Drug toxicity is closely related to both clinical drug safety and new drug development. Therefore, it is vital to understand the mechanisms of drug toxicity fully and to use appropriate research models with advanced technologies. Zebrafish has become an important vertebrate animal model for high-throughput drug screening and toxicity assessment. At the same time, zebrafish has an intact biological complexity, reflecting the whole organism's toxicity, which gives it an advantage over other high-throughput models in toxicity studies. Despite the gradual increase in toxicity studies utilizing zebrafish, a comprehensive and systematic review of the underlying mechanisms and new techniques is still lacking. This review aims to analyze common toxicity mechanisms in zebrafish models, such as oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis, and macroscopic changes in biological processes like lipid metabolism disorders and neurotransmitter expression abnormalities. It also introduces new technologies applied in toxicity assessment, such as gene editing, novel fluorescence imaging technology, 3D imaging technology, and novel automated technology for high-throughput screening, such as fish capsules. In addition, it also summarizes the advantages and disadvantages of the model. By doing so, it will provide new suggestions for the development and improvement of the model, make it better serve the toxicity study of clinical drugs and provide a more comprehensive perspective for drug toxicity study, thus promoting the development of the field of drug toxicity study.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and macrophage polarization plays an important role in its pathogenesis. However, which molecule regulates macrophage polarization in NAFLD remains unclear. Herein, we showed NAFLD mice exhibited increased 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7) expression in hepatic macrophages concomitantly with elevated M1 polarization. Single-cell RNA sequencing on hepatic non-parenchymal cells isolated from wild-type littermates and macrophage-17β-HSD7 knockout mice fed with high fat diet (HFD) for 6 weeks revealed that lipid metabolism pathways were notably changed. Furthermore, 17β-HSD7 deficiency in macrophages attenuated HFD-induced hepatic steatosis, insulin resistance and liver injury. Mechanistically, 17β-HSD7 triggered NLRP3 inflammasome activation by increasing free cholesterol content, thereby promoting M1 polarization of macrophages and the secretion of pro-inflammatory cytokines. In addition, to help demonstrate that 17β-HSD7 is a potential drug target for NAFLD, fenretinide was screened out from an FDA-approved drug library based on its 17β-HSD7 dehydrogenase inhibitory activity. Fenretinide dose-dependently abrogated macrophage polarization and pro-inflammatory cytokines production, and subsequently inhibited fat deposition in hepatocytes co-cultured with macrophages. In conclusion, our findings suggest that blockade of 17β-HSD7 signaling by fenretinide would be a drug repurposing strategy for NAFLD treatment.

Infant, Newborn ; Infant ; Female ; Humans ; Infant, Extremely Premature ; Uterus ; Gestational Age

Objective:To study the past 10 years' experiences of neonatal hydrocephalus in a single-center.Methods:From January 2010 to December 2019, clinical data of infants with hydrocephalus admitted to Neonatology Department of our hospital were retrospectively analyzed. The infants were assigned into different groups according to gestational age, different etiologies and treatments. Their clinical characteristics and outcomes were compared.Results:A total of 223 infants with hydrocephalus were included. 136 (61.0%) infants were in the preterm group and 87 (39.0%) in the full-term group. The incidence of post-intracranial hemorrhage (ICH) hydrocephalus in preterm infants was significantly higher than full-term infants ( P<0.001). According to the etiologies, 58 infants (26.0%) had congenital hydrocephalus (congenital group), 82 cases (36.8%) developed post-ICH hydrocephalus (ICH group), 48 cases (21.5%) had post-CNS-infection hydrocephalus (infection group) and 35 cases (15.7%) had post-ICH+CNS-infection hydrocephalus (ICH+infection group). The incidences of perinatal asphyxia, neonatal resuscitation and endotracheal intubation within 3 d after birth in the ICH group were significantly higher than the other groups ( P<0.05). Among the four groups, the infection group had the highest incidence of neonatal sepsis, the congenital group had the highest incidence of patent ductus arteriosus and the ICH group had the highest incidence of respiratory diseases (all P<0.05).137 cases (61.4%) received non-surgical therapy, 48 cases (21.5%) had temporary drainage, 37 cases (16.6%) with permanent shunt and 1 case (0.4%) intracranial hematoma removal. The congenital group and ICH group with permanent shunt showed significantly higher rate of improvement than temporary drainage group and non-surgical group ( P<0.001). Conclusions:The main etiologies of neonatal hydrocephalus are ICH and CNS infection. The incidence of post-ICH hydrocephalus in premature infants was quite high. Hydrocephalus of different etiologies have different comorbidities. Maternal and infant care during pregnancy and delivery, prevention of neonatal sepsis and ICH are crucial in the prevention of hydrocephalus. More studies are needed for better treatment.

