Login Register Cart 0
Generic placeholder image

Recent Patents on Anti-Cancer Drug Discovery

Editor-in-Chief

ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Alpha-solanine Anti-tumor Effects in Non-small Cell Lung Cancer Through Regulating the Energy Metabolism Pathway

Author(s): Tao Zou, Li Gu, Liqiong Yang, Junsong Wei, Yueshui Zhao, Jing Shen, Mingxing Li, Xu Wu, Fukuan Du, Yu Chen, Yun Ye, Zhangang Xiao* and Zhigui Wu*

Volume 17, Issue 4, 2022

Published on: 30 March, 2022

Page: [396 - 409] Pages: 14

DOI: 10.2174/1574892817666220113144635

Price: $65

Abstract

Background: Lung cancer is a malignant tumor with a high incidence in China, especially non-small cell lung cancer (NSCLC), which is the main threat to human life, with terrible morbidity and mortality. The research on the treatment and mechanism of NSCLC has been the forefront and hotspot of research. Recent patents show that alpha-solanine (α-solanine) exhibits the best anti-cancer activity, although its target and related mechanism remain to be elucidated.

Objectives: This study aims to explore the possible targets and mechanisms of α-solanine in the treatment of NSCLC through network pharmacology and experimental verification.

Methods: Network pharmacology was applied to screen the possible targets of α-solanine on NSCLC, construct core networks, and perform GO enrichment and KEGG pathway analysis to predict the mechanism of α-solanine against NSCLC. Experiments were implemented to verify the results of network pharmacology in vitro. The A549 and PC-9 cells were exposed to α-solanine to assess the anti-tumor effect. Cell apoptosis was determined by the Annexin-V/PI assay. Targeted energy metabolomics was used to validate the network pharmacology results, and energy metabolism pathway- related proteins were detected by immunofluorescence and western blot.

Results: Network pharmacology showed that there were 130 potential targets of α-solanine and NSCLC. GO, and KEGG analysis showed that the energy metabolism pathway is the main pathway for α-solanine to exert anti-tumor effects on NSCLC. Experimental results showed that α-solanine inhibited cell proliferation, migration, invasion and promoted cell apoptosis. At the same time, after α-solanine treatment, the energy metabolism pathway-related proteins, including GPI, ALDOA, TPI1, PKLR, LDHA, and ALDH3, were expressed reduced. In addition, α-solanine also affects the amino acid metabolism of A549 and PC-9 cells.

Conclusion: Based on a combination of network pharmacological prediction and experimental verification, α-solanine may exert anti-NSCLC effects by regulating the energy metabolism pathway.

Keywords: NSCLC, alpha-solanine, network pharmacology, metabolomics, energy metabolism pathway, anti-tumor.

