WORLD JOURNAL OF MICROBIOLOGY & BIOTECHNOLOGY
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2024
·Vol. 41
·期 1
·1-12
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IF 4
Li Yang-Nan,Zhu Chen-Yuan,Xu Chen-Lu,Yu Shen,Huan Tong,Zhang Ye-Wang
A heparinase III ( Ns Hep-III) from Niabella sp . was identified, cloned, and expressed as soluble form in E. coli BL21 (DE3). With heparin as substrate, the maximum activity of Ns Hep-III of 90.0 U·mg − 1 was achieved at pH 7.1 Tris-HCl (containing 15 mM Mg 2+ ) and 30 o C. The half-life of Ns Hep-III was determined to be 5 h at 30 o C. The interactions between Ns Hep-III and substrates were studied by molecular docking. The combination of Ns Hep-III and a heparinase I from Bacteroides eggthii ( Be Hep-I) was employed to cleave heparin. Analysis of the enzymatic products of Ns Hep-III by SAX-HPLC showed seven different modified disaccharides, indicating that Ns Hep-III has a wide range of substrate specificity. The results of GPC analysis demonstrated that the average molecular weight of the product of heparin cleavage by the combination of Ns Hep-III/ Be Hep-I was reduced to 3969 Da, which accounted for 90% of all the components, and complied with the requirements of the European Pharmacopoeia. Ns Hep-III has notable activity and efficiency in cleaving heparin, which is potentially useful for the industrial production of low molecular weight heparin.
研究领域:
生物化学
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药学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR CARCINOGENESIS
·
2018
·Vol. 57
·期 10
·1371-1382
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IF 3.851
Jie Gao,Zhao Wang,Gao-Ju Wang,Na Gao,Jing Li,Yun-Fei Zhang,Jun Zhou,Hong-Xin Zhang,Qiang Wen,Han Jin,Hai-Ling Qiao
Hepatofibrosis is an important susceptibility factor for hepatocarcinogenesis. However, only a handful of cases of hepatofibrosis will develop into hepatocellular carcinoma (HCC). As cytochrome P450 2E1 (CYP2E1) is involved in the metabolism and activation of many known environmental toxicants and procarcinogens, this enzyme may play a role in the development of hepatocarcinogenesis subsequent to hepatofibrosis. Herein, we evaluated whether higher CYP2E1 activity is a risk factor for the development of hepatocarcinogenesis from hepatofibrosis. CYP2E1 activity in fibrotic tissues from 72 HCC patients and in normal liver tissues from 59 control subjects was determined along with the severity of hepatofibrosis in hepatocarcinogenesis patients. Similarly, using a rat diethylnitrosamine-induced hepatocarcinogenesis model, CYP2E1 activity at the hepatofibrosis and hepatocarcinogenesis stages was determined, the correlation between CYP2E1 activity at the hepatofibrosis stage and hepatocarcinogenesis was explored, and the impact of inhibition of CYP2E1 activity on hepatocarcinogenesis was studied. The results showed that while CYP2E1 activity in HCC patients with underlying hepatofibrosis was increased, the severity of hepatofibrosis did not correlate with CYP2E1 activity. In the rat hepatocarcinogenesis model, unexpectedly, CYP2E1 activity was found to decrease from hepatofibrosis to hepatocarcinogenesis. Importantly, however, hepatofibrotic rats with higher CYP2E1 activity developed a more severe form of HCC. Moreover, inhibition of CYP2E1 activity could decrease the occurrence and development of HCC in rats. In conclusion, higher CYP2E1 activity may be a risk factor for hepatocarcinogenesis from hepatofibrosis, which raises the possibility of screening patients with hepatofibrosis for CYP2E1 activity to better estimate their risk for hepatocarcinogenesis.