【Objective】 To analyze the blood transfusion and adverse reactions in myelodysplastic syndroms (MDS) patients, so as to improve transfusion management in MDS patients. 【Methods】 The diagnosis and treatment information of MDS patients with blood transfusion in our hospital from January 2003 to December 2022 were collected, and the component transfusion and adverse reactions were investigated. 【Results】 The average infusion volume of red blood cells(RBCs) and platelets were respectively (27.46±43.11 ) and (16.41±24.81 ) in 799 MDS patients, which had no correlation with gender and blood type. The incidence of adverse reactions was 18.27% (146/799), with the most common adverse reactions as delayed serologic transfusion reaction (DSTR) (9.01%, 72/799), followed by non hemolytic fever reaction (4.76%, 38/799) and allergic reaction (4.38%, 35/799). Compared with all patients with transfusion, DSTR was more common in females (P<0.05), with elder age and had more RBCs consumption (all P<0.01). 86.11%(62/72) were Rh system, and 40.28% (29/72) had 2 or more antibodies. The occurrence time of DSTR in some patients was not related to the volume of RBCs trans infusion. 【Conclusion】 MDS patients, with more average transfusion volume and higher incidence of adverse reactions especially DSTR, were recommended a strictly limited transfusion schedule and Rh phenotype matching RBC products. The investigation of immune status of MDS patients at different periods is helpful to provide new aspects and therapeutic measures for the pathogenesis of DSTR, and the antibody screening time may adjusted appropriately.

Sarcopenia is an age-related disease that mainly involves decreases in muscle mass, muscle strength and muscle function. At the same time, the body fat content increases with aging, especially the visceral fat content. Adipose tissue is an endocrine organ that secretes biologically active factors called adipokines, which act on local and distant tissues. Studies have revealed that some adipokines exert regulatory effects on muscle, such as higher serum leptin levels causing a decrease in muscle function and adiponectin inhibits the transcriptional activity of Forkhead box O3 (FoxO3) by activating peroxisome proliferators-activated receptor-γ coactivator -1α (PGC-1α) and sensitizing cells to insulin, thereby repressing atrophy-related genes (atrogin-1 and muscle RING finger 1 [MuRF1]) to prevent the loss of muscle mass. Here, we describe the effects on muscle of adipokines produced by adipose tissue, such as leptin, adiponectin, resistin, mucin and lipocalin-2, and discuss the importance of these adipokines for understanding the development of sarcopenia.
Humans ; Adipokines ; Leptin ; Adiponectin ; Sarcopenia ; Muscles

