NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2025
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IF 3.1
Li Yue,Li Hailan,Sun Minhui,Chen Hong,Xiao Yao,Wang Jieman,Zhang Yuanyuan,Fang Shuhua,Kou Junping
Silibinin (Sil) is a major bioactive component of silymarin, extracted from the fruit and seeds of Silybum marianum . Silibinin meglumine (SM) is a water-soluble derivative of silibinin that has shown significant potential in liver fibrosis. However, the potential effects and underlying mechanisms of SM on acute liver failure (ALF) are still not fully understood. This study aims to find the likely mechanism. An ALF mouse model and a cell model were established with GalN/LPS. SM was administered to mice via the tail vein or to a hepatocyte line (alpha mouse liver 12, AML12). The results showed that SM particularly lowered the mortality and improved liver pathological lesions in ALF mice. Meanwhile, SM improved the levels of GSH, SOD, TNF-α, IL-6, IL-1β, and IL-10 in the liver tissues and serum. Additionally, SM enhanced cell viability and reduced oxidative stress in vitro. In the AKT/GSK3β/Nrf2/GPX4 pathway, the subpathway of AKT/GSK3β was inhibited, and the subpathway of Nrf2/GPX4 was activated by SM both in vivo and in vitro. In addition, ferrostatin-1, a ferroptosis inhibitor, and the silencing of AKT using siRNA weakened the protective effect of SM, indicating that this process is mediated in an AKT-dependent manner. All the results suggested that SM inhibits inflammation and oxidative stress by modulating the AKT/GSK3β/Nrf2/GPX4 pathway.
研究领域:
药理学
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肝脏病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Yamin Liu,Ze-Kun Wang,Chuan-Zhi Liu,Yue-Yang Liu,Qian Li,Hui Wang,Fengchao Cui,Dan-Wei Zhang,Zhan-Ting Li
Excess bilirubin accumulates in the bodies of patients suffering from acute liver failure (ALF) to cause much irreversible damage and bring about serious clinical symptoms such as kernicterus, hepatic coma, or even death. Hemoperfusion is a widely used method for removing bilirubin from the blood, but clinically used adsorbents have unsatisfactory adsorption capacity and kinetics. In this study, we prepared four supramolecular organic framework microcrystals SOF-1–4 via slow evaporation of their aqueous solutions under infrared light. SOF-1–4 possess good regularity and excellent stability. We demonstrate that all the four SOFs could serve as adsorbents for bilirubin with fast adsorption kinetics within 20 min and ultrahigh adsorption capacity of 609.1 mg g–1, driven by electrostatic interaction and hydrophobicity. The superior adsorption performance of the SOFs outperformed most of the reported bilirubin adsorbents. Remarkably, SOF-3 could remove about 90% of bilirubin in the presence of 40 g L–1 BSA with a minimal loss of albumin and was thus further processed to a bead-shaped composite with a diameter of 2 mm with poly(ether sulfone) (PES). This PES-loaded SOF could efficiently adsorb bilirubin to the normal level from human plasma with an adsorption equilibrium concentration of 7.8 mg L–1 in 6 h through a dynamic hemoperfusion process. This work provides a new vitality for the development of novel bilirubin adsorbents for hemoperfusion therapy.
研究领域:
医学
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材料科学
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生物化学
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DOI
PubMed
高影响因子
Hepatology Communications
·
2023
·Vol. 7
·期 10
·e0257
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IF 5.1
Tang Shima,Zhang Junlei,Zhang Lingjian,Zhao Yalei,Xiao Lanlan,Zhang Fen,Li Qian,Yang Ya,Liu Qiuhong,Xu Jinxian,Li Lanjuan
Background: Acute-on-chronic liver failure (ACLF) is an acute decompensated syndrome based on chronic liver disease, while neutrophil recruitment is the most critical early step. C-X-C motif chemokine ligand 1 (CXCL1), a cytokine that recruits neutrophils, was significantly upregulated in both ACLF mice and patients with ACLF. This present study aims to explore the role of CXCL1 in the pathogenesis of ACLF. Methods: We established an ACLF mouse model induced by carbon tetrachloride, lipopolysaccharide, and D-galactosamine, and used adeno-associated virus to achieve overexpression and knockdown of Cxcl1 . We employed mass cytometry, flow cytometry, multiplex cytokine and chemokine analysis, Western blot, and reactive oxygen species (ROS) detection in mice blood and liver. ACLF patients (n = 10) and healthy controls (n = 5) were included, and their liver samples were stained using multiplex immunohistochemistry techniques. Results: CXCL1 was significantly elevated in both ACLF mice and patients. CXCL1 recruits neutrophils by binding to the C-X-C motif chemokine receptor 2 on the surface of neutrophils, affects ACLF prognosis by generating ROS and mitochondrial depolarization and modulating caspase3-related apoptotic pathways. We found that the knockdown of CXCL1 attenuated the infiltration of neutrophils in the mouse liver, reduced the expression of inflammatory cytokines, and also significantly downregulated ROS production and caspase3-related hepatocyte apoptosis, thereby ameliorating the liver injury of ACLF. Conclusions: CXCL1 is a core player in the mobilization of neutrophils in ACLF, and the knockdown of Cxcl1 improves neutrophil infiltration, reduces ROS levels, and reduces hepatocyte apoptosis, thereby attenuating inflammation and liver injury in ACLF. Our results revealed a previously unknown link between CXCL1-induced neutrophil recruitment and ACLF, providing evidencing for potential therapies targeting ACLF.
