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Lei S, Luo M, Wang Y. Pin1 as a central node in oncogenic signaling: Mechanistic insights and clinical prospects (Review). Mol Med Rep 2025; 31:80. [PMID: 39886975 PMCID: PMC11795255 DOI: 10.3892/mmr.2025.13445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 01/14/2025] [Indexed: 02/01/2025] Open
Abstract
Peptidyl‑prolyl cis‑trans isomerase NIMA-interacting 1 (Pin1) is a specific phosphorylated serine/threonine-proline cis-trans isomerase, which is involved in the regulation of a variety of physiological and pathological processes, including cell cycle progression, proliferation and apoptosis. Pin1 plays a key role in tumorigenesis and tumor development and it promotes the proliferation and metastasis of cancer cells by regulating the cell cycle, signaling pathways and the function of tumor suppressors. Upregulated expression of Pin1 is closely associated with a poor prognosis in several types of cancers. Thus, Pin1 is may have potential as a novel potential biomarker for tumor diagnosis and prognosis, as well as a promising anticancer target. The aim of the present review was to discuss the mechanism of Pin1 in tumors and recent research progress in this field.
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Affiliation(s)
- Shuning Lei
- Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Min Luo
- Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Yuxue Wang
- Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
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Niu T, Wang J, Xun L, Zheng B, Deng Z, Chen Z, Jia K, Zhao P, Zhao Q. Deciphering the impact and mechanism of total flavonoids from Cortex Juglandis Mandshuricae on alcoholic fatty liver employing LC-MS/MS, network pharmacology analysis and in vitro validation. J Chromatogr B Analyt Technol Biomed Life Sci 2024; 1248:124334. [PMID: 39514994 DOI: 10.1016/j.jchromb.2024.124334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 08/01/2024] [Accepted: 10/01/2024] [Indexed: 11/16/2024]
Abstract
The Cortex Juglandis Mandshuricae (CJM) has the efficacy of penetrating the liver meridian, removing heat and dampness, and alleviating the liver, which corresponds to the pathogenesis of alcoholic fatty liver disease (AFLD) with damp heat accumulation. Modern research has shown that total flavonoids from Cortex Juglandis Mandshuricae (TFC) have hepatoprotective, antioxidant and antitumour pharmacological effects. However, there is no any investigation on the mechanism of TFC improving AFLD. In this work, a valid strategy combining UPLC-Q-Exactive Orbitrap-MS, network pharmacology and in vitro cellular experimental validation is proposed to predict the targets and pathways of TFC to ameliorate AFLD and to explore its mechanism of action. As a result, 26 flavonoids and 182 targets linked to TFC and AFLD were identified. These compounds realize their critical targets via various signaling pathways and perform multiple biological functions on the basis of the constructed compound-disease target networks. In vitro experiments demonstrated TFC had a protective impact on ethanol-treated L02 cells to a certain extent and could diminished lipid accretion. In addition, RT-qPCR and western blot results illustrated that TFC could regulate the expression of PPARα, CPT-1, SREBP-1c and FAS, and inhibit alcohol-induced lipid accumulation in L02 cells thereby alleviating AFLD. The present study further provides experimental justification for TFC to ameliorate AFLD in practical applications.
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Affiliation(s)
- Tianmei Niu
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China
| | - Jiaxin Wang
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China
| | - Liying Xun
- School of Basic Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China
| | - Bingqing Zheng
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China
| | - Zhipeng Deng
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China
| | - Zhi Chen
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China
| | - Kaijie Jia
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China
| | - Pan Zhao
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China.
| | - Qitao Zhao
- School of Basic Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China.