研究领域:
医学
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药理学
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毒理学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Hu Chen,Minglei Teng,Qihui Hu,Xiaoliu Liang,Hui Liu,Zhenjie Li,Xing Gao,Yisheng Peng,Xiaoyong Wang,Syed Faheem Askari Rizvi,Yi Lv,Hongwei Cheng,Rui Tao,Gang Liu
Anatomical hepatectomy is a widely employed surgical technique due to its capacity to excise hepatic lesions and minimize risk variables associated with postoperative recurrence. However, preserving the anatomical and functional integrity of the liver remains a critical concern and a significant challenge in determining the boundaries of targeted liver segments. This study utilized a super-stable pure-nanomedicine formulation technology (SPFT) to synthesize methylene blue nanosheets (nanoMB) without external carrier, nanoMB did not alter the chemical composition of methylene blue (MB), it was purely a physical aggregation of molecules. The nanosize and morphology of nanoMB enhanced the internalization and retention in hepatocytes and liver tissues, addressing the limitations of unclear staining due to the rapid diffusion of MB during liver segment resection. The in vivo model of blue staining of liver segments in rats and rabbits confirmed that nanoMB can extend the staining duration of liver segments by over 3 h, whereas free MB continues for <1 min, thereby addressing the time constraints associated with liver resection. In subsequent human clinical trials, a single low-dose nanoMB injection was employed to mark hepatic segment boundaries during anatomical hepatectomy for hepatocellular carcinoma and hepatolithiasis. The boundaries continued to be distinct for over 30 min, effectively guiding the surgical resection. The postoperative liver function recovered to normal, with no complications or disease recurrence reported. In conclusion, carrier-free nanomedicine enhances hepatic visualization by improving cellular uptake and hepatic segment retention. This advancement facilitates precise surgery and establishes a new paradigm for translational research from bench to clinic.
研究领域:
纳米医学
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肝脏外科
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转化医学
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生物医学工程
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肿瘤外科学
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产品关联
DOI
高影响因子
Cell Metabolism
·
2022
·
IF 31.373
Ke Lu,Tian-Shu Shi,Si-Yu Shen,Yong Shi,Hong-Liang Gao,Jing Wu,Xiang Lu,Xiang Gao,Huang-xian Ju,Wei Wang,Yi Cao,Di Chen,Chao-Jun Li,Bin Xue,Qing Jiang
Summary Hepatic osteodystrophy (HOD) is a metabolic bone disease that is often associated with chronic liver disease and is marked by bone loss. Here, we demonstrate that hepatic expression of the phosphatase PP2Acα is upregulated during HOD, leading to the downregulation of expression of the hepatokine lecithin-cholesterol acyltransferase (LCAT). Loss of LCAT function markedly exacerbates the bone loss phenotype of HOD in mice. In addition, we found that alterations in cholesterol levels are involved in the regulation of osteoblast and osteoclast activities. We also found that LCAT improves liver function and relieves liver fibrosis in the mouse HOD model by promoting reversal of cholesterol transport from the bone to the liver. In summary, defects in a liver-bone axis occur during HOD that can be targeted to ameliorate disease progression.
研究领域:
肝病学
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内分泌学
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代谢性疾病
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骨生物学
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DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2024
·
IF 4.7
Shaofei Song,Hong Peng,Yuan Li,Tingting Zhao,Renjie Cao,Lei Zheng,Min Huang,Yiming Jiang
Liver regeneration after liver tumor resection or liver transplantation is crucial, the remaining liver frequently fails to regenerate in some patients. Oleanolic acid (OA), a pentacyclic triterpenoid compound which has been shown to protect against various liver diseases. However, the effect of OA on liver regeneration after partial hepatectomy (PHx) is still unclear. In this study, the results showed that OA (50 mg/kg, twice daily) treatment induced liver mass restoration and increased the liver-to-body weight ratio of mice following PHx. Meanwhile, OA promoted hepatocyte proliferation and increased the number of BrdU-, Ki67-and PCNA-positive cells. Furthermore, OA increased the nuclear accumulation of PXR and induced the expression of PXR downstream proteins such as CYP3A11, UGT1A1 and GSTM2 in mice, as well as in AML12 and HepRG cells. Luciferase reporter assay and nuclear localization of PXR further demonstrated the effect of OA on PXR activation in vitro . Molecular docking simulation showed that OA could interact with the PXR active sites. Moreover, OA inhibited the expression of FOXO1, RBL2 and CDKN1B, and increased the expression of PCNA, CCND1 and CCNE1 in vivo and in vitro . Silencing of Pxr further confirmed that OA-mediated upregulation of proliferation-related proteins depended on PXR. The current study illustrated that OA exhibited a significant promoting effect on liver regeneration following PHx, potentially through regulation of the PXR signaling pathway to accelerate liver recovery.
