AMPK's Natural Activators and Relationships with Diseases

Yıl 2021, Sayı: 21, 389 - 401, 31.01.2021

Sena Nur Tanyıldız Hatice Yıldırım Halime Uğur Mustafa Yaman

https://doi.org/10.31590/ejosat.762959

Cited By: 1

Öz

Protein kinase (AMPK) activated by AMP (Adenosine monophosphate) is a regulator that provides energy homeostasis by activating energy-producing pathways and inactivating energy-consuming pathways. AMPK belongs to the serine / threonine kinase family and consists of three subunits (α, β and γ) structurally. AMPK can be activated with two mechanisms, one of which is an increase in cellular AMP levels, the other is LKB1 (serine – threonine kinase liver kinase B1), CaMKKβ (Ca2 + / calmodulin-dependent protein kinase β), TAK1 or MLK3 and phosphorylation of Thr172 in the activation cycle of the α subunit. While activation of AMPK provides inhibition of fatty acids, glycogen and cholesterol synthesis; fatty acid oxidation, GLUT4 (glucose transporter type 4) translocation without being dependent on insulin and activation of the autophagy process are provided. AMPK shows its effect on diseases by regulating many metabolic and physiological pathways, after activation with various factors. It has been observed that increasing AMPK activation plays an important role in the treatment of various diseases such as prediabetes, diabetes, obesity and cancer. There are many factors that affect AMPK activity. Synthetic drugs, natural components and exercise are among these activators. Research in recent years has focused especially on natural components that affect the activation of AMPK among these products. The purpose of this review is to examine the effect on AMPK activation and diseases, of natural components such as berberine, resveratrol, curcumin, ginseng, etc

Anahtar Kelimeler

AMPK, Activator, Mechanism of Action, Disease, Natural Component

AMPK’nın Doğal Aktivatörleri ve Hastalıklarla İlişkisi

Öz

AMP (Adenozin monofosfat) ile aktifleştirilen protein kinaz (AMPK), enerji üreten yolları aktive edip enerji tüketen yolları inaktive ederek enerji homeostazını sağlayan bir düzenleyicidir. AMPK, serin/treonin kinaz ailesine aittir ve yapısal olarak üç alt birimden (α, β ve γ) oluşmaktadır. Biri hücresel AMP seviyelerinde artış, diğeri LKB1 (serine–threonine kinase liver kinase B1), CaMKKβ (Ca2+/calmodulin-dependent protein kinase β), TAK1 veya MLK3 ile α alt biriminin aktivasyon döngüsünde Thr172’nin fosforilasyonu yolu olmak üzere, AMPK iki mekanizma ile aktive edilebilmektedir. AMPK’nın aktivasyonu ile yağ asitleri, glikojen ve kolesterol sentezinin inhibasyonu sağlanırken; yağ asidi oksidasyonu, insüline bağımlı olmaksızın GLUT4 (glukoz taşıyıcı tip 4) translokasyonu ve otofaji işleminin aktivasyonu sağlanmaktadır. AMPK hastalıklar üzerine olan etkisini, çeşitli faktörler ile aktive olduktan sonra birçok metabolik ve fizyolojik yolağı düzenleyerek göstermektedir. AMPK aktivasyonunun arttırılmasının prediyabet, diyabet, obezite ve kanser gibi çeşitli hastalıkların tedavisinde önemli bir rol oynadığı görülmüştür. AMPK aktivitesini etkileyen pek çok etken bulunmaktadır. Sentetik ilaçlar, doğal bileşenler ve egzersiz bu aktivatörler arasında yer almaktadır. Son yıllarda yapılan araştırmalar, özellikle bu ürünler arasında AMPK’nın aktivasyonunu etkileyen doğal bileşenlere odaklanmıştır. Bu derlemenin amacı berberin, resveratrol, kurkumin, ginseng vb. gibi doğal bileşenlerin AMPK aktivasyonu ve hastalıklar üzerine etkisini incelemektir.

