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Qayoom H, Bashir S, Khan R, Hussain MU, Wani S, Mir MA. Exploring SALL4 as a significant prognostic marker in breast cancer and its association with progression pathways involved in cancer genesis. Comput Biol Chem 2024; 112:108164. [PMID: 39098137 DOI: 10.1016/j.compbiolchem.2024.108164] [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: 06/10/2024] [Revised: 07/20/2024] [Accepted: 07/25/2024] [Indexed: 08/06/2024]
Abstract
Breast carcinoma is the leading factor in women's cancer-related fatalities. Due to its numerous inherent molecular subtypes, breast cancer is an extremely diverse illness. The human epidermal growth factor receptor 2 (HER2) positive subtypes stands out among these subtypes as being especially prone to cancer development and illness recurrence. The regulation of embryonic stem cells' pluripotency and self-renewal is carried out by the SALL4 (Spalt-like transcription factor 4) family member. Numerous molecular pathways operating at the transcriptional, post-transcriptional, and epigenomic levels regulate the expression of SALL4. Many transcription factors control the expression of SALL4, with STAT3 being the primary regulator in hepatocellular carcinoma (HCC) and breast carcinoma. Moreover, this oncogene has been connected to a number of cellular functions, including invasion, apoptosis, proliferation, and resistance to therapy. Reduced patient survival rates and a worse prognosis have been linked to higher levels of SALL4. In order to target the undruggable SALL4 that is overexpressed in breast carcinoma, we investigated the prognostic levels of SALL4 in breast carcinoma and its interaction with various related proteins. Using TIMER 2.0 analysis, the expression pattern of SALL4 was investigated across all TCGA datasets. The research revealed that SALL4 expression was elevated in various cancers. The UALCAN findings demonstrated that SALL4 was overexpressed in all tumor samples including breast cancer especially TNBC (Triple negative breast cancer). The web-based ENRICHR program was used for gene ontology analysis that revealed SALL4 was actively involved in the development of the nervous system, positive regulation of stem cell proliferation, regulation of stem cell proliferation, regulation of the activin receptor signaling pathway, regulation of transcription using DNA templates, miRNA metabolic processes, and regulation of transcription by RNA Polymerase I. Using the STRING database, we analyzed the interaction and involvement of SALL4 with other abruptly activated proteins and used Cytoscape 3.8.0 for visualization. Additionally, using bc-GenExMiner, we studied the impact of SALL4 on pathways abruptly activated in different breast cancer subtypes that revealed SALL4 was highly correlated with WNT2B, NOTCH4, AKT3, and PIK3CA. Furthermore, to target SALL4, we evaluated and analyzed the impact of CLP and its analogues, revealing promising outcomes.
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Affiliation(s)
- Hina Qayoom
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Sania Bashir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Rumaisa Khan
- Department of Biotechnology, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Mahboob Ul Hussain
- Department of Biotechnology, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Shameema Wani
- Department of Surgical Oncology, Super Specialty Hospital, Govt Medical College Srinagar, 190001, India
| | - Manzoor A Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India.
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El-Aarag B, Shalaan ES, Ahmed AAS, El Sayed IET, Ibrahim WM. Cryptolepine Analog Exhibits Antitumor Activity against Ehrlich Ascites Carcinoma Cells in Mice via Targeting Cell Growth, Oxidative Stress, and PTEN/Akt/mTOR Signaling Pathway. Anticancer Agents Med Chem 2024; 24:436-442. [PMID: 38305388 DOI: 10.2174/0118715206274318231128072821] [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: 07/26/2023] [Revised: 10/12/2023] [Accepted: 10/18/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND The efficacy of chemotherapy continues to be limited due to associated toxicity and chemoresistance. Thus, synthesizing and investigating novel agents for cancer treatment that could potentially eliminate such limitations is imperative. OBJECTIVE The current study aims to explore the anticancer potency of cryptolepine (CPE) analog on Ehrlich ascites carcinoma cells (EACs) in mice. METHODS The effect of a CPE analog on EAC cell viability and ascites volume, as well as malonaldehyde, total antioxidant capacity, and catalase, were estimated. The concentration of caspase-8 and mTOR in EACs was also measured, and the expression levels of PTEN and Akt were determined. RESULTS Results revealed that CPE analog exerts a cytotoxic effect on EAC cell viability and reduces the ascites volume. Moreover, this analog induces oxidative stress in EACs by increasing the level of malonaldehyde and decreasing the level of total antioxidant capacity and catalase activity. It also induces apoptosis by elevating the concentration of caspase-8 in EACs. Furthermore, it decreases the concentration of mTOR in EACs. Moreover, it upregulates the expression of PTEN and downregulates the expression of Akt in EACs. CONCLUSION Our findings showed the anticancer activity of CPE analog against EACs in mice mediated by regulation of the PTEN/Akt/mTOR signaling pathway.
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Affiliation(s)
- Bishoy El-Aarag
- Biochemistry Division, Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koom, 32512, Egypt
- Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA, 92618, USA
- Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama, 7008530, Japan
| | - Eman S Shalaan
- Biochemistry Division, Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koom, 32512, Egypt
| | - Abdullah A S Ahmed
- Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koom, Egypt
| | | | - Wafaa M Ibrahim
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt
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Al-Sanea MM, Abdel-Maksoud MS, El-Behairy MF, Hamdi A, Ur Rahman H, Parambi DGT, Elbargisy RM, Mohamed AAB. Anti-inflammatory effect of 3-fluorophenyl pyrimidinylimidazo[2,1-b]thiazole derivatives as p38α inhibitors. Bioorg Chem 2023; 139:106716. [PMID: 37459825 DOI: 10.1016/j.bioorg.2023.106716] [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: 03/06/2023] [Revised: 05/21/2023] [Accepted: 07/06/2023] [Indexed: 08/13/2023]
Abstract
In the present work, the anti-inflammatory effect of 30 compounds containing 3-fluorophenyl pyrimidinylimidazo[2,1-b]thiazole was investigated. All final target compounds showed significant Inhibitory effect on p38α. P38α is considered one of the key kinases in the inflammatory process due to its regulatory effect on pro-inflammatory mediators. The final target compounds divided into four group based on the type of terminal moiety (amide and sulfonamide) and the linker between pyrimidine ring and terminal moiety (ethyl and propyl). Most compounds with terminal sulfonamide moiety and propyl linker between the sulfonamide and pyrimidine ring were the most potent among all synthesized final target compounds with sub-micromolar IC50s. Compound 24g (with p-Cl benzene sulfonamide and propyl linker) exhibited the highest activity over P38α with IC50 0.68 µM. All final target compounds were tested for their ability to inhibit nitric oxide release and prostaglandin E2 production. Compounds having amide terminal moiety with ethyl linker showed higher inhibitory activity for nitric oxide release and compound 21d exhibited the highest activity for nitric oxide release with IC50 1.21 µM. Compounds with terminal sulfonamide moiety and propyl linker showed the highest activity for inhibiting PGE2 production and compounds 24i and 24g had the lowest IC50s with value 0.87 and 0.89 µM, respectively. Compounds 21d, 22d and 24g were tested for their ability to inhibit over expression of iNOS, COX1, and COX2. In addition the ability of compounds 21d, 22d and 24g to inhibit inflammatory cytokines were determined. Finally molecular docking of the three compounds were performed on P38α crystal structure to expect their mode of binding.