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Suyal S, Choudhury C, Kaur D, Bachhawat AK. Identification of inhibitors of human ChaC1, a cytoplasmic glutathione degrading enzyme through high throughput screens in yeast. Biochem J 2024; 481:1475-1495. [PMID: 39400295 DOI: 10.1042/bcj20240447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/21/2024] [Accepted: 09/24/2024] [Indexed: 10/15/2024]
Abstract
The cytosolic glutathione-degrading enzyme, ChaC1, is highly up-regulated in several cancers, with the up-regulation correlating to poor prognosis. The ability to inhibit ChaC1 is therefore important in different pathophysiological situations, but is challenging owing to the high substrate Km of the enzyme. As no inhibitors of ChaC1 are known, in this study we have focussed on this goal. We have initially taken a computational approach where a systemic structure-based virtual screening was performed. However, none of the predicted hits proved to be effective inhibitors. Synthetic substrate analogs were also not inhibitory. As both these approaches targeted the active site, we shifted to developing two high-throughput, robust, yeast-based assays that were active site independent. A small molecule compound library was screened using an automated liquid handling system using these screens. The hits were further analyzed using in vitro assays. Among them, juglone, a naturally occurring naphthoquinone, completely inhibited ChaC1 activity with an IC50 of 8.7 µM. It was also effective against the ChaC2 enzyme. Kinetic studies indicated that the inhibition was not competitive with the substrate. Juglone is known to form adducts with glutathione and is also known to selectively inhibit enzymes by covalently binding to active site cysteine residues. However, juglone continued to inhibit a cysteine-free ChaC1 variant, indicating that it was acting through a novel mechanism. We evaluated different inhibitory mechanisms, and also analogues of juglone, and found plumbagin effective as an inhibitor. These compounds are the first inhibitor leads against the ChaC enzymes using a robust yeast screen.
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Affiliation(s)
- Shradha Suyal
- Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali, S.A.S. Nagar, Punjab 140306, India
| | - Chinmayee Choudhury
- Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali, S.A.S. Nagar, Punjab 140306, India
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh 160012, India
| | - Deepinder Kaur
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh 160012, India
| | - Anand K Bachhawat
- Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali, S.A.S. Nagar, Punjab 140306, India
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Pan T, Shi X, Bao Y, Wang S, Li T, Diao Y, Meng X. Metabolomics research on treatment of primary liver cancer with Cortex Juglandis Mandshuricae on LC-MS/MS technology. J Pharm Biomed Anal 2024; 248:116320. [PMID: 38959758 DOI: 10.1016/j.jpba.2024.116320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 06/12/2024] [Accepted: 06/20/2024] [Indexed: 07/05/2024]
Abstract
Diethylnitrosamine (DEN) was applied to create the primary liver cancer (PLC) animal model. In the study, the normal group, model group, cyclophosphamide (CTX) group, Cortex Juglandis Mandshuricae (CJM) extract group, myricetin group and myricitrin group were divided. LC-MS/MS technology was applied to determine the metabolites of liver tissue samples from different locations (nodular and non-nodular parts of liver tissue) in each group of rats. Through metabolomics research, the connection and difference of anti-PLC induced by the CJM extract, myricetin and myricitrin was analyzed. The surface of the liver tissues of rats in the model group was rough, dimly colored, inelastic, on which there were scattered gray white cancer nodules and blood stasis points. The number of cancer nodules was significantly reduced, and the degree of cell malignancy was low, but there were some inflammatory cell infiltrations, necrosis area and karyokinesis in the CJM extract group, myricetin group, myricitrin group and CTX group. The result of metabolic research indicated that 45 potential biomarkers of the PLC were found, as gamma-aminoisobutyrate, taurochenodeoxycholate, xanthurenic acid, etc. There were 22 differential metabolites in the CTX group, 16 differential metabolites in the CJM extract group, 14 differential metabolites in the myricetin group, 14 differential metabolites in the myricitrin group.
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Affiliation(s)
- Taowen Pan
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian 11644, China
| | - Xiaoli Shi
- Pharmacy Department of Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Yongrui Bao
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Shuai Wang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Tianjiao Li
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Yunpeng Diao
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian 11644, China
| | - Xiansheng Meng
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China.