Anahtar Kelimeler

AMPK, Aktivatör, Etki Mekanizması, Hastalık, Doğal Bileşen

Destekleyen Kurum

İstanbul Sabahttin Zaim Üniveristesi

Kaynakça

• Aggarwal, B. B., Bhardwaj, A., Aggarwal, R. S., Seeram, N. P., Shishodia, S., & Takada, Y. (2004). Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer research, 24(5A), 2783-2840.
• Ahmadian, M., Abbott, M. J., Tang, T., Hudak, C. S., Kim, Y., Bruss, M., ... & Wang, Y. (2011). Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell metabolism, 13(6), 739-748.
• Amritpal, S., Sanjiv, D., Navpreet, K., & Jaswinder, S. (2010). Berberine: alkaloid with wide spectrum of pharmacological activities. Journal of Natural Products (India), 3, 64-75.
• Atta-ur-Rahman, F. R. S. (2018). Studies in natural products chemistry. Amsterdam: Elsevier.
• Attele, A. S., Wu, J. A., & Yuan, C. S. (1999). Ginseng pharmacology: multiple constituents and multiple actions. Biochemical pharmacology, 58(11), 1685-1693.
• Badran, M., Abuyassin, B., Golbidi, S., Ayas, N., & Laher, I. (2019). Alpha lipoic acid improves endothelial function and oxidative stress in mice exposed to chronic intermittent hypoxia. Oxidative medicine and cellular longevity, 2019.
• Bagchi, D., Garg, A., Krohn, R. L., Bagchi, M., Tran, M. X., & Stohs, S. J. (1997). Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro. Research communications in molecular pathology and pharmacology, 95(2), 179-189.
• Bai, L., Gao, J., Wei, F., Zhao, J., Wang, D., & Wei, J. (2018). Therapeutic potential of ginsenosides as an adjuvant treatment for diabetes. Frontiers in pharmacology, 9, 423.
• Banerjee, S., Ghoshal, S., & Porter, T. D. (2012). Phosphorylation of hepatic AMP-activated protein kinase and liver kinase B1 is increased after a single oral dose of green tea extract to mice. Nutrition research, 32(12), 985-990.
• Beecher, G. R. (2004). Proanthocyanidins: Biological activities associated with human health. Pharmaceutical Biology, 42(sup1), 2-20.
• Beg, Z. H., Allmann, D. W., & Gibson, D. M. (1973). Modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity with cAMP and with protein fractions of rat liver cytosol. Biochemical and biophysical research communications, 54(4), 1362-1369.
• Benedec, D. A. N. I. E. L. A., Hanganu, D. A. N. I. E. L. A., Filip, L., Oniga, I., Tiperciuc, B. R. Î. N. D. U. Ș. A., Olah, N. K., ... & Vlase, L. A. U. R. I. A. N. (2017). Chemical, antioxidant and antibacterial studies of Romanian Heracleum sphondylium. Farmacia (Bucharest, Rom), 65, 252-256.
• Beslenme, B. A. (2004). Hatipoğlu Yayınevi. Ankara.
• Bischoff, S. C. (2008). Quercetin: potentials in the prevention and therapy of disease. Current Opinion in Clinical Nutrition & Metabolic Care, 11(6), 733-740.
• Boots, A. W., Haenen, G. R., & Bast, A. (2008). Health effects of quercetin: from antioxidant to nutraceutical. European journal of pharmacology, 585(2-3), 325-337.
• Bravo, L. (1998). Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutrition reviews, 56(11), 317-333.
• Butt, M. S.,& Sultan, M. T. (2011). Ginger and its health claims: molecular aspects. Critical reviews in food science and nutrition, 51(5), 383-393.
• Carling, D., Zammit, V. A., & Hardie, D. G. (1987). A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS letters, 223(2), 217-222.
• Carlson, C. A.,& Kim, K. H. (1973). Regulation of hepatic acetyl coenzyme A carboxylase by phosphorylation and dephosphorylation. Journal of Biological Chemistry, 248(1), 378-380.
• Chen, C., Yu, Z., Li, Y., Fichna, J., & Storr, M. (2014). Effects of berberine in the gastrointestinal tract—a review of actions and therapeutic implications. The American journal of Chinese medicine, 42(05), 1053-1070.