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Affiliation(s)
- Mohammad M Al-Sanea
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia.
| | - Mohammed S Abdel-Maksoud
- Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre (ID: 60014618), Dokki, Giza, Egypt.
| | - Mohammed Farrag El-Behairy
- Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Menoufiya 32897, Egypt
| | - Abdelrahman Hamdi
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Hidayat Ur Rahman
- Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia
| | - Della G T Parambi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia
| | - Rehab M Elbargisy
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Ahmed A B Mohamed
- Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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Thobokholt EN, Simonetti SO, Kaufman TS, Larghi EL, Bracca ABJ. Efficient Buchwald-Hartwig and nitrene-mediated five-membered ring closure approaches to the total synthesis of quindoline. Unexpected direct conversion of a nitro group into a phosphazene. RSC Adv 2023; 13:13715-13724. [PMID: 37152581 PMCID: PMC10162371 DOI: 10.1039/d3ra02468g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 04/25/2023] [Indexed: 05/09/2023] Open
Abstract
Two total syntheses of quindoline, which take place through the intermediacy of 3-nitroquinoline derivatives, are reported. The general synthetic sequence involves construction of the latter by mechanochemical condensation of benzaldehydes with 2-amino-nitrostyrene, followed either by reduction of the nitro group of the heterocycle and Buchwald-Hartwig cyclization or by a nitrene-mediated cyclization under solventless conditions. Use of PPh3 to generate the nitrene resulted in the unprecedented formation of a phosphazene in place of quindoline. This unexpected transformation was explained by means of DFT computations.
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Affiliation(s)
- Elida N Thobokholt
- Instituto de Química Rosario (IQUIR, CONICET-UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario Suipacha 531 2000 Rosario Argentina
| | - Sebastián O Simonetti
- Instituto de Química Rosario (IQUIR, CONICET-UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario Suipacha 531 2000 Rosario Argentina
| | - Teodoro S Kaufman
- Instituto de Química Rosario (IQUIR, CONICET-UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario Suipacha 531 2000 Rosario Argentina
| | - Enrique L Larghi
- Instituto de Química Rosario (IQUIR, CONICET-UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario Suipacha 531 2000 Rosario Argentina
| | - Andrea B J Bracca
- Instituto de Química Rosario (IQUIR, CONICET-UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario Suipacha 531 2000 Rosario Argentina
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Discovery of cryptolepine derivatives as novel promising agents against phytopathogenic bacteria. Front Chem Sci Eng 2022. [DOI: 10.1007/s11705-022-2196-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2022]
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The Pharmacologically Active Alkaloid Cryptolepine Activates a Type 1 Interferon Response That Is Independent of MAVS and STING Pathways. J Immunol Res 2022; 2022:8873536. [PMID: 35928633 PMCID: PMC9345703 DOI: 10.1155/2022/8873536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 05/25/2022] [Accepted: 07/01/2022] [Indexed: 11/18/2022] Open
Abstract
Type 1 interferons (IFN-1) are pleiotropic cytokines with well-established anticancer and antiviral properties, particularly in mucosal tissues. Hence, natural IFN-1-inducing treatments are highly sought after in the clinic. Here, we report for the first time that cryptolepine, a pharmacoactive alkaloid in the medicinal plant Cryptolepis sanguinolenta, is a potent IFN-1 pathway inducer. Cryptolepine increased the transcript levels of JAK1, TYK2, STAT1, STAT2, IRF9, and OAS3, as well as increased the accumulation of STAT1 and OAS3 proteins, similar to recombinant human IFN-α. Cryptolepine effects were observed in multiple cell types including a model of human macrophages. This response was maintained in MAVS and STING-deficient cell lines, suggesting that cryptolepine effects are not mediated by nucleic acids released upon nuclear or organelle damage. In agreement, cryptolepine did not affect cell viability in concentrations that triggered potent IFN-1 activation. In addition, we observed no differences in the presence of a pharmacological inhibitor of TBK1, a pleiotropic kinase that is a converging point for Toll-like receptors (TLRs) and nucleic acid sensors. Together, our results demonstrate that cryptolepine is a strong inducer of IFN-1 response and suggest that cryptolepine-based medications such as C. sanguinolenta extract could be potentially tested in resource-limited regions of the world for the management of chronic viral infections as well as cancers.
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Chu QR, He YH, Tang C, Zhang ZJ, Luo XF, Zhang BQ, Zhou Y, Wu TL, Du SS, Yang CJ, Liu YQ. Design, Synthesis, and Antimicrobial Activity of Quindoline Derivatives Inspired by the Cryptolepine Alkaloid. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:2851-2863. [PMID: 35226498 DOI: 10.1021/acs.jafc.1c07536] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Based on the structural characteristics of the cryptolepine alkaloid, a series of new quindoline derivatives bearing various substituents were prepared and evaluated for their fungicidal and antibacterial activities. Bioassay results showed that compound D7 displayed superior in vitro fungicidal activities against Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum, and Rhizoctonia solani with EC50 values of 0.780, 3.62, 1.59, and 2.85 μg/mL, respectively. Compound A7 showed apparent antibacterial activities toward Xanthomonas oryzae pv. oryzae with a minimum inhibitory concentration (MIC) value of 3.12 μg/mL. Significantly, in vivo antifungal activity suggested that the curative effect (98.3%) of compound D7 was comparable to that of the positive control azoxystrobin (96.7%) at 100 μg/mL. Preliminary mechanistic studies showed that compound D7 might cause mycelial abnormality of S. sclerotiorum, cell membrane breakage, accumulation of reactive oxygen species (ROS), and inhibition of sclerotia formation. Therefore, compound D7 could be a novel broad-spectrum fungicidal candidate against plant fungal diseases.
