Academic literature on the topic 'Yi zhuang lou'

Abstract Breast cancer is the leading cause of cancer in women and poses a massive social economic burden worldwide. CDK4/6 inhibitors have roles as standard of care in advanced and adjuvant setting for hormone positive (HR (+)), HER2 negative breast cancer. CDK6 amplification has been proposed to confer resistance to CDK4/6 inhibitors. By a small molecule screen, we discovered a multi-kinase inhibitor PIK-75 that suppressed the Hippo-YAP pathway and significantly downregulated CDK6, resulting in reversal of CDK6 amplification mediated CDK4/6 inhibitor resistance. To further probe the mechanism, we discovered that PIK-75 suppressed phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (RNAPII) which then resulted in downregulation of YAP expression and the Hippo pathway. Chromatin immunoprecipitation (ChIP) confirmed suppression of RNAPII Ser5 occupancy at YAP promoter after PIK-75 or shCDK7 treatment. Integrating results from RNA sequencing and proteomic analysis in breast cancer cells treated with PIK-75 revealed widespread transcription suppression and substantial spliceosome defect. Alternative splicing analysis by PIK-75 treated cells revealed a widespread splicing defect affecting multiple genes, including YAP, providing an alternative pathway for PIK-75-CDK7 mediated transcriptional regulation. We then investigated the phenotypic impact mediated by PIK-75 and CDK7 inhibition. We discovered that CDK7 silenced cells showed downregulation of YAP intranuclear translocation, impairment of cell migration, and cell cycle progression. ChiP-sequencing of RNAPII was also performed to investigate changes in global RNAPII occupancy and impact on promoter proximal pausing. In vivo studies confirmed that PIK-75 treatment demonstrated tumoricidal efficacy in CDK6 amplified HR (+) breast cancer cells, while the CDK4/6 inhibitor abemaciclib showed minimal cytotoxicity. In conclusion, we discovered a novel CDK7-RNAPII phosphorylation-Hippo/YAP-CDK6 regulation axis that when perturbed, could regulate CDK4/6 inhibitor resistance in HR (+) breast cancer. Molecular studies and multi-omic profiling elucidated the role of CDK7 in hippo pathway and characterizes multiple roles of PIK-75. Our study provides intriguing novel insights into the link between "transcriptional CDKs" and the hippo pathway that could potentially be further probed for therapeutics in HR (+) breast cancer. Citation Format: Chung-Jen Yu, Yong-Ji Zhuang, Chih-Yi Lin, Yi-Ru Tseng, Ting-Yi Lin, Hsiu-Man Shih, Chun-Yu Liu, Ta-Chung Chao, Ling-Ming Tseng, Chi-Cheng Huang, Yi-Fang Tsai, Feng chiao Tsai, Jiun-I Lai. CDK7 modulation of Hippo-YAP activity by RNAPII phosphorylation regulates CDK4/6 inhibitor resistance in hormone positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5715.

Abstract Breast cancer is one of the most prevalent cancer type in human, and the majority (~70%) is the hormone positive (HR+) subtype. The current frontline treatment of choice in metastatic HR(+) breast cancer is CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy. Current guidelines recommend CDK4/6i treatment as 1st or 2nd line, as CDK4/6i provides survival benefit and good quality of life. However, resistance eventually emerges, leading to discontinuation of CDK4/6i and switching to subsequent treatment. Investigation of mechanisms to CDK4/6i resistance is an active area of intense research. CDK6 overexpression has been reported as an important mechanism for CDK4/6i resistance by several independent groups. We incidentally discovered a point mutation in the CDK6 protein that abolishes the CDK4/6i resistance conferred by CDK6 overexpression. When treated with CDK4/6i, overexpression of wild type CDK6 did not suppress G1/S, while both non-transfected and overexpression of mutant CDK6 both had similar suppression of G1/S. We hypothesized that a binding partner to CDK6 demonstrated differential binding activity to the mutant which abolished the resistance by CDK6 overexpression. To assess this hypothesis, we performed proximity labeling (PL) by APEX2. Both wild type and mutant CDK6 were cloned into APEX-Flag/V5 vectors with either cytoplasm (NES) or nuclear (NLS) signals. Mass spectrometry following treatment by H2O2 induced biotinylation produced candidate peptides that bound with overexpressed CDK6. We identified leading candidates of differentially binding partners that bound to mutant CDK6. Further experimental validation was performed to confirm physical proximity between CDK6 and the candidate protein. Our research uncovered novel insights to how CDK6 conferred resistance towards CDK4/6i and expands knowledge into further therapeutic development. Citation Format: Chung Wei Ting, Yong-Ji Zhuang, Chih-Yi Lin, Chung-Jen Yu, Ta-Chung Chao, Ling-Ming Tseng, Chun-Yu Liu, Yi-Fang Tsai, Chi-Cheng Huang, Jiun-I Lai. Identification of CDK6 binding proteins by proximity labeling reveals novel mechanisms for CDK4/6 inhibitor resistance in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 526.

Abstract Hormone positive (HR+) breast cancer is the most common subtype in this population. The current standard of care in advanced HR+ breast cancer includes endocrine therapy (tamoxifen, aromatase inhibitors, etc) and CDK4/6 inhibitors. CDK4/6 inhibitors significantly prolong survival and is now the general accepted choice of drug in first line. Despite the enormous clinical benefit, there remains a substantial portion of patients who ultimately develop resistance against CDK4/6 inhibitors. Many mechanisms have been proposed for CDK4/6 inhibitor resistant, including upregulation of CDK4, CDK6, Cyclin E, and others. Recently studies have linked the hippo pathway to CDK6 upregulation and resulting in CDK4/6 inhibitor resistance. We have set up a kinase library screen for kinase inhibitors that downregulate CDK6 amplification and further assess for reversal of resistance. We discovered staurosporine and the PI3K inhibitor PIK-75 as small molecules that potently downregulate CDK6 expression in breast cancer cells. We further confirmed that these compounds reverse the resistance towards CDK4/6 inhibitors in CDK6 amplification cells. By kinase profiling combined with a small hairpin RNA (shRNA) screen, we discovered the mechanisms that resulted in CDK6 downregulation and modulation of the hippo pathway to reverse the CDK4/6 inhibitor resistance. Our discovery has implications for therapeutic development in this group of patients posing a huge unmet need. Citation Format: Chung-Jen Yu, Yong-Ji Zhuang, Ting-Yi Lin, Ta-Chung Chao, Chun-Yu Liu, Ling-Ming Tseng, Jiun-I Lai. Discovery of mechanisms that modulate the hippo pathway and CDK6 expression in CDK4/6 inhibitor resistant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5975.

