AMPK activators for the prevention and treatment of neurodegenerative diseases

References

• Rotermund C, Machetanz G, Fitzgerald JC. The therapeutic potential of metformin in neurodegenerative diseases [Review]. Front Endocrinol (Lausanne). 2018 Jul 19;9:400. doi: https://doi.org/10.3389/fendo.2018.00400. PMID: 30072954; PMCID: PMC6060268.
   Google Scholar
• Alzheimer’s Disease International. World alzheimer report 2015: the global impact of dementia: alzheimer’s disease international, London; 2015 [cited 2020 Dec 18]. Available from: https://www.alzint.org/u/WorldAlzheimerReport2015.pdf
   Google Scholar
• United Nations. World population prospects 2019: highlights. Department of Economic and Social Affairs, Population Division. 2019 May 27.
   Google Scholar
• Shah H, Albanese E, Duggan C, et al. Research priorities to reduce the global burden of dementia by 2025. Lancet Neurol. 2016;15(12):1285–1294.
   PubMed Web of Science ®Google Scholar
• Prince M, Bryce R, Albanese E, et al. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9(1):63–75. e2.
   PubMed Web of Science ®Google Scholar
• Garg G, Singh S, Singh AK, et al. Antiaging effect of metformin on brain in naturally aged and accelerated senescence model of rat. Rejuvenation Res. 2017;20(3):173–182.
   PubMed Web of Science ®Google Scholar
• Markowicz-Piasecka M, Sikora J, Szydłowska A, et al. Metformin–a future therapy for neurodegenerative diseases. Pharm Res. 2017;34(12):2614–2627.
   PubMed Web of Science ®Google Scholar
• Campbell JM, Stephenson MD, De Courten B, et al., Metformin use associated with reduced risk of dementia in patients with diabetes: a systematic review and meta-analysis. J Alzheimers Dis. 65(4): 1225–1236. 2018.
   PubMed Web of Science ®Google Scholar
• Hawley SA, Fullerton MD, Ross FA, et al., The ancient drug salicylate directly activates AMP-activated protein kinase. Science. 336(6083): 918–922. 2012.
   PubMed Web of Science ®Google Scholar
• Nilsson SE, Johansson B, Takkinen S, et al. Does aspirin protect against Alzheimer’s dementia? A study in a Swedish population-based sample aged≥ 80 years. Eur J Clin Pharmacol. 2003;59(4):313–319.
   PubMed Web of Science ®Google Scholar
• Tan M-J, Ye J-M, Turner N, et al. Antidiabetic activities of triterpenoids isolated from bitter melon associated with activation of the AMPK pathway. Chem Biol. 2008 March 21;15(3):263–273.
   PubMedGoogle Scholar
• Fuangchan A, Sonthisombat P, Seubnukarn T, et al. Hypoglycemic effect of bitter melon compared with metformin in newly diagnosed type 2 diabetes patients. J Ethnopharmacol. 2011 March 24 134(2):422–428.
   PubMed Web of Science ®Google Scholar
• Nerurkar PV, Orias D, Soares N, et al. Momordica charantia (bitter melon) modulates adipose tissue inflammasome gene expression and adipose-gut inflammatory cross talk in high-fat diet (HFD)-fed mice. J Nutr Biochem. 2019;68:16–32.
   PubMed Web of Science ®Google Scholar
• Przedborski S, Vila M, Jackson-Lewis V. Series Introduction: Neurodegeneration: What is it and where are we? J Clin Invest. 2003;111(1):3–10.
   PubMed Web of Science ®Google Scholar
• National Institute of Environmental Health Sciences. Neurodegenerative diseases: program description 2019 [updated 2019 Sept 10; cited 2021 Jan 4]. Available from: https://www.niehs.nih.gov/research/supported/health/neurodegenerative/index.cfm
   Google Scholar
• EU Joint Programme - Neurodegenerative Disease Research. What is neurodegenerative disease?: JPND research. 2019 [cited 2021 January 4]. Available from: https://www.neurodegenerationresearch.eu/what/
   Google Scholar
• Portfolio N. Neurodegenerative diseases: springer nature limited. 2021 [cited 2021 Jan 4]. Available from: https://www.nature.com/subjects/neurodegenerative-diseases
   Google Scholar
• Knopman DS, Petersen RC, editors. Mild cognitive impairment and mild dementia: a clinical perspective. Mayo Clinic Proceedings; 2014: Elsevier.
   Google Scholar
• Knopman DS, Boeve BF, Petersen RC, editors. Essentials of the proper diagnoses of mild cognitive impairment, dementia, and major subtypes of dementia. Mayo Clinic Proceedings; 2003: Elsevier.
   Google Scholar
• T O’Brien J, Thomas A. Vascular dementia. Lancet. 2015;386(10004):1698–1706.
   PubMed Web of Science ®Google Scholar
• Petersen RC. Clinical practice. Mild Cognitive Impairment New England J Med. 2011;364(23):2227.
   PubMed Web of Science ®Google Scholar
• Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56(3):303–308.
   PubMed Web of Science ®Google Scholar
• Johnson GV, Stoothoff WH. Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci. 2004;117(24):5721–5729.
   PubMed Web of Science ®Google Scholar
• Duyckaerts C, Delatour B, Potier M-C. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118(1):5–36.
   PubMed Web of Science ®Google Scholar
• Chen G-F, Xu T-H, Yan Y, et al. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin. 2017;38(9):1205–1235.
   PubMed Web of Science ®Google Scholar
• Deane R, Du Yan S, Submamaryan RK, et al. RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003;9(7):907–913.
   PubMed Web of Science ®Google Scholar
• Guillozet AL, Weintraub S, Mash DC, et al. Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol. 2003;60(5):729–736.
