TOXICOLOGY
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2025
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IF 4.6
Jin Zhou,Pinpin Sui,Jianxin Zhao,Xiurong Cheng,Tao Yu,Shiwei Cui,Xiangrong Song,Caihong Xing
Patients with benzene-induced leukemia undergo a continuous transformation from myelosuppression to malignant proliferation. However, the underlying mechanisms in this process remain unknown. Our previous studies have shown that the pathways involved in self-renewal capacity of bone marrow (BM) cells in Mll-Af9 mice exposed to benzene for life are significantly activated after severe blood toxicity. In order to investigate the hematotoxicity effects of benzene on the self-renewal capacity of HSCs, Mll-Af9 chimeric mice were exposed to benzene and hematological parameters were dynamically monitored after benzene exposure. Transcriptomic analysis were used to analyze different time points during benzene exposure and after competitive bone marrow transplantation (BMT). Results showed that despite severe hematotoxicity in mice, but the chimerism rate of Mll-Af9 cells in peripheral blood (PB) cells was significantly increased after 10 weeks benzene exposure ( P < 0.001). After competitive BMT, the chimerism rate of Mll-Af9 cells from 10 weeks benzene-exposed mice was gradually increased and significantly surpassed that of the control at 26 weeks of bone marrow reconstruction (benzene group 86 % VS control group 78 %, P = 0.03). Transcriptome analysis revealed that the expression levels of self-renewal related genes, such as Hox genes ( Hoxb4 , Hoxa7 , Hoxa10 ), Mecom and Ms4a in BM cells of 10 weeks benzene-exposed mice were relatively higher compared to those in the control group, but no significant difference were observed. Interestingly, Hoxa7 , Hoxa10 and Mecom were significantly up-regulated at 26 weeks after bone marrow transplantation. In conclusion, our study suggests that abnormal expression of self-renewal-related genes may be potential early biomarkers for benzene-induced hematotoxicity. This hematotoxicity may contribute to the acquisition of evolutionary advantages by leukemic precursor cells and accelerate malignant transformation.
研究领域:
血液学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2023
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IF 10
Chen Zhuang,Guanglin Zhu,Yingjun Wang,Lin Wang,Xuetao Shi,Chuanbin Mao
Insoluble metal bisphosphonates (BPs) are considered an ideal alternative to the soluble counterparts in regenerative medicine due to their increased BP release profile, but still present undesired properties (e.g., low stability, uncontrolled degradation, and poor biocompatibility). Through a simple crystallization on a solid calcium hydroxyapatite (HA)-based substrate from a BP precursor solution in 30 days, a series of insoluble calcium BP (CaBP) crystals are developed. These crystals, including calcium alendronate (CaAln), calcium pamidronate (CaPam), calcium incadronate (CaInc), calcium risedronate (CaRis), calcium zoledronate (CaZol), and calcium di-minodronate (Ca(Min) 2 ), present high purity, regular morphologies and excellent biodegradability. It is demonstrated that these CaBPs can induce osteogenic differentiation of adipose-derived mesenchymal stem cells in vitro in the absence of other osteogenic inducers. It is further found that CaBP induces bone formation more effectively in a femur defect rabbit model in three months but with a lower in vivo hematotoxicity than the clinically used HA during osteogenesis. It is believed that these desired biological properties arise from the capability of the insoluble CaBPs in releasing BPs in a sustained manner for stimulating osteogenesis. This work provides a significant strategy for turning CaBPs into novel biomaterials for tissue regeneration and demonstrates their great potential in the clinic.
研究领域:
再生医学
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材料科学
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生物材料
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组织工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2018
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IF 7.877
Huipeng Li,Xue Yang,Fang Gao,Chenggen Qian,Chenzi Li,David Oupicky,Minjie Sun
In present study, gene concentrated as well as bioreduction-ruptured nanogel with local enrichment positive charge while low cytotoxicity was developed for Bcl2 siRNA delivery featured in intracellular switch on/off controlled release. Dynamic covalent bond crosslinked nanogel was formed by thiolated PEI of 1.8 kDa(PEI-1.8 kDa)and biodegradable dextrin . Once nanogel was uptake by tumor cells, high concentration of glutathione (GSH) in cytosol could bioreducible -degrade and rupture the crosslink of this dextrin nanogel (DSP) into hypotoxic PEI-1.8 kDa and dextrin, following by burst release of packed siRNA and minimizing the restriction of polymer material for siRNA transcription. This switch on/off siRNA release strategy for gene therapy exhibited equal level of the deregulation of Bcl2 protein expression determined by western blot analysis compared with cationic PEI with 25 kDa molecular weight (PEI-25 kDa) in vitro . Moreover, the gene concentrated DSP based on hypotoxic PEI-1.8 kDa and biodegradable dextrin could be administrated intravenously for systematic therapy on safely. Tumor suppression study of DSP also exhibited a superior antitumor activity in 4T1-luc tumor cell bearing BALB/C mice. Furthermore, it exhibited lower cytotoxicity, almost none hemotoxicity , moreover avoiding recognition and clearance by RES system in healthy mice. Overall, these findings suggest that this reduction-sensitive while bioreduction-ruptured polymer nanogel is an innovative strategy and holds great promise for gene and drug delivery.