Abstract An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple cell types in the TME and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo, exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti-cancer immune responses and offers a new avenue for treating various types of cancer such as melanoma. Citation Format: Lei Wang, Yufeng Xiao, Yuewan Luo, Rohan Master, Jiao Mo, Myung-Chul Kim, Yi Liu, Chandra Maharjan, Urvi Patel, Xiangming Li, Donald Shaffer, Guertin Kevin, Haoyang Zhuang, Emily Moser, Keiran Smalley, Daohong Zhou, Guangrong Zheng, Weizhou Zhang. PROTAC mediated NR4A1 degradation as a novel strategy for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2469.

Abstract Background and rationale: Metastatic HR (+) breast cancer currently still remains an incurable disease. CDK4/6 inhibitors in combination with endocrine therapy have emerged as standard 1st and 2nd lines in metastatic HR (+) breast cancer. Resistance to CDK4/6 inhibitors eventually occurs, and currently the optimal subsequent treatment for these patients remains unsettled. Based on the excellent tolerability and efficacy of CDK4/6 inhibitors, it remains a clinical interest to identify mechanisms of resistance towards CDK4/6 inhibitors in breast cancer. This is currently an area of intense research, with many resistance models being proposed, including loss of Rb, upregulation of cell cycle components (CDK2, cyclin E, AURKA), activation of growth factors (HER2, FGFGR), and the Hippo pathway. The activation of the Hippo pathway downstream gene YAP resulted in CDK6 overexpression that further led to CDK4/6 inhibitor resistance. This was confirmed in preclinical models and in patients developing resistance towards CDK4/6 inhibitors. The mechanism for how increased CDK6 activity restricts efficacy towards CDK4/6 inhibitors is unknown. We sought to discover kinase inhibitors that could downregulate CDK6 expression and CDK6 overexpression mediated resistance. Our goal is to develop therapeutics that could be added on CDK4/6 inhibitors upon progression to reverse the resistance, and to uncover pathways that modulate the relevant interactions. Results: We individually overexpressed YAP and CDK6 in the HR(+) breast cancer cell line MCF-7 and T47D and confirmed that each could increase the IC50 of CDK4/6 inhibitors. We screened a small library of 160 kinase inhibitors for candidates that could decrease CDK6 expression in a luciferase reporter assay and identified several PI3K inhibitors as well as the PKC inhibitor staurosporine that could significantly decrease CDK6 expression. Interestingly, we demonstrated that staurosporine could modulate the Hippo-YAP signaling pathway and thus modulate CDK6 expression. We further confirmed that when combined to CDK4/6 inhibitors, the addition of these candidates reversed the resistance in YAP or CDK6 overexpressing cells. Incidentally, we discovered that a mutant (D224Y) in CDK6 abolished the resistance in CDK6 overexpressing cells. CDK6-D224Y overexpressing MCF7 cells lost their resistance towards CDK4/6 inhibitors, despite that CDK6-D224Y was indistinguishable from CDK6 in kinase activity and function. D224Y resides in an alpha helix far apart from the activation loop of the CDK6 active site, therefore suggesting that mutations in CDK6 that leads to possible conformation changes could modulate the resistance to CDK4/6 inhibitors. We performed BRET (bioluminescence resonance energy transfer) and confirmed that the D224Y changed the BRET values for a palbociclib luminescent tracer, suggesting that this mutant could modulate the binding affinity of CDK4/6 inhibitors towards CDK6. In summary, we identified several novel candidates as well as a CDK6 mutant (D224Y) that could therapeutically reverse CDK4/6 inhibitor resistance conferred by CDK6 overexpression. Conclusions: We identified the PI3K pathway and the Hippo pathway as potential pathways that could modulate the CDK4/6 inhibitors resistance from CDK6 amplification. We further identified the D224Y mutant as a point mutation that abolished resistance. Our findings highlight the role of CDK6 and conformational variants in modulating CDK4/6 inhibitor resistance and uncover potential pathways that could be exploited for therapeutic development for subsequent treatment. Citation Format: Jiun-I Lai, Yong-Ji Zhuang, Ting-Yi Lin, Ta-Chung Chao, Chun-Yu Liu, Ling-Ming Tseng. A kinase inhibitor library screen reveals novel candidates that reverse CDK4/6 inhibitor resistance in CDK6 amplified HR(+) breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-10.

Abstract Metastatic breast cancer (MBC) remains incurable due to inevitable development of therapeutic resistance. Although tumor cell intrinsic mechanisms of resistance in MBC are beginning to be elucidated by bulk sequencing studies, the roles of the tumor microenvironment and intratumor heterogeneity in therapeutic resistance remain underexplored due to both technological barriers and limited availability of samples. To comprehensively capture these characteristics we have adapted a research biopsy protocol to collect tissue for an array of single-cell and spatio-molecular assays whose performance we have optimized for MBC, including single-cell and single-nucleus RNA sequencing, Slide-Seq, Multiplexed Error-Robust FISH (MERFISH), Expansion Sequencing (ExSEQ), Co-detection by Indexing (CODEX) and Multiplexed Ion Beam Imaging (MIBI). To date, we have successfully performed single-cell or single-nucleus RNAseq in 67 MBC biopsies and generated detailed accompanying clinical annotations for each. These samples provide a representation of the clinicopathological diversity of MBC including different breast cancer subtypes (44 HR+/HER2-, 3 HR-/HER2+, 3 HR+/HER2+, 16 TNBC, 1 unknown), common anatomic sites of metastasis (37 liver, 9 axilla, 7 breast, 5 bone, 3 chest