Advanced Science
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2024
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IF 14.3
Jiabin Zhang,Xiaodie Chen,Yurong Chai,Chenya Zhuo,Yanteng Xu,Tiantian Xue,Dan Shao,Yu Tao,Mingqiang Li
The emerging stem cell-derived hepatocyte-like cells (HLCs) are the alternative cell sources of hepatocytes for treatment of highly lethal acute liver failure (ALF). However, the hostile local environment and the immature cell differentiation may compromise their therapeutic efficacy. To this end, human adipose-derived mesenchymal stromal/stem cells (hASCs) are engineered into different-sized multicellular spheroids and co-cultured with 3D coaxially and hexagonally patterned human umbilical vein endothelial cells (HUVECs) in a liver lobule-like manner to enhance their hepatic differentiation efficiency. It is found that small-sized hASC spheroids, with a diameter of ≈50 µm, show superior pro-angiogenic effects and hepatic differentiation compared to the other counterparts. The size-dependent functional enhancements are mediated by the Wnt signaling pathway. Meanwhile, co-culture of hASCs with HUVECs, at a HUVECs/hASCs seeding density ratio of 2:1, distinctly promotes hepatic differentiation and vascularization both in vitro and in vivo, especially when endothelial cells are patterned into hollow hexagons. After subcutaneous implantation, the mini-liver, consisting of HLC spheroids and 3D-printed interconnected vasculatures, can effectively improve liver regeneration in two ALF animal models through amelioration of local oxidative stress and inflammation, reduction of liver necrosis, as well as increase of cell proliferation, thereby showing great promise for clinical translation.
研究领域:
组织工程
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再生医学
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干细胞生物学
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肝病
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生物打印
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产品关联
DOI
PubMed
高影响因子
Cancer Cell International
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2022
·Vol. 22
·期 1
·1-18
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IF 6.429
Wang Shunxi,Chen Long,Liu Wanqian
Background Ferroptosis have been implicated in tumorigenesis, tumor progression, and chemo- and immuno-therapy in cirrhotic hepatocellular carcinoma (HCC), indicating its association with matrix stiffness and clinical benefit of targeting drugs or immune checkpoint inhibitor. Here, we postulated that increased matrix stiffness reduces ferroptosis and impairs tumor immunity by regulating the expression of ferroptosis- and immune-related genes in HCC, which might be a robust predictor of therapeutic efficacy. Methods Using publicly available tissue microarray datasets, liver cancer rat model, and clinical specimen, ferroptosis-related differential genes in HCV-infected cirrhotic HCC and its mechanical heterogeneous pattern of expression were screened and identified. Further investigation on the underlying mechanism of matrix stiffness-regulated ferroptosis and the expression of immune mediator were performed. Finally, threshold analysis of HCC cases with sorafenib treatment revealed the value of clinical applications of these potential predictors. Results STEAP3 was identified as the ferroptosis-related differential genes in HCV-infected cirrhotic HCC. Stiffer matrix decreased STEAP3 in the invasive front area of HCC and the liver cirrhotic tissue. Contrarily, softer matrix induced STEAP3 in the central area of HCC and the normal liver tissue. Immunological correlation of STEAP3 in cirrhotic HCC showed that STEAP3-mediated immune infiltration of CD4+ T and CD8+ T cells, macrophages, neutrophils, and dendritic cells and HCC prognosis, predicting to regulate immune infiltration. Overexpression of STEAP3 induced ferroptosis and inhibited the expression of immune mediator of PD-L2 on a stiff matrix. Especially, the ferroptosis- and immune-related gene predictive biomarker (FIGPB), including STEAP3 and PD-L2, predicts better clinical benefit of sorafenib in HCC patients. Conclusions This finding identifies matrix stiffness impairs ferroptosis and anti-tumor immunity by mediating STEAP3 and PD-L2. More importantly, coordinated with PD-L2, matrix stiffness-dependent STEAP3 could be applied as the independent predictors to favorable sorafenib response, and thus targeting it could be a potential diagnosis and treatment strategy for HCC.
