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Systems pharmacology and multi-scale mechanism of Enicostema axillare bioactives in treating Alzheimer disease

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Abstract

As a progressive neurological disease with increased morbidity and mortality, Alzheimer Disease (AD) is characterized by neuron damage that controls memory and mental functions. Enicostema axillare (EA), an herb with a history of combativeness and effectiveness in treating Rheumatoid Arthritis, Cancer, and Diabetes, is used in Indian folk medicine from a holistic point of view. Though the herb is used for many illnesses, the molecular mechanism of its bioactive on AD has not been deciphered by intricate research. A unique pharmacology approach based on ADME drug screening and targeting, pathway enrichment (GO and KEGG), and network pharmacology, was established to explore the molecular mechanisms of E. axillare (EA) bioactive compounds for the treatment of AD. In brief, we bring to light the three active compounds of EA and seven potential molecular targets of AD, which are mainly implicated in four signaling pathways, i.e., MAPK, Apoptosis, neurodegeneration, and the TNF pathway. Moreover, the network analysis of the active compounds, molecular targets, and their pathways reveals the pharmacological nature of the compounds. Further, molecular docking studies were carried out to explore the interactions between the EA bioactive compounds and the targets and examine the binding affinity. The outcome of the work reflects the potential therapeutic effects of the compounds for treating AD through the modulation of the key proteins, which further corroborates the reliability of our network pharmacology analysis. This study not only helps in understanding the molecular mechanism of the drugs but also helps in finding and sorting new drugs for the treatment of AD, and other complex diseases through modern medicine.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

Abbreviations

AD:

Alzheimer’s disease

EA:

Enicostema axillare

TNF:

Tumor necrosis factor

References

  • Ahmad SS, Sinha M, Ahmad K, Khalid M, Choi I (2020) Study of caspase 8 inhibition for the management of Alzheimer’s disease: a molecular docking and dynamics simulation. Molecules 25(9):2071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ahmad S, Ahmed SB, Khan A, Wasim M, Tabassum S, Haider S, Ahmed F, Batool Z, Khaliq S, Rafiq H, Tikmani P, Gilani AU (2023) Natural remedies for Alzheimer's disease: A systematic review of randomized controlled trials. Metab Brain Dis 38(1):17–44

    Article  CAS  PubMed  Google Scholar 

  • Allen M, Kachadoorian M, Quicksall Z, Zou F, Chai HS, Younkin C et al (2014) Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels. Alzheimer’s Res Ther 6(4):39

    Article  Google Scholar 

  • Atanasov AG, Zotchev SB, Dirsch VM, Supuran CT, International Natural Product Sciences Taskforce (2021) Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov 20(3):200–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ayaz M, Sadiq A, Junaid M, Ullah F, Ovais M, Ullah I, Shahid M (2019) Flavonoids as Prospective Neuroprotectants and Their Therapeutic Propensity in Aging Associated Neurological Disorders. Front Aging Neurosci 11

  • Bakoyiannis I, Daskalopoulou A, Pergialiotis V, Perrea D (2019) Phytochemicals and cognitive health: Are flavonoids doing the trick. Biomed Pharmacother 109:1488–1497

    Article  CAS  PubMed  Google Scholar 

  • Barone E, Di Domenico F, Cenini G, Sultana R, Coccia R, Preziosi P et al (2011) Oxidative and nitrosative modifications of biliverdin reductase-A in the brain of subjects with Alzheimer’s disease and amnestic mild cognitive impairment. J Alzheimer’s Dis 25(4):623–633

    Article  CAS  Google Scholar 

  • Bekris LM, Yu CE, Bird TD, Tsuang DW (2010) Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol 23(4):213–227

    Article  PubMed  PubMed Central  Google Scholar 

  • Bellenguez C, Grenier-Boley B, Lambert JC (2020) Genetics of Alzheimer’s disease: where we are, and where we are going. Curr Opin Neurobiol 61:40–48

    Article  CAS  PubMed  Google Scholar 

  • Berger SI, Iyengar R (2009) Network analyses in systems pharmacology. J Bioinform 25(19):2466–2472

