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  1. Book ; Online: Shuo Wen Jie Zi

    Wang, Yuxuan / Wang, Jianghui / Zhao, Dongyan / Zheng, Zilong

    Rethinking Dictionaries and Glyphs for Chinese Language Pre-training

    2023  

    Abstract: We introduce CDBERT, a new learning paradigm that enhances the semantics understanding ability of the Chinese PLMs with dictionary knowledge and structure of Chinese characters. We name the two core modules of CDBERT as Shuowen and Jiezi, where Shuowen ... ...

    Abstract We introduce CDBERT, a new learning paradigm that enhances the semantics understanding ability of the Chinese PLMs with dictionary knowledge and structure of Chinese characters. We name the two core modules of CDBERT as Shuowen and Jiezi, where Shuowen refers to the process of retrieving the most appropriate meaning from Chinese dictionaries and Jiezi refers to the process of enhancing characters' glyph representations with structure understanding. To facilitate dictionary understanding, we propose three pre-training tasks, i.e., Masked Entry Modeling, Contrastive Learning for Synonym and Antonym, and Example Learning. We evaluate our method on both modern Chinese understanding benchmark CLUE and ancient Chinese benchmark CCLUE. Moreover, we propose a new polysemy discrimination task PolyMRC based on the collected dictionary of ancient Chinese. Our paradigm demonstrates consistent improvements on previous Chinese PLMs across all tasks. Moreover, our approach yields significant boosting on few-shot setting of ancient Chinese understanding.

    Comment: To appear at ACL 2023 Findings
    Keywords Computer Science - Computation and Language
    Subject code 401
    Publishing date 2023-05-30
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Qing Xia Jie Yi Formula granules alleviated acute pancreatitis through inhibition of M1 macrophage polarization by suppressing glycolysis.

    Han, Xiao / Bao, Jingpiao / Ni, Jianbo / Li, Bin / Song, Pengli / Wan, Rong / Wang, Xingpeng / Hu, Guoyong / Chen, Congying

    Journal of ethnopharmacology

    2024  Volume 325, Page(s) 117750

    Abstract: ... of the study: This study aimed to evaluate the effect of Qing Xia Jie Yi Formula (QXJYF) granules on AP and ...

    Abstract Ethnopharmacological relevance: Herbal formulas from Traditional Chinese Medicine are common and well-established practice for treating acute pancreatitis (AP) patients. However, little is known about their bioactive ingredients and mechanisms, such as their targets and pathways to inhibit inflammation.
    Aim of the study: This study aimed to evaluate the effect of Qing Xia Jie Yi Formula (QXJYF) granules on AP and discuss the molecular mechanisms involved.
    Materials and methods: Major compounds in QXJYF granules were identified using UPLC-quadrupole-Orbitrap mass spectrometry (UPLC-Q-Orbitrap MS). The effect of QXJYF granules on experimental AP models both in vitro and in vivo, and detailed mechanisms were clarified. Two AP models were induced in mice by intraperitoneally injections of caerulein or L-arginine, and QXJYF granules were used to treat AP mice in vivo. Histological evaluation of pancreas and lung, serum amylase and lipase levels, serum inflammatory cytokines, inflammatory cell infiltration and macrophage phenotype were assessed. Bone marrow derived macrophages (BMDMs) were cultured and treated with QXJYF granules in vitro. BMDM phenotype and glycolysis levels were measured. Lastly, clinical effect of QXJYF granules on AP patients was verified. Predicted severe AP (pSAP) patients eligible for inclusion were assessed for enrollment.
    Results: Nine major compounds were identified in QXJYF granules. Data showed that QXJYF granules significantly alleviated AP severity both in caerulein and L-arginine-induced AP models in vivo, pancreatic injury and inflammatory cell infiltration, systematic inflammation, lung injury and inflammatory cell infiltration were all improved after QXJYF treatment. QXJYF granules significantly reduced M1 macrophages during AP both in vivo and in vitro; besides, the mRNA expression levels of M1 genes such as inos, Tnfα, Il1β and Il6 were significantly lower after QXJYF treatment in M1 macrophages. Mechanistically, we found that HK2, PFKFB3, PKM, LDHα levels were increased in M1 macrophages, but significantly decreased after QXJYF treatment. Clinical data indicated that QXJYF granules could significantly reduce CRP levels and shorten the duration of organ failure, thereby reducing the incidence of SAP and preventing pSAP patients from progressing to SAP.
    Conclusion: QXJYF granules alleviated AP through the inhibition of M1 macrophage polarization by suppressing glycolysis.
    MeSH term(s) Humans ; Mice ; Animals ; Pancreatitis/metabolism ; Ceruletide/adverse effects ; Acute Disease ; Inflammation/drug therapy ; Macrophages ; Arginine
    Chemical Substances Ceruletide (888Y08971B) ; Arginine (94ZLA3W45F)
    Language English
    Publishing date 2024-01-10
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 134511-4
    ISSN 1872-7573 ; 0378-8741
    ISSN (online) 1872-7573
    ISSN 0378-8741
    DOI 10.1016/j.jep.2024.117750
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Qing-Xin-Jie-Yu Granule inhibits ferroptosis and stabilizes atherosclerotic plaques by regulating the GPX4/xCT signaling pathway.