研究领域:
肿瘤学
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免疫学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Bioanalysis
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2019
·Vol. 11
·期 10
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IF 2.321
Yu Zhang,Jing Yang,Jiayi Wang,Ling Chen,Huiming Huang,Yuanzhen Xiong,Baogang Xie
Aim: In order to differential diagnosis of chronic hepatitis B (HBV-I) and hepatocellular carcinoma (HCC), a UPLC–MS/MS method for measuring purine metabolites was developed. Methodology & results: serum samples from 26 HBV-I and 35 HCC patients were collected. Ten purine metabolites were simultaneously quantified by UPLC–MS/MS with tubercidin and uric acid-1,3-15N2 as internal standards. The method was validated to meet the requirements of clinical sample analysis. A logistic equation was established for differential diagnosis of HBV-I and HCC by combination of xanthosine and guanine with the area under the receiver operating characteristic curve of 0.885. Conclusion: Guanine and xanthosine are intermediates in the metabolism of purine, which play an important role in gene synthesis, and metabolism regulation. The alteration of serum purine metabolite may contribute to differential diagnosis of HBV-I and HCC.
研究领域:
医学
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生物化学
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DOI
PubMed
高影响因子
Small Methods
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2025
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IF 9.1
Xinlong Liu,Yimeng Li,Xinhua Liu,Yangyang Huang,Fujun Wang,Jiafeng Li,Yuqi Guo,Xinyuan Zhu,Lijuan Zhu,Chuan Zhang
Plasmids are widely used gene vectors in gene therapy, yet their efficient delivery remains a major challenge for achieving optimal therapeutic outcomes. Recently, poly(β-amino esters) (PBAEs) have emerged as promising carriers for non-viral gene delivery due to their tunable structures and high delivery efficiency. Nonetheless, the cationic nature of PBAEs raises toxicity concerns, and their lack of tissue-specific targeting capability limits their clinical application. Herein, a novel PBAE for efficient plasmid delivery is constructed, which contains disulfide bonds in the backbone and N-acetylgalactosamine (GalNAc) moieties at the terminals (GalNAc-PBAEs). To address the potential reduction in nucleic acid condensing capacity caused by end-capping PBAE with GalNAc, the commonly used end-capping amines in conventional PBAE are employed as monomers to create GalNAc-PBAEs with tertiary amine side chains. Through side-chain screening, the optimized GalNAc-PBAE exhibits enhanced transfection efficiency, surpassing that of the conventional top-performing PBAE, C28-E7, and rivaling the commercial transfection reagent Lipo2000. Importantly, the GalNAc moieties enable the plasmid-PBAE polyplex to efficiently target the liver. In a mouse model with acute liver fibrosis, the efficient delivery and expression of a representative plasmid encoding HGF significantly mitigate liver fibrosis and improve liver function, demonstrating the potential of the designed PBAE in gene therapy.
研究领域:
生物医学工程
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基因治疗
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Xiaofeng Liu,Yong Zhao,Chenyue Liu,Chunying Li,Yan Yi,Suyan Liu,Xuan Tang,Chen Pan,Yushi Zhang,Jingzhuo Tian,Jiayin Han,Xingnan Yue,Aihua Liang
Ethnopharmacological relevance Psoraleae Fructus (PF), the dried mature fruit of the leguminous plant Psoralea corylifolia L., is often used as a nutraceutical and to treat ulcerative colitis (UC). However, recently there have been reports of PF-induced liver injury. Aim of the study To investigate the difference and mechanism of hepatotoxicity between normal and UC rats oral administration with PF, and clarify the relationship between PF risk and disease status. Materials and Methods PF water extracts (at the human equivalent dosage and 8-fold greater; 0.7 and 5.6 g/kg/day, respectively) were given to normal and UC rats for 4 weeks, and the general behaviors and colonic mucosal conditions were observed. The liver injury and its mechanism were studied by blood biochemistry, coagulation time, liver hematoxylin and eosin (H&E) staining, bile acids (BAs) metabolism, transcriptome analysis, quantitative real-time polymerase chain reaction (qRT‒PCR) and western blot (WB)experiments. Results Normal rats receiving 5.6 g/kg PF water extract showed significantly increased serum levels of total bilirubin (TBIL) and total bile acids (TBA), significantly prolonged activated partial thromboplastin time (APTT), prothrombin time (PT) and thromboplastin time (TT), and slightly swollen hepatocytes, and obvious hepatobiliary hyperplasia. These liver injuries may be related to disordered BAs metabolism: the levels of farnesoid x receptor (FXR) and sulfotransferase family 2A member 1/2 (SULT2a1/a2) were down-regulated, whereas the levels of microsomal epoxide hydrolase (mEH), organic anion transporting polypeptide (OATP) and multidrug resistance-associated protein 3 (MRP3) were up-regulated, leading to liver and blood UnconBA and GlycineBA accumulation. However, at the same dose, UC model rats exhibited no obvious liver damage. Conclusion Normal rats, but not UC rats, displayed signs of liver injury in response to 5.6 g/kg PF water extract administration. Therefore, we recommend that healthy individuals should be aware of the potential risks associated with PF, and other patients should take PF according to their physician’s guidance.