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Men L, Gu Z, Wang E, Li J, Li Z, Li K, Li C, Gong X. Fufang Muji Granules Ameliorate Liver Fibrosis by Reducing Oxidative Stress and Inflammation, Inhibiting Apoptosis, and Modulating Overall Metabolism. Metabolites 2024; 14:446. [PMID: 39195542 DOI: 10.3390/metabo14080446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 07/26/2024] [Accepted: 08/07/2024] [Indexed: 08/29/2024] Open
Abstract
Fufang Muji granules (FMGs) are a prominent modern prescription Chinese patent formulation derived from the Muji decoction. Utilized in clinical practice for nearly four decades, FMGs have demonstrated efficacy in treating liver diseases. However, the precise mechanism of action remains unclear. This study investigates the hepatoprotective effects of FMGs against liver fibrosis in rats based on untargeted metabolomics and elucidates their underlying mechanisms. A comprehensive model of liver fibrosis was established with 30% CCl4 (2 mL/kg) injected intraperitoneally, and a fat and sugar diet combined with high temperatures and humidity. Rats were orally administered FMGs (3.12 g/kg/d) once daily for six weeks. FMG administration resulted in improved liver fibrosis and attenuated hepatic oxidative stress and apoptosis. Furthermore, FMGs inhibited hepatic stellate cell activation and modulated transforming growth factor β1/Smad signaling. Additionally, FMG treatment influenced the expression levels of interleukin-6, interleukin-1β, and tumour necrosis factor alpha in the injured liver. Metabolic pathways involving taurine and hypotaurine metabolism, as well as primary bile acid biosynthesis, were identified as mechanisms of action for FMGs. Immunohistochemistry, quantitative reverse transcription polymerase chain reaction (RT-qPCR), and quantitative analysis also revealed that FMGs regulated taurine and hypotaurine metabolism and bile acid metabolism. These findings provide a valuable understanding of the role of FMGs in liver fibrosis management.
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Affiliation(s)
- Lei Men
- Department of Biological Engineering, College of Life Science, Dalian Minzu University, Dalian 116600, China
- Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Zhihong Gu
- Department of Biological Engineering, College of Life Science, Dalian Minzu University, Dalian 116600, China
- Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Enhua Wang
- Department of Biological Engineering, College of Life Science, Dalian Minzu University, Dalian 116600, China
- Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Jiwen Li
- Department of Biological Engineering, College of Life Science, Dalian Minzu University, Dalian 116600, China
- Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Zhongyu Li
- Department of Biological Engineering, College of Life Science, Dalian Minzu University, Dalian 116600, China
- Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Keke Li
- Department of Biological Engineering, College of Life Science, Dalian Minzu University, Dalian 116600, China
- Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Chunbin Li
- Department of Biological Engineering, College of Life Science, Dalian Minzu University, Dalian 116600, China
- Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Xiaojie Gong
- Department of Biological Engineering, College of Life Science, Dalian Minzu University, Dalian 116600, China
- Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, Dalian Minzu University, Dalian 116600, China
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Topal O, Topal BG, Baş Y, Ongan B, Sadi G, Aslan E, Yavaş BD, Pektaş MB. Impact of Juglone, a PIN1 İnhibitor, on Oral Carcinogenesis Induced by 4-Nitroquinoline-1-Oxide (4NQO) in Rat Model. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1192. [PMID: 39202474 PMCID: PMC11356210 DOI: 10.3390/medicina60081192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/04/2024] [Accepted: 07/16/2024] [Indexed: 09/03/2024]
Abstract
Background and Objectives: PIN1 is overexpressed in several human cancers, including prostate cancer, breast cancer, and oral squamous carcinomas. Juglone (J), derived from walnut, was reported to selectively inhibit PIN1 by modifying its sulfhydryl groups. In this study, the potential effects of juglone, also known as PIN1 inhibitor, on oral cancer and carcinogenesis were investigated at the molecular level. Materials and Methods: 4-Nitroquinoline N-oxide (4-NQO) was used to create an oral cancer model in animals. Wistar rats were divided into five groups: Control, NQO, Juglone, NQO+J, and NQO+J*. The control group received the basal diet and tap water throughout the experiment. The NQO group received 4-NQO for 8 