    Zhang, Jie / Wang, Xinyi / Guan, Baoyi / Wang, Xue / An, Xiaojing / Wang, Tong / Chen, Xuanye / Zhao, Lin / Jia, Jundi / Song, Luxia / Ma, Dan / Li, Qiuyi / Zhang, He / Ju, Jianqing / Xu, Hao

    Journal of ethnopharmacology

    2022  Volume 301, Page(s) 115852

    Abstract: Ethnopharmacological relevance: Qing-Xin-Jie-Yu Granule (QXJYG) is an integrated ...

    Abstract Ethnopharmacological relevance: Qing-Xin-Jie-Yu Granule (QXJYG) is an integrated traditional Chinese medicine formula used to treat atherosclerotic (AS) cardiovascular diseases. A randomized controlled trial found that QXJYG reduced cardiovascular events and experiments also verified that QXJYG attenuated AS by remodeling the intestinal flora.
    Aim of the study: To determine whether QXJYG would attenuate AS and plaque vulnerability by regulating ferroptosis in high-fat diet-induced atherosclerotic ApoE
    Methods: AS models in ApoE
    Results: QXJYG attenuated AS progression and plaque vulnerability. Characteristic morphological changes of ferroptosis in the QXJYG-treated animals were rare. Total iron was significantly lower in the QXJYG group than in the model group (P < 0.05); QXJYG suppressed the lipid peroxidation (LPO) levels (malondialdehyde), enhanced the antioxidant capacity (superoxide dismutase and glutathione), and reduced inflammatory factors (interleukin [IL]-6, IL-1β, tumor necrosis factor-α) associated with ferroptosis. Expression of GPX4/xCT in aorta tissues was remarkably increased in the QXJYG group. QXJYG inhibited ferroptosis in J744A.1 macrophages disturbed using RSL3. The Fe
    Conclusion: QXJYG inhibits ferroptosis in vulnerable AS plaques partially via the GPX4/xCT signaling pathway.
    MeSH term(s) Animals ; Mice ; Amino Acid Transport Systems, Acidic/metabolism ; Apolipoproteins E ; Ferroptosis ; Plaque, Atherosclerotic/drug therapy ; Signal Transduction
    Chemical Substances Amino Acid Transport Systems, Acidic ; Apolipoproteins E ; glutathione peroxidase 4, mouse (EC 1.11.1.9) ; qing-xin-jie-yu granules
    Language English
    Publishing date 2022-10-20
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 134511-4
    ISSN 1872-7573 ; 0378-8741
    ISSN (online) 1872-7573
    ISSN 0378-8741
    DOI 10.1016/j.jep.2022.115852
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Intervention Mechanism of Hunag-Lian Jie-Du Decoction on Canonical Wnt/