   PubMedGoogle Scholar
• Cho H, Choi JY, Hwang MS, et al. Tau PET in Alzheimer disease and mild cognitive impairment. Neurology. 2016;87(4):375–383.
   PubMed Web of Science ®Google Scholar
• Kahn BB, Alquier T, Carling D, et al. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005;1(1):15–25.
   PubMed Web of Science ®Google Scholar
• Jeon S-M. Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016;48(7):e245–e245.
   PubMed Web of Science ®Google Scholar
• Hardie D. AMPK: a key regulator of energy balance in the single cell and the whole organism. Int J Obesity. 2008;32(4):S7–S12.
   Google Scholar
• O’Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature. 2013;493(7432):346–355.
   PubMed Web of Science ®Google Scholar
• Curry DW, Stutz B, Andrews ZB, et al. Targeting AMPK signaling as a neuroprotective strategy in Parkinson’s disease. J Parkinsons Dis. 2018;8(2):161–181.
   PubMedGoogle Scholar
• Kulkarni AS, Gubbi S, Barzilai N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 2020;32:15–30.
   PubMed Web of Science ®Google Scholar
• Ruderman NB, Xu XJ, Nelson L, et al. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab. 2010;298:E751–E760.
   PubMed Web of Science ®Google Scholar
• Saisho Y. Metformin and inflammation: its potential beyond glucose-lowering effect. Endocrine Metab Immune Disorders-Drug Targets (Formerly Current Drug Targets-Immune, Endocrine & Metabolic Disorders). 2015;15(3):196–205.
   PubMed Web of Science ®Google Scholar
• Assefa BT, Tafere GG, Wondafrash DZ, et al. The bewildering effect of AMPK activators in alzheimer’s disease: review of the current evidence. Biomed Res Int. 2020;2020:1–18.
   Web of Science ®Google Scholar
• Won J-S, Im Y-B, Kim J, et al. Involvement of AMP-activated-protein-kinase (AMPK) in neuronal amyloidogenesis. Biochem Biophys Res Commun. 2010;399(4):487–491.
   PubMed Web of Science ®Google Scholar
• Caberlotto L, Lauria M, Nguyen T-P, et al. The central role of AMP-kinase and energy homeostasis impairment in Alzheimer’s disease: a multifactor network analysis. PLoS One. 2013;8(11):e78919.
   PubMed Web of Science ®Google Scholar
• Vingtdeux V, Giliberto L, Zhao H, et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-β peptide metabolism. J Biol Chem. 2010;285(12):9100–9113.
   PubMed Web of Science ®Google Scholar
• Lu J, Wu D, Zheng Y, et al. Quercetin activates AMP‐activated protein kinase by reducing PP2C expression protecting old mouse brain against high cholesterol‐induced neurotoxicity. J Pathol. 2010;222(2):199–212.
   PubMed Web of Science ®Google Scholar
• Yang -T-T, Shih Y-S, Chen Y-W, et al. Glucose regulates amyloid β production via AMPK. J Neural Transm. 2015;122(10):1381–1390.
   PubMed Web of Science ®Google Scholar
• Cai Z, Li B, Li K, et al. Down-regulation of amyloid-β through AMPK activation by inhibitors of GSK-3β in SH-SY5Y and SH-SY5Y-AβPP695 cells. J Alzheimers Dis. 2012;29(1):89–98.
   PubMed Web of Science ®Google Scholar
• Ou Z, Kong X, Sun X, et al. Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav Immun. 2018;69:351–363.
   PubMed Web of Science ®Google Scholar
• Chiang M-C, Cheng Y-C, Chen S-J, et al. Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against Amyloid-beta-induced mitochondrial dysfunction. Exp Cell Res. 2016;347(2):322–331.
   PubMed Web of Science ®Google Scholar
• Garza-Lombó C, Schroder A, Reyes-Reyes EM, et al. mTOR/AMPK signaling in the brain: cell metabolism, proteostasis and survival. Curr Opin Toxicol. 2018;8:102–110.
   PubMedGoogle Scholar
• Kim J, Park Y-J, Jang Y, et al. AMPK activation inhibits apoptosis and tau hyperphosphorylation mediated by palmitate in SH-SY5Y cells. Brain Res. 2011;1418:42–51.
   PubMed Web of Science ®Google Scholar
• Kim H-S, Moon S, Paik J-H, et al. Activation of the 5′-AMP-activated protein kinase in the cerebral cortex of young senescence-accelerated P8 mice and association with GSK3β-and PP2A-dependent inhibition of p-tau 396 expression. J Alzheimers Dis. 2015;46(1):249–259.
   PubMed Web of Science ®Google Scholar
• Julien C, Tremblay C, Émond V, et al. Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol. 2009;68(1):48–58.
   PubMed Web of Science ®Google Scholar
• Kickstein E, Krauss S, Thornhill P, et al. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc Nat Acad Sci. 2010 107(50):21830–21835.
   PubMed Web of Science ®Google Scholar
• Pérez-Revuelta B, Hettich M, Ciociaro A, et al. Metformin lowers Ser-129 phosphorylated α-synuclein levels via mTOR-dependent protein phosphatase 2A activation. Cell Death Dis. 2014;5(5):e1209–e1209.
   PubMed Web of Science ®Google Scholar
• Duka V, Lee J-H, Credle J, et al. Identification of the sites of tau hyperphosphorylation and activation of tau kinases in synucleinopathies and Alzheimer’s diseases. PLoS One. 2013;8(9):e75025.
   PubMed Web of Science ®Google Scholar
• Min S-W, Cho S-H, Zhou Y, et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron. 2010;67(6):953–966.
   PubMed Web of Science ®Google Scholar
• Cantó C, Gerhart-Hines Z, Feige JN, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009;458(7241):1056–1060.