• Cheng, P. W., Lee, H. C., Lu, P. J., Chen, H. H., Lai, C. C., Sun, G. C., Yeh, T. C., Hsiao, M., Lin, Y. T., Liu, C. P., & Tseng, C. J. (2016). Resveratrol Inhibition of Rac1-Derived Reactive Oxygen Species by AMPK Decreases Blood Pressure in a Fructose-Induced Rat Model of Hypertension. Scientific reports, 6, 25342.
• Cheng, Z., Pang, T., Gu, M., Gao, A. H., Xie, C. M., Li, J. Y., ... & Li, J. (2006). Berberine-stimulated glucose uptake in L6 myotubes involves both AMPK and p38 MAPK. Biochimica et Biophysica Acta (BBA)-General Subjects, 1760(11), 1682-1689.
• CHOI, K. T. (2008). Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng CA Meyer. Acta Pharmacologica Sinica, 29(9), 1109-1118.
• Choi, J. A., Kim, J. Y., Lee, J. Y., Kang, C. M., Kwon, H. J., Yoo, Y. D., ... & Lee, S. J. (2001). Induction of cell cycle arrest and apoptosis in human breast cancer cells by quercetin. International journal of oncology, 19(4), 837-844.
• Chowdhury, A., Sarkar, J., Chakraborti, T., Pramanik, P. K., & Chakraborti, S. (2016). Protective role of epigallocatechin-3-gallate in health and disease: a perspective. Biomedicine & Pharmacotherapy, 78, 50-59.
• Chuengsamarn, S., Rattanamongkolgul, S., Luechapudiporn, R., Phisalaphong, C., & Jirawatnotai, S. (2012). Curcumin extract for prevention of type 2 diabetes. Diabetes care, 35(11), 2121-2127.
• Claussnitzer, M., Skurk, T., Hauner, H., Daniel, H., & Rist, M. J. (2011). Effect of flavonoids on basal and insulin‐stimulated 2‐deoxyglucose uptake in adipocytes. Molecular nutrition & food research, 55(S1), S26-S34.
• Davaatseren, M., Hur, H. J., Yang, H. J., Hwang, J. T., Park, J. H., Kim, H. J., ... & Sung, M. J. (2013). Taraxacum official (dandelion) leaf extract alleviates high-fat diet-induced nonalcoholic fatty liver. Food and chemical toxicology, 58, 30-36.
• Deng, X., Zhang, S., Wu, J., Sun, X., Shen, Z., Dong, J., & Huang, J. (2019). Promotion of Mitochondrial Biogenesis via Activation of AMPK‐PGC1ɑ Signaling Pathway by Ginger (Zingiber officinale Roscoe) Extract, and Its Major Active Component 6‐Gingerol. Journal of food science, 84(8), 2101-2111.
• Dong, G. Z., Jang, E. J., Kang, S. H., Cho, I. J., Park, S. D., Kim, S. C., & Kim, Y. W. (2013). Red ginseng abrogates oxidative stress via mitochondria protection mediated by LKB1-AMPK pathway. BMC complementary and alternative medicine, 13, 64. https://doi.org/10.1186/1472-6882-13-64
• Dong, H., Wang, N., Zhao, L., & Lu, F. (2012). Berberine in the treatment of type 2 diabetes mellitus: a systemic review and meta-analysis. Evidence-based complementary and alternative medicine, 2012.
• Ejaz, A., Wu, D., Kwan, P., & Meydani, M. (2009). Curcumin inhibits adipogenesis in 3T3-L1 adipocytes and angiogenesis and obesity in C57/BL mice. The Journal of nutrition, 139(5), 919-925.
• Elzebroek, A. T. G. (2008). Guide to cultivated plants. CABI.
• Faubert, B., Vincent, E. E., Poffenberger, M. C., & Jones, R. G. (2015). The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator. Cancer letters, 356(2), 165-170.
• Ford, R. J., Fullerton, M. D., Pinkosky, S. L., Day, E. A., Scott, J. W., Oakhill, J. S., ... & Marcinko, K. (2015). Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity. Biochemical Journal, 468(1), 125-132.
• Gonçalves-de-Albuquerque, C. F., Medeiros-de-Moraes, I. M., de Jesus Oliveira, F. M., Burth, P., Bozza, P. T., Faria, M. V. C., ... & de Castro-Faria-Neto, H. C. (2016). Omega-9 oleic acid induces fatty acid oxidation and decreases organ dysfunction and mortality in experimental sepsis. PLoS One, 11(4).
• Govindarajan, V. S.,& Connell, D. W. (1983). Ginger—chemistry, technology, and quality evaluation: part 1. Critical Reviews in Food Science & Nutrition, 17(1), 1-96.