    Yang, Xuesong / Luo, Guangyun / Fu, Lan / Huang, Hong / Wang, Lifen / Yin, Lihua / Zhang, Xuelian / Wang, Tingting / Ma, Xuan / Feng, Tianyu / Ye, Jianzhou

    Evidence-based complementary and alternative medicine : eCAM

    2022  Volume 2022, Page(s) 3193572

    Abstract: ... characterized by abnormal proliferation and differentiation of keratinocytes. Huang-Lian Jie-Du decoction (HLJDD ...

    Abstract Background: Psoriasis is a common chronic inflammatory skin disease with multifactor etiology, characterized by abnormal proliferation and differentiation of keratinocytes. Huang-Lian Jie-Du decoction (HLJDD) is a traditional Chinese medicine prescription with good clinical curative effect on psoriasis. However, its therapeutic mechanisms are still unclear.
    Methods: The psoriasis model of SKH-1 nude mice was established by imiquimod-induced and HLJDD gavage was given. Hematoxylin and eosin staining were used to evaluate pathological morphologies, and immunohistochemistry was used to detect the expressions of Wnt1,
    Results: In this study, HLJDD reduced skin erythema and lesions, decreased the thickness of epidermal and downregulated the expressions of Wnt1,
    Conclusions: HLJDD can effectively treat psoriasis and inhibit the Wnt/
    Language English
    Publishing date 2022-04-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2171158-6
    ISSN 1741-4288 ; 1741-427X
    ISSN (online) 1741-4288
    ISSN 1741-427X
    DOI 10.1155/2022/3193572
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Elucidation of the anti-lung cancer mechanism of Juan-Liu-San-Jie prescription based on network pharmacology and experimental validation.

    Wang, Yuli / Pan, Yanbin / Luo, Yingbin / Wu, Jianchun / Fang, Zhihong / Teng, Wenjing / Guan, Yu / Li, Yan

    Heliyon

    2023  Volume 9, Issue 8, Page(s) e18298

    Abstract: ... being the most prevalent subtype. Our preliminary studies have demonstrated that the Juan-Liu-San-Jie ...

    Abstract Lung cancer is a malignancy characterized by high morbidity and mortality, with lung adenocarcinoma being the most prevalent subtype. Our preliminary studies have demonstrated that the Juan-Liu-San-Jie (JLSJ) prescription, a Traditional Chinese Medicine prescription, possesses anti-lung adenocarcinoma cancer properties. However, the molecular mechanism underlying the therapeutic effects of the JLSJ prescription for lung adenocarcinoma remains incompletely elucidated. To address the knowledge gap, the present study employed network pharmacology to identify potential therapeutic targets. Specifically, the study utilized TCMSP, TCMID, and related references, as well as ChemMapper, to identify and predict the main active components and potential targets. Additionally, differentially expressed genes associated with the disease were obtained from the microarray dataset GSE19804 and GSE118370. The protein-protein Interaction network and Target-pathway network were then constructed. We also conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and subsequently presented the top 20 enriched pathways. The results indicated that the anti-lung cancer effects of JLSJ prescription may be attributed to its ability to mediate apoptosis of tumor cells, potentially through the PI3K/Akt signaling pathway. Then, a series of in vitro and in vivo experiments were conducted to validate the molecular mechanism predicted by network pharmacology. The findings of the in vivo study suggested that the JLSJ prescription could inhibit the growth of xenograft tumors of lung adenocarcinoma with fewer adverse effects. Also, the in vitro experiments corroborated that the JLSJ prescription could induce apoptosis of A549 cells. Furthermore, the upregulation of pro-apoptosis-related proteins and mRNAs, coupled with the downregulation of anti-apoptotic-related proteins and mRNAs, was observed. In conclusion, inducing apoptosis by inhibiting the PI3K/Akt signaling pathway was one of the underlying mechanisms by which the JLSJ prescription exerted its anti-lung adenocarcinoma effect.
    Language English
    Publishing date 2023-07-23
    Publishing country England
    Document type Journal Article
    ZDB-ID 2835763-2
    ISSN 2405-8440
    ISSN 2405-8440
    DOI 10.1016/j.heliyon.2023.e18298
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Xue-Jie-San restricts ferroptosis in Crohn's disease via inhibiting FGL1/NF-κB/STAT3 positive feedback loop.