« Previous Next »
[1]
Henley SJ, Ward EM, Scott S, et al. Annual report to the nation on the status of cancer, part I: National cancer statistics. Cancer 2020; 126(10): 2225-49.
[http://dx.doi.org/10.1002/cncr.32802] [PMID: 32162336]
[2]
Abbasi J. Potential new immune-checkpoint inhibitor partner for lung cancer. JAMA 2021; 326(10): 901.
[http://dx.doi.org/10.1001/jama.2021.14765] [PMID: 34519817]
[3]
Xu Y, Chen Y, Yao Y, et al. VIRMA contributes to non-small cell lung cancer progression via N(6)-methyladenosine-dependent DAPK3 post-transcriptional modification. Cancer Lett 2021; 522: 142-54.
[http://dx.doi.org/10.1016/j.canlet.2021.08.027]
[4]
Li H, Lin PH, Gupta P, et al. MG53 suppresses tumor progression and stress granule formation by modulating G3BP2 activity in non-small cell lung cancer. Mol Cancer 2021; 20(1): 118.
[http://dx.doi.org/10.1186/s12943-021-01418-3] [PMID: 34521423]
[5]
Xia Y, Wang WC, Shen WH, et al. Thalidomide suppresses angiogenesis and immune evasion via lncRNA FGD5-AS1/miR-454-3p/ZEB1 axis-mediated VEGFA expression and PD-1/PD-L1 checkpoint in NSCLC. Chem Biol Interact 2021; 349: 109652.
[http://dx.doi.org/10.1016/j.cbi.2021.109652] [PMID: 34520751]
[6]
Judd J, Borghaei H. Combining immunotherapy and chemotherapy for non-small cell lung cancer. Thorac Surg Clin 2020; 30(2): 199-206.
[http://dx.doi.org/10.1016/j.thorsurg.2020.01.006] [PMID: 32327178]
[7]
Hu X, Wang P, Qu C, Zhang H, Li L. Circular RNA Circ_0000677 promotes cell proliferation by regulating microRNA-106b-5p/CCND1 in non-small cell lung cancer. Bioengineered 2021; 12(1): 6229-39.
[http://dx.doi.org/10.1080/21655979.2021.1965697] [PMID: 34519258]
[8]
Duma N, Santana-Davila R, Molina JR. Non-small cell lung cancer: epidemiology, screening, diagnosis, and treatment. Mayo Clin Proc 2019; 94(8): 1623-40.
[http://dx.doi.org/10.1016/j.mayocp.2019.01.013] [PMID: 31378236]
[9]
Ma Q, Geng K, Xiao P, Zeng L. Identification and prognostic value exploration of radiotherapy sensitivity-associated genes in non-small-cell lung cancer. BioMed Res Int 2021; 2021: 5963868.
[http://dx.doi.org/10.1155/2021/5963868] [PMID: 34518802]
[10]
Abdel Karim N, Kelly K. Role of targeted therapy and immune checkpoint blockers in advanced non-small cell lung cancer: A review. Oncologist 2019; 24(9): 1270-84.
[http://dx.doi.org/10.1634/theoncologist.2018-0112] [PMID: 30914465]
[11]
Shin JY, Yoon JK, Marwaha G. Progress in the treatment and outcomes for early-stage non-small cell lung cancer. Lung 2018; 196(3): 351-8.
[http://dx.doi.org/10.1007/s00408-018-0110-1] [PMID: 29550987]
[12]
Giraud N, Abdiche S, Trouette R. Stereotactic radiotherapy in targeted therapy treated oligo-metastatic oncogene-addicted (non-small-cell) lung cancer. Cancer Radiother 2019; 23(4): 346-54.
[http://dx.doi.org/10.1016/j.canrad.2019.01.002] [PMID: 31130373]
[13]
Gu T, Yuan W, Li C, et al. α-Solanine inhibits proliferation, invasion, and migration, and induces apoptosis in human choriocarcinoma JEG-3 cells in vitro and in vivo. Toxins (Basel) 2021; 13(3): 210.
[http://dx.doi.org/10.3390/toxins13030210] [PMID: 33805658]
[14]
Yan M, Wang L, Cheng CY. Testis toxicants: lesson from traditional Chinese medicine (TCM). Adv Exp Med Biol 2021; 1288: 307-19.
[http://dx.doi.org/10.1007/978-3-030-77779-1_15] [PMID: 34453743]
[15]
Gebhardt C. The historical role of species from the Solanaceae plant family in genetic research. Theor Appl Genet 2016; 129(12): 2281-94.