   PubMed Web of Science ®Google Scholar
• Salminen A, Hyttinen JM, Kaarniranta K. AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J Mol Med. 2011;89(7):667–676.
   PubMed Web of Science ®Google Scholar
• Massey AC, Zhang C, Cuervo AM. Chaperone‐mediated autophagy in aging and disease. Curr Top Dev Biol. 2006;73:205–235.
   PubMed Web of Science ®Google Scholar
• Li L, Zhang X, Le W. Autophagy dysfunction in Alzheimer’s disease. Neurodegen Dis. 2010;7(4):265–271.
   PubMed Web of Science ®Google Scholar
• Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science. 2000;290(5497):1717–1721.
   PubMed Web of Science ®Google Scholar
• Wei Y, Zhou J, Wu J, et al. ERβ promotes Aβ degradation via the modulation of autophagy. Cell Death Dis. 2019;10(8):1–13.
   Google Scholar
• Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013;19(8):983–997.
   PubMed Web of Science ®Google Scholar
• Chen J-L, Luo C, Pu D, et al. Metformin attenuates diabetes-induced tau hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance. Exp Neurol. 2019;311:44–56.
   PubMed Web of Science ®Google Scholar
• Jiang T, Yu JT, Zhu XC, et al. Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre‐activation of AMPK‐dependent autophagy. Br J Pharmacol. 2014;171(13):3146–3157.
   PubMed Web of Science ®Google Scholar
• Kim J, Kundu M, Viollet B, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13(2):132–141.
   PubMed Web of Science ®Google Scholar
• Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011;13(9):1016–1023.
   PubMed Web of Science ®Google Scholar
• Peixoto CA, de Oliveira WH, da Racho Araújo SM, et al. AMPK activation: role in the signaling pathways of neuroinflammation and neurodegeneration. Exp Neurol. 2017;298:31–41.
   PubMed Web of Science ®Google Scholar
• Mairet-Coello G, Courchet J, Pieraut S, et al. The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Aβ oligomers through Tau phosphorylation. Neuron. 2013;78(1):94–108.
   PubMed Web of Science ®Google Scholar
• Wang X, Zimmermann HR, Ma T. Therapeutic potential of AMP-activated protein kinase in Alzheimer’s disease. J Alzheimers Dis. 2019;68(1):33–38.
   PubMed Web of Science ®Google Scholar
• Bettcher BM, Kramer JH. Longitudinal inflammation, cognitive decline, and Alzheimer’s disease: a mini‐review. Clin Pharmacol Ther. 2014;96(4):464–469.
   PubMed Web of Science ®Google Scholar
• Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol. 2007;7(2):161–167.
   PubMed Web of Science ®Google Scholar
• Glass CK, Saijo K, Winner B, et al. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918–934.
   PubMed Web of Science ®Google Scholar
• Darweesh SK, Wolters FJ, Ikram MA, et al. Inflammatory markers and the risk of dementia and Alzheimer’s disease: a meta-analysis. Alzheimers Dement. 2018;14(11):1450–1459.
   PubMed Web of Science ®Google Scholar
• Nguyen JC, Killcross AS, Jenkins TA. Obesity and cognitive decline: role of inflammation and vascular changes. Front Neurosci. 2014;8:375.
   PubMed Web of Science ®Google Scholar
• Nikolaev A, McLaughlin T, O’Leary DD, et al. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009;457(7232):981–989.
   PubMed Web of Science ®Google Scholar
• Bailey CJ, Day C. Traditional plant medicines as treatments for diabetes. Diabetes Care. 1989;12(8):553–564.
   PubMed Web of Science ®Google Scholar
• Goodarzi MO, Bryer‐Ash M. Metformin revisited: re‐evaluation of its properties and role in the pharmacopoeia of modern antidiabetic agents. Diabetes Obesity Metab. 2005;7(6):654–665.
   PubMed Web of Science ®Google Scholar
• Viollet B, Guigas B, Garcia NS, et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci. 2012;122(6):253–270.
   PubMed Web of Science ®Google Scholar
• Lin HZ, Yang SQ, Chuckaree C, et al. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000;6(9):998–1003.
   PubMed Web of Science ®Google Scholar
• Hundal RS, Inzucchi SE. Metformin. Drugs. 2003;63(18):1879–1894.
   PubMed Web of Science ®Google Scholar
• Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. Bmj. 2005;330(7503):1304–1305.
   PubMed Web of Science ®Google Scholar
• Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy. Ann Transl Med. 2014;2:6.
   PubMedGoogle Scholar
• Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100(5):1082–1090.
   PubMed Web of Science ®Google Scholar
• Campbell JM, Bellman SM, Stephenson MD, et al. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. Ageing Res Rev. 2017;40:31–44.
   PubMed Web of Science ®Google Scholar
• International AsD. About alzheimer’s and dementia. 2020.
   Google Scholar
• Hsu -C-C, Wahlqvist ML, Lee M-S, et al. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis. 2011;24(3):485–493.
   PubMed Web of Science ®Google Scholar
• Cheng C, Lin C-H, Tsai Y-W, et al. Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J Gerontol Ser A Biomed Sci Med Sci. 2014;69(10):1299–1305.
   PubMed Web of Science ®Google Scholar
• Orkaby AR, Cho K, Cormack J, et al. Metformin vs sulfonylurea use and risk of dementia in US veterans aged≥ 65 years with diabetes. Neurology. 2017;89(18):1877–1885.
   PubMed Web of Science ®Google Scholar
• Ng TP, Feng L, Yap KB, et al. Long-term metformin usage and cognitive function among older adults with diabetes. J Alzheimers Dis. 2014;41(1):61–68.
