cyclohexenes exhibited potent anti-tumor activity, such as zeylenone, which is a natural product isolated from Uvaria grandiflora Roxb. This article will attempt to establish a gram-scale synthesis method of (+)-zeylenone and explain the structure-activity relationship of this kind of compound. Total synthesis of (+)-zeylenone was completed in 13 steps with quinic acid as the starting material in 9.8% overall yield. The highlight of the route was the control of the three carbon's chirality by single step dihydroxylation. In addition, different kinds of derivatives were designed and synthesized. Cell Counting Kit-8 (CCK8) assay was used for evaluating antitumor activity against three human cancer cell lines. The structure--activity relationship suggested that compounds with both absolute configurations exhibited tumor-suppressive effects. Moreover, hydroxyls at the C-1/C-2 position were crucial to the activity, and the esterification of large groups at C-1 hydroxyl eliminated the activity. Hydroxyl at the C-3 position was also important as proper ester substituent could increase the potency.

Association between blood lead level during pregnancy and birth weight: A meta-analysis.

BACKGROUND: We aimed to provide a quantitative summary of evidence for a relationship between prenatal lead (Pb) exposure and birth weight. METHODS: PubMed and Web of Science databases were searched for eligible epidemiological studies. We transformed findings in eligible studies with different effect-size metrics to standardized regression coefficients, and used fixed-effects or random-effects models to assess the pooled effects of prenatal Pb exposure on birth weight. RESULTS: There was a significant negative association between prenatal Pb exposure and birth weight. Birth weight reduction was associated with elevated lead levels in maternal blood (ß = -0.094; 95% confidence interval [CI]: -0.157 to -0.030) and cord blood (ß = -0.120; 95% CI: -0.239 to -0.001). CONCLUSIONS: This meta-analysis is the first to provide a quantitative assessment of Pb exposure during pregnancy and an increased risk of lower birth weight.

Mother-to-child transmission of hepatitis B virus after amniocentesis: A retrospective matched cohort study.

OBJECTIVE: The objective of this study is to determine whether amniocentesis increases the risk of mother-to-child transmission (MTCT) of hepatitis B virus (HBV) and evaluate risk factors for MTCT. METHODS: One hundred forty-three hepatitis B surface antigen (HBsAg)-positive women with amniocentesis were enrolled into the amniocentesis group. Six hundred five nonamniocentesis cases were matched with amniocentesis cases based on maternal viral loads, antiviral therapy regimens, and delivery dates. MTCT of HBV was defined as HBsAg and/or DNA positivity in infants from birth to age 7 to 12 months. RESULTS: Mother-to-child transmission rate was significantly higher in HBsAg-positive women with amniocentesis than in those without amniocentesis (2.80% vs 0.50%; relative risk [RR], 5.64; 95% CI, 1.28-24.93). In the amniocentesis group, maternal HBV DNA more than or equal to 7.0 log10 IU/mL and hepatitis B e-antigen (HBeAg) positivity were associated with higher MTCT rates than maternal HBV DNA less than 7.0 log10 IU/mL (10.81% vs 0%, p = .004) and HBeAg negativity (8.16% vs 0%, p = .013), and antiviral therapy reduced MTCT rate from 14.3% to 0% (p = .554) when maternal HBV DNA was more than or equal to 7.0 log10 IU/mL. CONCLUSIONS: Amniocentesis increases the risk of MTCT in women with hepatitis B, and maternal HBV DNA more than or equal to 7.0 log10 IU/mL and HBeAg positivity are risk factors for MTCT. Antiviral therapy may be effective to prevent MTCT after amniocentesis in highly viremic mothers.

Efficient light focusing through an MMF based on two-step phase shifting and parallel phase compensating.

Based on a parallel phase compensation scheme, we propose an efficient wavefront shaping method using a spatial light modulator (SLM) for quickly generating a series of focused spots through a multimode fiber (MMF). The compensated phase mask obtained by a two-step phase-shifting technique is loaded to the SLM for generating a focused spot at an arbitrary target position out of the fiber facet. Furthermore, the parallel algorithm we present makes it possible to obtain a series of compensated phase masks, which could be used to generate a series of focused spots at different locations. We experimentally obtained 100 tightly focused spots, with an average focused efficiency of 21.60% and an average focused diameter of 1.9240 µm, and only one-time parallel-compensated phase retrieval is required without multiple iteration optimization.