[http://dx.doi.org/10.1007/s00122-016-2804-1] [PMID: 27744490]
[16]
Nakayasu M, Umemoto N, Akiyama R, et al. Characterization of C-26 aminotransferase, indispensable for steroidal glycoalkaloid biosynthesis. Plant J 2021; 108(1): 81-92.
[http://dx.doi.org/10.1111/tpj.15426] [PMID: 34273198]
[17]
Yi YJ, Jia XH, Zhu C, et al. Solanine reverses multidrug resistance in human myelogenous leukemia K562/ADM cells by downregulating MRP1 expression. Oncol Lett 2018; 15(6): 10070-6.
[http://dx.doi.org/10.3892/ol.2018.8563] [PMID: 29928376]
[18]
Yan X, Li M, Chen L, et al. α-Solanine inhibits growth and metastatic potential of human colorectal cancer cells. Oncol Rep 2020; 43(5): 1387-96.
[http://dx.doi.org/10.3892/or.2020.7519] [PMID: 32323807]
[19]
Hassan SH, Gul S, Zahra HS, et al. Alpha Solanine: A novel natural bioactive molecule with anticancer effects in multiple human malignancies. Nutr Cancer 2021; 73(9): 1541-52.
[http://dx.doi.org/10.1080/01635581.2020.1803932] [PMID: 32762370]
[20]
A composition containing alpha-solanine from potato for inhibiting liver cancer. US patent, 20060023400A. 2006.
[21]
Friedman M. Chemistry and anticarcinogenic mechanisms of glycoalkaloids produced by eggplants, potatoes, and tomatoes. J Agric Food Chem 2015; 63(13): 3323-37.
[http://dx.doi.org/10.1021/acs.jafc.5b00818] [PMID: 25821990]
[22]
Pharmaceutical composition for preventing or treating male reproductive disease comprising -solanine. US patent, 20210067153A. 2021.
[23]
Sun H, Lv C, Yang L, et al. Solanine induces mitochondria-mediated apoptosis in human pancreatic cancer cells. BioMed Res Int 2014; 2014: 805926.
[http://dx.doi.org/10.1155/2014/805926] [PMID: 24949471]
[24]
Mohsenikia M, Farhangi B, Alizadeh AM, et al. Therapeutic effects of dendrosomal solanine on a metastatic breast tumor. Life Sci 2016; 148: 260-7.
[http://dx.doi.org/10.1016/j.lfs.2016.02.008] [PMID: 26854999]
[25]
Lv C, Kong H, Dong G, et al. Antitumor efficacy of α-solanine against pancreatic cancer in vitro and in vivo. PLoS One 2014; 9(2): e87868.
[http://dx.doi.org/10.1371/journal.pone.0087868] [PMID: 24505326]
[26]
Wang Y, Wu J, Guo W, et al. α-Solanine modulates the radiosensitivity of esophageal cancer cells by inducing microRNA 138 expression. Cell Physiol Biochem 2016; 39(3): 996-1010.
[http://dx.doi.org/10.1159/000447807] [PMID: 27536892]
[27]
Ji YB, Gao SY, Ji CF, Zou X. Induction of apoptosis in HepG2 cells by solanine and Bcl-2 protein. J Ethnopharmacol 2008; 115(2): 194-202.
[http://dx.doi.org/10.1016/j.jep.2007.09.023] [PMID: 18022776]
[28]
Lu MK, Shih YW, Chang Chien TT, Fang LH, Huang HC, Chen PS. α-Solanine inhibits human melanoma cell migration and invasion by reducing matrix metalloproteinase-2/9 activities. Biol Pharm Bull 2010; 33(10): 1685-91.
[http://dx.doi.org/10.1248/bpb.33.1685] [PMID: 20930376]
[29]
Amankwatia EB, Chakravarty P, Carey FA, et al. MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms. Br J Cancer 2015; 112(9): 1480-90.
[http://dx.doi.org/10.1038/bjc.2015.125] [PMID: 25919696]
[30]
Asuthkar S, Velpula KK, Chetty C, Gorantla B, Rao JS. Epigenetic regulation of miRNA-211 by MMP-9 governs glioma cell apoptosis, chemosensitivity and radiosensitivity. Oncotarget 2012; 3(11): 1439-54.
[http://dx.doi.org/10.18632/oncotarget.683] [PMID: 23183822]
[31]
Shin JS, Lee KG, Lee HH, et al. α-Solanine isolated from solanum tuberosum L. cv jayoung abrogates LPS-induced inflammatory responses via NF-κB inactivation in RAW 264.7 macrophages and endotoxin-induced shock model in Mice. J Cell Biochem 2016; 117(10): 2327-39.