研究领域:
药理学
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分子生物学
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中医药学
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DOI
PubMed
高影响因子
JOURNAL OF BIOMATERIALS APPLICATIONS
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2024
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IF 2.3
Qingxia Guan,Yumeng Liu,Zhaorui Xia,Yue Zhang,Liping Wang,Yanhong Wang,Shujun Zou,Shaowa Lv,Xiaoying Zhou
Background: Glycyrrhetinic acid-mediated brucine self-assembled nanomicelles enhance the anti-hepatitis B properties of brucine by improving its water solubility, short half-life, toxicity, and side effects. Brucine (B) is an indole alkaloid extracted from the seeds of Strychnos nux-vomica (Loganiaceae). Purpose: To assess the efficacy of the Brucine-Glycyrrhetnic acid-Polyethylene glycol-3,3’-dithiodipropionic acid-Glycerin monostearate (B-GPSG) in treating hepatitis B, its potential to protect against acute liver injury caused by d-galactosamine and its anti-hepatoma activities were studied. Research Design: The concentration of B-GPSG used in the in vivo and in vitro experiments was 0.63 mg/mL. The rats injected with d-GalN (450 mg/kg) were used as liver injury models. The rats were separated into normal, model, positive, positive control, B-PSG and B-GPSG groups. Hepatoma cells expressing HBV HepG2.2.15 were used for in vitro experiments. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, plate cloning, Hoechst staining and flow cytometry were conducted to explore the mechanism of B-GPSG against hepatitis B. Results: Compared with the model group, the liver coefficient of B-GPSG group decreased (4.59 ± 0.17 vs 5.88 ± 0.42), the content of MDA in rat liver homogenate decreased (12.54 ± 1.81 vs 23.05 ± 2.98), the activity of SOD increased, the activity of ALT and AST in rat serum decreased. In vitro, the IC50 values of B-GPSG group decreased. B-GPSG group effectively inhibited the proliferation and migration of HepG2.2.15 cells. Conclusions: The hepatoprotective effects of B-GPSG nanomicelles, which are attributed to their GA-mediated liver targeting and synergistic actions with brucine, suggest their therapeutic potential against hepatitis B. This development opens up new possibilities for the application of traditional Chinese medicine and nanomedicine in anti-hepatitis B.
研究领域:
药理学
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纳米医学
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病毒学
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
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2019
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IF 6.044
Juan-Juan Cao,Qing-Qing Lv,Bao Zhang,Han-Qing Chen
Two polysaccharide fractions (TSP-1 and TSP-2) with molecular weights of 833.6 kDa and 81.6 kDa were isolated from Toona sinensis leaves (Meliaceae) by hot water extraction, DEAE Cellulose-52 chromatography and Sephacryl S-400 gel permeation chromatography. Structural analysis indicated that TSP-1 and TSP-2 consisted of Man p , Glc p A, Glc p , Gal p , Xyl p and Ara f with different molar ratios. Methylation and NMR analysis revealed that the backbone of TSP-1 might consist of 1,6-linked-Glc p , 1,3,6-linked-Man p and 1,6-linked-Gal p , while TSP-2 was mainly composed of 1,3,5-linked-Ara f , 1,6-linked-Glc p , 1,4-linked-Xyl p and 1,6-linked-Gal p . Congo red assay indicated that TSP-1 and TSP-2 had no triple-helix structure, which was consistent with the results of AFM. In vivo hepatoprotective activity showed that TSP-1 and TSP-2 could improve CCl 4 -induced mice liver injury by reducing the activities of AST, ALT and the level of MDA, increasing the activities of SOD, GSH-Px, and CAT and the level of GSH in liver and decreasing the expression levels of TNF-α and IL-6 in liver. These results suggest that TSP-1 and TSP-2 have promising potential to serve as hepatoprotective agents.