研究领域:
肝脏病学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
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IF 12.8
Yuanyuan Jin,Jiabin Zhang,Xiaodie Chen,Fenfang Li,Tiantian Xue,Ke Yi,Yanteng Xu,Haixia Wang,Yeh-Hsing Lao,Hon Fai Chan,Dan Shao,Mingqiang Li,Yu Tao
Acute liver failure (ALF) is a highly fatal disease, necessitating the advancement and optimization of alternative therapeutic strategies to benefit patients awaiting liver transplantation. In this study, we innovatively established the antioxidant nanozyme-hepatocyte-like cells (HLCs) microtissue sheets (HS/N–Au@composite) for ALF therapy. We first prepared a 3D-printed hyaluronic acid/gelatin/sodium alginate scaffold with N-acetylcysteine (NAC)-capped gold nanoclusters (NAC-Au NCs), forming the N–Au@hydrogel. For the encapsulation of HLC spheroids, we used a biocompatible hybrid hydrogel composed of decellularized extracellular matrix (dECM), thrombin, and fibrinogen, resulting in the HS@dECM hydrogel. Utilizing 3D printing technology, we integrated the N–Au@hydrogel with the HS@dECM hydrogel to create the HS/N–Au@composite for in situ transplantation to treat ALF. Our results demonstrated that NAC-Au NCs effectively mitigated reactive oxygen species (ROS)-induced liver necrosis in ALF. Additionally, the N–Au@hydrogel provided mechanical support, ensuring the proper landing and effective functioning of the transplanted HLC spheroids. The HS/N–Au@composite synergistically decreased serum transaminase levels, reduced the accumulation of pro-inflammatory cytokines, accelerated liver function recovery, and promoted liver regeneration in ALF treatment. This combination of HLC spheroids and NAC-Au NCs nanozymes via 3D-printed composite scaffolds represents a promising strategy for enhancing hepatocyte transplantation and advancing stem cell regenerative medicine in ALF therapy.
研究领域:
生物医学工程
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再生医学
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肝脏病学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2020
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IF 4.545
Huiyong Jiang,Ren Yan,Kaicen Wang,Qiangqiang Wang,Xiaoxiao Chen,Lifeng Chen,Lanjuan Li,Longxian Lv
Liver failure is a serious hepatic dysfunction with high mortality. This work aimed to investigate the effect of a famous probiotic and drug, Lactobacillus reuteri DSM 17938, on liver failure in rats. Sprague-Dawley rats were gavaged with 3 × 10 9 CFU of DSM 17938 for 7 days. d -galactosamine was intraperitoneally injected to induce acute liver failure on the eighth day. Samples were collected to determine the liver function, serum cytokines levels, terminal ileum and liver histology, gut microbiota, metabolome and transcriptome. Our results showed that pretreatment with DSM 17938 not only reduced the elevation in serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, IL-1α, IL-2, IL-18, M-CSF, and MIP-3α levels but also alleviated histological abnormalities of both the terminal ileum and liver induced by d -galactosamine. Additionally, DSM 17938 reduced d -galactosamine-induced enrichment of some taxa of gut Actinobacteria or Firmicutes, including abundant pathogens such as Actinomycetales , Coriobacteriaceae , Staphylococcaceae and Enterococcaceae . Furthermore, DSM 17938 reduced the d -galactosamine-induced increase in not only fecal metabolites such as trisaminol and lithocholic acid but also the transcription of liver inflammatory genes, such as Ccl2 , Ccl7 , Ccl11 , Ccl12 , Il6 , Il11 , Il20rb , Mmp3 and Mmp10 . Downregulation of retinol metabolism and PPAR signaling pathway as well as upregulation of viral protein interaction with cytokine and cytokine receptor and central carbon metabolism in cancer signaling pathway were involved in the mechanism of L. reuteri DSM 17938 alleviating liver failure. Our findings suggested that DSM 17938 is a potential probiotic for the prevention or treatment of liver failure.