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Affiliation(s)
- Qing-Ru Chu
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Ying-Hui He
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Chen Tang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Zhi-Jun Zhang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Xiong-Fei Luo
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Bao-Qi Zhang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Yong Zhou
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Tian-Lin Wu
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Sha-Sha Du
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Cheng-Jie Yang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Ying-Qian Liu
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
- State Key Laboratory of Grassland Agro-ecosystems, Lanzhou University, Lanzhou 730000, People's Republic of China
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Wang MR, Huang LF, Guo C, Yang J, Dong S, Tang JJ, Gao JM. Identification of NLRP3 as a covalent target of 1,6-O,O-diacetylbritannilactone against neuroinflammation by quantitative thiol reactivity profiling (QTRP). Bioorg Chem 2021; 119:105536. [PMID: 34894577 DOI: 10.1016/j.bioorg.2021.105536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/29/2021] [Accepted: 11/30/2021] [Indexed: 11/02/2022]
Abstract
Neuroinflammation plays a key etiological role in the progressive neuronal damage of neurodegenerative diseases. Our phenotypic-based screening discovered 1,6-O,O-diacetylbritannilactone (OABL, 1) from Inula britannica exhibited the potential anti-neuroinflammatory activity as well as a favorable blood-brain barrier penetration. 1 and its active derivative Br-OABL (2) with insert of Br at the C-14 position both modulated TLR4/NF-kB/MAPK pathways. However, proteome-wide identification of 1 binding proteins remains unclear. Here, we employed an adapted isoTOP-ABPP, quantitative thiol reactivity profiling (QTRP) approach, to identify and quantify thiol reactivity binding proteins in murine microglia BV-2 cells. We screened out 15 proteins co-targeted by 1 and 2, which are involved in cellular response to oxidative stress and negative regulation NF-κB transcription factor in biological processes. In site-specific profiling, NLRP3 was identified as a covalent target of 1 and 2 for the first time, and the Cys483 of NLRP3 NACHT domain was identified as one active-site of NLRP3 cysteine residues that can be covalently modified by the α-methylene-γ-lactone moiety. Furthermore, NLRP3 was validated to be directly binded by 1 and 2 by cellular thermo shift assay (CETSA) and activity-based protein profiling (ABPP), and NLRP3 functions were also verified by small interfering RNA approach. Notably, OABL treatment (i.p., 20 mg/kg/day) for 21 days reduced inflammation in 5XFAD mice brain. Together, we applied the QTRP to uncover the binding proteins of OABL in BV-2 cells, among which NLRP3 was revealed as a new covalent target of 1 and 2 against neuroinflammation.
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Affiliation(s)
- Min-Ran Wang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing, Beijing Institute of Lifeomics, Beijing, China
| | - Lan-Fang Huang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China
| | - Cong Guo
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China
| | - Jing Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing, Beijing Institute of Lifeomics, Beijing, China
| | - Shuai Dong
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, Hainan, China
| | - Jiang-Jiang Tang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China.
| | - Jin-Ming Gao
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China.
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Chowdhury S, Kanrar K, Bhuiya S, Das S. The alkaloid cryptolepine as a source of polyadenylate targeting therapeutic agent: Induction of self-assembly in the polyadenylate moiety. Arch Biochem Biophys 2021; 712:109042. [PMID: 34562470 DOI: 10.1016/j.abb.2021.109042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 09/04/2021] [Accepted: 09/20/2021] [Indexed: 10/20/2022]
Abstract
RNAs have become a well-known target for chemotherapeutic agents in the recent years. The tails of most eukaryotic m-RNA are characterized by the presence of a long polyadenylate sequence which plays an important role in its growth and maturation. This lays emphasis on development of molecular probes that target the polyadenylate sequence. Cryptolepine (hereafter, CRP) is an indoloquinoline alkaloid well known for its anti-malarial activities. A series of spectroscopic experiments namely absorption studies, fluorimetric studies and circular dichroism studies show that cryptolepine binds with single-stranded polyriboadenylic acid (hereafter, ss-poly (rA)) with a binding constant of ∼5 × 103 M-1 at 25 °C. Moreover thermal denaturation experiments show that the bound form of polyriboadenylic acid shows a characteristic transition profile. Such a profile is indicative of the ability of cryptolepine to induce self-assembly in the polyriboadenylic acid sequence on binding to it. Such ability of CRP to modulate the structural conformation of poly (rA), which in turn may cause functional aspects of the RNA to change, may give us a chance to develop effective alkaloid based chemotherapeutic agents.
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Affiliation(s)
- Susmita Chowdhury
- Biophysical Chemistry Laboratory, Physical Chemistry Section, Department of Chemistry, Jadavpur University, 188, Raja S. C. Mallick Road, Kolkata, 700032, India
| | - Kasturi Kanrar
- Biophysical Chemistry Laboratory, Physical Chemistry Section, Department of Chemistry, Jadavpur University, 188, Raja S. C. Mallick Road, Kolkata, 700032, India
| | - Sutanwi Bhuiya
- Biophysical Chemistry Laboratory, Physical Chemistry Section, Department of Chemistry, Jadavpur University, 188, Raja S. C. Mallick Road, Kolkata, 700032, India
| | - Suman Das
- Biophysical Chemistry Laboratory, Physical Chemistry Section, Department of Chemistry, Jadavpur University, 188, Raja S. C. Mallick Road, Kolkata, 700032, India.
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Domfeh S, Narkwa P, Quaye O, Kusi K, Rivera O, Danaah M, Musah B, Awandare G, Mensah K, Mutocheluh M. Cryptolepine and Nibima inhibit hepatitis B virus replication. SCIENTIFIC AFRICAN 2021. [DOI: 10.1016/j.sciaf.2021.e00942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
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Domfeh SA, Narkwa PW, Quaye O, Kusi KA, Awandare GA, Ansah C, Salam A, Mutocheluh M. Cryptolepine inhibits hepatocellular carcinoma growth through inhibiting interleukin-6/STAT3 signalling. BMC Complement Med Ther 2021; 21:161. [PMID: 34078370 PMCID: PMC8170807 DOI: 10.1186/s12906-021-03326-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 05/11/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Diverse signalling pathways are involved in carcinogenesis and one of such pathways implicated in many cancers is the interleukin 6/signal transducer and activator of transcription 3 (IL-6/STAT3) signalling pathway. Therefore, inhibition of this pathway is targeted as an anti-cancer intervention. This study aimed to establish the effect of cryptolepine, which is the main bioactive alkaloid in the medicinal plant Cryptolepis sanguinolenta, on the IL-6/STAT3 signalling pathway. METHODS First, the effect of cryptolepine on the IL-6/STAT3 pathway in human hepatoma cells (HepG2 cells) was screened using the Cignal Finder Multi-Pathway Reporter Array. Next, to confirm the effect of cryptolepine on the IL-6/STAT3 signalling pathway, the pathway was activated using 200 ng/mL IL-6 in the presence of 0.5-2 μM cryptolepine. The levels of total STAT3, p-STAT3 and IL-23 were assessed by ELISA. RESULTS Cryptolepine downregulated 12 signalling pathways including the IL-6/STAT3 signalling pathway and upregulated 17 signalling pathways. Cryptolepine, in the presence of IL-6, decreased the levels of p-STAT3 and IL-23 in a dose-dependent fashion. CONCLUSION Our results demonstrated that cryptolepine inhibits the IL-6/STAT3 signalling pathway, and therefore cryptolepine-based remedies such as Cryptolepis sanguinolenta could potentially be used as an effective immunotherapeutic agent for hepatocellular carcinoma and other cancers.