研究领域:
药理学
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生物化学
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植物科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2023
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IF 8
Xianchuang Liu,Xinyang Zhu,Xun Qi,Xianwei Meng,Ke Xu
Purpose Hepatocellular carcinoma (HCC) is one of the most common fatal cancers, with no curative therapy available. The concept of ferroptosis is attracting increasing attention in cancer research. Herein, we describe the use of a nanodevice as an effective strategy for inducing ferroptosis to manage HCC.Methods To improve ferroptosis-induced treatment of HCC, we constructed sorafenib (sor)-loaded MIL-101(Fe) nanoparticles (NPs) [MIL-101(Fe)@sor] and evaluated the efficacy of ferroptosis-based HCC therapy after co-administration with the iRGD peptide both in vitro and in vivo.Results The prepared MIL-101(Fe) NPs have several promising characteristics including drug-loading, controllable release, peroxidase activity, biocompatibility, and T2 magnetic resonance imaging ability. MIL-101(Fe)@sor NPs significantly induced ferroptosis in HepG2 cells, increased the levels of lipid peroxidation and malondialdehyde, and reduced those of glutathione and glutathione peroxidase 4 (GPX-4). The in vivo results showed that the MIL-101(Fe)@sor NPs significantly inhibited tumor progression and decreased GPX-4 expression levels, with negligible long-term toxicity. Meanwhile, co-administration of MIL-101(Fe)@sor NPs with iRGD significantly accelerated ferroptosis.Conclusion Our findings suggest that MIL-101(Fe)@sor NPs co-administered with iRGD are a promising strategy for inducing HCC ferroptosis.
研究领域:
肿瘤学
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药理学
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纳米医学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
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2016
·
IF 4.758
Dan Yan,Yu He,Yili Ge,Gongwu Song
A novel fluorescence “turn on-off” method for sensitive and selective detection of heparin and heparinase I was developed based on near infrared Polyethyleneimine Capped Ag 2 S Quantum Dots (PEI-Ag 2 S QDs). The fluorescence “turn-on” arose from aggregation-induced emission enhancement (AIEE) characteristics of PEI-Ag 2 SQDs induced by electrostatic interaction between PEI-Ag 2 SQDs and heparin. Heparinase I, which can specifically hydrolyze heparin into short fragments would de-aggregate PEI-Ag 2 S QDs/heparin system and lead to fluorescence “turn-off”. Under optimal conditions described, the fluorescence enhancement at 685 nm was linearly related to the concentration of heparin and heparinase I in the range of 0.069–2.275 μM and 0–103 ng mL −1 with the relative correlation coefficient of R 2 = 0.997 and 0.99 and detection limit as low as 6 nM and 0.5 ng mL −1 , respectively. The activity of the heparinase I was further investigated using steady-state kinetic for the reaction. In ddition, the proposed method was successfully utilized in serum samples, which presaged more opportunities for application in related biochemical and biomedical researches.