[http://dx.doi.org/10.1002/jcb.25530] [PMID: 26931732]
[32]
Zhang F, Yang R, Zhang G, et al. Anticancer function of α-solanine in lung adenocarcinoma cells by inducing microRNA-138 expression. Tumour Biol 2016; 37(5): 6437-46.
[http://dx.doi.org/10.1007/s13277-015-4528-2] [PMID: 26631041]
[33]
Lin LT, Choong CY, Tai CJ. Solanine attenuated hepatocarcinoma migration and invasion induced by acetylcholine. Integr Cancer Ther 2020; 19: 1534735420909895.
[http://dx.doi.org/10.1177/1534735420909895] [PMID: 32975458]
[34]
Friedman JR, Richbart SD, Merritt JC, et al. Acetylcholine signaling system in progression of lung cancers. Pharmacol Ther 2019; 194: 222-54.
[http://dx.doi.org/10.1016/j.pharmthera.2018.10.002] [PMID: 30291908]
[35]
Gao J, Ying Y, Wang J, Cui Y. Solanine inhibits immune escape mediated by hepatoma treg cells via the TGFβ/smad signaling pathway. BioMed Res Int 2020; 2020: 9749631.
[http://dx.doi.org/10.1155/2020/9749631] [PMID: 33204731]
[36]
Karaboğa Arslan AK, Yerer MB. α-Chaconine and α-Solanine inhibit RL95-2 endometrium cancer cell proliferation by reducing expression of Akt (Ser473) and ERα (Ser167). Nutrients 2018; 10(6): E672.
[http://dx.doi.org/10.3390/nu10060672] [PMID: 29799481]
[37]
Li H, Li Y. Network pharmacology analysis of molecular mechanism of Curcuma longa L. extracts regulating glioma immune inflammatory factors: implications for precise cancer treatment. Curr Top Med Chem 2021. Online ahead of print.
[http://dx.doi.org/10.2174/1568026621666210910123749] [PMID: 34515002]
[38]
Li L, Yang M, Li C, Xue H, Shi M, Liu Y. Strategy of virtual screening based discovery of hsp90 c-terminal inhibitors and network pharmacological analysis. Curr Pharm Biotechnol 2021.
[http://dx.doi.org/10.2174/1389201022666210910101419] [PMID: 34514987]
[39]
Huang S, Chen Y, Pan L, et al. Exploration of the potential mechanism of Tao Hong Si Wu decoction for the treatment of breast cancer based on network pharmacology and in vitro experimental verification. Front Oncol 2021; 11: 731522.
[http://dx.doi.org/10.3389/fonc.2021.731522] [PMID: 34513708]
[40]
Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 2008; 4(11): 682-90.
[http://dx.doi.org/10.1038/nchembio.118] [PMID: 18936753]
[41]
Wang N, Zhu F, Shen M, et al. Network pharmacology-based analysis on bioactive anti-diabetic compounds in Potentilla discolor bunge. J Ethnopharmacol 2019; 241: 111905.
[http://dx.doi.org/10.1016/j.jep.2019.111905] [PMID: 31022565]
[42]
Kibble M, Saarinen N, Tang J, Wennerberg K, Mäkelä S, Aittokallio T. Network pharmacology applications to map the unexplored target space and therapeutic potential of natural products. Nat Prod Rep 2015; 32(8): 1249-66.
[http://dx.doi.org/10.1039/C5NP00005J] [PMID: 26030402]
[43]
Gao Y, Hu K, Yang J, et al. Tetrahydroxy stilbene glycoside regulates TGF-β/fractalkine/CX3CR1 based on network pharmacology in APP/PS1 mouse model. Neuropeptides 2021; 90: 102197.
[http://dx.doi.org/10.1016/j.npep.2021.102197] [PMID: 34509715]
[44]
Yuan M, Kremer DM, Huang H, et al. Ex vivo and in vivo stable isotope labelling of central carbon metabolism and related pathways with analysis by LC-MS/MS. Nat Protoc 2019; 14(2): 313-30.
[http://dx.doi.org/10.1038/s41596-018-0102-x] [PMID: 30683937]
[45]