   PubMed Web of Science ®Google Scholar
• Yokoyama H, Ogawa M, Honjo J, et al. Risk factors associated with abnormal cognition in Japanese outpatients with diabetes, hypertension or dyslipidemia. Diabetol Int. 2015;6(4):268–274.
   Web of Science ®Google Scholar
• Shi Q, Liu S, Fonseca VA, et al. Effect of metformin on neurodegenerative disease among elderly adult US veterans with type 2 diabetes mellitus. BMJ Open. 2019;9(7):e024954.
   PubMed Web of Science ®Google Scholar
• Gupta A, Bisht B, Dey CS. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology. 2011;60(6):910–920.
   PubMed Web of Science ®Google Scholar
• Imfeld P, Bodmer M, Jick SS, et al. Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population‐based case–control study. J Am Geriatr Soc. 2012;60(5):916–921.
   PubMed Web of Science ®Google Scholar
• Moore EM, Mander AG, Ames D, et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care. 2013;36(10):2981–2987.
   PubMed Web of Science ®Google Scholar
• De Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010 May 20;340:c2181. doi: https://doi.org/10.1136/bmj.c2181. PMID: 20488910; PMCID: PMC2874129.
   Google Scholar
• Reinstatler L, Qi YP, Williamson RS, et al. Association of biochemical B12 deficiency with metformin therapy and vitamin B12 supplements: the national health and nutrition examination survey, 1999–2006. Diabetes Care. 2012;35(2):327–333.
   PubMed Web of Science ®Google Scholar
• Luchsinger JA, Perez T, Chang H, et al. Metformin in amnestic mild cognitive impairment: results of a pilot randomized placebo controlled clinical trial. J Alzheimers Dis. 2016;51(2):501–514.
   PubMed Web of Science ®Google Scholar
• Koenig AM, Mechanic-Hamilton D, Xie SX, et al. Effects of the insulin sensitizer metformin in Alzheimer’s disease: pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis Assoc Disord. 2017;31(2):107.
   PubMed Web of Science ®Google Scholar
• Lin Y, Wang K, Ma C, et al. Evaluation of metformin on cognitive improvement in patients with non-dementia vascular cognitive impairment and abnormal glucose metabolism. Front Aging Neurosci. 2018;10:227.
   PubMed Web of Science ®Google Scholar
• Luchsinger JA, de la Torre JC. Type 2 diabetes, related conditions, in relation and dementia: an opportunity for prevention? J Alzheimers Dis. 2010;20(3):723–736.
   PubMed Web of Science ®Google Scholar
• Cameron AR, Morrison VL, Levin D, et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res. 2016;119(5):652–665.
   PubMed Web of Science ®Google Scholar
• Zhou G, Myers R, Li Y, et al., Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 108(8): 1167–1174. 2001.
   PubMed Web of Science ®Google Scholar
• Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: old or new insights? Diabetologia. 2013;56(9):1898–1906.
   PubMed Web of Science ®Google Scholar
• Fujita Y, Hosokawa M, Fujimoto S, et al. Metformin suppresses hepatic gluconeogenesis and lowers fasting blood glucose levels through reactive nitrogen species in mice. Diabetologia. 2010;53(7):1472–1481.
   PubMed Web of Science ®Google Scholar
• He L, Wondisford FE. Metformin action: concentrations matter. Cell Metab. 2015;21(2):159–162.
   PubMed Web of Science ®Google Scholar
• Foretz M, Hébrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120(7):2355–2369.
   PubMed Web of Science ®Google Scholar
• Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310(5754):1642–1646.
   PubMed Web of Science ®Google Scholar
• Zhang C-S, Jiang B, Li M, et al. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab. 2014;20(3):526–540.
   PubMed Web of Science ®Google Scholar
• Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348(3):607–614.
   PubMed Web of Science ®Google Scholar
• M-y E-M, Nogueira V, Fontaine E, et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275(1):223–228.
   PubMed Web of Science ®Google Scholar
• Oliveira WH, Nunes AK, MER F, et al. Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice. Brain Res. 2016;1644:149–160.
   PubMed Web of Science ®Google Scholar
• Barini E, Antico O, Zhao Y, et al. Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy. Mol Neurodegener. 2016;11(1):16.
   PubMed Web of Science ®Google Scholar
• Allard JS, Perez EJ, Fukui K, et al. Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice. Behav Brain Res. 2016;301:1–9.
   PubMed Web of Science ®Google Scholar
• Sapkota B, Subramanian A, Priamvada G, et al. Association of APOE polymorphisms with diabetes and cardiometabolic risk factors and the role of APOE genotypes in response to anti-diabetic therapy: results from the AIDHS/SDS on a South Asian population. J Diabetes Complications. 2015 Nov-Dec;29(8):1191–1197.
   PubMed Web of Science ®Google Scholar
• Zhang J, Lin Y, Dai X, et al. Metformin treatment improves the spatial memory of aged mice in an apoe genotype–dependent manner. FASEB J. 2019;33(6):7748–7757.
   PubMed Web of Science ®Google Scholar
• Sahra IB, Regazzetti C, Robert G, et al. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 2011;71(13):4366–4372.
   PubMed Web of Science ®Google Scholar
• Chen SC, Brooks R, Houskeeper J, et al. Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. Mol Cell Endocrinol. 2017 Jan;15(440):57–68.
   Google Scholar
• Sena CM, Matafome P, Louro T, et al. Metformin restores endothelial function in aorta of diabetic rats. Br J Pharmacol. 2011;163(2):424–437.
   PubMed Web of Science ®Google Scholar
• Liu NH, Zhu L, Zhang XB, et al. Metformin with propofol enhances the scavenging ability of free radicals and inhibits lipid peroxidation in mice. Eur Rev Med Pharmacol Sci. 2019 Jun;23(11):4980–4987.