• Grahame Hardie, D. (2014). AMP‐activated protein kinase: a key regulator of energy balance with many roles in human disease. Journal of internal medicine, 276(6), 543-559.
• Güzel, N. (2010). Nar suyu konsantresi üretim aşamalarında prosiyanidinlerdeki değişimler (Doctoral dissertation, Yüksek Lisans Tezi, Fen Bilimleri Enstitüsü, Ankara Üniversitesi, Ankara.
• Gwinn, D. M., Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., Vasquez, D. S., ... & Shaw, R. J. (2008). AMPK phosphorylation of raptor mediates a metabolic checkpoint. Molecular cell, 30(2), 214-226.
• Habtemariam, S. (2011). The therapeutic potential of Berberis darwinii stem-bark: quantification of berberine and in vitro evidence for Alzheimer's disease therapy. Natural product communications, 6(8).
• Habtemariam, S. (2013). The hidden treasure in Europe’s garden plants: Case examples; Berberis darwinni and Bergenia cordifolia. Medicinal & Aromatic Plants, 2(4).
• Habtemariam, S. (2016). Berberine and inflammatory bowel disease: A concise review. Pharmacological research, 113, 592-599.
• Hardie, D. G. (2007). AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nature reviews Molecular cell biology, 8(10), 774-785.
• Hardie, D. G. (2013). AMPK: a target for drugs and natural products with effects on both diabetes and cancer. Diabetes, 62(7), 2164-2172.
• Hardie, D. G. (2016). Regulation of AMP-activated protein kinase by natural and synthetic activators. Acta Pharmaceutica Sinica B, 6(1), 1-19.
• Hardie, D. G., Carling, D., & Sim, A. T. (1989). The AMP-activated protein kinase: a multisubstrate regulator of lipid metabolism. Trends in Biochemical Sciences, 14(1), 20-23.
• Hashem, R. M., Rashed, L. A., Hassanin, K. M., Hetta, M. H., & Ahmed, A. O. (2017). Effect of 6-gingerol on AMPK-NF-κB axis in high fat diet fed rats. Biomedicine & Pharmacotherapy, 88, 293-301.
• Hawkins, H. J., Malgas, R., & Biénabe, E. (2011). Ecotypes of wild rooibos (Aspalathus linearis (Burm. F) Dahlg., Fabaceae) are ecologically distinct. South African Journal of Botany, 77(2), 360-370.
• Hawley, S. A., Fullerton, M. D., Ross, F. A., Schertzer, J. D., Chevtzoff, C., Walker, K. J., ... & Kemp, B. E. (2012). The ancient drug salicylate directly activates AMP-activated protein kinase. Science, 336(6083), 918-922.
• Hirpara, K. V., Aggarwal, P., Mukherjee, A. J., Joshi, N., & Burman, A. C. (2009). Quercetin and its derivatives: synthesis, pharmacological uses with special emphasis on anti-tumor properties and prodrug with enhanced bio-availability. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 9(2), 138-161.
• Hoppe, S., Bierhoff, H., Cado, I., Weber, A., Tiebe, M., Grummt, I., & Voit, R. (2009). AMP-activated protein kinase adapts rRNA synthesis to cellular energy supply. Proceedings of the National Academy of Sciences, 106(42), 17781-17786.
• Huang, C. H., Tsai, S. J., Wang, Y. J., Pan, M. H., Kao, J. Y., & Way, T. D. (2009). EGCG inhibits protein synthesis, lipogenesis, and cell cycle progression through activation of AMPK in p53 positive and negative human hepatoma cells. Molecular nutrition & food research, 53(9), 1156-1165.
• Huang, H. C.,& Lin, J. K. (2012). Pu-erh tea, green tea, and black tea suppresses hyperlipidemia, hyperleptinemia and fatty acid synthase through activating AMPK in rats fed a high-fructose diet. Food & function, 3(2), 170-177.
• Huang, Q., Wang, T., Yang, L., & Wang, H. Y. (2017). Ginsenoside Rb2 Alleviates Hepatic Lipid Accumulation by Restoring Autophagy via Induction of Sirt1 and Activation of AMPK. International journal of molecular sciences, 18(5).