weeks in drinking water only. The Juglone group was administered intraperitoneally in a juglone solution for 10 weeks (1 mg/kg/day). The NQO+J group received 4-NQO in drinking water for 8 weeks, starting 1 week after the cessation of 4-NQO treatment. They were then administered intraperitoneally in a juglone solution for 10 weeks. (1 mg/kg/day). NQO+J* group: received 4 NQO for 8 weeks in drinking water and administered intraperitoneally in a juglone solution for 10 weeks (1 mg/kg/day). They were sacrificed at the end of the 22-week experimental period. The tongue tissues of the rats were isolated after the experiment, morphological changes were investigated by histological examinations, and the molecular apoptotic process was investigated by rt-qPCR and western blot. Results: Histological results indicate that tumors are formed in the tongue tissue with 4-NQO, and juglone treatment largely corrects the epithelial changes that developed with 4-NQO. It has been determined that apoptotic factors p53, Bax, and caspases are induced by the effect of juglone, while antiapoptotic factors such as Bcl-2 are suppressed. However, it was observed that the positive effects were more pronounced in rats given juglone together with 4-NQO. Conclusions: The use of PIN1 inhibitors such as juglone in place of existing therapeutic approaches might be a promising and novel approach to the preservation and treatment of oral cancer and carcinogenesis. However, further research is required to investigate the practical application of such inhibitors.
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Affiliation(s)
- Olgun Topal
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Afyonkarahisar Health Sciences University, 03200 Afyonkarahisar, Turkey; (O.T.); (Y.B.); (B.O.)
| | - Burcu Güçyetmez Topal
- Department of Pedodontics, Faculty of Dentistry, Afyonkarahisar Health Sciences University, 03200 Afyonkarahisar, Turkey;
| | - Yunus Baş
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Afyonkarahisar Health Sciences University, 03200 Afyonkarahisar, Turkey; (O.T.); (Y.B.); (B.O.)
| | - Bünyamin Ongan
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Afyonkarahisar Health Sciences University, 03200 Afyonkarahisar, Turkey; (O.T.); (Y.B.); (B.O.)
| | - Gökhan Sadi
- Department of Biology, K.O. Science Faculty, Karamanoglu Mehmetbey University, 70100 Karaman, Turkey;
| | - Esra Aslan
- Department of Histology and Embryology, Faculty of Medicine, Afyonkarahisar Health Sciences University, 03200 Afyonkarahisar, Turkey;
| | - Betül Demirciler Yavaş
- Private Practice, Traditional and Complementary Treatment Center, 03200 Afyonkarahisar, Turkey;
| | - Mehmet Bilgehan Pektaş
- Department of Medical Pharmacology, Faculty of Medicine, Afyonkarahisar Health Sciences University, 03200 Afyonkarahisar, Turkey
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Wnorowska S, Grzegorczyk A, Kurzepa J, Maggi F, Strzemski M. Fractionation of Carlina acaulis L. Root Methanolic Extract as a Promising Path towards New Formulations against Bacillus cereus and Methicillin-Resistant Staphylococcus aureus. Molecules 2024; 29:1939. [PMID: 38731430 PMCID: PMC11085459 DOI: 10.3390/molecules29091939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/19/2024] [Accepted: 04/21/2024] [Indexed: 05/13/2024] Open
Abstract
The root of Carlina acaulis L. has been widely used in traditional medicine for its antimicrobial properties. In this study, the fractionation of methanol extract from the root was conducted. Four fractions (A, B, C, and D) were obtained and tested against a range of bacteria and fungi. The results showed promising antibacterial activity, especially against Bacillus cereus, where the minimal inhibitory concentration (MIC) was determined to be equal to 0.08 mg/mL and 0.16 mg/mL for heptane (fraction B) and ethyl acetate (fraction C), respectively. In the case of the methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300 strain, the same fractions yielded higher MIC values (2.5 and 5.0 mg/mL, respectively). This was accompanied by a lack of apparent cytotoxicity to normal human BJ foreskin fibroblasts, enterocytes derived from CaCo2 cells, and zebrafish embryos. Further analyses revealed the presence of bioactive chlorogenic acids in the fractionated extract, especially in the ethyl acetate fraction (C). These findings support the traditional use of the root from C. acaulis and pave the way for the development of new formulations for treating bacterial infections. This was further evaluated in a proof-of-concept experiment where fraction C was used in the ointment formulation, which maintained high antimicrobial activity against MRSA and displayed low toxicity towards cultured fibroblasts.