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Affiliation(s)
- Seth A Domfeh
- West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Legon, Ghana.,Department of Biochemistry, Cell and Molecular Biology, School of Biological Sciences, University of Ghana, Legon, Ghana
| | - Patrick W Narkwa
- Department of Clinical Microbiology, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Osbourne Quaye
- West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Legon, Ghana.,Department of Biochemistry, Cell and Molecular Biology, School of Biological Sciences, University of Ghana, Legon, Ghana
| | - Kwadwo A Kusi
- West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Legon, Ghana.,Department of Biochemistry, Cell and Molecular Biology, School of Biological Sciences, University of Ghana, Legon, Ghana.,Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Ghana
| | - Gordon A Awandare
- West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Legon, Ghana.,Department of Biochemistry, Cell and Molecular Biology, School of Biological Sciences, University of Ghana, Legon, Ghana
| | - Charles Ansah
- Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | | | - Mohamed Mutocheluh
- Department of Clinical Microbiology, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
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Chen YJ, Liu H, Zhang SY, Li H, Ma KY, Liu YQ, Yin XD, Zhou R, Yan YF, Wang RX, He YH, Chu QR, Tang C. Design, Synthesis, and Antifungal Evaluation of Cryptolepine Derivatives against Phytopathogenic Fungi. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:1259-1271. [PMID: 33496176 DOI: 10.1021/acs.jafc.0c06480] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Inspired by the widely antiphytopathogenic application of diversified derivatives from natural sources, cryptolepine and its derivatives were subsequently designed, synthesized, and evaluated for their antifungal activities against four agriculturally important fungi Rhizoctonia solani, Botrytis cinerea, Fusarium graminearum, and Sclerotinia sclerotiorum. The results obtained from in vitro assay indicated that compounds a1-a24 showed great fungicidal property against B. cinerea (EC50 < 4 μg/mL); especially, a3 presented significantly prominent inhibitory activity with an EC50 of 0.027 μg/mL. In the pursuit of further expanding the antifungal spectrum of cryptolepine, ring-opened compound f1 produced better activity with an EC50 of 3.632 μg/mL against R. solani and an EC50 of 5.599 μg/mL against F. graminearum. Furthermore, a3 was selected to be a candidate to investigate its preliminary antifungal mechanism to B. cinerea, revealing that not only spore germination was effectively inhibited and the normal physiological structure of mycelium was severely undermined but also detrimental reactive oxygen was obviously accumulated and the normal function of the nucleus was fairly disordered. Besides, in vivo curative experiment against B. cinerea found that the therapeutic action of a3 was comparable to that of the positive control azoxystrobin. These results suggested that compound a3 could be regarded as a novel and promising agent against B. cinerea for its valuable potency.
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Affiliation(s)
- Yong-Jia Chen
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Hua Liu
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Shao-Yong Zhang
- Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, College of Life Science, Huzhou University, Huzhou 313000, China
| | - Hu Li
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Kun-Yuan Ma
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Ying-Qian Liu
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Xiao-Dan Yin
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Rui Zhou
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Yin-Fang Yan
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Ren-Xuan Wang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Ying-Hui He
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Qing-Ru Chu
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Chen Tang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, People's Republic of China
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Discovery of natural anti-inflammatory alkaloids: Potential leads for the drug discovery for the treatment of inflammation. Eur J Med Chem 2021; 213:113165. [PMID: 33454546 DOI: 10.1016/j.ejmech.2021.113165] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 02/07/2023]
Abstract
Inflammation is an adaptive response of the immune system to tissue malfunction or homeostatic imbalance. Corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) are frequently applied to treat varieties of inflammatory diseases but are associated with gastrointestinal, cardiovascular, and kidney side effects. Developing more effective and less toxic agents remain a challenge for pharmaceutical chemist due to the complexity of the different inflammatory processes. Alkaloids are widely distributed in plants with diverse anti-inflammatory activities, providing various potential lead compounds or candidates for the design and discovery of new anti-inflammatory drug candidates. Therefore, re-examining the anti-inflammatory alkaloid natural products is advisable, bringing more opportunities. In this review, we summarized and described the recent advances of natural alkaloids with anti-inflammatory activities and possible mechanisms in the period from 2009 to 2020. It is hoped that this review of anti-inflammatory alkaloids can provide new ideas for researchers engaged in the related fields and potential lead compounds for the discovery of anti-inflammatory drugs.
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Shnyder SD, Wright CW. Recent Advances in the Chemistry and Pharmacology of Cryptolepine. PROGRESS IN THE CHEMISTRY OF ORGANIC NATURAL PRODUCTS 2021; 115:177-203. [PMID: 33797643 DOI: 10.1007/978-3-030-64853-4_4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Cryptolepine, the principal constituent of the West African climbing shrub Cryptolepis sanguinolenta, continues to be of interest as a lead to new therapeutic agents, especially for the treatment of protozoal infections and cancer. This contribution reviews the research published in the last decade, highlighting new synthesis routes to cryptolepine and to analogs of this alkaloid, as well as their pharmacology. Studies relating to the use of C. sanguinolenta as an herbal medicine for the treatment of malaria are discussed, as well as the development of analogs of cryptolepine as leads to new agents for the treatment of malaria, trypanosomiasis, and cancer with an emphasis on the pharmacological mechanisms involved. Other potential therapeutic applications include antimicrobial, antidiabetic, and anti-inflammatory activities; the pharmacokinetics and toxicity of cryptolepine are also reviewed.
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Affiliation(s)
- Steven D Shnyder
- Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK
| | - Colin W Wright
- School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK.
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15
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Meza-Menchaca T, Lizano-Soberón M, Trigos A, Zepeda RC, Medina ME, Galindo-Murillo R. Elucidating Molecular Interactions of Ten Natural Compounds Targeting E6 HPV High Risk Oncoproteins Using Microsecond Molecular Dynamics Simulations. Med Chem 2021; 17:587-600. [PMID: 31995016 DOI: 10.2174/1573406416666200129145733] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 12/03/2019] [Accepted: 12/16/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Cervical cancer is a major public health issue worldwide, occurring in the vast majority of cases (85%) in low-income countries. Human papillomavirus (HPV) mainly infects the mucosal epithelium, and a small portion causes over 600,000 cases every year worldwide at various anatomical spots, mainly leading to anogenital and head and neck. INTRODUCTION The E6 oncoprotein encoded by cancer-associated alpha HPV can transform epithelial cells into tumorigenic tissue. Therapy for this infection and blocking of the HPV E6 oncoprotein could be provided with cost-effective and abundant natural products which are an exponentially growing topic in the literature. Finding an active natural compound that readily blocks HPV E6 oncoprotein which could be available for developing countries without expensive extraction processes or costly synthetic pathways is of major interest. METHODS Molecular dynamics simulation was performed using the most up-to-date AMBER protein force field ff14SB and a GPU enabled high performance computing cluster. RESULTS In this research, we present a study of the binding properties between 10 selected natural compounds that are readily available with two variants of the E6 oncoprotein types (HPV-16 and HPV-18) using 10+ microsecond molecular dynamics simulations. CONCLUSION Our results suggest that crocetin, ergosterol peroxide and κ-carrageenan natural products bind strongly to both HPV-16 and HPV-18 and could potentially serve as a scaffolding for further drug development.