wall, 3 neck, 1 brain, 1 lung, 1 skin), metastatic presentations (53 recurrent, 14 de novo) and histologic subtypes in the breast (45 IDC, 7 ILC, 6 mixed, 3 DCIS, 1 mucinous, 5 unknown/NA). Following optimization, both single-cell and single-nucleus RNA seq perform well in these MBC biopsies recovering all expected cell types including the malignant, stromal (e.g. fibroblasts, endothelial cells), myeloid (e.g. monocytes, macrophages) and lymphoid compartments (e.g. T cells, B cells, NK cells) as well as relevant oncogenic programs (e.g. cell cycle programs in all compartments; EMT-like and ER signaling programs in the malignant compartment, immune checkpoint programs in the lymphoid compartment; and fibroblast activation and vascular homeostasis programs in the stromal compartment). In addition to differences between the two techniques, these data demonstrate substantial intratumor heterogeneity in cell type composition. For example in liver biopsies the average number of cells per sample compartment by single nucleus RNA-seq was 6745 malignant (56%, SD 4216), 4637 stromal (41%, SD 3727), 1196 lymphoid (8%, SD 1617) and 874 myeloid (6%, SD 852); in breast biopsies the average number of cells per compartment by single nucleus RNA-seq was 6421 malignant (70%, SD 3497), 1628 stromal (24%, SD 117), 333 lymphoid (4%, SD 170) and 213 myeloid (3%, SD 117). Additionally, we find both inter- and intra-tumor heterogeneity in expression patterns and programs including, for example, expression of ER, PR and HER2 within clinical receptor subtypes (log normalized counts for ER expression in tumor cells by single cell RNA-seq: HR+/HER2- 0.921 (SD 0.714); HR+/HER2+ 0.768 (SD 0.624); HR-/HER2+ 0.018 (SD 0.122); and HR-/HER2- 0.005 (SD 0.066). For a subset of 13 biopsies we are also completing the spatiomolecular characterization methods on serial sections of a single adjacent biopsy. This unique experimental setup was designed to enable efficient comparison and integration of these assays. In spite of differences between experimental techniques and readouts, cell typing can be approached by annotation transfer from matching single cell or single nucleus RNAseq data, enabling exploratory analyses including evaluation of spatial phenotypes and cell type colocalization. Overall, these single cell and spatial data afford a comprehensive atlas including cell types, cell states/programs, cell interactions and spatial organization in MBC lesions. Future analyses will include serial biopsies over time and integration of clinicopathologic data including therapeutic response and resistance. Citation Format: Daniel L Abravanel, Johanna Klughammer, Timothy Blosser, Yury Goltsev, Sizun Jiang, Yunjao Bai, Evan Murray, Shahar Alon, Yi Cui, Daniel R Goodwin, Anubhav Sinha, Ofir Cohen, Michal Slyper, Orr Ashenberg, Danielle Dionne, Judit Jané-Valbuena, Caroline BM Porter, Asa Segerstolpe, Julia Waldman, Sébastien Vigneau, Karla Helvie, Allison Frangieh, Laura DelloStritto, Miraj Patel, Jingyi We, Kathleen Pfaff, Nicole Cullen, Ana Lako, Madison Turner, Isaac Wakiro, Sara Napolitano, Abhay Kanodia, Rebecca Ortiz, Colin MacKichan, Stephanie Inga, Judy Chen, Aaron R Thorner, Asaf Rotem, Scott Rodig, Fei Chen, Edward S Boyden, Garry P Nolan, Xiaowei Zhuang, Orit Rozenblatt-Rosen, Bruce E Johnson, Aviv Regev, Nikhil Wagle. Spatio-molecular dissection of the breast cancer metastatic microenvironment [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD6-03.

Objective: To investigate the expression of TNF-a and NF-kB in the uterus of chronic pelvic inflammatory disease (CPID) model rats. Methods: 40 female rats that adaptive fed for 5 days were randomly divided into normal group, model group, high dose group, medium dose group and low dose group. In addition to the normal group, the rats in each group were made chronic pelvic inflammatory model by mechanical injury combined with implantation of bacteria. The rats in each group were administrated by gavage for 20 days. After the last administration, the level of TNF-a and NF-kB in serum was measured by ELASA method. Results: (1) after the establishment of the model, the uterus of the chronic pelvic inflammatory model rats showed the pathological damage of chronic inflammation; the levels of TNF-a and NF-kB in serum were higher than those in the normal group, the difference was statistically significant (P<0.05). (2) After the drug intervention, the uterine tissue morphology of the rats in the Zhuang Yi Liu Fang Teng Fang Group was basically restored to normal, with only a small amount of inflammatory cell infiltration and other pathological changes; compared with the rats in the model group, the TNF-a in serum of the rats in each treatment group was lower, the difference was statistically significant (P<0.05). The expression of NF-kB in serum of each treatment group was lower than that of the model group (P<0.05). Conclusion: Zhuang Yi Liu Teng Fang can effectively improve the endometrial histomorphology of CPID model rats, and regulate the levels of TNF-a and NF-kB in the uterus of chronic pelvic inflammatory model rats.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus , is causing a serious worldwide COVID-19 pandemic. The emergence of strains with rapid spread and unpredictable changes is the cause of the increase in morbidity and mortality rates. A number of drugs as well as vaccines are currently being used to relieve symptoms, prevent and treat the disease caused by this virus. However, the number of approved drugs is still very limited due to their effectiveness and side effects. In such a situation, medicinal plants and bioactive compounds are considered a highly valuable source in the development of new antiviral drugs against SARS-CoV-2. This review summarizes medicinal plants and bioactive compounds that have been shown to act on molecular targets involved in the infection and replication of SARS-CoV-2. Keywords: Medicinal plants, bioactive compounds, antivirus, SARS-CoV-2, COVID-19 References [1] R. Lu, X. Zhao, J. Li, P. Niu, B. Yang, H. Wu et al., Genomic Characterisation and Epidemiology of 2019, Novel Coronavirus: Implications for Virus Origins and Receptor Binding, The Lancet, Vol. 395, 2020, pp. 565-574, https://doi.org/10.1016/S0140-6736(20)30251-8.