    Gao, Ying / Zhang, Zhaozheng / Du, Jun / Yang, Xiao / Wang, Xiaopeng / Wen, Ke / Sun, Xueliang

    Frontiers in pharmacology

    2023  Volume 14, Page(s) 1148770

    Abstract: ... Xue-Jie-San (XJS) is an effective prescription for treating CD. However, its therapeutic mechanism has ...

    Abstract Crohn's disease (CD) is an incurable inflammatory bowel disease due to unclear etiology and pathogenesis. Accumulating evidences have shown the harmful role of ferroptosis in CD onset and development. Additionally, fibrinogen-like protein 1 (FGL1) has been verified to be a potential therapeutic target of CD. Xue-Jie-San (XJS) is an effective prescription for treating CD. However, its therapeutic mechanism has not been fully elucidated. This study aimed to determine whether XJS alleviating CD via regulating ferroptosis and FGL1 expression. A colitis rat model was induced by 2,4,6-trinitrobenzene sulfonic acid and treated with XJS. The disease activity indices of the colitis rats were scored. Histopathological damage was assessed using HE staining. ELISA was performed to examine inflammatory cytokines. Transmission electron microscopy was utilized to observe ultrastructure changes in intestinal epithelial cells (IECs). Iron load was evaluated by examining iron concentrations, the expressions of FPN, FTH and FTL. Lipid peroxidation was investigated through detecting the levels of ROS, 4-HNE, MDA and PTGS2. Furthermore, the SLC7A11/GSH/GPX4 antioxidant system and FGL1/NF-κB/STAT3 signaling pathway were examined. The results showed that colitis was dramatically ameliorated in the XJS-treated rats as evidenced by relief of clinical symptoms and histopathological damages, downregulation of pro-inflammatory cytokines IL-6, IL-17 and TNF-α, and upregulation of anti-inflammatory cytokine IL-10. Furthermore, XJS administration led to ferroptosis inhibition in IECs by reducing iron overload and lipid peroxidation. Mechanistically, XJS enhanced the SLC7A11/GSH/GPX4 antioxidant system negatively regulated by the FGL1/NF-κB/STAT3 positive feedback loop. In conclusion, XJS might restrain ferroptosis in IECs to ameliorate experimental colitis by inhibition of FGL1/NF-κB/STAT3 positive feedback loop.
    Language English
    Publishing date 2023-04-19
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2023.1148770
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Xue-Jie-San prevents the early development of colitis-associated intestinal fibrosis by blocking Notch1 and FGL1 signaling pathways.

    Gao, Ying / Lu, Li-Juan / Zhang, Zhao-Zheng / Yang, Xiao / Du, Jun / Wen, Ke / Huang, Hua / Wang, Xiao-Peng / Sun, Xue-Liang

    Journal of ethnopharmacology

    2023  Volume 315, Page(s) 116678

    Abstract: Ethnopharmacological relevance: Xue-Jie-San (XJS), as a traditional Chinese herb prescription, has ...