    Article  CAS  Google Scholar 

  • Breijyeh Z, Karaman R (2020) Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules 25(24):5789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bui TT, Nguyen TH (2017) Natural product for the treatment of Alzheimer’s disease. J Basic Clin Physiol Pharmacol 28(5):413–423

    Article  CAS  PubMed  Google Scholar 

  • Butterfield DA, Di Domenico F, Barone E (2014) Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain. Biochem Biophys Acta 1842(9):1693–1706

    CAS  PubMed  Google Scholar 

  • Cai FF, Bian YQ, Wu R, Sun Y, Chen XL, Yang MD et al (2019) Yinchenhao decoction suppresses rat liver fibrosis involved in an apoptosis regulation mechanism based on network pharmacology and transcriptomic analysis. Biomed Pharmacother 114:108863

    Article  CAS  PubMed  Google Scholar 

  • Castro RE, Santos MMM, Glória PMC, Ribeiro CJ, Ferreira DM, Xavier JM et al (2010) Cell death targets and potential modulators in alzheimer’s disease. Curr Pharm Des 16(25):2851–2864

    Article  CAS  PubMed  Google Scholar 

  • Chae HS, Xu R, Won JY, Chin YW, Yim H (2019) Molecular targets of genistein and its related flavonoids to exert anticancer effects. Int J Mol Sci 20(10):2420

    Article  PubMed  PubMed Central  Google Scholar 

  • Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B (2015) Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. Front Cell Neurosci 9:124

    Article  PubMed  PubMed Central  Google Scholar 

  • Chang YJ, Linh NH, Shih YH, Yu HM, Li MS, Chen YR (2016) Alzheimer’s amyloid-β sequesters caspase-3 in vitro via Its C-terminal tail. ACS Chem Neurosci 7(8):1097–1106

    Article  CAS  PubMed  Google Scholar 

  • Chang R, Yee KL, Sumbria RK (2017) Tumor necrosis factor α Inhibition for Alzheimer’s disease. J Cent Nerv Syst 9:1179573517709278

    Google Scholar 

  • Chaudhuri RK, Singh AK, Ghosal S (1975) Chemical constituents of gentianaceae XVIII Structure of Enicoflavine Monoterpene alkaloid from Enecostimma hyssopifolium. Chem Ind London 3:127–128

    Google Scholar 

  • Chopra RN, Nayar SL, Chopra IC (1956) Glossary of Indian medicinal plants. CSIR, New Delhi, pp 107

  • Deore SI, Khadabadi SS, Bhagure L, Ghorpade DS (2008) In vitro antimicrobial and antioxidant studies on Enicostemma axillare Raynal leaves. Nat prod radiance 7(5):409–412

    Google Scholar 

  • de Andrade Teles RB, Diniz TC, Costa Pinto TC, de Oliveira Junior RG, Gama E Silva M, de Lavor EM, Fernandes AWC, de Oliveira AP, de Almeida Ribeiro FPR, da Silva AAM, Cavalcante TCF, Quintans Junior LJ,  da Silva Almeida JRG (2018) Flavonoids as Therapeutic Agents in Alzheimer's and Parkinson's Diseases: A Systematic Review of Preclinical Evidences. Oxid Med Cell Longev 2018:7043213

    Article  PubMed  PubMed Central  Google Scholar 

  • De la Rosa A, Olaso-Gonzalez G, Arc-Chagnaud C, Millan F, Salvador-Pascual A, García-Lucerga C, Gomez-Cabrera MC (2020) Physical exercise in the prevention and treatment of Alzheimer’s disease. J Sport Health Sci 9:394–404

  • Devi S, Kumar V, Singh SK, Dubey AK, Kim JJ (2021) Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders. Biomedicines 9(2):99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dolan H, Crain B, Troncoso J, Resnick SM, Zonderman AB, Obrien RJ (2010) Atherosclerosis, dementia, and Alzheimer disease in the Baltimore longitudinal study of aging cohort. Ann Neurol 68(2):231–240