研究领域:
医学
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微生物学
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肝脏病学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Jing Li,Rui Hu,Xingning Liu,Lanfen Peng,Jinyu Yi,Xin Zhong,Qi Huang,Jialing Sun,Wenxing Feng,Wenfeng Ma,Xiaozhou Zhou
Ethnopharmacological relevance Mitophagy regulates cellular homeostasis and liver inflammation; however, it is inhibited in acute-on-chronic liver failure (ACLF), which drives disease progression. The JianPi LiShi YangGan formula (YGF) has the potential to improve inflammatory responses and reduce mortality in patients with ACLF. However, the precise mechanisms underlying these effects remain unknown. Aim of the study We investigated the role of S100A9/RAGE signaling in mitophagy and the protective effects of traditional Chinese medicinal compounds on ACLF. Materials and methods An ACLF mouse model was established using carbon tetrachloride, lipopolysaccharide, and d-galactose. Hematoxylin and eosin staining and enzyme-linked immunosorbent assay were employed to evaluate the hepatoprotective effect of YGF in ACLF mice. Mitochondrial damage was assessed using transmission electron microscopy. Protein levels of mitophagy-related indicators were assessed through immunohistochemistry and western blotting, and immunofluorescence staining was performed to observe Lamp2 and COX-IV co-localization. Results The hepatocytes of ACLF mice contained damaged mitochondria, decreased mitophagy-related protein (Pink1, Parkin, and LC3B) expression and activated S100A9/RAGE signaling. Inhibiting S100A9 or RAGE improved liver injury in ACLF mice and enhanced Lamp2-COX-IV co-localization. In alpha mouse liver 12 (AML12) cells overexpressing RAGE, recombinant S100A9 protein inhibited mitophagy induced by 3-chlorocarbonyl benzoyl chloride. YGF reduced mitochondrial damage, increased Pink1, Parkin, and LC3B levels, and enhanced mitophagy while inhibiting S100A9/RAGE activation in the hepatocytes of ACLF mice. Conclusions This study found that S100A9/RAGE pathway activation impairs mitophagy, and YGF alleviates liver injury by downregulating S100A9 and RAGE signaling, which may be a novel therapeutic strategy for ACLF.
研究领域:
药理学
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肝脏病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Genetics
·
2021
·
IF 4.599
Zhang Jing,Gao Juan,Lin Dengna,Xiong Jing,Wang Jialei,Chen Junfeng,Lin Bingliang,Gao Zhiliang
Acute-on-chronic liver failure (ACLF) is a severe syndrome associated with high mortality. Alterations in the liver microenvironment are one of the vital causes of immune damage and liver dysfunction. Human bone marrow mesenchymal stem cells (hBMSCs) have been reported to alleviate liver injury via exosome-mediated signaling; of note, miRNAs are one of the most important cargoes in exosomes. Importantly, the miRNAs within exosomes in the hepatic microenvironment may mediate the mesenchymal stem cell (MSC)-derived regulation of liver function. This study investigated the hepatocyte exosomal miRNAs which are regulated by MSCs and the target genes which have potential in the treatment of liver failure. Briefly, ACLF was induced in mice using carbon tetrachloride and primary hepatocytes were isolated and co-cultured (or not) with MSCs under serum-free conditions. Exosomes were then collected, and the expression of exosomal miRNAs was assessed using next-generation sequencing; a comparison was performed between liver cells from healthy versus ACLF animals. Additionally, to identify the intracellular targets of exosomal miRNAs in humans, we focused on previously published data, i.e., microarray data and mass spectrometry data in liver samples from ACLF patients. The biological functions and signaling pathways associated with differentially expressed genes were predicted using gene ontology and Kyoto Encyclopedia of Genes and Genomics enrichment analyses; hub genes were also screened based on pathway analysis and the prediction of protein-protein interaction networks. Finally, we constructed the hub gene-miRNA network and performed correlation analysis and qPCR validation. Importantly, our data revealed that MSCs could regulate the miRNA content within exosomes in the hepatic microenvironment. MiR-20a-5p was down-regulated in ACLF hepatocytes and their exosomes, while the levels of chemokine C-X-C Motif Chemokine Ligand 8 (CXCL8; interleukin 8) were increased in hepatocytes. Importantly, co-culture with hBMSCs resulted in up-regulated expression of miR-20a-5p in exosomes and hepatocytes, and down-regulated expression of CXCL8 in hepatocytes. Altogether, our data suggest that the exosomal miR-20a-5p/intracellular CXCL8 axis may play an important role in the reduction of liver inflammation in ACLF in the context of MSC-based therapies and highlights CXCL8 as a potential target for alleviating liver injury.