• Hurley, R. L., Anderson, K. A., Franzone, J. M., Kemp, B. E., Means, A. R., & Witters, L. A. (2005). The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. Journal of Biological Chemistry, 280(32), 29060-29066.
• Hwang, J. T., Ha, J., Park, I. J., Lee, S. K., Baik, H. W., Kim, Y. M., & Park, O. J. (2007). Apoptotic effect of EGCG in HT-29 colon cancer cells via AMPK signal pathway. Cancer letters, 247(1), 115-121.
• Hwang, J. T., Kim, S. H., Lee, M. S., Kim, S. H., Yang, H. J., Kim, M. J., ... & Kwon, D. Y. (2007). Anti-obesity effects of ginsenoside Rh2 are associated with the activation of AMPK signaling pathway in 3T3-L1 adipocyte. Biochemical and biophysical research communications, 364(4), 1002-1008.
• Hwang, J. T., Lee, M. S., Kim, H. J., Sung, M. J., Kim, H. Y., Kim, M. S., & Kwon, D. Y. (2009). Antiobesity effect of ginsenoside Rg3 involves the AMPK and PPAR‐γ signal pathways. Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives, 23(2), 262-266.
• Imenshahidi, M.,& Hosseinzadeh, H. (2019). Berberine and barberry (Berberis vulgaris): A clinical review. Phytotherapy Research, 33(3), 504-523.
• Jamshaid, F., Dai, J., & Yang, L. X. (2020). New Development of Novel Berberine Derivatives against Bacteria. Mini reviews in medicinal chemistry.
• Jang, M., Cai, L., Udeani, G. O., Slowing, K. V., Thomas, C. F., Beecher, C. W., ... & Moon, R. C. (1997). Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science, 275(5297), 218-220.
• Jeon, M. J., Kim, W. G., Lim, S., Choi, H. J., Sim, S., Kim, T. Y., ... & Kim, W. B. (2016). Alpha lipoic acid inhibits proliferation and epithelial mesenchymal transition of thyroid cancer cells. Molecular and cellular endocrinology, 419, 113-123.
• Jeon, S. M. (2016). Regulation and function of AMPK in physiology and diseases. Experimental & molecular medicine, 48(7), e245-e245.
• Jiménez-Flores, L. M., López-Briones, S., Macías-Cervantes, M. H., Ramírez-Emiliano, J., & Pérez-Vázquez, V. (2014). A PPARγ, NF-κB and AMPK-dependent mechanism may be involved in the beneficial effects of curcumin in the diabetic db/db mice liver. Molecules, 19(6), 8289-8302.
• Jochmann, N., Baumann, G., & Stangl, V. (2008). Green tea and cardiovascular disease: from molecular targets towards human health. Current Opinion in Clinical Nutrition & Metabolic Care, 11(6), 758-765.
• Johnson, R., de Beer, D., Dludla, P. V., Ferreira, D., Muller, C. J., & Joubert, E. (2018). Aspalathin from rooibos (Aspalathus linearis): a bioactive C-glucosyl dihydrochalcone with potential to target the metabolic syndrome. Planta medica, 84(09/10), 568-583.
• Johnson, R., Dludla, P. V., Muller, C. J., Huisamen, B., Essop, M. F., & Louw, J. (2017). The transcription profile unveils the cardioprotective effect of aspalathin against lipid toxicity in an in vitro H9c2 model. Molecules, 22(2), 219.
• Johnson, R., Dludla, P., Joubert, E., February, F., Mazibuko, S., Ghoor, S., ... & Louw, J. (2016). Aspalathin, a dihydrochalcone C‐glucoside, protects H9c2 cardiomyocytes against high glucose induced shifts in substrate preference and apoptosis. Molecular nutrition & food research, 60(4), 922-934.
• Jolad, S. D., Lantz, R. C., Solyom, A. M., Chen, G. J., Bates, R. B., & Timmermann, B. N. (2004). Fresh organically grown ginger (Zingiber officinale): composition and effects on LPS-induced PGE2 production. Phytochemistry, 65(13), 1937-1954.
• Joubert, E. D. B. D.,& de Beer, D. (2011). Rooibos (Aspalathus linearis) beyond the farm gate: From herbal tea to potential phytopharmaceutical. South African Journal of Botany, 77(4), 869-886.
• Kahn, B. B., Alquier, T., Carling, D., & Hardie, D. G. (2005). AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell metabolism, 1(1), 15-25.