研究领域:
生物化学
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医学检测
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纳米技术
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产品关联
DOI
高影响因子
Nutrients
·
2022
·Vol. 14
·期 13
·2636
·
IF 6.706
Baichang Xu,Kaiyuan Hao,Xiaogang Chen,Enyun Wu,Dongyang Nie,Geyin Zhang,Hongbin Si
Liver injury caused by an overdose of acetaminophen (APAP) is a major public health problem. This study aimed to evaluate the effects ofBroussonetia papyriferapolysaccharide (BPP) on liver injury and intestinal flora induced by APAP. The results showed that BPP could protect against APAP-induced liver injury, alleviate liver apoptosis, improve antioxidant capacity and enhance the liver’s detoxification ability to APAP. At the same time, BPP improved the intestinal flora disorder caused by APAP. More importantly, we found that the hepatoprotective effect of BPP disappeared after the depletion of gut microbiota in mice. Further, we reconstructed the intestinal flora structure of mice through fecal microbiota transplantation and found that the symptoms of APAP—induced liver injury were effectively alleviated. Overall, BPP was a potential hepatoprotective drug that could protect against APAP-induced liver injury and might be mediated by intestinal flora.Keywords:Broussonetia papyriferapolysaccharide;liver injury;intestinal flora
研究领域:
药理学
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肝病学
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微生物学
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产品关联
DOI
PubMed
高影响因子
METABOLISM-CLINICAL AND EXPERIMENTAL
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2024
·
IF 10.8
Xu Zhang,Tianxing Chen,Zhenhan Li,Lingfeng Wan,Zhihang Zhou,Ying Xu,Dong Yan,Wei Zhao,Hao Chen
Background & aims Abnormal expression of long noncoding RNAs is strongly linked to metabolic dysfunction-associated steatotic liver disease (MASLD). However, the precise molecular mechanisms remain unclear. This study explores the roles of noncoding RNA activated by DNA damage (NORAD)/miR-511-3p/Rho-associated protein kinase 2 ( Rock2 ) axis and the NORAD/ROCK2 interaction in the development of MASLD. Methods In vitro and in vivo models of MASLD were created using high-fat diet-fed mice and free fatty acid (FFA)-treated hepatocytes. To examine the relationships between NORAD, miR-511-3p, and ROCK2, we employed bioinformatics, luciferase assays, RNA immunoprecipitation, and biotinylated NORAD pull-down assays. MASLD progression was assessed based on food intake, energy expenditure, insulin resistance, hepatic steatosis, inflammation, white fat growth, and liver fibrosis. Results NORAD and ROCK2 were upregulated, while miR-511-3p was downregulated in MASLD liver tissues and FFA-treated hepatocytes. Mechanistically, NORAD competitively interacted with miR-511-3p to modulate Rock2 mRNA expression, and directly stabilized ROCK2 protein by abrogating its ubiquitination degradation. Functionally, liver-specific knockdown of NORAD or overexpression of miR-511-3p significantly slowed MASLD progression. Overexpression of NORAD or ROCK2 partially reversed miR-511-3p-induced inhibition of MASLD. Additionally, ROCK2 knockdown attenuated NORAD-induced worsening of MASLD. Moreover, overexpressing NORAD or ROCK2 or interfering miR-511-3p influenced resmetirom treatment to suppress MASLD development. Finally, metabolic changes in liver driven by the NORAD/miR-511-3p/ Rock2 axis and NORAD/ROCK2 interaction also influenced white adipose growth, pancreatic β-cell dedifferentiation, and liver fibrosis. Conclusions The NORAD/miR-511-3p/ Rock2 axis and the NORAD/ROCK2 interaction play critical roles in MASLD progression, identifying potential therapeutic targets for its treatment.
研究领域:
分子生物学
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肝脏病学
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代谢研究
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非编码RNA研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ANIMAL SCIENCE
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2024
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IF 2.7
Liu Jie,Zhang Ke,Zhao Mindie,Chen Liang,Chen Huimin,Zhao Yulan,Zhao Ruqian
The aim of this study was to investigate the alleviating effects and mechanisms of bile acids (BA) on corticosterone-induced fatty liver in broiler chickens. Male Arbor Acres chickens were randomly divided into three groups: control group (CON), stress model group (CORT), and BA-treated group (CORT-BA). The CORT-BA group received a diet with 250 mg/kg BA from 21 days of age. From day 36 to 43, both the CORT and CORT-BA groups received subcutaneous injections of corticosterone to simulate chronic stress. The results indicated that BA significantly mitigated the body weight loss, liver enlargement, and hepatic lipid deposition caused by corticosterone (P < 0.05). Liver RNA-seq analysis showed that BA alleviated corticosterone-induced fatty liver by inhibiting lipid metabolism pathways, including fatty acid biosynthesis, triglyceride biosynthesis, and fatty acid transport. Additionally, BA improved corticosterone-induced downregulation of glucocorticoid receptor (GR) expression (P < 0.05). Molecular docking and cellular thermal shift assays revealed that hyodeoxycholic acid (HDCA), a major component of compound bile acids, could bind to GR and enhance its stability. In conclusion, BA alleviated corticosterone-induced fatty liver in broilers by inhibiting lipid synthesis pathways and mitigating the suppression of hepatic GR expression.
研究领域:
动物科学
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分子生物学
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营养学
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产品关联
DOI
PubMed
高影响因子
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