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
DRUG METABOLISM AND DISPOSITION
·
2025
·
IF 4
Yue Gao,Chenghui Cai,Wanyu Zheng,Shicheng Fan,Yifei Zhang,Yanying Zhou,Huilin Li,Jie Yang,Shaoxing Guan,Huichang Bi
Constitutive androstane receptor (CAR, NR1I3), a nuclear receptor superfamily member, plays a pivotal role in liver size regulation. Murine CAR agonist TCPOBOP was reported to induce hepatomegaly in mice, accompanied by hepatocyte hypertrophy and proliferation. However, whether CAR activation-induced hepatomegaly is reversible and the histological changes during reversal process remain elusive. In the current study, C57BL/6 mice were administered TCPOBOP for 5 days and sacrificed at different time points after drug withdrawal. The results showed that TCPOBOP-induced hepatomegaly required a long time to reverse, as evidenced by the liver-to-body weight ratio in the TCPOBOP group remained significantly higher than that in the Vehicle group even 120 days after withdrawal. CTNNB1 and CCND1 staining indicated a reduction in hepatocyte size and proliferating cells. To investigate the involved mechanisms, we measured proteins associated with hepatomegaly and liver regeneration termination. The results suggested that YAP, C-MYC, CTNNB1, FOXM1 and HNF4α changed significantly after TCPOBOP withdrawal and functioned at different stages during reversal. Furthermore, we established a UPLC-MS/MS method to quantify TCPOBOP concentration. The results indicated a long-term hepatic retention of TCPOBOP, which constantly activated CAR and led to sustained hepatomegaly after TCPOBOP withdrawal. Overall, these findings revealed the reversibility of CAR activation-induced hepatomegaly and provided new insights into the safety of CAR as a drug target. Additionally, the results highlighted the importance of considering long-term TCPOBOP accumulation in the liver to avoid potential adverse effects and experimental biases.
研究领域:
药理学
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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
·
IF 12.8
Kai Wang,Xu-Yang Chen,Ren-Wei-Yang Zhang,Ying Yue,Xiao-Lin Wen,Yu-Shun Yang,Chen-Yang Han,Yuan Ma,Hong-Ji Liu,Hai-Liang Zhu
Hepatocellular carcinoma (HCC) seriously threatens the human health. Previous investigations revealed that γ -glutamyltranspeptidase (GGT) was tightly associated with the chronic injury, hepatic fibrosis, and the development of HCC, therefore might act as a potential indicator for monitoring the HCC-related processes. Herein, with the contribution of a structurally optimized probe ETYZE-GGT , the bimodal imaging in both far red fluorescence (FL) and photoacoustic (PA) modes has been achieved in multiple HCC-related models. To our knowledge, this work covered the most comprehensive models including the fibrosis and developed HCC processes as well as the premonitory induction stages (autoimmune hepatitis, drug-induced liver injury, non-alcoholic fatty liver disease). ETYZE-GGT exhibited steady and practical monitoring performances on reporting the HCC stages via visualizing the GGT dynamics. The two modes exhibited working consistency and complementarity with high spatial resolution, precise apparatus and desirable biocompatibility. In cooperation with the existing techniques including testing serum indexes and conducting pathological staining, ETYZE-GGT basically realized the universal application for the accurate pre-clinical diagnosis of as many HCC stages as possible. By deeply exploring the mechanically correlation between GGT and the HCC process, especially during the premonitory induction stages, we may further raise the efficacy for the early diagnosis and treatment of HCC.
研究领域:
医学影像
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癌症生物学
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分子生物学
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药学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Chen-Lu Xu,Chen-Yuan Zhu,Yang-Nan Li,Jian Gao,Ye-Wang Zhang
A novel heparinase III from Pedobacter schmidteae (PsHep-III) with high activity and good stability was successfully cloned, expressed, and characterized. PsHep-III displayed the highest specific activity ever reported of 192.8 U mg–1 using heparin as the substrate. It was stable at 25 °C with a half-life of 323 h in an aqueous solution. PsHep-III was employed for the depolymerization of heparin, and the enzymatic hydrolyzed products were analyzed with gel permeation chromatography and high-performance liquid chromatography. PsHep-III can break glycosidic bonds in heparin like →4]GlcNAc/GlcNAc6S/GlcNS/GlcNS6S/GlcN/GlcN6S(1 → 4)ΔUA/ΔUA2S[1 → and efficiently digest heparin into seven disaccharides including N-acetylated, N-sulfated, and N-unsubstituted modification, with molecular masses of 503, 605, 563, 563, 665, 360, and 563 Da, respectively. These results indicated that PsHep-III with broad substrate specificity could be combined with heparinase I to overcome the low selectivity at the N-acetylated modification binding sites of heparinase I. This work will contribute to the application of PsHep-III for characterizing heparin and producing low-molecular-weight heparin effectively.