    Abstract Ethnopharmacological relevance: Xue-Jie-San (XJS), as a traditional Chinese herb prescription, has satisfactory effects on improving clinical symptoms and facilitating the healing of intestinal ulcers in patients with Crohn's disease (CD). This motivates the application of XJS on CD-associated complications.
    Aim of the study: Intestinal fibrosis is a debilitating complication of CD. Currently, there is no effective medication available for preventing or reversing CD-related intestinal fibrosis. This study aimed to assess the efficacy and underlying mechanisms of XJS in the treatment of colitis-associated intestinal fibrosis.
    Materials and methods: A rat model of CD-related intestinal fibrosis was induced by 2,4,6-trinitrobenzene sulfonic acid administration and treated with XJS. The pathological changes of intestinal fibrosis were evaluated using Masson staining. Collagen deposition and epithelial-to-mesenchymal transition (EMT) were verified by immunohistochemical staining and Western blot analysis. Endothelial-to-mesenchymal transition (EndoMT) was assessed with immunofluorescence and immunohistochemical staining as well as Western blot analysis. Transmission electron microscopy was utilized to observe autophagosomes. The levels of autophagy-related proteins were detected via immunofluorescence staining and Western blot. Finally, the mTOR/ULK1 signaling pathway regulated by Notch1 or FGL1 was analyzed by Western blot.
    Results: The results found that XJS ameliorated intestinal fibrosis through reducing the deposition of collagens such as Collagen 1 and Collagen 3. XJS inhibited the EMT process by increasing E-cadherin levels and decreasing the expressions of N-cadherin, Vimentin and Snail, which played a crucial role in collagen secretion and intestinal fibrosis. In addition, XJS also repressed the EndoMT process as reflected by the upregulation of CD31 and VE-cadherin levels and the downregulation of FSP1 and α-SMA expressions. Autophagy was activated following XJS treatment via suppression of the mTOR/ULK1 signaling pathway. Furthermore, XJS acted as an inhibitor of Notch1 and FGL1 signals, both of which regulated the mTOR signaling.
    Conclusions: Our findings validated that XJS prevented the early development of CD-related intestinal fibrosis by blocking the Notch1 and FGL1 signaling pathways to activate autophagy and thereby inhibit EMT and EndoMT.
    MeSH term(s) Rats ; Animals ; Intestines/pathology ; Colitis/chemically induced ; Colitis/complications ; Colitis/drug therapy ; Fibrosis ; Signal Transduction ; TOR Serine-Threonine Kinases ; Epithelial-Mesenchymal Transition ; Receptor, Notch1
    Chemical Substances TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Notch1 protein, rat ; Receptor, Notch1
    Language English
    Publishing date 2023-05-30
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 134511-4
    ISSN 1872-7573 ; 0378-8741
    ISSN (online) 1872-7573
    ISSN 0378-8741
    DOI 10.1016/j.jep.2023.116678
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: The Herbal Combination Shu Gan Jie Yu Regulates the SNCG/ER-a/AKT-ERK Pathway in DMBA-Induced Breast Cancer and Breast Cancer Cell Lines Based on RNA-Seq and IPA Analysis.

    Zhao, Yi / Zhao, Linan / Wang, Tao / Liu, Zhenghao / Tang, Suyuan / Huang, Hongxia / Wu, Li / Sun, Youzhi

    Integrative cancer therapies

    2024  Volume 23, Page(s) 15347354241233258

    Abstract: Background: Soothing the liver (called : The aim of the study: To investigate the inhibiting effect of SGJY on breast cancer in vivo and vitro, and to explore the potential mechanisms.: Materials and methods: SGJY herbal combination was extracted ... ...