    Article  PubMed  PubMed Central  Google Scholar 

  • Du Y, Du Y, Zhang Y, Huang Z, Fu M, Li J et al (2019) MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer’s disease models. Signal Transduct Target Ther 4:58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duong MT, Nasrallah IM, Wolk DA, Chang CCY, Chang TY (2021) Cholesterol atherosclerosis and APOE in vascular contributions to cognitive impairment and dementia (VCID): potential mechanisms and therapy. Front Aging Neurosci 13:647990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fish PV, Steadman D, Bayle ED, Whiting P (2019) New approaches for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 29(2):125–133

    Article  CAS  PubMed  Google Scholar 

  • Ghosal S, Singh AK, Sharma PV, Chaudhuri RK (1974) Chemical constituents of Gentianaceae IX. Natural occurrence of erythrocentaurin in E. hyssopifolium and Swertia lawii. J Pharm Sci 63:944–745

    Article  CAS  PubMed  Google Scholar 

  • Hicks DA, Nalivaeva NN, Turner AJ (2012) Lipid rafts and Alzheimer’s disease: protein-lipid interactions and perturbation of signaling. Front Physiol 3:189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hiebl V, Ladurner A, Latkolik S, Dirsch VM (2018) Natural products as modulators of the nuclear receptors and metabolic sensors LXR. FXR and RXR Biotechnol Adv 36(6):1657–1698

    Article  CAS  PubMed  Google Scholar 

  • Hole KL, Williams RJ (2021) Flavonoids as an Intervention for Alzheimer’s Disease Progress and Hurdles Towards Defining a Mechanism of Action. Brain Plast 6:167–192

    Article  PubMed  PubMed Central  Google Scholar 

  • Honório KM, Moda TL, Andricopulo AD (2013) Pharmacokinetic properties and in silico ADME modeling in drug discovery. Med Chem 9(2):163–176

    Article  PubMed  Google Scholar 

  • Hopkins AL (2008) Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 4(11):682–690

    Article  CAS  PubMed  Google Scholar 

  • Huang LK, Chao SP, Hu CJ (2020) Clinical trials of new drugs for Alzheimer disease. J Biomed Sci 27(1):18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hussain G, Rasul A, Anwar H, Aziz N, Razzaq A, Wei W et al (2018a) Role of plant derived alkaloids and their mechanism in neurodegenerative disorders. Int J Biol Sci 14(3):341–357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hussain R, Zubair H, Pursell S, Shahab M (2018b) neurodegenerative diseases: regenerative mechanisms and novel therapeutic approaches. Brain Sci 8(9):177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Itakura M, Nakajima H, Kubo T, Semi Y, Kume S, Higashida S et al (2015) Glyceraldehyde-3-phosphate dehydrogenase aggregates accelerate amyloid-β amyloidogenesis in Alzheimer disease. J Biol Chem 290(43):26072–26087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaishree VS, Badami M, Kumar R, Tamizhmani T (2009) Antinociceptive activity of swertiamarin isolated from Enicostemma axillare. J Phytomedicine 16:227–232

    Article  CAS  PubMed  Google Scholar 

  • Jamal S, Grover A, Grover S (2019) Machine learning from molecular dynamics trajectories to predict caspase-8 inhibitors against Alzheimer’s disease. Front Pharmacol 10:780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji HF, Li XJ, Zhang HY (2009) Natural products and drug discovery, Can thousands of years of ancient medical knowledge lead us to new and powerful drug combinations in the fight against cancer and dementia. EMBO Rep 10(3):194–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang RW, Wong K, Chan Y, Xu H, But PPH, Shaw PC (2005) Isolation of iridoid and secoiridiod glycosides and comparative study on Radix gentiane and related adulterants by HPLC analysis. Phytochem 66:2674–2680

    Article  CAS  Google Scholar 

  • Kamm MA (2002) Review article: the complexity of drug development for irritable bowel syndrome. Aliment Pharmacol Ther 16(3):343–351

    Article  CAS  PubMed  Google Scholar 

  • Kamran M, Kousar R, Ullah S, Khan S, Haroon MFU, Rashid U et al (2020) Taxonomic Distribution of medicinal plants for Alzheimer disease: a cue to novel drugs. J Alzheimers Dis. https://doi.org/10.1155/2020/7603015