Hypoxia-Induced Activation of JAK/STAT3 Signaling Pathway Promotes Trophoblast Cell Viability and Angiogenesis in Preeclampsia.

BACKGROUND To explore the effect of hypoxic preconditioning on the JAK/STAT3 signaling pathway and its effect on trophoblast cell viability and angiogenesis in preeclampsia (PE). MATERIAL AND METHODS Placental tissues from normal pregnant women and PE patients were collected to detect the expression levels of JAK and STAT3. Trophoblast cells separated from the PE patients were assigned to 4 groups. The expression levels of phosphorylated p-JAK and p-STAT3 were measured by Western blot. Cell viability, colony-forming ability, and cell apoptosis were assessed. The levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS The expression levels of JAK and STAT3 were higher in the placental tissues of PE patients than in those of normal pregnant women. Compared with the blank group, in the hypoxia group the expression levels of p-JAK and p-STAT3 were increased, cell viability was promoted, the number of colonies was increased, cell apoptosis was inhibited, and the levels of VEGF, bFGF, and HGF were all elevated. However, in comparison with the hypoxia group, the expression levels of p-JAK and p-STAT3 were reduced, the cell viability was inhibited, the colonies were decreased, the levels of VEGF, bFGF, and HGF were all decreased, and cell apoptosis was promoted in the hypoxia + si-JAK group. CONCLUSIONS These findings indicate that hypoxic preconditioning may contribute to activation of the JAK/STAT3 signaling pathway, thus promoting trophoblast cell viability and angiogenesis in PE.

Intestinal obstruction due to congenital malrotation complicating a multiple pregnancy: A rare case report.

Intestinal obstruction due to congenital intestinal malrotation is usually diagnosed in neonates but may, in rare cases, occur during pregnancy. The absence of specific symptoms in combination with its low incidence makes timely detection of intestinal malrotation-related obstruction difficult in expectant mothers. We present a rare case of a 23-year-old woman with a twin pregnancy following in vitro fertilization-embryo transfer (IVF-ET) who presented with symptoms of intestinal obstruction at 22+4 weeks of gestation. This diagnosis was not confirmed by imaging and the patient was managed conservatively. Following caesarean section, she gave birth to two healthy full-term infants. During the operation, malposition of the bowel and the typical Ladd's band confirmed intestinal malrotation. This is the first report of a congential malrotation complicating a multiple pregnancy, and highlights that malrotation without volvulus can be managed conservatively.

Overexpression of RBM15 modulated the effect of trophoblast cells by promoting the binding ability between YTHDF2 and the CD82 3'UTR to decrease the expression of CD82.

Background: Pre-eclampsia (PE) is a syndrome with no specific pathological mechanism and is specific to pregnancy. The combined analysis of proteomics and transcriptomics possesses many benefits for treating this disease. m6A modification plays a major role in PE; however, mechanism have not been studied clearly. This study investigated the potential mechanism underlying the role of m6A in PE. Methods: Mass spectrometry-based label-free quantitative proteomics and transcriptomics experiments were conducted on the placenta of patients with pre-eclampsia and normal pregnancies, and the two omics were followed by joint analysis. Total m6A modification in placental tissues, HTR8/SVneo cells, and JEG-3 cells was measured by dot blot. The levels of RBM15 and CD82 in tissues and cells were detected using qPCR. The protein levels of G3BP1, RBM15, MMP-2, YTHDF2, and MMP-9 were measured by western blotting. The function, migration, and invasion characteristics of HTR8/SVneo and JEG-3 cells were measured using Transwell assays. SRAMP predicted the m6A modification site in the CD82 mRNA 3'UTR, and this was confirmed using luciferase activity and YTHDF2-RIP. Results: m6A modification was promoted in the PE group, and the RBM15 abundance was increased. Overexpression of RBM15 increased m6A modification. However, overexpression of RBM15 suppressed the expression of MMP-2 and MMP-9 and also the migratory and invasive capabilities of HTR8/SVneo and JEG-3 cells. CD82 expression levels were decreased in PE, and CD82 expression was confirmed via qPCR, western blotting and immunofluorescence. Furthermore, RBM15 overexpression reduced CD82 mRNA and protein levels. Luciferase activity and YTHDF2-RIP results verified that overexpression of RBM15 promoted the binding ability between YTHDF2 and the CD82 3'UTR, thereby decreasing CD82 expression. Finally, CD82 overexpression reversed the effect of RBM15 overexpression on the expression of MMP-2 and MMP-9 and on the migratory and invasive capabilities of the cells. Conclusions: Overexpression of RBM15 hindered the migratory and invasive capabilities of trophoblasts, while concurrently enhancing m6A modification. The potential mechanism was that overexpression of RBM15 promoted the binding capability between YTHDF2 and CD82 3'UTR and decrease the expression of CD82. Thus, this study provides a theoretical basis for the treatment of PE.