• Kang, O. H., Shon, M. Y., Kong, R., Seo, Y. S., Zhou, T., Kim, D. Y., Kim, Y. S., & Kwon, D. Y. (2017). Anti-diabetic effect of black ginseng extract by augmentation of AMPK protein activity and upregulation of GLUT2 and GLUT4 expression in db/db mice. BMC complementary and alternative medicine, 17(1), 341.
• Kanwar, J., Taskeen, M., Mohammad, I., Huo, C., Chan, T. H., & Dou, Q. P. (2012). Recent advances on tea polyphenols. Frontiers in bioscience (Elite edition), 4, 111.
• Kawano, A., Nakamura, H., Hata, S. I., Minakawa, M., Miura, Y., & Yagasaki, K. (2009). Hypoglycemic effect of aspalathin, a rooibos tea component from Aspalathus linearis, in type 2 diabetic model db/db mice. Phytomedicine, 16(5), 437-443.
• Kayahan, M. (2009). Sağlıklı beslenme açısından trans yağ asitleri. II. Geleneksel Gıdalar Sempozyumu, 27-29.
• Kim, H. S., Montana, V., Jang, H. J., Parpura, V., & Kim, J. A. (2013). Epigallocatechin Gallate (EGCG) Stimulates Autophagy in Vascular Endothelial Cells a potential role for reducing lipid accumulation. Journal of Biological Chemistry, 288(31), 22693-22705.
• Kim, S. G., Sung, J. Y., Kim, J. R., & Choi, H. C. (2020). Quercetin-induced apoptosis ameliorates vascular smooth muscle cell senescence through AMP-activated protein kinase signaling pathway. The Korean journal of physiology &pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology, 24(1), 69–79.
• Kim, S. J., Tang, T., Abbott, M., Viscarra, J. A., Wang, Y., & Sul, H. S. (2016). AMPK phosphorylates desnutrin/ATGL and hormone-sensitive lipase to regulate lipolysis and fatty acid oxidation within adipose tissue. Molecular and cellular biology, 36(14), 1961-1976.
• Kim, S., Lee, M. S., Jung, S., Son, H. Y., Park, S., Kang, B., ... & Kim, Y. (2018). Ginger extract ameliorates obesity and inflammation via regulating microRNA-21/132 expression and AMPK activation in white adipose tissue. Nutrients, 10(11), 1567.
• Kişmiroğlu, C., Cengiz, S., & Yaman, M. (2020). AMPK'nin Biyokimyası: Etki Mekanizmaları ve Diyabetin Tedavisindeki Önemi. Avrupa Bilim ve Teknoloji Dergisi, (18), 162-170.
• Kobayashi-Hattori, K., Mogi, A., Matsumoto, Y., & Takita, T. (2005). Effect of caffeine on the body fat and lipid metabolism of rats fed on a high-fat diet. Bioscience, biotechnology, and biochemistry, 69(11), 2219-2223.
• Kris-Etherton, P. M. (1999). Monounsaturated fatty acids and risk of cardiovascular disease. Circulation, 100(11), 1253-1258.
• Krishan, S., Richardson, D. R., & Sahni, S. (2015). Adenosine monophosphate–activated kinase and its key role in catabolism: Structure, regulation, biological activity, and pharmacological activation. Molecular pharmacology, 87(3), 363-377.
• Kuo, P. C., Liu, H. F., & Chao, J. I. (2004). Survivin and p53 modulate quercetin-induced cell growth inhibition and apoptosis in human lung carcinoma cells. Journal of Biological Chemistry, 279(53), 55875-55885.
• Kurimoto, Y., Shibayama, Y., Inoue, S., Soga, M., Takikawa, M., Ito, C., ... & Tsuda, T. (2013). Black soybean seed coat extract ameliorates hyperglycemia and insulin sensitivity via the activation of AMP-activated protein kinase in diabetic mice. Journal of agricultural and food chemistry, 61(23), 5558-5564.
• Laher, I. (2011). Diabetes and alpha lipoic acid. Frontiers in pharmacology, 2, 69.
• Landis-Piwowar, K. R., Huo, C., Chen, D. I., Milacic, V., Shi, G., Chan, T. H., & Dou, Q. P. (2007). A novel prodrug of the green tea polyphenol (−)-epigallocatechin-3-gallate as a potential anticancer agent. Cancer research, 67(9), 4303-4310.