Ferrara MG, Di Noia V, D’Argento E, et al. Oncogene-addicted non-small-cell lung cancer: Treatment opportunities and future perspectives. Cancers (Basel) 2020; 12(5): E1196.
[http://dx.doi.org/10.3390/cancers12051196] [PMID: 32397295]
[46]
Wen Z, Huang C, Xu Y, et al. α-Solanine inhibits vascular endothelial growth factor expression by down-regulating the ERK1/2-HIF-1α and STAT3 signaling pathways. Eur J Pharmacol 2016; 771: 93-8.
[http://dx.doi.org/10.1016/j.ejphar.2015.12.020] [PMID: 26688571]
[47]
Mohsenikia M, Alizadeh AM, Khodayari S, et al. The protective and therapeutic effects of alpha-solanine on mice breast cancer. Eur J Pharmacol 2013; 718(1-3): 1-9.
[http://dx.doi.org/10.1016/j.ejphar.2013.09.015] [PMID: 24051269]
[48]
Potatoes, alpha-carnitine in potatoes, and method for determining alpha-solanine. US patent, CN110940747A. 2020.
[49]
Separation and extraction device for potato glucoside alkaloid. US patent, CN211189177U. 2019.
[50]
Boezio B, Audouze K, Ducrot P, Taboureau O. Network-based approaches in pharmacology. Mol Inform 2017; 36 (10).
[http://dx.doi.org/10.1002/minf.201700048] [PMID: 28692140]
[51]
Zhang R, Zhu X, Bai H, Ning K. Network pharmacology databases for traditional Chinese medicine: review and assessment. Front Pharmacol 2019; 10: 123.
[http://dx.doi.org/10.3389/fphar.2019.00123] [PMID: 30846939]
[52]
Yuan H, Ma Q, Cui H, et al. How can synergism of traditional medicines benefit from network pharmacology? Molecules 2017; 22(7): 1135.
[http://dx.doi.org/10.3390/molecules22071135] [PMID: 28686181]
[53]
Zou T, Huang Y, Hu Y, et al. Study on the anti-tumor mechanism and target of triptolide based on network pharmacology and molecular docking. Recent Pat Anticancer Drug Discov 2021; 16(6): 426-35.
[54]
Wang Y, Sun YW, Wang YM, Ju Y, Meng DL. Virtual screening of active compounds from Artemisia argyi and potential targets against gastric ulcer based on Network pharmacology. Bioorg Chem 2019; 88: 102924.
[http://dx.doi.org/10.1016/j.bioorg.2019.102924] [PMID: 31005783]
[55]
Fang T, Liu L, Liu W. Network pharmacology-based strategy for predicting therapy targets of Tripterygium wilfordii on acute myeloid leukemia. Medicine (Baltimore) 2020; 99(50): e23546.
[http://dx.doi.org/10.1097/MD.0000000000023546] [PMID: 33327305]
[56]
Jiang X, Zhao W, Zhu F, et al. Ligustilide inhibits the proliferation of non-small cell lung cancer via glycolytic metabolism. Toxicol Appl Pharmacol 2021; 410: 115336.
[http://dx.doi.org/10.1016/j.taap.2020.115336] [PMID: 33212065]
[57]
Rodríguez-Enríquez S, Marín-Hernández Á, Gallardo-Pérez JC, et al. Transcriptional regulation of energy metabolism in cancer cells. Cells 2019; 8(10): 1225.
[http://dx.doi.org/10.3390/cells8101225] [PMID: 31600993]
[58]
Guan X. Cancer metastases: challenges and opportunities. Acta Pharm Sin B 2015; 5(5): 402-18.
[http://dx.doi.org/10.1016/j.apsb.2015.07.005] [PMID: 26579471]
[59]
Ribeiro Franco PI, Rodrigues AP, de Menezes LB, Pacheco Miguel M. Tumor microenvironment components: Allies of cancer progression. Pathol Res Pract 2020; 216(1): 152729.
[http://dx.doi.org/10.1016/j.prp.2019.152729] [PMID: 31735322]
[60]
Schömel N, Geisslinger G, Wegner MS. Influence of glycosphingolipids on cancer cell energy metabolism. Prog Lipid Res 2020; 79: 101050.
[http://dx.doi.org/10.1016/j.plipres.2020.101050] [PMID: 32592726]
[61]
Zheng Y, Li L, Gao Q, Niu B, Wang H. Solanine inhibits proliferation and promotes apoptosis of the human leukemia cells by targeting the miR-16/Bcl-2 axis. J BUON 2020; 25(3): 1614-8.