    Article  Google Scholar 

  • Kelley BJ, Knopman DS (2008) Alternative medicine and Alzheimer disease. Neurologist 14:299–306

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim N, Lee HJ (2020) Target enzymes considered for the treatment of alzheimer’s disease and parkinson’s disease. Biomed Res Int 2010:728

    Google Scholar 

  • Kim N, Lee HJ (2021) Redox-Active metal ions and amyloid-degrading enzymes in Alzheimer’s disease. Int J Mol Sci 22(14):7697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kirtikar KR, Basu BD (1999) Indian medicinal plants. 2nd edn. Bishen Sing, Dehradun, Mahendra Pal Sing Publication, pp 1655–1656

  • Lane CA, Hardy J, Schott JM (2018) Alzheimer’s disease. Eur Neurol 25(1):59–70

    Article  CAS  Google Scholar 

  • Lazarev VF, Guzhova IV, Margulis BA (2020) Glyceraldehyde-3-phosphate dehydrogenase is a multifaceted therapeutic target. Pharmaceutics 12:416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lazarev VF, Tsolaki M, Mikhaylova ER, Benken KA, Shevtsov MA, Nikotina AD et al (2021) Extracellular GAPDH promotes Alzheimer’s disease progression by enhancing amyloid-β aggregation and cytotoxicity. Aging Dis 12(5):1223–1237

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee JK, Kim NJ (2017) Recent advances in the inhibition of p38 MAPK as a potential strategy for the treatment of Alzheimer’s disease. Molecules 22(8):1287

    Article  MathSciNet  PubMed  PubMed Central  Google Scholar 

  • Li J, Sun M, Cui X, Li C (2022) Protective Effects of Flavonoids against Alzheimer's Disease: Pathological Hypothesis, Potential Targets, and Structure-Activity Relationship. Int J Mol Sci 23(17):10020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li S, Zhang B (2013) Traditional Chinese medicine network pharmacology: theory, methodology and application. Chin J Nat Med 11(2):110–120

    Article  PubMed  ADS  Google Scholar 

  • Li CQ, Zheng Q, Wang Q, Zeng QP (2016) Biotic/abiotic stress-driven Alzheimer’s disease. Front Cell Neurosci 10:269

    Article  PubMed  PubMed Central  Google Scholar 

  • Liang JW, Wang MY, Olounfeh KM, Zhao N, Wang S, Meng FH (2019) Network pharmacology-based identification of potential targets of the flower of Trollius chinensis Bunge acting on anti-inflammatory effects. Sci Rep 9(1):8109

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  • Lubitz I, Ricny J, Atrakchi-Baranes D, Shemesh C, Kravitz E, Liraz-Zaltsman S et al (2016) High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model. Aging Cell 15(2):309–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo TT, Lu Y, Yan SK, Xiao X, Rong XL, Guo J (2020) Network pharmacology in research of chinese medicine formula: methodology application and prospective. J Integr Med 26(1):72–80

    CAS  Google Scholar 

  • Meng-Zhen S, Ju L, Lan-Chun Z, Cai-Feng D, Shu-da Y, Hao-Fei Y et al (2022) Potential therapeutic use of plant flavonoids in AD and PD. Heliyon 8(11):e11440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minocha T, Birla H, Obaid AA, Rai V, Sushma P, Shivamallu C, Moustafa M, Al-Shehri M, Al-Emam A, Tikhonova MA, Yadav SK, Poeggeler B, Singh D, Singh SK (2022) Flavonoids as Promising Neuroprotectants and Their Therapeutic Potential against Alzheimer's Disease. Oxid Med Cell longev 2022:6038996

    Article  PubMed  PubMed Central  Google Scholar 

  • Mummery CJ, Börjesson-Hanson A, Blackburn DJ et al (2023) Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial. Nat Med 29:1437–1447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murali B, Upadhyaya UM, Goyal RK (2002) Effect of chronic treatment with Enicostemma littorale in non-insulin-dependent diabetic (NIDDM) rats. J  ethnopharmacology 81(2):199–204