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Affiliation(s)
- Thuluz Meza-Menchaca
- Facultad de Medicina, Laboratorio de Genomica Humana, Universidad Veracruzana. Medicos y Odontologos, Col. Unidad del Bosque, 91010, Xalapa, Veracruz, Mexico
| | - Marcela Lizano-Soberón
- Unidad de Investigacion Biomedica en Cáncer, Instituto Nacional de Cancerologia-Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, 14080, Ciudad de Mexico, Mexico
| | - Angel Trigos
- Centro de Investigacion en Micologia Aplicada, Universidad Veracruzana, Xalapa, Veracruz, Mexico
| | - Rossana C Zepeda
- Centro de Investigaciones Biomedicas, Universidad Veracruzana, Av. Luis Castelazo Ayala, Xalapa-Enriquez, Veracruz 91190, Mexico
| | - Manuel E Medina
- Centro de Investigacion en Micologia Aplicada, Universidad Veracruzana, Xalapa, Veracruz, Mexico
| | - Rodrigo Galindo-Murillo
- Department of Medicinal Chemistry, L.S. Skaggs Pharmacy Institute, University of Utah, Salt Lake City, Utah 84112, United States
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Yardım A, Kucukler S, Özdemir S, Çomaklı S, Caglayan C, Kandemir FM, Çelik H. Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, inflammation and apoptosis in rats. Gene 2020; 769:145239. [PMID: 33069805 DOI: 10.1016/j.gene.2020.145239] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/22/2020] [Accepted: 10/11/2020] [Indexed: 12/18/2022]
Abstract
Docetaxel (DTX) is a chemotherapeutic agent used in the treatment of various malignancies but is often associated with central and peripheral neurotoxicity. The aim of this study was to investigate the neuroprotective effect of silymarin (SLM) against DTX-induced central and peripheral neurotoxicities in rats. Rats received 25 and 50 mg/kg body weight SLM orally for seven consecutive days after receiving a single injection of 30 mg/kg body weight DTX on the first day. SLM significantly decreased brain lipid peroxidation level and ameliorated brain glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities in DTX-administered rats. SLM attenuated levels of nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP) and activity of p38α mitogen-activated protein kinase (p38α MAPK) whereas caused an increase in levels of neural cell adhesion molecule (NCAM) in the brain and sciatic nerve of DTX-induced rats. In addition, SLM improved the histological structure of the brain and sciatic nerve tissues and decreased the expression of c-Jun N-terminal kinase (JNK) in the sciatic nerve whereas increased cyclic AMP response element binding protein (CREB) expression in the brain induced by DTX. Additionally, SLM markedly up-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and B-cell lymphoma-2 (Bcl-2) and downregulated the expression of Bcl-2 associated X protein (Bax) in the brain and sciatic nerve tissues of DTX-induced rats. Our results show that SLM can protect DTX-induced brain and sciatic nerve injuries by enhancing the antioxidant defense system and suppressing apoptosis and inflammation.
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Affiliation(s)
- Ahmet Yardım
- Department of Neurosurgery, Private Buhara Hospital, Erzurum, Turkey
| | - Sefa Kucukler
- Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, 25240 Erzurum, Turkey
| | - Selçuk Özdemir
- Department of Genetics, Faculty of Veterinary Medicine, Atatürk University, 25240 Erzurum, Turkey
| | - Selim Çomaklı
- Department of Pathology, Faculty of Veterinary Medicine, Atatürk University, 25240 Erzurum, Turkey
| | - Cuneyt Caglayan
- Department of Biochemistry, Faculty of Veterinary Medicine, Bingol University, 12000 Bingol, Turkey.
| | - Fatih Mehmet Kandemir
- Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, 25240 Erzurum, Turkey.
| | - Hamit Çelik
- Department of Neurology, Private Buhara Hospital, Erzurum, Turkey
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17
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Tuyiringire N, Deyno S, Weisheit A, Tolo CU, Tusubira D, Munyampundu JP, Ogwang PE, Muvunyi CM, Heyden YV. Three promising antimycobacterial medicinal plants reviewed as potential sources of drug hit candidates against multidrug-resistant tuberculosis. Tuberculosis (Edinb) 2020; 124:101987. [DOI: 10.1016/j.tube.2020.101987] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 08/13/2020] [Accepted: 08/13/2020] [Indexed: 01/03/2023]
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18
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Batiha GES, Beshbishy AM, Alkazmi LM, Nadwa EH, Rashwan EK, Yokoyama N, Igarashi I. In vitro and in vivo growth inhibitory activities of cryptolepine hydrate against several Babesia species and Theileria equi. PLoS Negl Trop Dis 2020; 14:e0008489. [PMID: 32853247 PMCID: PMC7451656 DOI: 10.1371/journal.pntd.0008489] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 06/16/2020] [Indexed: 12/13/2022] Open
Abstract
Piroplasmosis treatment has been based on the use of imidocarb dipropionate or diminazene aceturate (DA), however, their toxic effects. Therefore, the discovery of new drug molecules and targets is urgently needed. Cryptolepine (CRY) is a pharmacologically active plant alkaloid; it has significant potential as an antiprotozoal and antibacterial under different in vitro and in vivo conditions. The fluorescence assay was used for evaluating the inhibitory effect of CRY on four Babesia species and Theileria equi in vitro, and on the multiplication of B. microti in mice. The toxicity assay was evaluated on Madin–Darby bovine kidney (MDBK), mouse embryonic fibroblast (NIH/3T3), and human foreskin fibroblast (HFF) cell lines. The half-maximal inhibitory concentration (IC50) values of CRY on Babesia bovis, B. bigemina, B. divergens, B. caballi, and T. equi were 1740 ± 0.377, 1400 ± 0.6, 790 ± 0.32, 600 ± 0.53, and 730 ± 0.025 nM, respectively. The toxicity assay on MDBK, NIH/3T3, and HFF cell lines showed that CRY affected the viability of cells with a half-maximum effective concentration (EC50) of 86.67 ± 4.43, 95.29 ± 2.7, and higher than 100 μM, respectively. In mice experiments, CRY at a concentration of 5 mg/kg effectively inhibited the growth of B. microti, while CRY–atovaquone (AQ) and CRY–DA combinations showed higher chemotherapeutic effects than CRY alone. Our results showed that CRY has the potential to be an alternative remedy for treating piroplasmosis. The development and evaluation of new treatment strategies against Babesia and Theileria parasites have become increasingly urgent due to the emergence of parasite resistance and unwanted toxicity side effects by current chemotherapies. On the other hand, vaccination is a cheaper, reliable and sustainable option. Unfortunately, it has not worked well for the protozoan diseases because they possess ingenious mechanisms to evade the host immune system, rendering treatment the most suitable approach for their control. Sadly, only diminazene aceturate (DA) and imidocarb dipropionate have passed clinical trials for the treatment of piroplasmosis. However, these drugs cause many adverse effects and not approved yet for human medicine. Cryptolepine (CRY) is a pharmacologically active indoloquinoline alkaloid isolated from the roots of the shrub Cryptolepis sanguinolenta. CRY is reported to possess various pharmacological activities, including antifungal, anti-mycobacterial, and potent antiplasmodial activities. In the present study we evaluated the effects of CRY against the growth of Babesia bovis, B. bigemina, B. divergens, B. caballi and Theileria equi in vitro and its chemotherapeutic potential on Babesia microti in mice. Furthermore, we investigated the effect of combination between CRY with the current babesiocidal drugs such as DA, atovaquone (AQ) and clofazimine (CF) in vitro and in vivo.