Origin of the neonatal gut microbiota and probiotic intervention: a randomized controlled trial.

Objective: This study aims to evaluate the origin of the neonatal gut microbiota on the 14th day and probiotic intervention in the third trimester. Methods: Samples were obtained from a total of 30 pregnant individuals and their offspring, divided into a control group with no intervention and a probiotic group with live combined Bifidobacterium and Lactobacillus tablets, analyzing by 16S rRNA amplicon sequencing of the V4 region to evaluate the composition of them. Non-metric multidimensional scaling and SourceTracker were used to evaluate the origin of neonatal gut microbiota. Results: We found that the microbiota in the neonatal gut at different times correlated with that in the maternal microbiota. The placenta had more influence on meconium microbiota. Maternal gut had more influence on neonatal gut microbiota on the 3rd day and 14th day. We also found that the maternal gut, vaginal, and placenta microbiota at full term in the probiotic group did not have a significantly different abundance of Bifidobacterium, Lactobacillus, or Streptococcus. However, some other bacteria changed in the maternal gut and their neonatal gut in the probiotic group.

Microbiota of pregnancy, placenta and newborns in the third trimester: A randomized controlled study.

Microbiota in pregnant time is vital to healthy of pregnant women and their offspring. However, few study evaluate the composition of the microbiota of health pregnancy, placenta and their newborns at different stages and the origin of the placental microbiota. Samples were obtained from a total of 31 pregnant individuals and their offspring, analyzing by 16S rRNA amplicon sequencing of the V4 region to evaluate the composition and variation of them. We found that the microbiota of pregnant individuals changes in the third trimester. The placental microbiota has its own specific dominant microbiota. The placental microbiota is correlated with the pregnancy microbiota in the gut and vagina at 32-34 weeks but not at full term. The gut microbiota in newborns changes over the first 14 days.

The PTM profiling of CTCF reveals the regulation of 3D chromatin structure by O-GlcNAcylation.

CCCTC-binding factor (CTCF), a ubiquitously expressed and highly conserved protein, is known to play a critical role in chromatin structure. Post-translational modifications (PTMs) diversify the functions of protein to regulate numerous cellular processes. However, the effects of PTMs on the genome-wide binding of CTCF and the organization of three-dimensional (3D) chromatin structure have not been fully understood. In this study, we uncovered the PTM profiling of CTCF and demonstrated that CTCF can be O-GlcNAcylated and arginine methylated. Functionally, we demonstrated that O-GlcNAcylation inhibits CTCF binding to chromatin. Meanwhile, deficiency of CTCF O-GlcNAcylation results in the disruption of loop domains and the alteration of chromatin loops associated with cellular development. Furthermore, the deficiency of CTCF O-GlcNAcylation increases the expression of developmental genes and negatively regulates maintenance and establishment of stem cell pluripotency. In conclusion, these results provide key insights into the role of PTMs for the 3D chromatin structure.

Melatonin alleviates alcoholic liver disease via EGFR-BRG1-TERT axis regulation.