[2] World Health Organization, WHO Coronavirus (COVID-19) Dashboard, https://covid19.who.int, 2021 (accessed on: August 27, 2021).[3] H. Wang, P. Yang, K. Liu, F. Guo, Y. Zhang et al., SARS Coronavirus Entry into Host Cells Through a Novel Clathrin- and Caveolae-Independent Endocytic Pathway, Cell Research, Vol. 18, No. 2, 2008, pp. 290-301, https://doi.org/10.1038/cr.2008.15.[4] A. Zumla, J. F. W. Chan, E. I. Azhar, D. S. C. Hui, K. Y. Yuen., Coronaviruses-Drug Discovery and Therapeutic Options, Nature Reviews Drug Discovery, Vol. 15, 2016, pp. 327-347, https://doi.org/10.1038/nrd.2015.37.[5] A. Prasansuklab, A. Theerasri, P. Rangsinth, C. Sillapachaiyaporn, S. Chuchawankul, T. Tencomnao, Anti-COVID-19 Drug Candidates: A Review on Potential Biological Activities of Natural Products in the Management of New Coronavirus Infection, Journal of Traditional and Complementary Medicine, Vol. 11, 2021, pp. 144-157, https://doi.org/10.1016/j.jtcme.2020.12.001.[6] R. E. Ferner, J. K. Aronson, Chloroquine and Hydroxychloroquine in Covid-19, BMJ, Vol. 369, 2020, https://doi.org/10.1136/bmj.m1432[7] J. Remali, W. M. Aizat, A Review on Plant Bioactive Compounds and Their Modes of Action Against Coronavirus Infection, Frontiers in Pharmacology, Vol. 11, 2021, https://doi.org/10.3389/fphar.2020.589044.[8] Y. Chen, Q. Liu, D. Guo, Emerging Coronaviruses: Genome Structure, Replication, and Pathogenesis, Medical Virology, Vol. 92, 2020, pp. 418‐423. https://doi.org/10.1002/jmv.25681.[9] B. Benarba, A. Pandiella, Medicinal Plants as Sources of Active Molecules Against COVID-19, Frontiers in Pharmacology, Vol. 11, 2020, https://doi.org/10.3389/fphar.2020.01189.[10] N. T. Chien, P. V. Trung, N. N. Hanh, Isolation Tribulosin, a Spirostanol Saponin from Tribulus terrestris L, Can Tho University Journal of Science, Vol. 10, 2008, pp. 67-71 (in Vietnamese).[11] V. Q. Thang Study on Extracting Active Ingredient Protodioscin from Tribulus terrestris L.: Doctoral dissertation, VNU University of Science, 2018 (in Vietnamese).[12] Y. H. Song, D. W. Kim, M. J. C. Long, H. J. Yuk, Y. Wang, N. Zhuang et al., Papain-Like Protease (Plpro) Inhibitory Effects of Cinnamic Amides from Tribulus terrestris Fruits, Biological and Pharmaceutical Bulletin, Vol. 37, No. 6, 2014, pp. 1021-1028, https://doi.org/10.1248/bpb.b14-00026.[13] D. Dermawan, B. A. Prabowo, C. A. Rakhmadina, In Silico Study of Medicinal Plants with Cyclodextrin Inclusion Complex as The Potential Inhibitors Against SARS-Cov-2 Main Protease (Mpro) and Spike (S) Receptor, Informatics in Medicine Unlocked, Vol. 25, 2021, pp. 1-18, https://doi.org/10.1016/j.imu.2021.100645.[14] R. Dang, S. Gezici, Immunomodulatory Effects of Medicinal Plants and Natural Phytochemicals in Combating Covid-19, The 6th International Mediterranean Symposium on Medicinal and Aromatic Plants (MESMAP-6), Izmir, Selcuk (Ephesus), Turkey, 2020, pp. 12-13.[15] G. Jiangning, W. Xinchu, W. Hou, L. Qinghua, B. Kaishun, Antioxidants from a Chinese Medicinal Herb–Psoralea corylifolia L., Food Chemistry, Vol. 9, No. 2, 2005, pp. 287-292, https://doi.org/10.1016/j.foodchem.2004.04.029.[16] B. Ruan, L. Y. Kong, Y. Takaya, M. Niwa, Studies on The Chemical Constituents of Psoralea corylifolia L., Journal of Asian Natural Products Research, Vol. 9, No. 1, 2007, pp. 41-44, https://doi.org/10.1080/10286020500289618.[17] D. T. Loi, Vietnamese Medicinal Plants and Herbs, Medical Publishing House, Hanoi, 2013 (in Vietnamese).[18] S. Mazraedoost, G. Behbudi, S. M. Mousavi, S. A. Hashemi, Covid-19 Treatment by Plant Compounds, Advances in Applied NanoBio-Technologies, Vol. 2, No. 1, 2021, pp. 23-33, https://doi.org/10.47277/AANBT/2(1)33.[19] B. A. Origbemisoye, S. O. Bamidele, Immunomodulatory Foods and Functional Plants for COVID-19 Prevention: A Review, Asian Journal of Medical Principles and Clinical Practice, 2020, pp. 15-26, https://journalajmpcp.com/index.php/AJMPCP/article/view/30124[20] A. Mandal, A. K. Jha, B. Hazra, Plant Products as Inhibitors of Coronavirus 3CL Protease, Frontiers in Pharmacology, Vol. 12, 2021, pp. 1-16, https://doi.org/10.3389/fphar.2021.583387[21] N. H. Tung, V. D. Loi, B. T. Tung, L.Q. Hung, H. B. Tien et al., Triterpenen Ursan Frame Isolated from the Roots of Salvia Miltiorrhiza Bunge Growing in Vietnam, VNU Journal of Science: Medical and Pharmaceutical Sciences, Vol. 32, No. 2, 2016, pp. 58-62, https://js.vnu.edu.vn/MPS/article/view/3583 (in Vietnamese).[22] J. Y. Park, J. H. Kim, Y. M. Kim, H. J. Jeong, D. W. Kim, K. H. Park et al., Tanshinones as Selective and Slow-Binding Inhibitors for SARS-CoV Cysteine Proteases. Bioorganic and Medicinal Chemistry, Vol. 20, No. 19, 2012, pp. 5928-5935, https://doi.org/10.1016/j.bmc.2012.07.038.[23] F. Hamdani, N. Houari, Phytotherapy of Covid-19. A Study Based on a Survey in North Algeria, Phytotherapy, Vol. 18, No. 5, 2020, pp. 248-254, https://doi.org/10.3166/phyto-2020-0241.[24] P. T. L. Huong, N. T. Dinh, Chemical Composition And Antibacterial Activity of The Essential Oil From The Leaves of Regrowth Eucalyptus Collected from Viet Tri City, Phu Tho Province, Vietnam Journal of Science, Technology and Engineering, Vol. 18, No. 1, 2020, pp. 54-61 (in Vietnamese).[25] M. Asif, M. Saleem, M. Saadullah, H. S. Yaseen, R. Al Zarzour, COVID-19 and Therapy with Essential Oils Having Antiviral, Anti-Inflammatory, and Immunomodulatory Properties, Inflammopharmacology, Vol. 28, 2020, pp. 1153-1161, https://doi.org/10.1007/s10787-020-00744-0.