    Abstract Background: Soothing the liver (called
    The aim of the study: To investigate the inhibiting effect of SGJY on breast cancer in vivo and vitro, and to explore the potential mechanisms.
    Materials and methods: SGJY herbal combination was extracted using water. A breast cancer rat model was developed by chemical DMBA by gavage, then treated with SGJY for 11 weeks. The tumor tissue was preserved for RNA sequencing and analyzed by IPA software. The inhibition effects of SGJY on MCF-7 and T47D breast cancer cells were investigated by SRB assay and cell apoptosis analysis, and the protein expression levels of SNCG, ER-α,
    Results: SGJY significantly reduced the tumor weight and volume, and the level of estradiol in serum. The results of IPA analysis reveal SGJY upregulated 7 canonical pathways and downregulated 16 canonical pathways. Estrogen receptor signaling was the key canonical pathway with 9 genes downregulated. The results of upstream regulator analysis reveal beta-estradiol was the central target; the upstream regulator network scheme showed that 86 genes could affect the expression of the beta-estradiol, including SNCG, CCL21 and MB. Additionally, SGJY was verified to significantly alter the expression of SNCG mRNA, CCL21 mRNA and MB mRNA which was consistent with the data of RNA-Seq. The inhibition effects of SGJY exhibited a dose-dependent response. The apoptosis rates of MCF7 and T47D cells were upregulated. The protein expression of SNCG, ER-α,
    Conclusion: The results demonstrate that SGJY may inhibit the growth of breast cancer. The mechanism might involve downregulating the level of serum estradiol, and suppressing the protein expression in the SNCG/ER-α/AKT-ERK pathway.
    MeSH term(s) Animals ; Female ; Humans ; Rats ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Estradiol ; gamma-Synuclein/genetics ; gamma-Synuclein/metabolism ; MAP Kinase Signaling System ; MCF-7 Cells ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Receptors, Estrogen/metabolism ; RNA, Messenger/metabolism ; RNA-Seq
    Chemical Substances Estradiol (4TI98Z838E) ; gamma-Synuclein ; Neoplasm Proteins ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Receptors, Estrogen ; RNA, Messenger ; SNCG protein, human
    Language English
    Publishing date 2024-02-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2182320-0
    ISSN 1552-695X ; 1534-7354
    ISSN (online) 1552-695X
    ISSN 1534-7354
    DOI 10.1177/15347354241233258
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Real-World Study on Chai-Shi-Jie-Du Granules for the Treatment of Dengue Fever and the Possible Mechanisms Based on Network Pharmacology.

    Yang, Huiqin / Ma, Dehong / Li, Qin / Zhou, Wen / Chen, Hongyi / Shan, Xiyun / Zheng, Haipeng / Luo, Chun / Ou, Zhiyue / Xu, Jielan / Wang, Changtai / Zhao, Lingzhai / Su, Rui / Chen, Yuehong / Liu, Qingquan / Tan, Xinghua / Lin, Luping / Jiang, Tao / Zhang, Fuchun

    Evidence-based complementary and alternative medicine : eCAM

    2023  Volume 2023, Page(s) 9942842

    Abstract: ... for dengue fever. This real-world study aimed to evaluate the effects of Chai-Shi-Jie-Du (CSJD) granules ...

    Abstract Objectives: Traditional Chinese medicine (TCM) is a widely used method for treating dengue fever in China. TCM improves the symptoms of patients with dengue, but there is no standard TCM prescription for dengue fever. This real-world study aimed to evaluate the effects of Chai-Shi-Jie-Du (CSJD) granules for the treatment of dengue fever and the underlying mechanisms.
    Methods: We implemented a multicenter real-world study, an
    Results: 137 pairs of patients were successfully matched according to age, sex, and the time from onset to presentation. The time to defervescence (1.7 days vs. 2.5 days,
    Conclusions: CSJD granules exhibit high potential for the treatment of dengue fever, and the therapeutic mechanisms involved could be related to regulating immunity, moderating the oxidative stress response, and the response to lipopolysaccharide.
    Language English
    Publishing date 2023-08-30
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2171158-6
    ISSN 1741-4288 ; 1741-427X
    ISSN (online) 1741-4288
    ISSN 1741-427X
    DOI 10.1155/2023/9942842
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: System analysis of Huang-Lian-Jie-Du-Tang and their key active ingredients for overcoming CML resistance by suppression of leukemia stem cells.