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Affiliation(s)
- Gaber El-Saber Batiha
- National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Albeheira, Egypt
| | - Amany Magdy Beshbishy
- National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
| | - Luay M. Alkazmi
- Biology department, Faculty of Applied Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Eman H. Nadwa
- Department of Pharmacology and Therapeutics, College of Medicine, Jouf University, Sakaka, Saudi Arabia
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Eman K. Rashwan
- Department of Physiology, College of Medicine, Al-Azhar University, Assuit, Egypt
- Department of Physiology, College of Medicine, Jouf University, Sakaka, Saudi Arabia
| | - Naoaki Yokoyama
- National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
| | - Ikuo Igarashi
- National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
- * E-mail:
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Feng J, Leone J, Schweig S, Zhang Y. Evaluation of Natural and Botanical Medicines for Activity Against Growing and Non-growing Forms of B. burgdorferi. Front Med (Lausanne) 2020; 7:6. [PMID: 32154254 PMCID: PMC7050641 DOI: 10.3389/fmed.2020.00006] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 01/09/2020] [Indexed: 12/14/2022] Open
Abstract
Lyme disease is the most common vector-borne disease in the US and Europe. Although the current recommended Lyme antibiotic treatment is effective for the majority of Lyme disease patients, about 10-20% of patients continue to suffer from persisting symptoms. There have been various anecdotal reports on the use of herbal extracts for treating patients with persisting symptoms with varying degree of improvements. However, it is unclear whether the effect of the herb products is due to their direct antimicrobial activity or their effect on host immune system. In the present study, we investigated the antimicrobial effects of 12 commonly used botanical medicines and three other natural antimicrobial agents for potential anti-Borrelia burgdorferi activity in vitro. Among them, 7 natural product extracts at 1% were found to have good activity against the stationary phase B. burgdorferi culture compared to the control antibiotics doxycycline and cefuroxime. These active botanicals include Cryptolepis sanguinolenta, Juglans nigra (Black walnut), Polygonum cuspidatum (Japanese knotweed), Artemisia annua (Sweet wormwood), Uncaria tomentosa (Cat's claw), Cistus incanus, and Scutellaria baicalensis (Chinese skullcap). In contrast, Stevia rebaudiana, Andrographis paniculata, Grapefruit seed extract, colloidal silver, monolaurin, and antimicrobial peptide LL37 had little or no activity against stationary phase B. burgdorferi. The minimum inhibitory concentration (MIC) values of Artemisia annua, Juglans nigra, and Uncaria tomentosa were quite high for growing B. burgdorferi, despite their strong activity against the non-growing stationary phase B. burgdorferi. On the other hand, the top two active herbs, Cryptolepis sanguinolenta and Polygonum cuspidatum, showed strong activity against both growing B. burgdorferi (MIC = 0.03-0.06% and 0.25-0.5%, respectively) and non-growing stationary phase B. burgdorferi. In subculture studies, only 1% Cryptolepis sanguinolenta extract caused complete eradication, while doxycycline and cefuroxime and other active herbs could not eradicate B. burgdorferi stationary phase cells as many spirochetes were visible after 21-day subculture. Further studies are needed to identify the active constituents of the effective botanicals and evaluate their combinations for more effective eradication of B. burgdorferi in vitro and in vivo. The implications of these findings for improving treatment of persistent Lyme disease are discussed.
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Affiliation(s)
- Jie Feng
- Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States
| | - Jacob Leone
- FOCUS Health Group, Naturopathic, Novato, CA, United States
| | - Sunjya Schweig
- California Center for Functional Medicine, Kensington, CA, United States
| | - Ying Zhang
- Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States
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Harry NA, Ujwaldev SM, Anilkumar G. Recent advances and prospects in the metal-free synthesis of quinolines. Org Biomol Chem 2020; 18:9775-9790. [DOI: 10.1039/d0ob02000a] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Metal-free synthesis of quinolines has recently gained attention, and this review focuses on the recent advances in the metal-free synthesis of quinolines.
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Affiliation(s)
- Nissy Ann Harry
- School of Chemical Sciences
- Mahatma Gandhi University
- Kottayam
- India 686560
| | | | - Gopinathan Anilkumar
- School of Chemical Sciences
- Mahatma Gandhi University
- Kottayam
- India 686560
- Advanced Molecular Materials Research Centre (AMMRC)
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21
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Anti-inflammatory treatment with β-asarone improves impairments in social interaction and cognition in MK-801 treated mice. Brain Res Bull 2019; 150:150-159. [DOI: 10.1016/j.brainresbull.2019.05.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 05/09/2019] [Accepted: 05/21/2019] [Indexed: 01/10/2023]
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22
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Méndez MV, Simonetti SO, Kaufman TS, Bracca ABJ. A concise Friedländer/Buchwald–Hartwig approach to the total synthesis of quindoline, a bioactive natural indoloquinoline alkaloid, and toward the unnatural 10-methylquindoline. NEW J CHEM 2019. [DOI: 10.1039/c9nj01961h] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Friedländer and Buchwald–Hartwig reactions were used to achieve an efficient total synthesis of quindoline and a new synthesis of the unnatural 10-methylquindoline. DFT calculations were employed to explain the outcome of a failed key transformation.
