Chronic liver diseases with common causes including viral infections， alcohol abuse， and autoimmune diseases. Alkaloids， as a class of plant-derived compounds， have shown significant potential in regulating chronic liver diseases. Recent studies have shown that alkaloids are able to exert a therapeutic effect on chronic liver diseases through multiple pathways. These compounds have a regulatory effect on key pathological processes such as liver fibrosis， inflammatory response， oxidative stress， and cell apoptosis， and they also regulate the metabolic homeostasis of hepatocytes by modulating multiple signaling pathways， thereby playing a role in regulating chronic liver diseases. This article reviews the role and mechanism of alkaloids in the treatment of chronic liver diseases， in order to provide new ideas and directions for the treatment of chronic liver diseases.

BACKGROUND:In recent years,the development of liver organoids has made it a hot spot in the field of international liver disease research,but there is still no article on the bibliometric analysis of liver organoids. OBJECTIVE:To explore the hot trends in liver organoids in the last 20 years based on bibliometrics and visualization analysis. METHODS:We searched the articles about liver organoids in the Web of Science Core Collection from January 1,2002 to November 12,2022.Origin,Office,and CiteSpace software were used for bibliometrics and visualization analysis.We statistically analyzed the number of annually published articles,countries,institutions,authors,journals,and keywords of the articles by generating charts. RESULTS AND CONCLUSION:The number of articles,citation frequency,institutions and personnel involved in the research about liver organoids showed an overall upward trend in the last 20 years,indicating that the field was growing rapidly and attention was increasing.The USA had published the most papers and had the strongest influence in this field.Although it had invested a lot of time and energy,the number of papers published by a single research institution in the USA was not the highest among many research institutions.China was second only to the USA in the number of publications,with the Chinese Academy of Sciences and Fudan University leading the list.Utrecht University in the Netherlands was the institution with the most publications.Clevers H was the author with the highest number of articles.The article with the highest co-citation frequency was"Long-term culture of genome-stable bipotent stem cells from adult human liver".The main fields of study for liver organoids were Molecular Science,Biology,and Immunology.The most frequently occurring keywords were stem cell,in vitro,and culture.The research hotspots in the liver organoids field were mainly focused on in vitro stem cell three-dimensional culture,differentiation and gene expression.

A 11-year old female patient with severe thalassemia, receipt a lentivirus-based cell and gene therapy (CGT) therapy in Shenzhen Children′s Hosptial on July 27th, 2021. At the two follow-up visits after discharge, patient were continuously tested positive for HIV screening through HIV Ag/Ab Combo assay (chemiluminescence Immunoassay), and the viral load results of HIV-1 nucleic acid testing (NAT) were both>5 000 copies/ml. The patient can be diagnosed with HIV infection according to the National Guideline for Detection of HIV/AIDS(2020 Revised Edition). The thorough investigation findings and supplementary experiment results indicated that the false-positive HIV-1 NAT results was caused by cross-reactivity between the target sites detected by conventional HIV-1 NAT reagents and the lentiviral vectors fragments integrated into the genome of patient′s hematopoietic stem/progenitor cells. In conclusion, it is important for laboratories to select appropriate HIV-1 NAT testing platforms which won′t cause cross-reactivity for the testing of samples from patients who have been treated with HIV-derived vectors. It is also recommended to design and develop NAT testing platforms with multiple target regions labeled by different fluorescents for HIV NAT supplementation experiment to reduce the risk of false-positive diagnoses of HIV infection.

Chronic liver disease(CLD)tends to have a high incidence rate and impose a serious burden on society and families.Studies have shown that metal ion metabolism is closely associated with CLD,and some Chinese herbal medicines can play a role in the prevention and treatment of CLD by regulating metal ion metabolism.At present,the synthetic drugs currently used for the treatment of CLD fail to achieve a satisfactory effect,and therefore,a variety of Chinese herbal medicines are being used as supplementary and alternative therapies for CLD.This article introduces the role of metal ion metabolism in CLD and the regulatory effect of Chinese herbal medicines and their active components on CLD,and the analysis shows that metal ion metabolism is expected to provide new ideas for the research on CLD and a theoretical basis for the clinical treatment of CLD.For the role of metal ion metabolism in the treatment of CLD,more prospective clinical study data are needed in the future to provide effective and safe treatment regimens for patients with CLD.