OBJECTIVE To reveal the role of the basal forebrain(BF)GABAergic neurons in the regulation of isoflurane anesthesia and to elucidate the underlying neural pathways.METHODS The activity of BF GABAer-gic neurons was monitored during isoflurane anesthesia using a genetically encoded calcium indicator in Vgat-Cre mice of both sexes.The activity of BF GABAer-gic neurons was manipulated by chemogenetic and opto-genetic approaches.Sensitivity,induction time and emer-gence time of isoflurane anesthesia were estimated by righting reflex.The electroencephalogram(EEG)power and burst-suppression were monitored by EEG recording.The effects of activation of GABAergic BF-thalamic reticu-lar nucleus(TRN)pathway on isoflurane anesthesia were investigated with optogenetics.RESULTS The activity of BF GABAergic neurons was generally inhibited during isoflurane anesthesia,obviously decreased during the induction of anesthesia and gradually restored during the emergence from anesthesia.Activation of BF GABAergic neurons with chemogenetics and optogenetics promoted behavioral emergence from isoflurane anesthesia,with decreased sensitivity to isoflurane,delayed induction and accelerated emergence from isoflurane anesthesia.Optogenetic activation of BF GABAergic neurons prom-oted cortical activity during isoflurane anesthesia,with decreased EEG delta power and burst suppression ratio during 0.8%and 1.4%isoflurane anesthesia,respectively.Similar to the effects of activating BF GABAergic cell bod-ies,photostimulation of BF GABAergic terminals in the TRN also strongly promoted cortical activation and behav-ioral emergence from isoflurane anesthesia.CONCLU-SION The GABAergic neurons in the BF is a key neural substrate for general anesthesia regulation that facilitates behavioral and cortical emergence from general anesthe-sia via the BF-TRN pathway.

Objective: To explore the effect of vaccination on viral negative conversion of children with COVID-19. Methods: A retrospective cohort study was conducted. A cohort of 189 children aged 3-14 years with COVID-19 admitted to Renji Hospital (South branch) of Shanghai Jiao Tong University School of Medicine from April 7^th to May 19^th 2022 was enrolled in the study. According to the vaccination status, the infected children were divided into an unvaccinated group and a vaccinated group. Age, gender, severity, clinical manifestations, and laboratory tests, etc. were compared between groups, by rank sum test or chi-square test. The effects of vaccination on viral negative conversion were analyzed by a Cox mixed-effects regression model. Additionally, a questionnaire survey was conducted among the parents of unvaccinated children to analyze the reasons for not being vaccinated. Results: A total of 189 children aged 3-14 years were enrolled, including 95 males (50.3%) and 94 females (49.7%), aged 5.7 (4.1,8.6) years. There were 117 cases (61.9%) in the unvaccinated group and 72 cases (38.1%) in the vaccinated group. The age of the vaccinated group was higher than that of the unvaccinated group (8.8 (6.8, 10.6) vs. 4.5 (3.6, 5.9) years, Z=9.45, P<0.001). No significant differences were found in clinical manifestations, disease severity, and laboratory results between groups (all P>0.05), except for the occurrence rate of cough symptoms, which was significantly higher in the vaccinated group than in the non-vaccinated group (68.1% (49/72) vs. 50.4% (59/117),χ²=5.67, P=0.017). The Kaplan-Meier survival curve and Cox mixed-effects regression model showed that the time to the viral negative conversion was significantly shorter in the vaccinated group compared with the unvaccinated group (8 (7, 10) vs. 11 (9, 12) d, Z=5.20, P<0.001; adjusted HR=2.19 (95%CI 1.62-2.97)). For questionnaire survey on the reasons for not receiving a vaccination, 115 questionnaires were distributed and 112 valid questionnaires (97.4%) were collected. The main reasons for not being vaccinated were that parents thought that their children were not in the range of appropriate age for vaccination (51 cases, 45.5%) and children were in special physical conditions (47 cases, 42.0%). Conclusion: Vaccination can effectively shorten the negative conversion time of children with COVID-19 and targeted programs should be developed to increase eligible children's vaccination rate for SARS-CoV-2 vaccination.
Child ; Female ; Male ; Humans ; COVID-19/prevention & control* ; COVID-19 Vaccines ; Retrospective Studies ; SARS-CoV-2 ; China/epidemiology* ; Vaccines

Humans ; Infant, Newborn ; Intensive Care Units, Neonatal ; Logistic Models ; Phenotype ; Risk Factors

A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-N