研究领域:
生物化学
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分子生物学
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制药工程
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Siqi Li,Tiemei Zheng,Yusen Li,Xiaoli Wang,Yanjun Jiang,Pengyu Huang
Therapeutic liver grafts (Livergraft, 10 mm × 3 mm) were developed by biocasting bioorthogonal gelatin with in vitro -expanded primary hepatocytes (3 × 10 7 cells/mL). The bioorthogonal gelatin composed of methyltetrazine-modified gelatin (Gel-T) and norbornene-modified gelatin (Gel N), which were synthesized by reacting methyltetrazine-NHS ester and cis-5-Norbornene- endo -2,3-dicarboxylic anhydride with the amino groups of gelatin, respectively. Uniform mixing of in vitro -expanded primary hepatocytes with Gel-T and Gel-N triggered an immediate bioorthogonal reaction between norbornene and methyltetrazine, resulting in solidification to form Livergraft within 10 min. The resulting Livergraft exhibited a well-defined 3D architecture with pore sizes of 100–400 μm. Remarkably, hepatocytes within Livergraft proliferated and self-organized into cell aggregates with an average diameter of 118 μm after three days of in vitro 3D culture. This strategy was faclie and efficient, requiring neither external triggers ( e.g. , UV light), Matrigel pre-incubation, nor specialized equipment. Livergraft transplantation effectively compensated liver function in mice undergoing 90 % hepatectomy, with five out of twelve mice surviving long-term. On the 5th day after hepatectomy, the caudate lobe was significantly enlarged, and the liver function indicators (ALT, AST, and ALP) were consistent with those of normal mice. Comparative characterization demonstrated that bioorthogonal gelatin outperformed GelMA in supporting hepatocyte function and tissue formation, demonstrating its potential as a promising material for functional liver tissue fabrication.
研究领域:
生物医学工程
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组织工程
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再生医学
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肝病学
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生物材料
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细胞生物学
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产品关联
DOI
高影响因子
Portal Hypertension & Cirrhosis
·
2024
·Vol. 3
·期 2
·86-95
·
IF 0
Kaibo Yang,Kunjin Wu,Zitong Lei,Tong Liu,Xing Zhang,Jing Li,Kun Yang,Qiuting Peng,Ting Lin,Chang Liu,Kai Qu
Aim Tumor budding (TB) has excellent prognostic value in many solid tumors, but there is little research on it in hepatocellular carcinoma (HCC). This study assessed the prognostic value of TB in patients with HCC who received hepatectomy. Methods This retrospective study included 210 patients with HCC who received curative hepatectomy at the First Affiliated Hospital of Xi'an Jiaotong University, between 2016 and 2018. TB was evaluated on hematoxylin- and eosin-stained slides according to the criteria established by the 2016 International Tumor Budding Consensus Conference. t -tests, Chi-squared tests, and rank-sum tests were used to correlate the extent of TB with clinicopathological parameters. Prognostic analysis was performed using Cox regression models and the Kaplan–Meier method. Results The positive detection rate of TB was 45.2% (95/210) in 210 patients with HCC. Patients positive for TB always exhibit lower tumor differentiation, higher hepatitis B virus DNA levels, and more severe liver fibrosis. Multivariate Cox analysis identified TB (hazard ratio [HR]: 2.232, 95% confidence interval [CI]: 1.479–3.368, p < 0.001) as an independent prognostic factor for patients' recurrence-free survival (RFS), similar to tumor size (HR: 1.070, 95% CI: 1.070–1.142, p = 0.042) and satellite nodule (HR: 2.266, 95% CI: 1.298–3.956, p = 0.004). Kaplan–Meier analysis also demonstrated that TB-positive patients had a significantly worse RFS. Interestingly, subgroup analysis revealed that among HCC patients with negative microvascular invasion (MVI), TB was also strongly associated with RFS (HR: 3.206, 95% CI: 1.667–6.168, p < 0.001). These findings suggest that TB may serve as a supplemental prognostic biomarker for HCC-negative MVI. Conclusions TB is an adverse prognostic biomarker for HCC, particularly in patients negative for MVI. TB evaluation should be considered in the postoperative pathological examination of HCC in clinical practice. Graphical This study assessed tumor budding (TB) in hepatocellular carcinoma patients. TB refers to the detachment of tumor cells from the primary tumor mass, infiltrating the adjacent matrix and forming separate clusters. It may represent two distinct pathological features compared to microvascular invasion, which involves the invasion of tumor cells into microvessels. ECM: extracellular matrix. Key points Significant findings of the study This single-center study found that tumor budding (TB) positivity was significantly associated with poor prognosis in patients with hepatocellular carcinoma (HCC). What this study adds TB could serve as a potential supplemental prognostic biomarker for HCC with negative microvascular invasion.