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Affiliation(s)
- María V. Méndez
- Instituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad de Ciencias Bioquímicas y Farmacéuticas
- Universidad Nacional de Rosario
- Rosario
- Argentina
| | - Sebastian O. Simonetti
- Instituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad de Ciencias Bioquímicas y Farmacéuticas
- Universidad Nacional de Rosario
- Rosario
- Argentina
| | - Teodoro S. Kaufman
- Instituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad de Ciencias Bioquímicas y Farmacéuticas
- Universidad Nacional de Rosario
- Rosario
- Argentina
| | - Andrea B. J. Bracca
- Instituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad de Ciencias Bioquímicas y Farmacéuticas
- Universidad Nacional de Rosario
- Rosario
- Argentina
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23
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Li YQ, Chen JT, Yin SM, Nie DN, He ZY, Xie SF, Wang XJ, Wu YD, Xiao J, Liu HY, Wang JY, Yang WJ, Ma LP. Regulation of mPGES-1 composition and cell growth via the MAPK signaling pathway in jurkat cells. Exp Ther Med 2018; 16:3211-3219. [PMID: 30214544 DOI: 10.3892/etm.2018.6538] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 06/22/2018] [Indexed: 12/15/2022] Open
Abstract
Previous studies have suggested that microsomal prostaglandin E synthase-1 (mPGES-1) is highly expressed and closely associated with mitogen-activated protein kinase (MAPK) signaling pathways in various types of malignant cells. However, their expression patterns and function with respect to T-cell acute lymphoblastic leukemia (T-ALL) remain largely unknown. The present study investigated whether mPGES-1 served a crucial role in T-ALL and aimed to identify interactions between mPGES-1 and the MAPK signaling pathway in T-ALL. The results indicated that mPGES-1 overexpression in T-ALL jurkat cells was significantly decreased by RNA silencing. Decreasing mPGES-1 on a consistent basis may inhibit cell proliferation, induce apoptosis and arrest the cell cycle in T-ALL jurkat cells. Microarray and western blot analyses revealed that c-Jun N-terminal kinase served a role in the mPGES-1/prostaglandin E2/EP4/MAPK positive feedback loops. In addition, P38 and extracellular signal-regulated kinase 1/2 exhibited negative feedback effects on mPGES-1. In conclusion, the results suggested that cross-talk between mPGES-1 and the MAPK signaling pathway was very complex. Therefore, the combined regulation of mPGES-1 and the MAPK signaling pathway may be developed into a new candidate therapy for T-ALL in the future.
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Affiliation(s)
- Yi-Qing Li
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Jiao-Ting Chen
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China.,Department of Hematology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Song-Mei Yin
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Da-Nian Nie
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Zhi-Yuan He
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Shuang-Feng Xie
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Xiu-Ju Wang
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Yu-Dan Wu
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Jie Xiao
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Hong-Yun Liu
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Jie-Yu Wang
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Wen-Juan Yang
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Li-Ping Ma
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
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Phytochemical and Pharmacological Review of Cryptolepis sanguinolenta (Lindl.) Schlechter. Adv Pharmacol Sci 2017; 2017:3026370. [PMID: 29750083 PMCID: PMC5661077 DOI: 10.1155/2017/3026370] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 08/14/2017] [Accepted: 09/12/2017] [Indexed: 11/18/2022] Open
Abstract
Ethnopharmacological Relevance Cryptolepis sanguinolenta is a scrambling thin-stemmed shrub found in Africa. Traditionally in West Africa, it is employed in the treatment of malaria, diarrhea, and respiratory conditions. This review discusses the traditional importance as well as the phytochemical, ethnomedical, pharmacological, and toxicological importance of this plant. Materials and Methods Excerpta Medica Database, Google Scholar, Springer, and PubMed Central were the electronic databases used to search for and filter primary studies on Cryptolepis sanguinolenta. Results The detailed review of various studies conducted on C. sanguinolenta and some of its constituents gives an important body of proof of its potential therapeutic benefits and also of its use as a source of lead compounds with therapeutic potentials. Conclusion The review on C. sanguinolenta is important in identifying grey areas in the research on this medicinal plant and also provides comprehensive data thus far to continue research on this plant.
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Pal HC, Prasad R, Katiyar SK. Cryptolepine inhibits melanoma cell growth through coordinated changes in mitochondrial biogenesis, dynamics and metabolic tumor suppressor AMPKα1/2-LKB1. Sci Rep 2017; 7:1498. [PMID: 28473727 PMCID: PMC5431443 DOI: 10.1038/s41598-017-01659-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 03/29/2017] [Indexed: 01/09/2023] Open
Abstract
Dysregulated mitochondrial dynamics and biogenesis have been associated with various pathological conditions including cancers. Here, we assessed the therapeutic effect of cryptolepine, a pharmacologically active alkaloid derived from the roots of Cryptolepis sanguinolenta, on melanoma cell growth. Treatment of human melanoma cell lines (A375, Hs294t, SK-Mel28 and SK-Mel119) with cryptolepine (1.0, 2.5, 5.0 and 7.5 μM) for 24 and 48 h significantly (P < 0.001) inhibited the growth of melanoma cells but not normal melanocytes. The inhibitory effect of cryptolepine was associated with loss of mitochondrial membrane potential and reduced protein expression of Mfn1, Mfn2, Opa1 and p-Drp1 leading to disruption of mitochondrial dynamics. A decrease in the levels of ATP and mitochondrial mass were associated with activation of the metabolic tumor suppressor AMPKα1/2-LKB1, and a reduction in mTOR signaling. Decreased expression of SDH-A and COX-I demonstrated that cryptolepine treatment reduced mitochondrial biogenesis. In vivo treatment of A375 xenograft-bearing nude mice with cryptolepine (10 mg/Kg body weight, i.p.) resulted in significant inhibition of tumor growth, which was associated with disruption of mitochondrial dynamics and a reduction in mitochondrial biogenesis. Our study suggests that low toxicity phytochemicals like cryptolepine may be tested for the treatment of melanoma.
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Affiliation(s)
- Harish C Pal
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ram Prasad
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.,Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
| | - Santosh K Katiyar
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA. .,Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL, USA. .,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. .,Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA.