Chronic alcohol consumption causes liver steatosis, cell death, and inflammation. Melatonin (MLT) is reported to alleviate alcoholic liver disease (ALD)-induced injury. However, its direct regulating targets in hepatocytes are not fully understood. In the current study, a cell-based screening model and a chronic ethanol-fed mice ALD model were used to test the protective mechanisms of MLT. MLT ameliorated ethanol-induced hepatocyte injury in both cell and animal models (optimal doses of 10 µmol/L and 5 mg/kg, respectively), including lowered liver steatosis, cell death, and inflammation. RNA-seq analysis and loss-of-function studies in AML-12 cells revealed that telomerase reverse transcriptase (TERT) was a key downstream effector of MLT. Biophysical assay found that epidermal growth factor receptor (EGFR) on the hepatocyte surface was a direct binding and regulating target of MLT. Liver specific knock-down of Tert or Egfr in the ALD mice model impaired MLT-mediated liver protection, partly through the regulation of nuclear brahma-related gene-1 (BRG1). Long-term administration (90 days) of MLT in healthy mice did not cause evident adverse effect. In conclusion, MLT is an efficacious and safe agent for ALD alleviation. Its direct regulating target in hepatocytes is EGFR and downstream BRG1-TERT axis. MLT might be used as a complimentary agent for alcoholics.

EGFR- and AKT-mediated reduction in PTEN expression contributes to tyrphostin resistance and is reversed by mTOR inhibition in endometrial cancer cells.

Loss or mutation of the PTEN (phosphatase and tensin homologue deleted on chromosome 10) gene is associated with resistance to epidermal growth factor receptor (EGFR) inhibitors. However, the mechanism underlying remains elusive. In this study, we aimed to explore whether sensitivity to the EGFR tyrosine kinase inhibitor (TKI) is affected by PTEN status in endometrial cancer cells. PTEN siRNA and the PTEN gene were transfected into HEC-1A and Ishikawa endometrial cancer cells using lentiviral vectors. Cells were treated under various concentrations of RG14620 and rapamycin, which are EGFR and mammalian target of rapamycin (mTOR) inhibitors, respectively. The IC(50) of RG16420 was determined by using the MTT method. Cell apoptosis and the cell cycle were studied, and activation of EGFR, AKT, and p70S6 were detected by Western blot analysis. Loss of PTEN promoted cell proliferation and led to significant increases in the levels of EGFR, phospho-EGFR, AKT, phospho-AKT, and phospho-mTOR proteins. Ishikawa and HEC-1A(PTENkd) cells that displayed loss and inactivation of PTEN function were resistant to RG14620. HEC-1A and Ishikawa(PTEN) cells with intact PTEN were sensitive to RG14620. The combination of two inhibitors was more effective than both monotherapies, particularly in carcinoma cells with PTEN dysfunction. Decreased phospho-EGFR protein expression was observed in all cell lines that were sensitive to RG14620. Decreased phospho-AKT and phospho-p70S6 protein expression was observed in PTEN-intact cells that were sensitive to RG14620. PTEN loss results in resistance to EGFR TKI, which was reversed by PTEN reintroduction or mTOR inhibitor treatment. The combined treatment of EGFR TKI and the mTOR inhibitor provided a synergistic effect by promoting cell death in PTEN-deficient and PTEN-intact endometrial cancer cells, particularly in PTEN-deficient carcinoma cells with up-regulated EGFR activation.

The Hepatoprotective and Hepatotoxic Roles of Sex and Sex-Related Hormones.

Most liver diseases, including acute liver injury, drug-induced liver injury, viral hepatitis, metabolic liver diseases, and end-stage liver diseases, are strongly linked with hormonal influences. Thus, delineating the clinical manifestation and underlying mechanisms of the "sexual dimorphism" is critical for providing hints for the prevention, management, and treatment of those diseases. Whether the sex hormones (androgen, estrogen, and progesterone) and sex-related hormones (gonadotrophin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin) play protective or toxic roles in the liver depends on the biological sex, disease stage, precipitating factor, and even the psychiatric status. Lifestyle factors, such as obesity, alcohol drinking, and smoking, also drastically affect the involving mechanisms of those hormones in liver diseases. Hormones deliver their hepatic regulatory signals primarily via classical and non-classical receptors in different liver cell types. Exogenous sex/sex-related hormone therapy may serve as a novel strategy for metabolic liver disease, cirrhosis, and liver cancer. However, the undesired hormone-induced liver injury should be carefully studied in pre-clinical models and monitored in clinical applications. This issue is particularly important for menopause females with hormone replacement therapy (HRT) and transgender populations who want to receive gender-affirming hormone therapy (GAHT). In conclusion, basic and clinical studies are warranted to depict the detailed hepatoprotective and hepatotoxic mechanisms of sex/sex-related hormones in liver disease. Prolactin holds a promising perspective in treating metabolic and advanced liver diseases.