[26] I. Jahan, O. Ahmet, Potentials of Plant-Based Substance to Inhabit and Probable Cure for The COVID-19, Turkish Journal of Biology, Vol. 44, No. SI-1, 2020, pp. 228-241, https://doi.org/10.3906/biy-2005-114.[27] A. D. Sharma, I. Kaur, Eucalyptus Essential Oil Bioactive Molecules from Against SARS-Cov-2 Spike Protein: Insights from Computational Studies, Res Sq., 2021, pp. 1-6, https://doi.org/10.21203/ rs.3.rs-140069/v1. [28] K. Rajagopal, P. Varakumar, A. Baliwada, G. Byran, Activity of Phytochemical Constituents of Curcuma Longa (Turmeric) and Andrographis Paniculata Against Coronavirus (COVID-19): An in Silico Approach, Future Journal of Pharmaceutical Sciences, Vol. 6, No. 1, 2020, pp. 1-10, https://doi.org/10.1186/s43094-020-00126-x[29] J. Lan, J. Ge, J. Yu, S. Shan, H. Zhou, S. Fan et al., Structure of The SARS-CoV-2 Spike Receptor-Binding Domain Bound to The ACE2 Receptor, Nature, Vol. 581, No. 7807, 2020, pp. 215-220, https://doi.org/10.1038/s41586-020-2180-5.[30] M. Letko, A. Marzi, V. Munster, Functional Assessment of Cell Entry and Receptor Usage for SARS-Cov-2 and Other Lineage B Betacoronaviruses, Nature Microbiology, Vol. 5, No. 4, 2020, pp. 562-569, https://doi.org/10.1038/s41564-020-0688-y.[31] C. Yi, X. Sun, J. Ye, L. Ding, M. Liu, Z. Yang et al., Key Residues of The Receptor Binding Motif in The Spike Protein of SARS-Cov-2 That Interact with ACE2 and Neutralizing Antibodies, Cellular and Molecular Immunology, Vol. 17, No. 6, 2020, pp. 621-630, https://doi.org/10.1038/s41423-020-0458-z.[32] N. T. Thom, Study on The Composition and Biological Activities of Flavonoids from The Roots of Scutellaria baicalensis: Doctoral Dissertation, Hanoi University of Science and Technology, 2018 (in Vietnamese).[33] Y. J. Tang, F. W. Zhou, Z. Q. Luo, X. Z. Li, H. M. Yan, M. J. Wang et al., Multiple Therapeutic Effects of Adjunctive Baicalin Therapy in Experimental Bacterial Meningitis, Inflammation, Vol. 33, No. 3, 2010, pp. 180-188, https://doi.org/10.1007/s10753-009-9172-9.[34] H. Liu, F. Ye, Q. Sun, H. Liang, C. Li, S. Li et al., Scutellaria Baicalensis Extract and Baicalein Inhibit Replication of SARS-Cov-2 and Its 3C-Like Protease in Vitro, Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 36, No. 1, 2021, pp. 497-503, https://doi.org/10.1080/14756366.2021.1873977.[35] Z. Iqbal, H. Nasir, S. Hiradate, Y. Fujii, Plant Growth Inhibitory Activity of Lycoris Radiata Herb. and The Possible Involvement of Lycorine as an Allelochemical, Weed Biology and Management, Vol. 6, No. 4, 2006, pp. 221-227, https://doi.org/10.1111/j.1445-6664.2006.00217.x.[36] S. Y. Li, C. Chen, H. Q. Zhang, H. Y. Guo, H. Wang, L. Wang et al., Identification of Natural Compounds with Antiviral Activities Against SARS-Associated Coronavirus, Antiviral Research, Vol. 67, No. 1, 2005, pp. 18-23, https://doi.org/10.1016/j.antiviral.2005.02.007.[37] S. Kretzing, G. Abraham, B. Seiwert, F. R. Ungemach, U. Krügel, R. Regenthal, Dose-dependent Emetic Effects of The Amaryllidaceous Alkaloid Lycorine in Beagle Dogs, Toxicon, Vol. 57, No. 1, 2011, pp. 117-124, https://doi.org/10.1016/j.toxicon.2010.10.012.[38] Y. N. Zhang, Q. Y. Zhang, X. D. Li, J. Xiong, S. Q. Xiao, Z. Wang, et al., Gemcitabine, Lycorine and Oxysophoridine Inhibit Novel Coronavirus (SARS-Cov-2) in Cell Culture, Emerging Microbes & Infections, Vol. 9, No. 1, 2020, pp. 1170-1173, https://doi.org/10.1080/22221751.2020.1772676.[39] Y. H. Jin, J. S. Min, S. Jeon, J. Lee, S. Kim, T. Park et al., Lycorine, a Non-Nucleoside RNA Dependent RNA Polymerase Inhibitor, as Potential Treatment for Emerging Coronavirus Infections, Phytomedicine, Vol. 86, 2021, pp. 1-8, https://doi.org/10.1016/j.phymed.2020.153440.[40] H. V. Hoa, P. V. Trung, N. N. Hanh, Isolation Andrographolid and Neoandrographolid from Andrographis Paniculata Nees, Can Tho University Journal of Science, Vol. 10, 2008, pp. 25-30 (in Vietnamese)[41] S. K. Enmozhi, K. Raja, I. Sebastine, J. Joseph, Andrographolide as a Potential Inhibitor Of SARS-Cov-2 Main Protease: An in Silico Approach, Journal of Biomolecular Structure and Dynamics, Vol. 39, No. 9, 2021, pp. 3092-3098, https://doi.org/10.1080/07391102.2020.1760136.[42] S. A. Lakshmi, R. M. B. Shafreen, A. Priya, K. P. Shunmugiah, Ethnomedicines of Indian Origin for Combating COVID-19 Infection by Hampering The Viral Replication: Using Structure-Based Drug Discovery Approach, Journal of Biomolecular Structure and Dynamics, Vol. 39, No. 13, 2020, pp. 4594-4609, https://doi.org/10.1080/07391102.2020.1778537.[43] N. P. L. Laksmiani, L. P. F. Larasanty, A. A. G. J. Santika, P. A. A. Prayoga, A. A. I. K. Dewi, N. P. A. K. Dewi, Active Compounds Activity from The Medicinal Plants Against SARS-Cov-2 Using in Silico Assay, Biomedical and Pharmacology Journal, Vol. 13, No. 2, 2020, pp. 873-881, https://dx.doi.org/10.13005/bpj/1953.[44] N. A. Murugan, C. J. Pandian, J. Jeyakanthan, Computational Investigation on Andrographis Paniculata Phytochemicals to Evaluate Their Potency Against SARS-Cov-2 in Comparison to Known Antiviral Compounds in Drug Trials, Journal of Biomolecular Structure and Dynamics, Vol. 39, No. 12, 2020, pp. 4415-4426, https://doi.org/10.1080/07391102.2020.1777901.[45] S. Hiremath, H. V. Kumar, M. Nandan, M. Mantesh, K. Shankarappa,V. Venkataravanappa et al., In Silico Docking Analysis Revealed The Potential of Phytochemicals Present in Phyllanthus Amarus and Andrographis Paniculata, Used in Ayurveda Medicine in Inhibiting SARS-Cov-2, 3 Biotech, Vol. 11, No. 2, 2021, pp. 1-18, https://doi.org/10.1007/s13205-020-02578-7.[46] K. S. Ngiamsuntorn, A. Suksatu, Y. Pewkliang, P. Thongsri, P. Kanjanasirirat, S. Manopwisedjaroen, et al., Anti-SARS-Cov-2 Activity of Andrographis Paniculata Extract and Its Major Component Andrographolide in Human Lung Epithelial Cells and Cytotoxicity Evaluation in Major Organ Cell Representatives, Journal of Natural Products, Vol. 84, No. 4, 2021, pp. 1261-1270, https://doi.org/10.1021/acs.jnatprod.0c01324.