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Affiliation(s)
- Sylwia Wnorowska
- Department of Medical Chemistry, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Agnieszka Grzegorczyk
- Department of Pharmaceutical Microbiology, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Jacek Kurzepa
- Department of Medical Chemistry, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Filippo Maggi
- Chemistry Interdisciplinary Project (ChIP), School of Pharmacy, University of Camerino, Via Madonna Delle Carceri, 62032 Camerino, Italy;
| | - Maciej Strzemski
- Department of Analytical Chemistry, Medical University of Lublin, 20-093 Lublin, Poland
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Pan Y, Luo X, Gong P. Spatholobi caulis: A systematic review of its traditional uses, chemical constituents, biological activities and clinical applications. JOURNAL OF ETHNOPHARMACOLOGY 2023; 317:116854. [PMID: 37393029 DOI: 10.1016/j.jep.2023.116854] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/19/2023] [Accepted: 06/26/2023] [Indexed: 07/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Spatholobi caulis (SC), the dried vine stem of Spatholobus suberectus Dunn, is known as Ji Xue Teng in China, and has long been used as traditional Chinese medicine (TCM) to treat anaemia, menstrual abnormalities, rheumatoid arthritis, purpura, etc. AIM OF THE REVIEW: The aim of this review is to provide a systematic and updated summary of the traditional uses, chemical constituents, biological activities and clinical applications of SC. In addition, several suggestions for future research on SC are also proposed. MATERIALS AND METHODS Extensive information and data on SC were obtained from electronic databases (ScienceDirect, Web of Science, PubMed, CNKI, Baidu Scholar, Google Scholar, ResearchGate, SpringerLink and Wiley Online). Additional information was collected from Ph.D. and MSc dissertations, published books, and classic material medica. RESULTS To date, phytochemical studies have revealed that approximately 243 chemical ingredients have been isolated from SC and identified, including flavonoids, glycosides, phenolic acids, phenylpropanoids, volatile oils, sesquiterpenoids and other compounds. Many studies have indicated that extracts and pure constituents from SC possess a wide spectrum of in vitro and in vivo pharmacological effects, such as anti-tumour, haematopoietic, anti-inflammatory, antidiabetic, antioxidant, antiviral and antibacterial effects, as well as other activities. SC could be applied to the treatment of leukopenia, aplastic anemic, endometriosis, etc. according to the clinical reports. The traditional efficacies of SC is due to the biological functions of its chemical compounds, especially flavonoids. However, research investigating the toxicological effects of SC is relatively limited. CONCLUSIONS SC is widely used in TCM formulae and its some traditional efficacies has been confirmed by extensive recent pharmacological and clinical studies. Most the biological activities of the SC may be attributed to flavonoids. However, in-depth studies on the molecular mechanisms of the effective ingredients and extracts of SC are limited. Further systematic studies focusing on pharmacokinetics, toxicology and quality control are needed to ensure the effective and safe application of SC.
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Affiliation(s)
- Yehua Pan
- College of Pharmacy, Southwest Minzu University, Chengdu, 610041, China.
| | - Xiaomin Luo
- College of Pharmacy, Southwest Minzu University, Chengdu, 610041, China.
| | - Puyang Gong
- College of Pharmacy, Southwest Minzu University, Chengdu, 610041, China.