研究领域:
癌症治疗
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基因递送
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纳米技术
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药学科学
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产品关联
DOI
PubMed
高影响因子
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
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2016
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IF 1.617
Dongfang Hu,Ziqiang Han,Chunling Li,Lin Lv,Zilong Cheng,Sidang Liu
Amphenicols are effective, broad-spectrum antibiotics that function by inhibiting the peptidyl transferase activity of bacteria, while the drugs can also inhibit mitochondrial protein synthesis in eukaryotes through the same mechanism, which leads to multi-organ toxicity. Some side effects of each drug have been studied, while differences in the severity of the hemotoxicities and immunotoxicities of amphenicols have not been reported. Thus, it is important to identify, evaluate, and compare the potential hemotoxicities and immunotoxicities to guide their proper use in humans and animals, which will guarantee food safety and animal welfare. Ovalbumin-immunized Kunming mice were gavaged daily with amphenicols for seven days. Blood samples were collected for hematology analysis, and measuring anti-ovalbumin antibody levels and serum intereukin-2 concentrations. The bone marrow, spleen and thymus were collected for histopathology and apoptosis analyzes. Bone marrow nucleated cells (BMNCs) and splenocytes were harvested to determine their cell cycle stages and to analyze lymphocyte proliferation. The results demonstrated that amphenicols, especially florfenicol (FLO), induced cell cycle arrest and apoptosis of hematopoietic cells, and it changed the bone marrow hematopoietic microenvironment by decreasing the number of peripheral blood cells. Moreover, amphenicols, especially FLO, induced hypoplasia and atrophy of the spleen and thymus, induced cell cycle arrest, as well as splenocyte apoptosis, and decreased the proliferation and viability of lymphocytes and the humoral and cellular immunity of the treated mice. These results suggest that amphenicols induce hemotoxicity and immunotoxicity to some extent, and that FLO induces more severe toxicity than equal doses of chloramphenicol (CAP) and thiamphenicol (TAP).
研究领域:
药理学
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毒理学
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免疫学
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血液学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2021
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IF 6.4
Wanzhen Li,Ping Song,Ying Xin,Zhao Kuang,Qin Liu,Fei Ge,Longbao Zhu,Xuguang Zhang,Yugui Tao,weiwei zhang
Background With the development of bacterial resistance, the range of effective antibiotics is increasingly becoming more limited. The effective use of nanoscale antimicrobial peptides (AP) in therapeutic and diagnostic methods is a strategy for new antibiotics.Methods Combining both AP and cadmium selenide (CdSe) into a composite material may result in a reagent with novel properties, such as enhanced antibacterial activity, fluorescence and favorable stability in aqueous solution.Results AP-loaded CdSe NPs (AP-CdSe NPs) showed strong antibacterial activity against multidrug-resistant (MDR) Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) in vitro and in vivo. Colony-forming unit (CFU) and minimum inhibitory concentration (MIC) assays showed that AP-CdSe NPs have highly effective antibacterial activity. The quantitative analysis of apoptosis by flow cytometry analysis further confirmed that MDR E. coli and S. aureus treated with AP-CdSe NPs had death rates of 98.76% and 99.13%, respectively. Also, AP-CdSe NPs was found to inhibit bacterial activity in an in vivo bacteremia model in mice infected with S. aureus. In addition, the antibacterial mechanism of AP-CdSe NPs was determined by RNA sequencing analysis. Gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed the molecular mechanism of the antibacterial effect of AP-CdSe NPs. Importantly, histopathology analysis, and hematological toxicity analysis indicated that AP-CdSe NPs had few side effects.Conclusion These results demonstrate that AP loaded on CdSe NPs had a higher water solubility, bioavailability and antibacterial effect compared with raw AP. This study reports findings that are helpful for the design and development of antibacterial treatment strategies based on AP.
研究领域:
纳米技术
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微生物学
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药学
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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 Science
·
2019
·Vol. 8
·期 5
·1418-1430
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IF 5.251
Tiankuan Li,Zhongqian Hu,Chao Wang,Jian Yang,Chuhui Zeng,Rui Fan,Jinhe Guo
Immunotherapy is gradually becoming as important as traditional therapy in the treatment of cancer, but adverse drug reactions limit patient benefits from PD1/PD-L1 checkpoint inhibitor drugs in the treatment of non-small cell lung cancer (NSCLC). As a chemotherapeutic drug for NSCLC, docetaxel (DTX) can synergize with PD1/PD-L1 checkpoint inhibitors but increase haematoxicity and neurotoxicity. Herein, anti-PD-L1 monoclonal antibody (mAb)-conjugated and docetaxel-loaded multifunctional lipid-shelled microbubbles (PDMs), which were designed with biologically safe phospholipids to produce synergistic antitumour effects, reduced the incidence of side effects and promoted therapeutic effects under ultrasound (US) irradiation. The PDMs were prepared by the acoustic-vibration method and then conjugated with an anti-PD-L1 mAb. The material features of the microbubbles and their cytotoxic effects, cellular apoptosis and cell cycle inhibition were studied. A subcutaneous tumour model was established to test the drug concentration-dependent and antitumour effects of the PDMs combined with US irradiation, and an orthotopic lung tumour model simultaneously confirmed the antitumour effect of this synergistic treatment. The PDMs achieved higher cellular uptake than free DTX, especially when combined with US irradiation. The PDMs combined with US irradiation also induced an increased rate of cellular apoptosis and an elevated G2-M arrest rate in cancer cells, which was positively correlated with PD-L1 expression. An in vivo study showed that synergistic treatment had relatively strong effects on tumour growth inhibition, increased survival time and decreased adverse effect rates. Our study possibly provides a well-controlled design for immunotherapy and chemotherapy and has promising potential for clinical application in NSCLC treatment.
研究领域:
肿瘤学
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药学
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生物医学工程
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免疫学
✓ 已验证
DOI
PubMed
高影响因子
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