   PubMed Web of Science ®Google Scholar
• Zheng Z, Chen H, Li J, et al. Sirtuin 1–mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin. Diabetes. 2012;61(1):217–228.
   PubMed Web of Science ®Google Scholar
• Vlot AC, Dempsey DMA, Klessig DF. Salicylic acid, a multifaceted hormone to combat disease. Annu Rev Phytopathol. 2009;47:177–206.
   PubMed Web of Science ®Google Scholar
• Higgs GA, Salmon JA, Henderson B, et al. Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity. Proc Nat Acad Sci. 1987;84(5):1417–1420.
   PubMed Web of Science ®Google Scholar
• Patrono C, Baigent C. Role of aspirin in primary prevention of cardiovascular disease. Nat Rev Cardiol. 2019;16(11):675–686.
   PubMed Web of Science ®Google Scholar
• Cuzick J, Otto F, Baron JA, et al. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol. 2009;10(5):501–507.
   PubMed Web of Science ®Google Scholar
• Thun MJ, Jacobs EJ, Patrono C. The role of aspirin in cancer prevention. Nat Rev Clin Oncol. 2012;9(5):259.
   PubMed Web of Science ®Google Scholar
• Hardie DG. AMPK: a target for drugs and natural products with effects on both diabetes and cancer. Diabetes. 2013;62(7):2164–2172.
   PubMed Web of Science ®Google Scholar
• Ryan J, Storey E, Murray AM, et al. Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline. Neurology. 2020;95(3):e320–e331.
   PubMed Web of Science ®Google Scholar
• Group AC. Aspirin in Alzheimer’s disease (AD2000): a randomised open-label trial. Lancet Neurol. 2008;7(1):41–49.
   PubMed Web of Science ®Google Scholar
• Matsumoto C, Ogawa H, Saito Y, et al. Sex difference in effects of low-dose aspirin on prevention of dementia in patients with type 2 diabetes: a long-term follow-up study of a randomized clinical trial. Diabetes Care. 2020;43(2):314–320.
   PubMed Web of Science ®Google Scholar
• Meyer JS, Rogers RL, McClintic K, et al. Randomized clinical trial of daily aspirin therapy in multi‐infarct dementia: a pilot study. J Am Geriatr Soc. 1989;37(6):549–555.
   PubMed Web of Science ®Google Scholar
• Kern S, Skoog I, Östling S, et al. Does low-dose acetylsalicylic acid prevent cognitive decline in women with high cardiovascular risk? A 5-year follow-up of a non-demented population-based cohort of Swedish elderly women. BMJ Open. 2012;2:5.
   Web of Science ®Google Scholar
• Chang C-W, Horng J-T, Hsu -C-C, et al. Mean daily dosage of aspirin and the risk of incident Alzheimer’s dementia in patients with type 2 diabetes mellitus: a nationwide retrospective cohort study in Taiwan. J Diabetes Res. 2016;2016:9027484. doi: https://doi.org/10.1155/2016/9027484. Epub 2016 Oct 27. PMID: 27868071; PMCID: PMC5102734.
   Google Scholar
• Jonker C, Comijs H, Smit J. Does aspirin or other NSAIDs reduce the risk of cognitive decline in elderly persons? Results from a population-based study. Neurobiol Aging. 2003;24(4):583–588.
   PubMed Web of Science ®Google Scholar
• Kang JH, Grodstein F. Regular use of nonsteroidal anti-inflammatory drugs and cognitive function in aging women. Neurology. 2003;60(10):1591–1597.
   PubMed Web of Science ®Google Scholar
• Yang Y-H, Chiu -C-C, Teng H-W, et al. Aspirin and risk of dementia in patients with late-onset depression: a population-based cohort study. Biomed Res Int. 2020Jan 29;2020:1704879. doi: https://doi.org/10.1155/2020/1704879. PMID: 32090069; PMCID: PMC7008294.
   Google Scholar
• Broe GA, Grayson DA, Creasey HM, et al. Anti-inflammatory drugs protect against Alzheimer disease at low doses. Arch Neurol. 2000;57(11):1586–1591.
   PubMed Web of Science ®Google Scholar
• Din FV, Valanciute A, Houde VP, et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology. 2012;142(7):1504–1515. e3.
   PubMed Web of Science ®Google Scholar
• Henry WS, Laszewski T, Tsang T, et al. Aspirin suppresses growth in PI3K-mutant breast cancer by activating AMPK and inhibiting mTORC1 signaling. Cancer Res. 2017;77(3):790–801.
   PubMed Web of Science ®Google Scholar
• O’Brien AJ, Villani LA, Broadfield LA, et al. Salicylate activates AMPK and synergizes with metformin to reduce the survival of prostate and lung cancer cells ex vivo through inhibition of de novo lipogenesis. Biochem J. 2015;469(2):177–187.
   PubMedGoogle Scholar
• Preston S, Arnold M, Beller E, et al. Comparative analgesic and anti‐inflammatory properties of sodium salicylate and acetylsalicylic acid (aspirin) in rheumatoid arthritis. Br J Clin Pharmacol. 1989;27(5):607–611.
   PubMed Web of Science ®Google Scholar
• Day R, Graham G, Bieri D, et al. Concentration‐response relationships for salicylate‐induced ototoxicity in normal volunteers. Br J Clin Pharmacol. 1989;28(6):695–702.
   PubMed Web of Science ®Google Scholar
• Grilli M, Pizzi M, Memo M, et al. Neuroprotection by aspirin and sodium salicylate through blockade of NF-κB activation. Science. 1996;274(5291):1383–1385.
   PubMed Web of Science ®Google Scholar
• Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science. 1994;265(5174):956–959.