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Li S, Sun Y. Phytochemicals targeting epidermal growth factor receptor (EGFR) for the prevention and treatment of HNSCC: A review. Medicine (Baltimore) 2023; 102:e34439. [PMID: 37800790 PMCID: PMC10553117 DOI: 10.1097/md.0000000000034439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 06/30/2023] [Indexed: 10/07/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) develops from the mucosal epithelium of the oral cavity, pharynx, and larynx, and is the most common malignancy of the head and neck, the incidence of which continues to rise. The epidermal growth factor receptor is thought to play a key role in the pathogenesis of HNSCC. Inhibition of epidermal growth factor receptor has been identified as an effective target for the treatment of HNSCC. Many phytochemicals have emerged as potential new drugs for the treatment of HNSCC. A systematic search was conducted for research articles published in PubMed, and Medline on relevant aspects. This review provides an overview of the available literature and reports highlighting the in vitro effects of phytochemicals on epidermal growth factor in various HNSCC cell models and in vivo in animal models and emphasizes the importance of epidermal growth factor as a current therapeutic target for HNSCC. Based on our review, we conclude that phytochemicals targeting the epidermal growth factor receptor are potentially effective candidates for the development of new drugs for the treatment of HNSCC. It provides an idea for further development and application of herbal medicines for cancer treatment.
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Affiliation(s)
- Shaling Li
- The Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University, Longmatan District, Luzhou City, Sichuan Province, China
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10
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Zhang YB, Bao YR, Wang S, Li TJ, Tai H, Leng JP, Yang XX, Wang BC, Meng XS. Possible mechanisms associated with immune escape and apoptosis on anti-hepatocellular carcinoma effect of Mu Ji Fang granules. World J Gastrointest Oncol 2023; 15:504-522. [PMID: 37009316 PMCID: PMC10052660 DOI: 10.4251/wjgo.v15.i3.504] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/19/2023] [Accepted: 03/02/2023] [Indexed: 03/14/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common digestive system cancers with high mortality rates worldwide. The main ingredients in Mu Ji Fang Granules (MJF) are alkaloids, flavonoids, and polysaccharides. MJF has been used in the clinical treatment of hepatitis, cirrhosis and HCC for more than 30 years. Few previous studies have focused on the mechanism of MJF on tumor immu-nology in the treatment of HCC.
AIM To explore the mechanism of action of MJF on tumor immunology in the treatment of HCC.
METHODS The absorbable ingredients of MJF were identified using Molecule Network related to High Performance Liquid Chromatography-Electron Spray Ionization-Time of Flight- Mass Spectrometry, and hub potential anti-HCC targets were screened using network pharmacology and pathway enrichment analysis. Forty male mice were randomly divided into the Blank, Model, and MJF groups (1.8, 5.4, and 10.8 g/kg/d) following 7 d of oral administration. Average body weight gain, spleen and thymus indices were calculated, tumor tissues were stained with hematoxylin and eosin, and Interferon gamma (IFN-γ), Tumor necrosis factor α (TNF-α), Interleukin-2, aspartate aminotransferase, alanine aminotransferase, alpha-fetoprotein (AFP), Fas, and FasL were measured by Enzyme-linked Immunosorbent Assay. Relevant mRNA expression of Bax and Bcl2 was evaluated by Real Time Quantitative PCR (RT-qPCR) and protein expression of Transforming growth factor β1 (TGF-β1) and Mothers against decapentaplegic homolog (SMAD) 4 was assessed by Western blotting. The HepG2 cell line was treated with 10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL of MJF, and another 3 groups were treated with TGF-β1 inhibitor (LY364947) and different doses of MJF. Relevant mRNA expression of TNF-α, IFN-γ, Bax and Bcl2 was evaluated by RT-qPCR and protein expression of TGF-β1, SMAD2, p-SMAD2, SMAD4, and SMAD7 was assessed by Western blotting.