研究领域:
病理学
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肿瘤学
·
外科学
✓ 已验证
DOI
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2024
·
IF 2.7
Guofang Bi,Fengting Liang,Ting Wu,Peng Wang,Xiaowen Jiang,Shuang Hu,Chenghua Wu,Wenhong Zhou,Jiayin Guo,Xiao Yang,Jian-hong Fang,Wenying Chen,Huichang Bi
Human pregnane X receptor (PXR) is critical for regulating the expression of key drug-metabolizing enzymes such as CYP3A and CYP2C. Our recent study revealed that treatment with rodent-specific PXR agonist pregnenolone-16α-carbonitrile (PCN) significantly induced hepatomegaly and promoted liver regeneration after two-thirds partial hepatectomy (PHx) in mice. However, it remains unclear whether PXR activation induces hepatomegaly and liver regeneration and simultaneously promotes metabolic function of the liver. Here, we investigated the metabolism activity of CYP1A2, CYP3A1/2 and CYP2C6/11 during PXR activation-induced liver enlargement and regeneration in rats after cocktail dosing of CYP probe drugs. For PCN-induced hepatomegaly, a notable increase in the metabolic activity of CYP3A1/2 and CYP2C6/11, as evidenced by the plasma exposure of probe substrates and the AUC ratios of the characteristic metabolites to its corresponding probe substrates. The metabolic activity of CYP1A2, CYP3A1/2 and CYP2C6/11 decreased significantly after PHx. However, PCN treatment obviously enhanced the metabolic activity of CYP2C6/11 and CYP3A1/2 in PHx rats. Furthermore, the protein expression levels of CYP3A1/2 and CYP2C6/11 in liver were up-regulated. Taken together, this study demonstrates that PXR activation not only induces hepatomegaly and liver regeneration in rats, but also promotes the protein expression and metabolic activity of the PXR downstream metabolizing enzymes such as CYP3A1/2 and CYP2C6/11 in the body.
研究领域:
药理学
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肝病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2022
·
IF 4.46
Lin Leilei,Qiu Wenke,Luo Yuyuan,Lin Sihang,Sun Xue,Chen Weiqiang,Ye Lianbao,Wang Ying,Li Yan,Li Ming
Liver fibrosis has the potential to progress into liver cirrhosis , liver failure, and even death. Hepatic stellate cells (HSCs) activation play a central role in liver fibrosis, and persistently damaged hepatocytes secrete soluble factors that activate transdifferentiation of HSCs into myofibroblasts. Our previous studies indicated that fine particulate matter (PM2.5) can activate HSCs by stimulating hepatocytes to secrete TGF-β1. However, whether PM2.5 activates HSCs by regulating oxidative stress in hepatocytes remains uncertain. Oleanolic acid (OA) has been widely used in the clinic for hepatoprotection in Chinese medicine. In the present study, OA-loaded nanoparticles (OA-NP) with high solubility were used to attenuate the activation of HSCs induced by PM2.5-treated hepatocytes, and further studies were performed to explore the mechanism in which OA-NP plays a vital part. Our results showed that consistently PM2.5 treatment induced oxidative stress in hepatocytes. Moreover, the activation of HSCs induced by PM2.5-treated hepatocytes was reversed by antioxidant N -acetylcysteine treatment. Hence, PM2.5 may participate in the activation of HSCs by regulating oxidative stress in hepatocytes. Using a co-cultivation system, our results proved pretreatment with OA-NP significantly attenuates the activation of HSCs induced by PM2.5-exposed hepatocytes. In addition, the TGF-β1 expression and oxidative stress in hepatocytes with PM2.5 treated were reduced by the incubation with OA-NP. These observations demonstrated that OA-NP protects against the activation of HSCs by decreasing the TGF-β1 level and oxidative stress in PM2.5-exposed hepatocytes.
研究领域:
药理学
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毒理学
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细胞生物学
·
环境健康
✓ 已验证
DOI
PubMed
高影响因子
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