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Dey A, Mukherjee A, Chaudhury M. Alkaloids From Apocynaceae. STUDIES IN NATURAL PRODUCTS CHEMISTRY 2017. [DOI: 10.1016/b978-0-444-63931-8.00010-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Pal HC, Katiyar SK. Cryptolepine, a Plant Alkaloid, Inhibits the Growth of Non-Melanoma Skin Cancer Cells through Inhibition of Topoisomerase and Induction of DNA Damage. Molecules 2016; 21:E1758. [PMID: 28009843 PMCID: PMC6273109 DOI: 10.3390/molecules21121758] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 12/13/2016] [Accepted: 12/17/2016] [Indexed: 01/03/2023] Open
Abstract
Topoisomerases have been shown to have roles in cancer progression. Here, we have examined the effect of cryptolepine, a plant alkaloid, on the growth of human non-melanoma skin cancer cells (NMSCC) and underlying mechanism of action. For this purpose SCC-13 and A431 cell lines were used as an in vitro model. Our study reveals that SCC-13 and A431 cells express higher levels as well as activity of topoisomerase (Topo I and Topo II) compared with normal human epidermal keratinocytes. Treatment of NMSCC with cryptolepine (2.5, 5.0 and 7.5 µM) for 24 h resulted in marked decrease in topoisomerase activity, which was associated with substantial DNA damage as detected by the comet assay. Cryptolepine induced DNA damage resulted in: (i) an increase in the phosphorylation of ATM/ATR, BRCA1, Chk1/Chk2 and γH2AX; (ii) activation of p53 signaling cascade, including enhanced protein expressions of p16 and p21; (iii) downregulation of cyclin-dependent kinases, cyclin D1, cyclin A, cyclin E and proteins involved in cell division (e.g., Cdc25a and Cdc25b) leading to cell cycle arrest at S-phase; and (iv) mitochondrial membrane potential was disrupted and cytochrome c released. These changes in NMSCC by cryptolepine resulted in significant reduction in cell viability, colony formation and increase in apoptotic cell death.
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Affiliation(s)
- Harish C Pal
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
| | - Santosh K Katiyar
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
- Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
- Birmingham Veterans Affairs Medical Center, Birmingham, AL 35294, USA.
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Kumar H, Lim JH, Kim IS, Choi DK. Differential regulation of HIF-3α in LPS-induced BV-2 microglial cells: Comparison and characterization with HIF-1α. Brain Res 2015; 1610:33-41. [DOI: 10.1016/j.brainres.2015.03.046] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 03/05/2015] [Accepted: 03/24/2015] [Indexed: 11/28/2022]
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Wu J, Du J, Gu R, Zhang L, Zhen X, Li Y, Chen H, Jiang B, Zheng L. Inhibition of neuroinflammation by synthetic androstene derivatives incorporating amino acid methyl esters on activated BV-2 microglia. ChemMedChem 2015; 10:610-6. [PMID: 25735986 DOI: 10.1002/cmdc.201500027] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Indexed: 11/10/2022]
Abstract
Androstene derivatives incorporating amino acid methyl esters were prepared, and their anti-inflammatory effects were evaluated in lipopolysaccharide (LPS)-activated BV-2 microglial cells. Several compounds exhibited dose-dependent inhibition. The most active compound, methyl ((3S,10R,13S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carbonyl)-L-phenylalaninate (10) significantly suppressed LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Mechanistic studies revealed that compound 10 markedly inhibits phosphorylation of p38 mitogen-activated protein kinases (MAPKs) and subsequent transcription factor (NF-κB) and activator protein-1 (AP-1) activation. Furthermore, compound 10 decreased LPS-activated microglial neurotoxicity in a condition medium/HT-22 neuroblastoma co-culture model. Taken together, these results suggest 10 is a potential lead compound for the development of a novel therapeutic agent for neurodegenerative diseases.
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Affiliation(s)
- Jing Wu
- Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou, 215123 (PR China)
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Lim HW, Kumar H, Kim BW, More SV, Kim IW, Park JI, Park SY, Kim SK, Choi DK. β-Asarone (cis-2,4,5-trimethoxy-1-allyl phenyl), attenuates pro-inflammatory mediators by inhibiting NF-κB signaling and the JNK pathway in LPS activated BV-2 microglia cells. Food Chem Toxicol 2014; 72:265-72. [DOI: 10.1016/j.fct.2014.07.018] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 06/19/2014] [Accepted: 07/09/2014] [Indexed: 11/27/2022]
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Olajide OA, Velagapudi R, Okorji UP, Sarker SD, Fiebich BL. Picralima nitida seeds suppress PGE2 production by interfering with multiple signalling pathways in IL-1β-stimulated SK-N-SH neuronal cells. JOURNAL OF ETHNOPHARMACOLOGY 2014; 152:377-383. [PMID: 24491645 DOI: 10.1016/j.jep.2014.01.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 12/19/2013] [Accepted: 01/24/2014] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The dried seed of Picralima nitida is used in rheumatic fever and as an antipyretic in West Africa. In this study we have investigated the effects of an extract obtained from the seeds of Picralima nitida (PNE) on PGE2 production in IL-1β-stimulated cells. MATERIALS AND METHODS Prostaglandin E2 (PGE2) was measured in supernatants of IL-1β-stimulated SK-N-SH cells using enzyme immunoassay (EIA) for PGE2. In Cell ELISA and western blot were used to evaluate the effects of PNE on protein expressions of COX-2, mPGES-1, IκB and IKK. To determine the effect of the extract on NF-κB transactivation, a reporter gene assay was carried out in HEK293 cells stimulated with TNFα. An ELISA was used to measure the roles of p38, ERK1/2 and JNK Mitogen Activated Protein Kinases (MAPKs) on anti-neuroinflammatory actions of PNE. RESULTS Results show that PNE significantly inhibited PGE2 production, as well as COX-2 and mPGES-1 protein expressions in IL-1β-stimulated SK-N-SH cells. Molecular targeting experiments showed that PNE interfered with NF-κB signalling pathway through attenuation of TNFα-stimulated NF-κB transcriptional activation in HEK 293 cells. Furthermore, IL-1β-mediated phosphorylation of IκB and IKK were inhibited in SK-N-SH cells. PNE (50-200 μg/ml) also produced significant inhibition of IL-1β-induced p38 MAPK phosphorylation in SK-N-SH cells. However, phosphorylation of ERK1/2 and JNK MAPKs were achieved at 100 and 200 μg/ml of the extract. CONCLUSIONS Taken together, these results clearly demonstrate that Picralima nitida suppresses PGE2 production by targeting multiple pathways involving NF-κB and MAPK signalling in IL-1β-stimulated SK-N-SH neuronal cells.
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Affiliation(s)
- Olumayokun A Olajide
- Division of Pharmacy, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, United Kingdom.
| | - Ravikanth Velagapudi
- Division of Pharmacy, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, United Kingdom
| | - Uchechukwu P Okorji
- Division of Pharmacy, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, United Kingdom
| | - Satyajit D Sarker
- Department of Pharmacy, School of Applied Sciences, University of Wolverhampton, Wulfruna Street, Wolverhampton WV1 1LY, United Kingdom
| | - Bernd L Fiebich
- Neurochemistry Research Laboratory, Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Hauptstrasse 5, 79104 Freiburg, Germany; VivaCell Biotechnology GmbH, Ferdinand-Porsche-Street 5, D-79211 Denzlingen, Germany
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