RESULTS It was shown that MJF improved body weight gain and tumor inhibition rate in H22 tumor-bearing mice, protected immune organs and liver function, reduced the HCC indicator AFP, affected immunity and apoptosis, and up-regulated the TGF-β1/SMAD signaling pathway, by increasing the relative expression of TGF-β1, SMAD2, p-SMAD2 and SMAD4 and decreasing SMAD7, reducing immune factors TNF-α and IFN-γ, decreasing apoptosis cytokines Fas, FasL and Bcl2/Bax, and inhibiting the effect of LY364947 in HepG2 cells.
CONCLUSION MJF inhibits HCC by activating the TGF-β1/SMAD signaling pathway, and affecting immune and apoptotic cytokines, which may be due to MJF adjusting immune escape and apoptosis.
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Affiliation(s)
- Yi-Bing Zhang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
- Department of Clinical Trail Institution Office, Dalian Municipal Central Hospital, Dalian 116033, Liaoning Province, China
| | - Yong-Rui Bao
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
- Technical Innovation Center of Multidimensional Analysis of Traditional Chinese Medicine of Liaoning Province, Dalian 116600, Liaoning Province, China
- Engineering Laboratory of Modern Chinese Medicine Research of Liaoning Province, Dalian 116600, Liaoning Province, China
| | - Shuai Wang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
- Technical Innovation Center of Multidimensional Analysis of Traditional Chinese Medicine of Liaoning Province, Dalian 116600, Liaoning Province, China
- Engineering Laboratory of Modern Chinese Medicine Research of Liaoning Province, Dalian 116600, Liaoning Province, China
| | - Tian-Jiao Li
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
- Technical Innovation Center of Multidimensional Analysis of Traditional Chinese Medicine of Liaoning Province, Dalian 116600, Liaoning Province, China
- Engineering Laboratory of Modern Chinese Medicine Research of Liaoning Province, Dalian 116600, Liaoning Province, China
| | - He Tai
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
| | - Jia-Peng Leng
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
| | - Xin-Xin Yang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
| | - Bo-Cai Wang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
| | - Xian-Sheng Meng
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
- Technical Innovation Center of Multidimensional Analysis of Traditional Chinese Medicine of Liaoning Province, Dalian 116600, Liaoning Province, China
- Engineering Laboratory of Modern Chinese Medicine Research of Liaoning Province, Dalian 116600, Liaoning Province, China
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Patil VM, Masand N, Gautam V, Kaushik S, Wu D. Multi-Target-Directed Ligand Approach in Anti-Alzheimer’s Drug Discovery. DECIPHERING DRUG TARGETS FOR ALZHEIMER’S DISEASE 2023:285-319. [DOI: 10.1007/978-981-99-2657-2_13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Gong CX, Dai CL, Liu F, Iqbal K. Multi-Targets: An Unconventional Drug Development Strategy for Alzheimer's Disease. Front Aging Neurosci 2022; 14:837649. [PMID: 35222001 PMCID: PMC8864545 DOI: 10.3389/fnagi.2022.837649] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/20/2022] [Indexed: 11/20/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that eventually leads to dementia and death of the patient. Despite the enormous amounts of resources and efforts for AD drug development during the last three decades, no effective treatments have been developed that can slow or halt the progression of the disease. Currently available drugs for treating AD can only improve clinical symptoms temporarily with moderate efficacies. In recent years, the scientific community has realized these challenges and reconsidered the future directions of AD drug development. The most significant recent changes in AD drug development strategy include shifting from amyloid-based targets to other targets, such as tau, and efforts toward better designs for clinical trials. However, most AD drug development is still focused on a single mechanism or target, which is the conventional strategy for drug development. Although multifactorial mechanisms and, on this basis, multi-target strategies have been proposed in recent years, this approach has not been widely recognized and accepted by the mainstream of AD drug development. Here, we emphasize the multifactorial mechanisms of AD and discuss the urgent need for a paradigm shift in AD drug development from a single target to multiple targets, either with the multi-target-directed ligands approach or the combination therapy approach. We hope this article will increase the recognition of the multifactorial nature of AD and promote this paradigm shift. We believe that such a shift will facilitate successful development of effective AD therapies.
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Affiliation(s)
- Cheng-Xin Gong
- Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, New York, NY, United States
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