   PubMed Web of Science ®Google Scholar
• Steinberg GR, Dandapani M, Hardie DG. AMPK: mediating the metabolic effects of salicylate-based drugs? Trends Endocrinol Metab. 2013;24(10):481–487.
   PubMed Web of Science ®Google Scholar
• Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231(25):232–235.
   PubMedGoogle Scholar
• Vane J, Bakhle Y, Botting R. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol. 1998;38(1):97–120.
   PubMed Web of Science ®Google Scholar
• Vane J, Botting R. The mechanism of action of aspirin. Thromb Res. 2003;110(5–6):255–258.
   PubMed Web of Science ®Google Scholar
• Amann R, Peskar BA. Anti-inflammatory effects of aspirin and sodium salicylate. Eur J Pharmacol. 2002;447(1):1–9.
   PubMed Web of Science ®Google Scholar
• Din F, Dunlop M, Stark L. Evidence for colorectal cancer cell specificity of aspirin effects on NF κ B signalling and apoptosis. Br J Cancer. 2004;91(2):381–388.
   PubMed Web of Science ®Google Scholar
• Grosser N, Schröder H. Aspirin protects endothelial cells from oxidant damage via the nitric oxide-cGMP pathway. Arterioscler Thromb Vasc Biol. 2003;23(8):1345–1351.
   PubMed Web of Science ®Google Scholar
• Jung S-B, Kim C-S, Naqvi A, et al. Histone deacetylase 3 antagonizes aspirin-stimulated endothelial nitric oxide production by reversing aspirin-induced lysine acetylation of endothelial nitric oxide synthase. Circ Res. 2010;107(7):877–887.
   PubMed Web of Science ®Google Scholar
• Kuhn W, Müller T, Büttner T, et al. Antioxidative properties of aspirin: dose dependence and clinical implications. Eur J Neurol. 1996 May;3(3):275–277.
   PubMed Web of Science ®Google Scholar
• Aubin N, Curet O, Deffois A, et al. Aspirin and salicylate protect against MPTP‐induced dopamine depletion in mice. J Neurochem. 1998;71(4):1635–1642.
   PubMed Web of Science ®Google Scholar
• Mohanakumar KP, Muralikrishnan D, Thomas B. Neuroprotection by sodium salicylate against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced neurotoxicity. Brain Res. 2000;864(2):281–290.
   PubMed Web of Science ®Google Scholar
• Thakur P, Nehru B. Anti-inflammatory properties rather than anti-oxidant capability is the major mechanism of neuroprotection by sodium salicylate in a chronic rotenone model of Parkinson’s disease. Neuroscience. 2013;231:420–431.
   PubMed Web of Science ®Google Scholar
• Farina N, Llewellyn D, Isaac MGEKN, et al. Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database Syst Rev. 2017:1.
   Google Scholar
• Krause D, Roupas P. Effect of vitamin intake on cognitive decline in older adults: evaluation of the evidence. J Nutr Health Aging. 2015;19(7):745–753.
   PubMed Web of Science ®Google Scholar
• Boothby LA, Doering PL. Vitamin C and vitamin E for Alzheimer’s disease. Ann Pharmacother. 2005;39(12):2073–2080.
   PubMed Web of Science ®Google Scholar
• McCleery J, Abraham RP, Denton DA, et al. Vitamin and mineral supplementation for preventing dementia or delaying cognitive decline in people with mild cognitive impairment. Cochrane Database Syst Rev. 2018;2019(11). https://doi.org/10.1002/14651858.CD011905.pub2.
   Google Scholar
• Burckhardt M, Herke M, Wustmann T, et al. Omega‐3 fatty acids for the treatment of dementia. Cochrane Database Syst Rev. 2016(4). https://doi.org/10.1002/14651858.CD009002.pub3.
   Google Scholar
• Grover J, Yadav S. Pharmacological actions and potential uses of Momordica charantia: a review. J Ethnopharmacol. 2004;93(1):123–132.
   PubMed Web of Science ®Google Scholar
• Raman A, Lau C. Anti-diabetic properties and phytochemistry of momordica charantia L. (Cucurbitaceae) Phytomedicine. 1996;2(4):349–362.
   PubMed Web of Science ®Google Scholar
• Ooi CP, Yassin Z, Hamid TA. Momordica charantia for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2012Aug 15;(8):CD007845. doi: https://doi.org/10.1002/14651858.CD007845.pub3. PMID: 22895968.
   Google Scholar
• Alam MA, Uddin R, Subhan N, et al. Beneficial role of bitter melon supplementation in obesity and related complications in metabolic syndrome. J Lipids. 2015;2015:496169. doi: https://doi.org/10.1155/2015/496169. Epub 2015 Jan 12. PMID: 25650336; PMCID: PMC4306384.
   Google Scholar
• Dandawate PR, Subramaniam D, Padhye SB, et al. Bitter melon: a panacea for inflammation and cancer. Chin J Nat Med. 2016;14(2):81–100.
   PubMed Web of Science ®Google Scholar
• Nakamura S, Murakami T, Nakamura J, et al. Structures of new cucurbitane-type triterpenes and glycosides, karavilagenins and karavilosides, from the dried fruit of Momordica charantia L. in Sri Lanka. Chem Pharm Bull. 2006;54(11):1545–1550.
   PubMed Web of Science ®Google Scholar
• Kwatra D, Venugopal A, Standing D, et al. Bitter melon extracts enhance the activity of chemotherapeutic agents through the modulation of multiple drug resistance. J Pharm Sci. 2013;102(12):4444–4454.
   PubMed Web of Science ®Google Scholar
• Chang C-I, Tseng H-I, Liao Y-W, et al. In vivo and in vitro studies to identify the hypoglycaemic constituents of Momordica charantia wild variant WB24. Food Chem. 2011;125(2):521–528.