[47] D. X. Em, N. T. T. Dai, N. T. T. Tram, D. X. Chu, Four Compounds Isolated from Azadirachta Indica Jus leaves. F., Meliaceae, Pharmaceutical Journal, Vol. 59, No. 7, 2019, pp. 33-36 (in Vietnamese).[48] V. V Do, N. T. Thang, N. T. Minh, N. N. Hanh, Isolation, Purification and Investigation on Antimicrobial Activity of Salanin from Neem Seed Kernel (Azadirachta Indica A. Juss) of The Neem Tree Planted in Ninh Thuan Province, Vietnam, Journal of Science and Technology, Vol. 44, No. 2, 2006, pp. 24-31 (in Vietnamese).[49] P. I. Manzano Santana, J. P. P. Tivillin, I. A. Choez Guaranda, A. D. B. Lucas, A. Katherine, Potential Bioactive Compounds of Medicinal Plants Against New Coronavirus (SARS-Cov-2): A Review, Bionatura, Vol. 6, No. 1, 2021, pp. 1653-1658, https://doi.org/10.21931/RB/2021.06.01.30[50] S. Borkotoky, M. Banerjee, A Computational Prediction of SARS-Cov-2 Structural Protein Inhibitors from Azadirachta Indica (Neem), Journal of Biomolecular Structure and Dynamics, Vol. 39, No. 11, 2021, pp. 4111-4121, https://doi.org/10.1080/07391102.2020.1774419.[51] R. Jager, R. P. Lowery, A. V. Calvanese, J. M. Joy, M. Purpura, J. M. Wilson, Comparative Absorption of Curcumin Formulations, Nutrition Journal, Vol. 13, No. 11, 2014, https://doi.org/10.1186/1475-2891-13-11.[52] D. Praditya, L. Kirchhoff, J. Bruning, H. Rachmawati, J. Steinmann, E. Steinmann, Anti-infective Properties of the Golden Spice Curcumin, Front Microbiol, Vol. 10, No. 912, 2019, https://doi.org/10.3389/fmicb.2019.00912.[53] C. C. Wen, Y. H. Kuo, J. T. Jan, P. H. Liang, S. Y. Wang, H. G. Liu et al., Specific Plant Terpenoids and Lignoids Possess Potent Antiviral Activities Against Severe Acute Respiratory Syndrome Coronavirus, Journal of Medicinal Chemistry, Vol. 50, No. 17, 2007, pp. 4087-4095, https://doi.org/10.1021/jm070295s.[54] R. Lu, X. Zhao, J. Li, P. Niu, B. Yang, H. Wu et al., Genomic Characterisation and Epidemiology of 2019 Novel Coronavirus: Implications for Virus Origins and Receptor Binding, The Lancet, Vol. 395, No. 10224, 2020, pp. 565-574, https://doi.org/10.1016/S0140-6736(20)30251-8.[55] M. Kandeel, M. Al Nazawi, Virtual Screening and Repurposing of FDA Approved Drugs Against COVID-19 Main Protease, Life Sciences, Vol. 251, No. 117627, 2020, pp. 1-5, https://doi.org/10.1016/j.lfs.2020.117627.[56] V. K. Maurya, S. Kumar, A. K. Prasad, M. L. B. Bhatt, S. K. Saxena, Structure-Based Drug Designing for Potential Antiviral Activity of Selected Natural Products from Ayurveda Against SARS-CoV-2 Spike Glycoprotein and Its Cellular Receptor, Virusdisease, Vol. 31, No. 2, 2020, pp. 179-193, https://doi.org/10.1007/s13337-020-00598-8.[57] M. Hoffmann, H. Kleine Weber, S. Schroeder, N. Kruger, T. Herrler, S. Erichsen et al., SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell, Vol. 181, No. 2, 2020, pp. 271-280, https://doi.org/10.1016/j.cell.2020.02.052.[58] S. Katta, A. Srivastava, R. L. Thangapazham, I. L. Rosner, J. Cullen, H. Li et al., Curcumin-Gene Expression Response in Hormone Dependent and Independent Metastatic Prostate Cancer Cells, International Journal of Molecular Sciences, Vol. 20, No. 19, 2019, pp. 4891-4907, https://doi.org/10.3390/ijms20194891.[59] D. Ting, N. Dong, L. Fang, J. Lu, J. Bi, S. Xiao et al., Multisite Inhibitors for Enteric Coronavirus: Antiviral Cationic Carbon Dots Based on Curcumin, ACS Applied Nano Materials, Vol. 1, No. 10, 2018, pp. 5451-5459, https://doi.org/10.1021/acsanm.8b00779.[60] T. Huynh, H. Wang, B. Luan, In Silico Exploration of the Molecular Mechanism of Clinically Oriented Drugs for Possibly Inhibiting SARS-CoV-2's Main Protease, the Journal of Physical Chemistry Letters, Vol. 11, No. 11, 2020, pp. 4413-4420, https://doi.org/10.1021/acs.jpclett.0c00994.[61] D. D'Ardes, A. Boccatonda, I. Rossi, M. T. Guagnano, COVID-19 and RAS: Unravelling an Unclear Relationship, International Journal of Molecular Sciences, Vol. 21, No. 8, 2020, pp. 3003-3011, https://doi.org/10.3390/ijms21083003. [62] X. F. Pang, L. H. Zhang, F. Bai, N. P. Wang, R. E. Garner, R. J. McKallip et al., Attenuation of Myocardial Fibrosis with Curcumin is Mediated by Modulating Expression of Angiotensin II AT1/AT2 Receptors and ACE2 in Rats, Drug Design Development Therapy, Vol. 9, 2015, pp. 6043-6054, https://doi.org/10.2147/DDDT.S95333.[63] Y. Yao, W. Wang, M. Li, H. Ren, C. Chen, J. Wang et al., Curcumin Exerts its Anti-Hypertensive Effect by Down-Regulating the AT1 Receptor in Vascular Smooth Muscle Cells, Scientific Reports, Vol. 6, No. 25579, 2016, pp. 1-6, https://doi.org/10.1038/srep25579.[64] V. J. Costela Ruiz, R. Illescas Montes, J. M. Puerta Puerta, C. Ruiz, L. Melguizo Rodríguez, SARS-CoV-2 Infection: The Role of Cytokines in COVID-19 Disease, Cytokine Growth Factor Reviews, Vol. 54, 2020, pp. 62-75, https://doi.org/10.1016/j.cytogfr.2020.06.001.[65] H. Valizadeh, S. Abdolmohammadi Vahid, S. Danshina, M. Ziya Gencer, A. Ammari, A. Sadeghi et al., Nano-Curcumin Therapy, a Promising Method in Modulating Inflammatory Cytokines in COVID-19 Patients, International Immunopharmacology, Vol. 89 (PtB), No. 107088, 2020, pp. 1-12, https://doi.org/10.1016/j.intimp.2020.107088.[66] Y. H. Lo, R. D. Lin, Y. P. Lin, Y. L. Liu, M. H. Lee, Active Constituents from Sophora Japonica Exhibiting Cellular Tyrosinase Inhibition in Human Epidermal Melanocytes, Journal of Ethnopharmacology, Vol. 124, No. 3, 2009, pp. 625-629, https://doi.org/10.1016/j.jep.2009.04.053.[67] A. Robaszkiewicz, A. Balcerczyk, G. Bartosz, Antioxidative and Prooxidative Effects of Quercetin on A549 Cells, Cell Biology International, Vol. 31, No. 10, 2007, pp. 1245-1250, https://doi.org/10.1016/j.cellbi.2007.04.009[68] N. Uchide, H. Toyoda, Antioxidant Therapy as a Potential Approach to Severe Influenza-associated Complications, Molecules (Basel, Switzerland), Vol. 16, No. 3, 2011, pp. 2032-2052, https://doi.org/10.3390/molecules16032032.