    Article  CAS  Google Scholar 

  • Noori T, Dehpour AR, Sureda A, Sobarzo-Sanchez E, Shirooie S (2021) Role of natural products for the treatment of Alzheimer’s disease. Eur J Pharmacol 898:73974

    Article  Google Scholar 

  • OBrien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 34:185–204

    Article  CAS  PubMed  Google Scholar 

  • Olajide OA, Sarker SD (2020) Alzheimer's disease: natural products as inhibitors of neuroinflammation. Inflammopharmacology 28(6):1439–1455

    Article  PubMed  PubMed Central  Google Scholar 

  • Pandey SN, Rangra NK, Singh S, Arora S, Gupta V (2021)Evolving Role of Natural Products from Traditional Medicinal Herbs in the Treatment of Alzheimer's Disease. ACS Chem Neurosci 12(15):2718–2728

    Article  CAS  PubMed  Google Scholar 

  • Perry RT, Collins JS, Wiener H, Acton R, Go RC (2001) The role of TNF and its receptors in Alzheimer’s disease. Neurobiol Aging 22(6):873–883

    Article  CAS  PubMed  Google Scholar 

  • Perumal S, Gopal Samy MV, Subramanian D (2021a) Developmental toxicity, antioxidant, and marker enzyme assessment of swertiamarin in zebrafish (Danio rerio). J Biochem Mol Toxicol 35(9):e22843

    Article  CAS  PubMed  Google Scholar 

  • Perumal S, Gopal Samy MV, Subramanian D (2021b) Selenium nanoparticle synthesis from endangered medicinal herb (Enicostema axillare). Bioprocess Biosyst Eng 44(9):1853–1863

    Article  CAS  PubMed  Google Scholar 

  • Perumal S, Gopal Samy MV, Subramanian D (2022a) In vitro and in silico screening of novel typhoid drugs from endangered herb (Enicostema axillare). J Biomol Struct Dyn 41:2926–2936

    Article  PubMed  Google Scholar 

  • Perumal S, Gopal Samy MV, Subramanian D (2022b) Effect of novel therapeutic medicine swertiamarin from Enicostema axillare in zebrafish infected with Salmonella typhi. Chem Biol Drug Des 100(6):1033–1041

    Article  CAS  PubMed  Google Scholar 

  • Rehker J, Rodhe J, Nesbitt RR, Boyle EA, Martin BK, Lord J et al (2017) Caspase-8, association with Alzheimer’s disease and functional analysis of rare variants. PLoS One 12(10):e0185777

    Article  PubMed  PubMed Central  Google Scholar 

  • Rushworth JV, Hooper NM (2010) Lipid rafts: linking Alzheimer’s amyloid-β production, aggregation, and toxicity at neuronal membranes. J Alzheimer’s Dis 2011:603052

    Google Scholar 

  • Sasidharan P, Jayachitra A (2017) Direct shoot bud regeneration from shoot tip explants of Enicostema axillare: an important medicinal plant. Agroforest Syst 91:471–477

    Article  Google Scholar 

  • Schachter AS, Davis KL (2000) Alzheimer’s disease. Dialogues Clin Neurosci 2(2):91–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharma P, Dwivedee BP, Bisht D, Dash AK, Kumar D (2019) The chemical constituents and diverse pharmacological importance of Tinospora cordifolia. Heliyon 5(9):e02437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharma M, Malim FM, Goswami A, Sharma N, Juvvalapalli SS, Chatterjee S et al (2022) Neuroprotective effect of swertiamarin in a rotenone model of Parkinson’s disease: role of neuroinflammation and alpha-synuclein accumulation. ACS Pharmacol Transl Sci 6(1):40–51

    Article  PubMed  PubMed Central  Google Scholar 

  • Shawky E (2019) Prediction of potential cancer-related molecular targets of North African plant constituents using network pharmacology-based analysis. J Ethnopharmacol 238:111826