   Web of Science ®Google Scholar
• Farooqi AA, Khalid S, Tahir F, et al. Bitter gourd (Momordica charantia) as a rich source of bioactive components to combat cancer naturally: are we on the right track to fully unlock its potential as inhibitor of deregulated signaling pathways. Food Chem Toxicol. 2018;119:98–105.
   PubMed Web of Science ®Google Scholar
• Ali L, Khan AKA, Mamun MIR, et al. Studies on hypoglycemic effects of fruit pulp, seed, and whole plant of Momordica charantia on normal and diabetic model rats. Planta Med. 1993;59(5):408–412.
   PubMed Web of Science ®Google Scholar
• Day C, Cartwright T, Provost J, et al. Hypoglycaemic effect of Momordica charantia extracts. Planta Med. 1990;56(5):426–429.
   PubMed Web of Science ®Google Scholar
• Inayat UR, Khan RU, Khalil UR, et al. Lower hypoglycemic but higher antiatherogenic effects of bitter melon than glibenclamide in type 2 diabetic patients. Nutr J. 2015;14:13.
   PubMed Web of Science ®Google Scholar
• Cunnick JE, Sakamoto K, Chapes SK, et al. Induction of tumor cytotoxic immune cells using a protein from the bitter melon (Momordica charantia). Cell Immunol. 1990;126(2):278–289.
   PubMed Web of Science ®Google Scholar
• Leung L, Birtwhistle R, Kotecha J, et al. Anti-diabetic and hypoglycaemic effects of Momordica charantia (bitter melon): a mini review. Br J Nutr. 2009;102(12):1703–1708.
   PubMed Web of Science ®Google Scholar
• Bourinbaiar AS, Leehuang S. Potentiation of anti-HIV activity of anti-inflammatory drugs, dexamethasone and indomethacin, by MAP30, the antiviral agent from bitter melon. Biochem Biophys Res Commun. 1995;208(2):779–785.
   PubMed Web of Science ®Google Scholar
• Muhammad N, Steele R, Isbell TS, et al. Bitter melon extract inhibits breast cancer growth in preclinical model by inducing autophagic cell death. Oncotarget. 2017;8(39):66226.
   PubMedGoogle Scholar
• Yung MM, Ross FA, Hardie DG, et al. Bitter melon (Momordica charantia) extract inhibits tumorigenicity and overcomes cisplatin-resistance in ovarian cancer cells through targeting AMPK signaling cascade. Integr Cancer Ther. 2016;15(3):376–389.
   PubMed Web of Science ®Google Scholar
• Kwatra D, Subramaniam D, Ramamoorthy P, et al. Methanolic extracts of bitter melon inhibit colon cancer stem cells by affecting energy homeostasis and autophagy. Evid Based Complement Alternat Med. 2013;2013:1–14.
   PubMed Web of Science ®Google Scholar
• Kaur M, Deep G, Jain AK, et al. Bitter melon juice activates cellular energy sensor AMP-activated protein kinase causing apoptotic death of human pancreatic carcinoma cells. Carcinogenesis. 2013;34(7):1585–1592.
   PubMed Web of Science ®Google Scholar
• Grossmann ME, Mizuno NK, Dammen ML, et al. Eleostearic acid inhibits breast cancer proliferation by means of an oxidation-dependent mechanism. Cancer Prev Res. 2009;2(10):879–886.
   PubMed Web of Science ®Google Scholar
• Joshi A, Soni P, Malviya S, et al. Memory enhancing activity of Momordica charantia by scopolamine induced amnesia in rats. IJCAP. 2017;2:11–18.
   Google Scholar
• Huang H-J, Chen S-L, Chang Y-T, et al. Administration of Momordica charantia enhances the neuroprotection and reduces the side effects of LiCl in the treatment of Alzheimer’s disease. Nutrients. 2018;10(12):1888.
   PubMed Web of Science ®Google Scholar
• Kim KB, Lee S, Kang I, et al. Momordica charantia ethanol extract attenuates H2O2-induced cell death by its antioxidant and anti-apoptotic properties in human neuroblastoma SK-N-MC cells. Nutrients. 2018;10(10):1368.
   Web of Science ®Google Scholar
• Gong J, Sun F, Li Y, et al. Momordica charantia polysaccharides could protect against cerebral ischemia/reperfusion injury through inhibiting oxidative stress mediated c-Jun N-terminal kinase 3 signaling pathway. Neuropharmacology. 2015;91:123–134.
   PubMed Web of Science ®Google Scholar
• Ma J, Fan H, Cai H, et al. Promotion of Momordica Charantia polysaccharides on neural stem cell proliferation by increasing SIRT1 activity after cerebral ischemia/reperfusion in rats. Brain Res Bull. 2021;170:254–263.
   PubMed Web of Science ®Google Scholar
• Malik ZA, Singh M, Sharma P. Neuroprotective effect of Momordica charantia in global cerebral ischemia and reperfusion induced neuronal damage in diabetic mice. J Ethnopharmacol. 2011;133(2):729–734.
   PubMed Web of Science ®Google Scholar
• Yu Y, Zhang XH, Ebersole B, et al. Bitter melon extract attenuating hepatic steatosis may be mediated by FGF21 and AMPK/Sirt1 signaling in mice. Sci Rep. 2013;3:3142.
   PubMed Web of Science ®Google Scholar
• Iseli TJ, Turner N, Zeng X-Y, et al. Activation of AMPK by bitter melon triterpenoids involves CaMKKβ. PLoS One. 2013;8(4):e62309.
   PubMed Web of Science ®Google Scholar
• Zha Q-B, Zhang X-Y, Lin Q-R, et al. Cucurbitacin E induces autophagy via downregulating mTORC1 signaling and upregulating AMPK activity. PloS One. 2015;10(5):e0124355.