Mesenchymal Stem Cell Therapy for Acetaminophen-related Liver Injury: A Systematic Review and Meta-analysis of Experimental Studies In Vivo.

OBJECTIVE: The efficacy of mesenchymal stem cell (MSC) therapy in acetaminophen-induced liver injury has been investigated in animal experiments, but individual studies with a small sample size cannot be used to draw a clear conclusion. Therefore, we conducted a systematic review and meta-analysis of preclinical studies to explore the potential of using MSCs in acetaminophen- induced liver injury. METHODS: Eight databases were searched for studies reporting the effects of MSCs on acetaminophen hepatoxicity. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were used. SYRCLE's risk of bias tool for animal studies was applied to assess the methodological quality. A meta-analysis was performed by using RevMan 5.4 and STATA/ SE 16.0 software. RESULTS: Eleven studies involving 159 animals were included according to PRISMA statement guidelines. Significant associations were found for MSCs with the levels of alanine transaminase (ALT) (standardized mean difference (SMD) - 2.58, p < 0.0001), aspartate aminotransferase (AST) (SMD - 1.75, p = 0.001), glutathione (GSH) (SMD 3.7, p < 0.0001), superoxide dismutase (SOD) (SMD 1.86, p = 0.022), interleukin 10 (IL-10) (SMD 5.14, p = 0.0002) and tumor necrosis factor-α (TNF-α) (SMD - 4.48, p = 0.011) compared with those in the control group. The subgroup analysis showed that the tissue source of MSCs significantly affected the therapeutic efficacy (p < 0.05). CONCLUSION: Our meta-analysis results demonstrate that MSCs could be a potential treatment for acetaminophen- related liver injury. The protocol for this meta-analysis was prospectively registered in PROSPERO (Number: CRD42020212677).

Development of S4A-BSA-Au NPs for enhanced anti-tumor therapy of canine breast cancer.

S4A ((1R,2R,3S)-1,2-propanediol acetal-zeylenone) is one of the derivatives of zeylenone and exhibits superior cytotoxicity against the canine breast cancer cell line CIPp. However, its poor aqueous solubility and toxicity to normal tissue limit its clinical application. Therefore, in order to enhance the anticancer effect of S4A, in this article, BSA/BSA-Au-nanocluster-aggregated core/shell nanoparticles (B-BANC-NPs) were prepared by using bovine serum albumin (BSA) and HAuCl4, and then we further synthesized S4A-BSA-Au NPs which were spherical, with a diameter of about 60 nm. In vitro cytotoxicity assessed by using CCK-8 assay demonstrated that the IC50 value of the S4A-BSA-Au NPs was 10.39 µg mL-1, which was not significantly different from that of S4A (10.45 µg mL-1). In vitro apoptosis assay showed that the apoptosis rate of cells treated with S4A-BSA-Au NPs was 20.12%, which was significantly higher than that of the control group treated with S4A (11.3%). Notably, S4A-BSA-Au NPs were shown to effectively accumulate at tumor sites with fluorescence tracing. Besides, the effect of S4A-BSA-Au NPs on SPARC expression was determined by western blotting, and the result showed that 24 h after applying S4A-BSA-Au NPs, SPARC expression in low, middle and high dosage groups was lower than that of the control group, and the tendency showed dose dependence. The results revealed that S4A-BSA-Au NPs could effectively improve the anti-tumor activity of S4A on canine breast cancer, which may be associated with their abilities to effectively accumulate within tumor and to reduce the expression of SPARC.