[69] M. P. Nair, C. Kandaswami, S. Mahajan, K. C. Chadha, R. Chawda, H. Nair et al., The Flavonoid, Quercetin, Differentially Regulates Th-1 (IFNgamma) and Th-2 (IL4) Cytokine Gene Expression by Normal Peripheral Blood Mononuclear Cells, Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1593, No. 1, 2002, pp. 29-36, https://doi.org/10.1016/s0167-4889(02)00328-2.[70] X. Chen, Z. Wang, Z. Yang, J. Wang, Y. Xu, R. X. Tan et al., Houttuynia Cordata Blocks HSV Infection Through Inhibition of NF-κB Activation, Antiviral Research, Vol. 92, No. 2, 2011, pp. 341-345, https://doi.org/10.1016/j.antiviral.2011.09.005.[71] T. N. Kaul, E. J. Middleton, P. L. Ogra, Antiviral Effect of Flavonoids on Human Viruses, Journal of Medical Virology, Vol. 15. No. 1, 1985, pp. 71-79, https://doi.org/10.1002/jmv.1890150110.[72] K. Zandi, B. T. Teoh, S. S. Sam, P. F. Wong, M. R. Mustafa, S. AbuBakar, Antiviral Activity of Four Types of Bioflavonoid Against Dengue Virus Type-2, Virology Journal, Vol. 8, No. 1, 2011, pp. 560-571, https://doi.org/10.1186/1743-422X-8-560.[73] J. Y. Park, H. J. Yuk, H. W. Ryu, S. H. Lim, K. S. Kim, K. H. Park et al., Evaluation of Polyphenols from Broussonetia Papyrifera as Coronavirus Protease Inhibitors, Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 32, No. 1, 2017, pp. 504-515, https://doi.org/10.1080/14756366.2016.1265519.[74] S. C. Cheng, W. C. Huang, J. H. S. Pang, Y. H. Wu, C. Y. Cheng, Quercetin Inhibits the Production of IL-1β-Induced Inflammatory Cytokines and Chemokines in ARPE-19 Cells via the MAPK and NF-κB Signaling Pathways, International Journal of Molecular Sciences, Vol. 20, No. 12, 2019, pp. 2957-2981, https://doi.org/10.3390/ijms20122957. [75] O. J. Lara Guzman, J. H. Tabares Guevara, Y. M. Leon Varela, R. M. Álvarez, M. Roldan, J. A. Sierra et al., Proatherogenic Macrophage Activities Are Targeted by The Flavonoid Quercetin, The Journal of Pharmacology and Experimental Therapeutics, Vol. 343, No. 2, 2012, pp. 296-303, https://doi.org/10.1124/jpet.112.196147.[76] A. Saeedi Boroujeni, M. R. Mahmoudian Sani, Anti-inflammatory Potential of Quercetin in COVID-19 Treatment, Journal of Inflammation, Vol. 18, No. 1, 2021, pp. 3-12, https://doi.org/10.1186/s12950-021-00268-6.[77] M. Smith, J. C. Smith, Repurposing Therapeutics for COVID-19: Supercomputer-based Docking to the SARS-CoV-2 Viral Spike Protein and Viral Spike Protein-human ACE2 Interface, ChemRxiv, 2020, pp. 1-28, https://doi.org/10.26434/chemrxiv.11871402.v4.[78] S. Khaerunnisa, H. Kurniawan, R. Awaluddin, S. Suhartati, S. Soetjipto, Potential Inhibitor of COVID-19 Main Protease (Mpro) from Several Medicinal Plant Compounds by Molecular Docking Study, Preprints, 2020, pp. 1-14, https://doi.org/10.20944/preprints202003.0226.v1.[79] J. M. Calderón Montaño, E. B. Morón, C. P. Guerrero, M. L. Lázaro, A Review on the Dietary Flavonoid Kaempferol, Mini Reviews in Medicinal Chemistry, Vol. 11, No. 4, 2011, pp. 298-344, https://doi.org/10.2174/138955711795305335.[80] A. Y. Chen, Y. C. Chen, A Review of the Dietary Flavonoid, Kaempferol on Human Health and Cancer Chemoprevention, Food Chem, Vol. 138, No. 4, 2013, pp. 2099-2107, https://doi.org/10.1016/j.foodchem.2012.11.139.[81] S. Schwarz, D. Sauter, W. Lu, K. Wang, B. Sun, T. Efferth et al., Coronaviral Ion Channels as Target for Chinese Herbal Medicine, Forum on Immunopathological Diseases and Therapeutics, Vol. 3, No. 1, 2012, pp. 1-13, https://doi.org/10.1615/ForumImmunDisTher.2012004378.[82] R. Zhang, X. Ai, Y. Duan, M. Xue, W. He, C. Wang et al., Kaempferol Ameliorates H9N2 Swine Influenza Virus-induced Acute Lung Injury by Inactivation of TLR4/MyD88-mediated NF-κB and MAPK Signaling Pathways, Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, Vol. 89, 2017, pp. 660-672, https://doi.org/10.1016/j.biopha.2017.02.081.[83] K. W. Chan, V. T. Wong, S. C. W. Tang, COVID-19: An Update on the Epidemiological, Clinical, Preventive and Therapeutic Evidence and Guidelines of Integrative Chinese-Western Medicine for the Management of 2019 Novel Coronavirus Disease, The American Journal of Chinese medicine, Vol. 48, No. 3, 2020, pp. 737-762, https://doi.org/10.1142/S0192415X20500378.[84] Y. F. Huang, C. Bai, F. He, Y. Xie, H. Zhou, Review on the Potential Action Mechanisms of Chinese Medicines in Treating Coronavirus Disease 2019 (COVID-19), Pharmacological Research, Vol. 158, No. 104939, 2020, pp. 1-10, https://doi.org/10.1016/j.phrs.2020.104939.[85] L. Xu, X. Zheng, Y. Wang, Q. Fan, M. Zhang, R. Li et al., Berberine Protects Acute Liver Failure in Mice Through Inhibiting Inflammation and Mitochondria-dependent Apoptosis, European Journal of Pharmacology, Vol. 819, 2018, pp. 161-168, https://doi.org/10.1016/j.ejphar.2017.11.013.[86] X. Chen, H. Guo, Q. Li, Y. Zhang, H. Liu, X. Zhang et al., Protective Effect of Berberine on Aconite‑induced Myocardial Injury and the Associated Mechanisms, Molecular Medicine Reports, Vol. 18, No. 5, 2018, pp. 4468-4476, https://doi.org/10.3892/mmr.2018.9476.[87] K. Hayashi, K. Minoda, Y. Nagaoka, T. Hayashi, S. Uesato, Antiviral Activity of Berberine and Related Compounds Against Human Cytomegalovirus, Bioorganic & Medicinal Chemistry Letters, Vol. 17, No. 6, 2007, pp. 1562-1564, https://doi.org/10.1016/j.bmcl.2006.12.085.[88] A. Warowicka, R. Nawrot, A. Gozdzicka Jozefiak, Antiviral Activity of Berberine, Archives of Virology, Vol. 165, No. 9, 2020, pp. 1935-1945, https://doi.org/10.1007/s00705-020-04706-3.[89] Z. Z. Wang, K. Li, A. R. Maskey, W. Huang, A. A. Toutov, N. Yang et al., A Small Molecule Compound Berberine as an Orally Active Therapeutic Candidate Against COVID-19 and SARS: A Computational and Mechanistic Study, FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, Vol. 35, No. 4, 2021, pp. e21360-21379, https://doi.org/10.1096/fj.202001792R.