研究领域:
肝病学
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干细胞生物学
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分子生物学
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基因组学
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产品关联
DOI
PubMed
高影响因子
Bioactive Materials
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2023
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IF 18.9
Hongyan Wei,Fenfang Li,Tiantian Xue,Haixia Wang,Enguo Ju,Mingqiang Li,Yu Tao
As the most abundant liver-specific microRNA, microRNA-122 (miR122) played a crucial role in the differentiation of stem cells into hepatocytes. However, highly efficient miR122 delivery still confronts challenges including poor cellular uptake and easy biodegradation. Herein, we for the first time demonstrated that the tetrahedral DNA (TDN) nanoplatform had great potential in inducing the differentiation of human mesenchymal stem cells (hMSCs) into functional hepatocyte-like cells (HLCs) by transferring the liver-specific miR122 to hMSCs efficiently without any extrinsic factors. As compared with miR122, miR122-functionalized TDN (TDN-miR122) could significantly up-regulate the protein expression levels of mature hepatocyte markers and hepatocyte-specific marker genes in hMSCs, indicating that TDN-miR122 could particularly activate the hepatocyte-specific properties of hMSCs for developing cell-based therapies in vitro . The transcriptomic analysis further indicated the potential mechanism that TDN-miR122 assisted hMSCs differentiated into functional HLCs. The TDN-miR122-hMSCs exhibited hepatic cell morphology phenotype, significantly up-regulated specific hepatocyte genes and hepatic biofunctions in comparison with the undifferentiated MSCs. Preclinical in vivo transplantation appeared that TDN-miR122-hMSCs in combination with or without TDN could efficiently rescue acute liver failure injury through hepatocyte function supplement, anti-apoptosis, cellular proliferation promotion, and anti-inflammatory. Collectively, our findings may provide a new and facile approach for hepatic differentiation of hMSCs for acute liver failure therapy. Further large animal model explorations are needed to study their potential in clinical translation in the future.
研究领域:
分子生物学
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干细胞研究
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肝病
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纳米技术
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再生医学
✓ 已验证
DOI
PubMed
高影响因子
Bioactive Materials
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2025
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IF 20.3
Jiabin Zhang,Xiaodie Chen,Yurong Chai,Yuanyuan Jin,Fenfang Li,Chenya Zhuo,Yanteng Xu,Haixia Wang,Enguo Ju,Yeh-Hsing Lao,Xi Xie,Mingqiang Li,Yu Tao
Acute liver failure (ALF) is a highly lethal condition characterized by massive tissue necrosis, excessive oxidative stress, and serious inflammatory storms, necessitating prompt medical intervention. Although hepatocyte-like cells (HLCs) derived from mesenchymal stromal/stem cells (MSCs) offer a promising alternative cell source for hepatocyte therapy, their low in-vivo integration and differentiation efficiency may compromise the eventual therapeutic efficacy. To this end, MSCs are bioengineered into multicellular spheroids in the present study. The proteomic analyses and experimental results reveal that extracellular vesicles (EVs) derived from these MSC spheroids (SpEV) contain abundant highly expressed bioactive proteins and can be efficiently endocytosed by recipient cells, resulting in enhanced pro-angiogenic and antioxidative effects. In addition, MSC spheroids exhibit superior hepatic cell differentiation compared to an equivalent number of dissociated single MSCs, particularly when being co-cultured with hexagonally patterned endothelial cells in a liver lobule-like arrangement. Following orthotopic implantation in the mouse model, the enhanced paracrine effects of SpEV, combined with an immunoregulatory decellularized extracellular matrix hydrogel carrier and functional artificial liver lobules (ALL), synergically contribute to the effective amelioration of ALF, highlighting the substantial potential for clinical translation.