[PMID: 32862612]
[62]
El-Daly SM, Gouhar SA, Gamal-Eldeen AM, Abdel Hamid FF, Ashour MN, Hassan NS. Synergistic effect of α-solanine and cisplatin induces apoptosis and enhances cell cycle arrest in human hepatocellular carcinoma cells. Anticancer Agents Med Chem 2019; 19(18): 2197-210.
[http://dx.doi.org/10.2174/1871520619666190930123520] [PMID: 31566136]
[63]
Seijo LM, Peled N, Ajona D, et al. Biomarkers in lung cancer screening: Achievements, promises, and challenges. J Thorac Oncol 2019; 14(3): 343-57.
[http://dx.doi.org/10.1016/j.jtho.2018.11.023] [PMID: 30529598]
[64]
Wang X, Zhang A, Sun H. Power of metabolomics in diagnosis and biomarker discovery of hepatocellular carcinoma. Hepatology 2013; 57(5): 2072-7.
[http://dx.doi.org/10.1002/hep.26130] [PMID: 23150189]
[65]
Zhang F, Zhang Y, Zhao W, et al. Metabolomics for biomarker discovery in the diagnosis, prognosis, survival and recurrence of colorectal cancer: a systematic review. Oncotarget 2017; 8(21): 35460-72.
[http://dx.doi.org/10.18632/oncotarget.16727] [PMID: 28389626]
[66]
Armitage EG, Ciborowski M. Applications of metabolomics in cancer studies. Adv Exp Med Biol 2017; 965: 209-34.
[http://dx.doi.org/10.1007/978-3-319-47656-8_9] [PMID: 28132182]
[67]
Wang H, Liu A, Zhao W, et al. Metabolomics research reveals the mechanism of action of astragalus polysaccharide in rats with digestive system disorders. Molecules 2018; 23(12): 3333.
[http://dx.doi.org/10.3390/molecules23123333] [PMID: 30558291]
[68]
DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv 2016; 2(5): e1600200.
[http://dx.doi.org/10.1126/sciadv.1600200] [PMID: 27386546]
[69]
Zhu J, Thompson CB. Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Biol 2019; 20(7): 436-50.
[http://dx.doi.org/10.1038/s41580-019-0123-5] [PMID: 30976106]
[70]
Vettore L, Westbrook RL, Tennant DA. New aspects of amino acid metabolism in cancer. Br J Cancer 2020; 122(2): 150-6.
[http://dx.doi.org/10.1038/s41416-019-0620-5] [PMID: 31819187]
[71]
Strmiska V, Michalek P, Eckschlager T, et al. Prostate cancer-specific hallmarks of amino acids metabolism: Towards a paradigm of precision medicine. Biochim Biophys Acta Rev Cancer 2019; 1871(2): 248-58.
[http://dx.doi.org/10.1016/j.bbcan.2019.01.001] [PMID: 30708041]
[72]
Lieu EL, Nguyen T, Rhyne S, Kim J. Amino acids in cancer. Exp Mol Med 2020; 52(1): 15-30.
[http://dx.doi.org/10.1038/s12276-020-0375-3] [PMID: 31980738]
[73]
Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab 2016; 23(1): 27-47.
[http://dx.doi.org/10.1016/j.cmet.2015.12.006] [PMID: 26771115]
[74]
Martinez-Outschoorn UE, Peiris-Pagés M, Pestell RG, Sotgia F, Lisanti MP. Cancer metabolism: A therapeutic perspective. Nat Rev Clin Oncol 2017; 14(1): 11-31.
[http://dx.doi.org/10.1038/nrclinonc.2016.60] [PMID: 27141887]
[75]
Geck RC, Toker A. Nonessential amino acid metabolism in breast cancer. Adv Biol Regul 2016; 62: 11-7.
[http://dx.doi.org/10.1016/j.jbior.2016.01.001] [PMID: 26838061]
[76]
Tabe Y, Lorenzi PL, Konopleva M. Amino acid metabolism in hematologic malignancies and the era of targeted therapy. Blood 2019; 134(13): 1014-23.
[http://dx.doi.org/10.1182/blood.2019001034] [PMID: 31416801]
[77]
Martínez-Reyes I, Chandel NS. Cancer metabolism: Looking forward. Nat Rev Cancer 2021; 21(10): 669-80.
[http://dx.doi.org/10.1038/s41568-021-00378-6] [PMID: 34272515]

Rights & Permissions Print Cite
Article Metrics
30
1
© 2024 Bentham Science Publishers | Privacy Policy