Objective To study the effect and mechanism of pearl hydrolysate on hepatic sinusoidal capillarization in liver fibrosis. Methods Hepatic sinusoidal endothelial cells (HSEC) and hepatic stellate cells (HSC-LX2) were incubated with Hepu pearl hydrolysate.The proliferation of HSEC and HSC-LX2 was examined by MTT colorimetry.The cell cycle and apoptosis of HSC-LX2 were measured by flow cytometry.The changes of the microstructures such as fenestra and basement membrane of HSEC were observed by transmission electron microscopy. Results The intervention with leptin increased the viability of HSC-LX2 (P=0.041),decreased the viability of HSEC (P=0.004),and caused capillarization signs such as decreased number and diameter of fenestrae and formation of continuous basement membrane.The treatment with pearl hydrolysate at different doses increased and expanded the fenestrae of HSEC (low dose:P=0.020;medium dose:P=0.028;high dose:P=0.032),disintegrated the extracellular basement membrane of HSEC (low dose:P=0.020;medium dose:P=0.028;high dose:P=0.032),decreased the viability of HSC-LX2 (low dose:P=0.018;medium dose:P=0.013;high dose:P=0.009),and induced the apoptosis of HSC-LX2 (low dose:P=0.012;medium dose:P=0.006;high dose:P=0.005).Pearl hydrolysate exerted therapeutic effect on capillarization in a dose-dependent manner (low dose:P=0.020;medium dose:P=0.028;high dose:P=0.032).Moreover,high-dose pearl hydrolysate showed stronger effect on capillarization of hepatic sinuses than colchicine (P=0.034) and salvianolic acid B (P=0.038). Conclusion Hepu pearl hydrolysate can increase the viability of HSEC,restore the area of fenestrae,disintegrate the basement membrane,and decrease the viability and induce the apoptosis of HSC-LX2,demonstrating significant pharmacological effects on the capillarization of HSEC and HSC-LX2.
Humans ; Endothelial Cells/metabolism* ; Liver Cirrhosis ; Liver/pathology*

Objective To investigate the role of miR-125b on hepatic angiogenesis,with the hope of providing new targets for the prevention and treatment of liver fibrosis.Methods The human hepatic sinusoidal endothelial cells were transfected with miR-125b mimics and inhibitors,and the mRNA and protein expression of vascular endotheli-al growth factor(VEGF),cluster of differentiation antigens 31(CD31),von Willebrand factor(vWF),collagenⅣ,and laminin(LN)were detected by qRT-PCR and ELISA,and the expression of nitric oxide(NO)was detec-ted by fluorescent probe,scanning electron microscopy detected the alteration of the window holes on the surface of human hepatic sinusoidal endothelial cells,angiogenesis assay was performed to observe the neovascularization of each group,and dual luciferase reporter gene assay was performed to validate the targeting relationship between miR-125b and VEGF.Results qRT-PCR and ELISA showed that compared with the negative control group,the mRNA and protein expressions of VEGF,CD31,vWF,Collagen Ⅳ,and LN significantly decreased after miR-125b mimic transfection(P＜0.05),while the mRNA and protein expressions of VEGF,CD31,vWF,CollagenⅣ,and LN were significantly increased after transfection with miR-125 b mimics(P＜0.05);fluorescent probe detection showed that compared with the negative control group,the average fluorescence of intensity expression NO decreased significantly(P＜0.05),while the average fluorescence intensity expression of NO increased significant-ly after miR-125b inhibitor transfection(P＜0.05);the number of fenestrations on the surface of human liver sinu-soidal endothelial cells significantly increased after miR-125b mimic transfection(P＜0.05),while the number of fenestrations on the surface of human liver sinusoidal endothelial cells decreased significantly after miR-125 b inhibi-tor transfection(P＜0.05);angiogenesis assay showed that compared with the negative control group,the number of angiogenesis significantly decreased after miR-125b mimic transfection(P＜0.05),while the number of angio-genesis significantly increased after miR-125b inhibitor transfection(P＜0.05);dual luciferase reporter gene assay showed that compared with negative control group,the expression of relative fluorescence intensity after transfection of miR-125b mimics in VEGF wild-typ significantly decreased(P＜0.05),while the expression of relative fluores-cence intensity after transfection of miR-125b mimics in VEGF mutant significantly decreased(P＞0.05).Con-clusion miR-125b can inhibit liver angiogenesis and thus play an anti-fibrosis role,which can provide a new ref-erence for the prevention and treatment of chronic liver disease and the development of new drugs.