研究领域:
再生医学
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肝脏疾病
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生物工程
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细胞治疗
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产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2024
·
IF 5.4
Yunzheng Du,Mengya Chen,Biao Wang,Yamin Chai,Lichun Wang,Nan Li,Yanjia Zhang,Zhuang Liu,Chen Guo,Xinbang Jiang,Boya Ma,Zimeng Wang,Ziying Tian,Lailiang Ou
The use of hemoperfusion adsorbents for the removal of bilirubin in patients with liver failure has become a critical treatment. However, the insufficient clearance of bilirubin and the possibility of bacterial infection during hemoperfusion limit the application. In this work, we designed a novel antibacterial bilirubin adsorbent (PSVT) through the suspension polymerization reaction between double-bond functionalized TiO2 nanoparticles and styrene. PSVT showed an excellent bilirubin adsorption ability and antibacterial performance, ensuring efficient clearance of bilirubin in liver failure patients during hemoperfusion and preventing bacterial infection. The experimental results indicated that TiO2 was uniformly dispersed in the microspheres, which improved the mesoporous structure and increased the specific surface area. Composite adsorbent PSVT showed an exceptional bilirubin adsorption capacity, with the maximum adsorption capacity reaching 24.3 mg/g. In addition, the introduction of TiO2 endowed PSVT with excellent antibacterial ability; the ultimate antibacterial rates against Escherichia coli and Staphylococcus aureus reached 97.31 and 96.47%, respectively. In summary, PSVT served as a novel antibacterial bilirubin adsorbent with excellent bilirubin clearance capacity and antibacterial performance, providing excellent application prospects for treating liver failure patients.
研究领域:
材料科学
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生物医学工程
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Liao Wenting,Jin Qiwen,Liu Junning,Ruan Yiling,Li Xinran,Shen Yueyue,Zhang Zhicheng,Wang Yong,Wu Shengming,Zhang Junying,Kang Lifeng,Wu Chunyong
Acute liver failure (ALF) is a serious clinical disorder with high fatality rates. Mahuang decoction (MHD), a well-known traditional Chinese medicine, has multiple pharmacological effects, such as anti-inflammation, anti-allergy, anti-asthma, and anti-hyperglycemia. In this study, we investigated the protective effect of MHD against ALF. In the lipopolysaccharide and D-galactosamine (LPS/D-GalN)-induced ALF mouse model, the elevated activities of the serum alanine and aspartate transaminases as well as the liver pathological damage were markedly alleviated by MHD. Subsequently, a metabolomics study based on the ultrahigh performance liquid chromatograph coupled with Q Exactive Orbitrap mass spectrometry was carried to clarify the therapeutic mechanisms of MHD against ALF. A total of 36 metabolites contributing to LPS/D-GalN-induced ALF were identified in the serum samples, among which the abnormalities of 27 metabolites were ameliorated by MHD. The analysis of metabolic pathways revealed that the therapeutic effects of MHD are likely due to the modulation of the metabolic disorders of tricarboxylic acid (TCA) cycle, retinol metabolism, tryptophan metabolism, arginine and proline metabolism, nicotinate and nicotinamide metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan synthesis, as well as cysteine and methionine metabolism. This study demonstrated for the first time that MHD exerted an obvious protective effect against ALF mainly through the regulation of TCA cycle and amino acid metabolism, highlighting the importance of metabolomics to investigate the drug-targeted metabolic pathways.
研究领域:
药理学
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肝病学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
Toxicology Research
·
2022
·Vol. 11
·期 2
·263-271
·
IF 2.68
Yu Ziqiang,Ding Yun,Zeng Tao,Zhao Xiulan,Zhang Cuili
Acute liver failure (ALF), characterized by the quick occurrence of disorder in liver, is a serious liver injury with extremely high mortality. Therefore, we investigated whether diallyl trisulfide (DATS), a natural product from garlic, protected against ALF in mice and studied underlying mechanisms. In the present study, lipopolysaccharide (LPS) (10 μg·kg−1)/D-galactosamine (D-gal) (500 mg·kg−1) was intraperitoneally injected to ICR mice to induce ALF. The mice were orally administered 20-, 40-, or 80-mg·kg−1 DATS) 1 h before LPS/D-gal exposure. Serum biochemical analyses and pathological study found that DATS pretreatment effectively prevented the ALF in LPS/D-gal-treated mice. Mechanistically, pretreatment of DATS inhibited the increase of the numbers of CD11b+ Kupffer cells and other macrophages in the liver, the release of tumor necrosis factor-α into the blood, and Caspase-1 activation induced by LPS/D-gal treatment in mice. Furthermore, DATS inhibited the activation of Caspase-3, downregulation of Bcl-2/Bax ratio, and increase of TUNEL positive staining. Altogether, our findings suggest that DATS exhibits hepatoprotective effects against ALF elicited by LPS/D-gal challenge, which probably associated with anti-inflammation and anti-apoptosis.
研究领域:
药理学
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肝病学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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