[90] A. Pizzorno, B. Padey, J. Dubois, T. Julien, A. Traversier, V. Dulière et al., In Vitro Evaluation of Antiviral Activity of Single and Combined Repurposable Drugs Against SARS-CoV-2, Antiviral Research, Vol. 181, No. 104878, 2020, https://doi.org/10.1016/j.antiviral.2020.104878.[91] B. Y. Zhang, M. Chen, X. C. Chen, K. Cao, Y. You, Y. J. Qian et al., Berberine Reduces Circulating Inflammatory Mediators in Patients with Severe COVID-19, The British Journal of Surgery, Vol. 108, No. 1, 2021, pp. e9-e11, https://doi.org/10.1093/bjs/znaa021.[92] K. P. Latté, K. E. Appel, A. Lampen, Health Benefits and Possible Risks of Broccoli - an Overview, Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association, Vol. 49, No. 12, 2011, pp. 3287-3309, https://doi.org/10.1016/j.fct.2011.08.019.[93] C. Sturm, A. E. Wagner, Brassica-Derived Plant Bioactives as Modulators of Chemopreventive and Inflammatory Signaling Pathways, International Journal of Molecular Sciences, Vol. 18, No. 9, 2017, pp. 1890-1911, https://doi.org/10.3390/ijms18091890.[94] R. T. Ruhee, S. Ma, K. Suzuki, Sulforaphane Protects Cells against Lipopolysaccharide-Stimulated Inflammation in Murine Macrophages, Antioxidants (Basel, Switzerland), Vol. 8, No. 12, 2019, pp. 577-589, https://doi.org/10.3390/antiox8120577.[95] S. M. Ahmed, L. Luo, A. Namani, X. J. Wang, X. Tang, Nrf2 Signaling Pathway: Pivotal Roles in Inflammation, Biochimica et Biophysica Acta Molecular Basis of Disease, Vol. 1863, No. 2, 2017, pp. 585-597, https://doi.org/10.1016/j.bbadis.2016.11.005.[96] Z. Sun, Z. Niu, S. Wu, S. Shan, Protective Mechanism of Sulforaphane in Nrf2 and Anti-Lung Injury in ARDS Rabbits, Experimental Therapeutic Medicine, Vol. 15, No. 6, 2018, pp. 4911-4951, https://doi.org/10.3892/etm.2018.6036.[97] H. Y. Cho, F. Imani, L. Miller DeGraff, D. Walters, G. A. Melendi, M. Yamamoto et al., Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease, American Journal of Respiratory and Critical Care Medicine, Vol. 179, No. 2, 2009, pp. 138-150, https://doi.org/10.1164/rccm.200804-535OC.[98] M. J. Kesic, S. O. Simmons, R. Bauer, I. Jaspers, Nrf2 Expression Modifies Influenza A Entry and Replication in Nasal Epithelial Cells, Free Radical Biology & Medicine, Vol. 51, No. 2, 2011, pp. 444-453, https://doi.org/10.1016/j.freeradbiomed.2011.04.027.[99] A. Cuadrado, M. Pajares, C. Benito, J. J. Villegas, M. Escoll, R. F. Ginés et al., Can Activation of NRF2 Be a Strategy Against COVID-19?, Trends in Pharmacological Sciences, Vol. 41, No. 9, 2020, pp. 598-610, https://doi.org/10.1016/j.tips.2020.07.003.[100] J. Gasparello, E. D'Aversa, C. Papi, L. Gambari, B. Grigolo, M. Borgatti et al., Sulforaphane Inhibits the Expression of Interleukin-6 and Interleukin-8 Induced in Bronchial Epithelial IB3-1 Cells by Exposure to the SARS-CoV-2 Spike Protein, Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, Vol. 87, No. 53583, 2021, https://doi.org/10.1016/j.phymed.2021.153583.

ABSTRACT With the development of carbonate reservoirs moves to the ultra-deep layer, the etched fracture would be closes quickly in the high stress. In this paper, high channel sanding method with acid fracturing technology are combined, the strength and spread ways of the different type proppant are optimized, and the fracture conductivity of continuous sanding and channel sanding are tested. The experiment result shows that high strength ceramic proppant can improve the conductivity of acid erosion fractures under high pressure. In the stress of 50MPa, fracture conductivity by high channel sanding with 86MPa ceramic could be increased by more than 51% than that of conventional acid etched fracture. The flow conductivity increase amplitude reaches more than 700% in the condition of 90MPa. By changing the sanding mode, the quantity of proppant can be saved, the pump risk can be reduced, and the stable and solid support channel can also be formed to improve the conductivity of acid etched fractures in ultra-deep carbonate reservoirs. INTRODUCTION With the gradual development of the Carbonate reservoir to the ultra-deep layer, the depth of the reservoir has reached 8,800 meters, and the temperature has been raised from 120°C to 180°C. The increase of reservoir depth and temperature brings many new challenges to reservoir stimulation. When the effective closure stress of the reservoir increases from 10 MPa to 55 MPa, the conventional acid etched fracture conductivity decreases by 95% (Yao et al., 2015). With the increase of closure stress, the insufficient support strength is the main reason for the rapid decrease of the fracture conductivity. In order to increase the fracture validity period after acid fracturing, the main objective is to improve the long-term etched fracture conductivity. The existing acid fracturing is to dissolve calcareous minerals on the fracture surface, leaving the unreacted rock skeleton as the supporting point. Due to the uneven distribution of each point and its low compressive resistance, it will be crushed gradually under high closure stress. Many scholars (Yi et al., 2006, 2008, 2010, Gao et al., 2015, Wang et al., 2012,2016, He et al., 2014) tried to improve the fracture conductivity by using cross-linked acid carrying sand or compound acid fracturing, and achieved certain effect in the oilfield application. However, with the increase of reservoir depth, it becomes more and more difficult to add sand into the carbonate reservoirs. In the meantime, proppant concentration cannot be effectively increased, making it difficult to achieve the effect of high concentration proppant placement (Zhuang et al., 2014). In recent years, many researchers try to use high channel pulse sand-adding method in low permeability reservoir (Zhong et al., 2012, Wu et al., 2014, Liu, 2015, Fu et al., 2016).