    Huang, Guiping / Yin, Zhao / Wang, Xiuyuan / Wen, Ziqi / Su, Rui / Li, Chuting / Liu, Yanjun / Yang, Juhua / Hu, Haiyan / Nie, Hong / Zeng, Xiaobin / Fei, Jia

    Phytomedicine : international journal of phytotherapy and phytopharmacology

    2023  Volume 117, Page(s) 154918

    Abstract: ... Purpose: To study the key active ingredients and corresponding target proteins in Huang-Lian-Jie-Du-Tang ...

    Abstract Background: BCR-ABL1-based resistance to imatinib, mainly resulting from BCR-ABL1 mutations, is largely solved after second- and third-generation tyrosine kinase inhibitors (TKIs) are discovered. Nonetheless, imatinib resistance without BCR-ABL1 mutations, including intrinsic resistance induced by stem cells within chronic myeloid leukemia (CML), remains the major clinical challenge for many patients.
    Purpose: To study the key active ingredients and corresponding target proteins in Huang-Lian-Jie-Du-Tang (HLJDT) against BCR-ABL1-independent CML resistance to therapeutics, and then explore its mechanism of against CML drug resistance.
    Methods: Cytotoxicity of HLJDT and its active ingredients in BCR-ABL1-independent imatinib resistance cells was analyzed through MTT assay. The cloning ability was measured through soft agar assay. Monitoring therapeutic effect on Xenografted mice CML model by in vivo imaging technology and mice survival time. Predicting the potential target protein binding sites by the technology of photocrosslinking sensor chip, molecular space simulation docking, and use Surface Plasmon Resonance (SPR) technology . Flow cytometry to detect the ratio of stem progenitor cells (CD34+). Constructing bone marrow transplantation mice CML leukemia model, detect the effects on leukemia stem cells LSK (Lin-\ Sca-1+ \C-kit+) self-renewal.
    Results: Treatment with HLJDT, berberine and baicalein inhibited cell viability and colony formation of BCR-ABL1-independent imatinib-resistant cells in vitro while prolonging survival in mouse with CML xenografts and transplatation CML-like mouse models in vivo. JAK2 and MCL1were identified as targets of berberine and baicalein. JAK2 and MCL1 are involved in multi-leukemia stem cell-related pathways. Moreover, the ratio of CD34+ cells in resistant CML cells is higher than in treatment-sensitive CML cells. Treatment with BBR or baicalein partially suppressed CML leukemic stem cells (LSCs) self-renewal in vitro and in vivo.
    Conclusion: From the above, we concluded that HLJDT and its key active ingredients (BBR and baicalein) allowed to overcome imatinib resistance with BCR-ABL1 independent by eradication of LSCs by targeting the JAK2 and MCL1 protein levels. Our results lay the foundation for applying HLJDT in patients with TKI-resistant CML.
    MeSH term(s) Humans ; Mice ; Animals ; Imatinib Mesylate/pharmacology ; Imatinib Mesylate/therapeutic use ; Fusion Proteins, bcr-abl/genetics ; Fusion Proteins, bcr-abl/metabolism ; Myeloid Cell Leukemia Sequence 1 Protein ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Berberine/pharmacology ; Drug Resistance, Neoplasm ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism ; Leukemia, Myeloid, Acute/drug therapy ; Stem Cells
    Chemical Substances Imatinib Mesylate (8A1O1M485B) ; Fusion Proteins, bcr-abl (EC 2.7.10.2) ; oren gedoku to ; Myeloid Cell Leukemia Sequence 1 Protein ; Protein Kinase Inhibitors ; Berberine (0I8Y3P32UF)
    Language English
    Publishing date 2023-06-09
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1205240-1
    ISSN 1618-095X ; 0944-7113
    ISSN (online) 1618-095X
    ISSN 0944-7113
    DOI 10.1016/j.phymed.2023.154918
    Database MEDical Literature Analysis and Retrieval System OnLINE

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