    Article  CAS  PubMed  Google Scholar 

  • Simons K, Ehehalt R (2002) Cholesterol, lipid rafts, and disease. J Clin Investig 110(5):597–603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su JH, Zhao M, Anderson AJ, Srinivasan A, Cotman CW (2001) Activated caspase-3 expression in Alzheimer’s and aged control brain: correlation with Alzheimer pathology. Brain Res 898(2):350–357

    Article  CAS  PubMed  Google Scholar 

  • Tang M, Xie X, Yi P, Kang J, Liao J, Li W, Li F (2020) Integrating Network Pharmacology with Molecular Docking to Unravel the Active Compounds and Potential Mechanism of Simiao Pill Treating Rheumatoid Arthritis. Evid Based Complement Alternat Med 2020:5786053

    Article  PubMed  PubMed Central  Google Scholar 

  • Thomford NE, Senthebane DA, Rowe A, Munro D, Seele P, Maroyi A, Dzobo K (2018) Natural products for drug discovery in the 21st century: innovations for novel drug discovery. Int J Mol Sci 19(6):1578

    Article  PubMed  PubMed Central  Google Scholar 

  • Tian G, Kong Q, Lai L, Ray-Chaudhury A, Lin CL (2010a) Increased expression of cholesterol 24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid rafts: a potential role in Alzheimer’s disease. J Neurochem 113(4):978–989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tian J, Shi J, Zhang X, Wang Y (2010b) Herbal therapy: a new pathway for the treatment of Alzheimer’s disease. Alzheimer’s Res Ther 2(5):30

    Article  ADS  Google Scholar 

  • Tsaioun K, Blaauboer BJ, Hartung T (2016) Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods. ALTEX 33(4): 343–358

    Article  PubMed  Google Scholar 

  • Tzvetkov NT, Atanasov AG (2018) Natural product-based multitargeted ligands for Alzheimer’s disease treatment. Future Med Chem 10(15): 1745–1748

    Article  CAS  PubMed  Google Scholar 

  • Ullah A, Munir S, Badshah SL, Khan N, Ghani L, Poulson BG et al (2020) Important flavonoids and their role as a therapeutic agent. Molecules 25(22):5243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Varier PS (1994) Indian medicinal plants. vol 2, Chennai, orient longman ltd, pp 374

  • Vishwakarma S, Rajani M, Bagul M, Goyal R (2004) A rapid method for the isolation of swertiamarin from Enicostemma littorale. Pharm Biol 42(6):400–403

    Article  CAS  Google Scholar 

  • Ygland E, van Weste D, Englund E, Rademakers R, Wszolek K, Nilsson K et al (2018) Slowly progressive dementia caused by MAPT R406W mutations: LONGITUDINAL report on a new kindred and systematic review. Alzheimers Res Ther 10(1):2

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang YW, Thompson R, Zhang H, Xu H (2011) APP processing in Alzheimer’s disease. Mol Brain 4:3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao J, Liu X, Xia W, Zhang Y, Wang C (2020) Targeting amyloidogenic processing of APP in Alzheimer’s disease. Front Mol Neurosci 413:137

    Article  Google Scholar 

  • Zheng Q, Song B, Li G, Cai F, Wu M, Zhao Y et al (2022) USP25 inhibition ameliorates Alzheimer’s pathology through the regulation of APP processing and Aβ generation. J Clin Investig 132(5):e152170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou M, Xu R, Kaelber DC, Gurney ME (2020) Tumor Necrosis factor (TNF) blocking agents are associated with lower risk for Alzheimer’s disease in patients with rheumatoid arthritis and psoriasis. PLoS One 15(3):e0229819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Cell and Molecular Biology Division, Biome Live Analytical Center, Karaikudi, Tamil Nadu, India

    Madhana Vigneshwari Gopal Samy & Sasidharan Perumal

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  1. Madhana Vigneshwari Gopal Samy
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MVGS performed work and proof correction for the manuscript. SP proposed the work plan.

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Samy, M.V.G., Perumal, S. Systems pharmacology and multi-scale mechanism of Enicostema axillare bioactives in treating Alzheimer disease. Inflammopharmacol 32, 575–593 (2024). https://doi.org/10.1007/s10787-023-01348-0

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