The causes for male sexual orientation are complicated, which have not yet been clarified. Recent years have witnessed fruitful progress in the field of biology, while the impact of environment has received little attention. Adverse childhood experiences (ACEs), identified as a special environment in the early stage of development, can affect the individual phenotype by DNA methylation. Given the relationships among male sexual orientation, ACEs, and DNA methylation, as well as based on the existing theory, this article proposes the model "ACEs-DNA methylation-male sexual orientation"from the perspective of environment and epigenetics, aiming to provide a theoretical basis for future research.
Adverse Childhood Experiences ; Child ; DNA Methylation ; Female ; Humans ; Male ; Sexual Behavior

ObjectiveTo investigate the molecular mechanism of the anti-liver fibrosis effect of curcumol by observing the effect of curcumol on the TLR4/NF-κB signaling pathway in liver sinusoidal endothelial cells. MethodsA total of 50 mice were randomly divided into blank group, model group, and curcumol group, and cells were divided into blank control group, LPS positive control group, curcumol intervention group, and PDTC group. HE staining and Masson staining were used to observe the change in liver structure; Western blot and quantitative real-time PCR (RT-PCR) were used to measure the protein and mRNA expression of the key molecules TLR4 and NF-κB in the TLR4/NF-κB signaling pathway; immunofluorescence assay was used to observe the expression and nuclear import of NF-κB in cells. A one-way analysis of variance was used for comparison between multiple 　groups, and the least　significant difference t-test was used for further comparison between two groups.　ResultsRT-PCR showed that compared with the positive control group, the curcumol intervention group had significant reductions in the mRNA expression of TLR4 and NF-κB (both P＜0.05). Western blot showed that compared with the positive control group, the curcumol intervention group had significant reductions in the expression of TLR4 and NF-κB (both P＜005). Immunofluorescence assay showed that compared with the positive control group, the curcumol intervention group had significant improvement in NF-κB nuclear import. ConclusionCurcumol can exert an anti-liver fibrosis effect possibly by inhibiting the activity of the TLR4/NF-κB signaling pathway.

Objective To investigate the associations between CYP2A6 polymorphisms and treatment outcomes of adjuvant S-1 in postoperative gastric cancer patients.Methods 188 patients after D2 radical resection received S-1 based adjuvant chemotherapy.PBMC cell specimen were collected for the genotyping of genetic variation and CYP2A6 gene mRNA expression.Univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis,and multivariate analysis were adjusted by COX regression analysis.Results The polymorphisms included in this study were collected in the NCBI database with the minor allele frequency ＞ 10％ in Chinese population (rs8192725,rs8192720 and rs28399433),with rs8192725 only of clinical significance.The prevalence of rs8192725 in CYP2A6 were CC genotype 131 cases (69.7％),CT genotype 51 cases (27.1％),TT genotype 6 cases (3.2％),minor allele frequency of rs8192725 was 0.17.The 3 year disease-free survival (DFS) rate in patients with CT/TT genotype and CC genotype were 61.5％ and 72.5％,respectively (x2 =8.233,P =0.004).The 3 year overall survival rate of the two genotypes were 73.7％ and 79.4％ (x2 =4.863,P =0.021).CT/TT genotypes were an independent factor for DFS (OR =1.81,P =0.012).The expression of CYP2A6 in PBMC of the patients with CT/TT genotypes were significantly lower than those of the CC genotype patients (P ＜ 0.001).Conclusions After D2 gastric cancer patients treated by S-1,the polymorphism rs8192725 of CYP2A6 may effect the clinical outcomes of adjuvant chemotherapy S-1 treatment through influencing the mRNA expression of CYP2A6.

Objective:To investigate the association between grade 3 hand-foot syndrome(HFS)in colorectal cancer(CRC)patients treated with capecitabine and variation of cytidine deaminase(CDA)genes.Methods:The polymorphisms of the key gene CDA in-volved in capecitabine metabolism were genotyped and 149 CRC patients were included in this study.The association between these polymorphisms and susceptibility to HFS were analyzed.Additionally,peripheral blood mononuclear cells(PBMCs)of 91 CRC patients were collected for mRNA expression analysis, and the levels of mRNA expression according to different CDA genotypes were com-pared.Results:The prevalence of the polymorphism-451G>A,which is located in the promoter region of CDA,were correlated with HFS. The results were as follows: GG genotype, 109 cases (73.15%); GA genotype, 38 cases (25.50%); and AA genotype, 2 cases (1.36%).The minor allele frequency of-451G>A was 0.14.The distribution of the three genotypes were in accordance with Hardy-Weinberg Equilibrium(P=0.516).Logistic analysis indicated that GA/AA genotypes were associated with grade 3 HFS(odds ratio=2.53, P=0.011).Additionally,another insert polymorphism-33delC located in the promoter region of CDA was in linkage disequilibrium with-451G>A (D'=0.92). Of the 91 PBMC mRNA expression analyses, the GA/AA genotype of-451G>A was associated with higher CDA mRNA expression compared with GG genotypes(4.01±0.53 vs.3.13±0.61,P<0.001).Conclusions:The polymorphism-451G>A of CDA may influence occurance of grade 3 HFS induced by capecitabine by influencing CDA mRNA expression.