   PubMed Web of Science ®Google Scholar
• Chen G-C, Su H-M, Lin Y-S, et al. A conjugated fatty acid present at high levels in bitter melon seed favorably affects lipid metabolism in hepatocytes by increasing NAD+/NADH ratio and activating PPARα, AMPK and SIRT1 signaling pathway. J Nutr Biochem. 2016;33:28–35.
   PubMed Web of Science ®Google Scholar
• Raish M, Ahmad A, Ansari MA, et al. Momordica charantia polysaccharides ameliorate oxidative stress, inflammation, and apoptosis in ethanol-induced gastritis in mucosa through NF-kB signaling pathway inhibition. Int J Biol Macromol. 2018;111:193–199.
   PubMed Web of Science ®Google Scholar
• Jones LD, Pangloli P, Krishnan HB, et al. BG-4, a novel bioactive peptide from Momordica charantia, inhibits lipopolysaccharide-induced inflammation in THP-1 human macrophages. Phytomedicine. 2018;42:226–232.
   PubMed Web of Science ®Google Scholar
• Horax R, Hettiarachchy N, Chen P. Extraction, quantification, and antioxidant activities of phenolics from pericarp and seeds of bitter melons (Momordica charantia) harvested at three maturity stages (immature, mature, and ripe). J Agric Food Chem. 2010;58(7):4428–4433.
   PubMed Web of Science ®Google Scholar
• Kumar R, Balaji S, Sripriya R, et al. In vitro evaluation of antioxidants of fruit extract of Momordica charantia L. On Fibroblasts and Keratinocytes J Agric Food Chem. 2010;58(3):1518–1522.
   PubMed Web of Science ®Google Scholar
• Wu S-J, Ng L-T. Antioxidant and free radical scavenging activities of wild bitter melon (Momordica charantia Linn. var abbreviata Ser) in Taiwan LWT-Food Sci Technol. 2008;41(2):323–330.
   Web of Science ®Google Scholar
• Tsai T-H, Huang W-C, Ying H-T, et al. Wild bitter melon leaf extract inhibits Porphyromonas gingivalis-induced inflammation: identification of active compounds through bioassay-guided isolation. Molecules. 2016;21(4):454.
   PubMed Web of Science ®Google Scholar
• Choo C, Waisundara VY, Hoon LY. Bittergourd (Momordica charantia) scavenges free radicals by enhancing the expression of superoxide dismutase in in vitro models of diabetes and cancer. CyTA-J Food. 2014;12(4):378–382.
   Web of Science ®Google Scholar
• Shurrab NT, Arafa E-SA. Metformin: a review of its therapeutic efficacy and adverse effects. Obes Med. 2020;17:100186.
   Google Scholar
• Åhsberg K, Höglund P, Kim W-H, et al. Impact of aspirin, NSAIDs, warfarin, corticosteroids and SSRIs on the site and outcome of non-variceal upper and lower gastrointestinal bleeding. Scand J Gastroenterol. 2010;45(12):1404–1415.
   PubMed Web of Science ®Google Scholar
• Sostres C, Lanas A. Gastrointestinal effects of aspirin. Nat Clin Pract Gastroenterol Hepatol. 2011;8(7):385–394.
   Google Scholar
• Brien J-A. Ototoxicity associated with salicylates. Drug Saf. 1993;9(2):143–148.
   PubMed Web of Science ®Google Scholar
• Palmer BF, Clegg DJ. Salicylate toxicity. N Engl J Med. 2020;382(26):2544–2555.
   PubMed Web of Science ®Google Scholar
• Wang GS, Hoyte C. Review of biguanide (Metformin) toxicity. J Intensive Care Med. 2019;34(11–12):863–876.
   PubMed Web of Science ®Google Scholar
• Basch E, Gabardi S, Ulbricht C. Bitter melon (Momordica charantia): a review of efficacy and safety. Am J Health Syst Pharm. 2003;60(4):356–359.
   PubMed Web of Science ®Google Scholar
• Müller T, Mueller BK, Riederer P. Perspective: treatment for disease modification in chronic neurodegeneration. Cells. 2021;10(4):873.
   PubMed Web of Science ®Google Scholar
• Infante-Garcia C, Ramos-Rodriguez JJ, Hierro-Bujalance C, et al. Antidiabetic polypill improves central pathology and cognitive impairment in a mixed model of Alzheimer’s disease and type 2 diabetes. Mol Neurobiol. 2018;55(7):6130–6144.
   PubMed Web of Science ®Google Scholar
• Paseban M, Mohebbati R, Niazmand S, et al. Comparison of the neuroprotective effects of aspirin, atorvastatin, captopril and metformin in diabetes mellitus. Biomolecules. 2019 Mar 27;9:4.
   Web of Science ®Google Scholar
• Atanasov AG, Zotchev SB, Dirsch VM, et al. Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov. 2021;20(3):200–216. 2021 March 01.
   PubMed Web of Science ®Google Scholar
• Chao J, Dai Y, Verpoorte R, et al. Major achievements of evidence-based traditional Chinese medicine in treating major diseases. Biochem Pharmacol. 2017;139:94–104.
   PubMed Web of Science ®Google Scholar
• Pan S-Y, Litscher G, Gao S-H, et al. Historical perspective of traditional indigenous medical practices: the current renaissance and conservation of herbal resources. Evid Based Complement Alternat Med. 2014;2014:525340. doi: https://doi.org/10.1155/2014/525340. Epub 2014 Apr 27. PMID: 24872833; PMCID: PMC4020364.
   Google Scholar
• Yuan H, Ma Q, Ye L, et al. The traditional medicine and modern medicine from natural products. Molecules. 2016;21(5)559.
   PubMed Web of Science ®Google Scholar