• Landis-Piwowar, K., Chen, D., Foldes, R., Chan, T. H., & Dou, Q. P. (2013). Novel epigallocatechin gallate analogs as potential anticancer agents: a patent review (2009–present). Expert opinion on therapeutic patents, 23(2), 189-202.
• Lee, K. T., Jung, T. W., Lee, H. J., Kim, S. G., Shin, Y. S., & Whang, W. K. (2011). The antidiabetic effect of ginsenoside Rb2 via activation of AMPK. Archives of pharmacal research, 34(7), 1201.
• Lee, W. J., Lee, I. K., Kim, H. S., Kim, Y. M., Koh, E. H., Won, J. C., ... & Park, I. S. (2005a). α-Lipoic acid prevents endothelial dysfunction in obese rats via activation of AMP-activated protein kinase. Arteriosclerosis, thrombosis, and vascular biology, 25(12), 2488-2494.
• Lee, W. J., Song, K. H., Koh, E. H., Won, J. C., Kim, H. S., Park, H. S., ... & Park, J. Y. (2005b). α-Lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochemical and biophysical research communications, 332(3), 885-891.
• Lee, Y. S., Kim, W. S., Kim, K. H., Yoon, M. J., Cho, H. J., Shen, Y., ... & Hohnen-Behrens, C. (2006a). Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes, 55(8), 2256-2264.
• Lee, Y., Naseem, R. H., Park, B. H., Garry, D. J., Richardson, J. A., Schaffer, J. E., & Unger, R. H. (2006b). α-Lipoic acid prevents lipotoxic cardiomyopathy in acyl CoA-synthase transgenic mice. Biochemical and biophysical research communications, 344(1), 446-452.
• Li, F., Gao, C., Yan, P., Zhang, M., Wang, Y., Hu, Y., Wu, X., Wang, X., & Sheng, J. (2018). EGCG Reduces Obesity and White Adipose Tissue Gain Partly Through AMPK Activation in Mice. Frontiers in pharmacology, 9, 1366.
• Li, J., Yu, S., Ying, J., Shi, T., & Wang, P. (2017). Resveratrol Prevents ROS-Induced Apoptosis in High Glucose-Treated Retinal Capillary Endothelial Cells via the Activation of AMPK/Sirt1/PGC-1α Pathway. Oxidative medicine and cellular longevity, 2017, 7584691.
• Li, W., Hua, B., Saud, S. M., Lin, H., Hou, W., Matter, M. S., ... & Young, M. R. (2015). Berberine regulates AMP‐activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice. Molecular carcinogenesis, 54(10), 1096-1109.
• Li, Y., Tran, V. H., Kota, B. P., Nammi, S., Duke, C. C., & Roufogalis, B. D. (2014). Preventative effect of Zingiber officinale on insulin resistance in a high‐fat high‐carbohydrate diet‐fed rat model and its mechanism of action. Basic & clinical pharmacology & toxicology, 115(2), 209-215.
• Liang, Y., Xu, X., Yin, M., Zhang, Y., Huang, L., Chen, R., & Ni, J. (2019). Effects of berberine on blood glucose in patients with type 2 diabetes mellitus: a systematic literature review and a meta-analysis. Endocrine journal, 66(1), 51-63.
• Lin, Y., Yngve, A., Lagergren, J., & Lu, Y. (2014). A dietary pattern rich in lignans, quercetin and resveratrol decreases the risk of oesophageal cancer. British journal of nutrition, 112(12), 2002-2009.
• Luo, L., Jiang, S., Huang, D., Lu, N., & Luo, Z. (2015). MLK3 phophorylates AMPK independently of LKB1. PLoS One, 10(4).
• Malgas, R. R., Potts, A. J., Oettlé, N. M., Koelle, B., Todd, S. W., Verboom, G. A., & Hoffman, M. T. (2010). Distribution, quantitative morphological variation and preliminary molecular analysis of different growth forms of wild rooibos (Aspalathus linearis) in the northern Cederberg and on the Bokkeveld Plateau. South African Journal of Botany, 76(1), 72-81.
• Mazibuko, S. E., Joubert, E., Johnson, R., Louw, J., Opoku, A. R., & Muller, C. J. (2015). Aspalathin improves glucose and lipid metabolism in 3T3‐L1 adipocytes exposed to palmitate. Molecular nutrition & food research, 59(11), 2199-2208.
• Mazibuko, S. E., Muller, C. J. F., Joubert, E., De Beer, D., Johnson, R., Opoku, A. R., & Louw, J. (2013). Amelioration of palmitate-induced insulin resistance in C2C12 muscle cells by rooibos (Aspalathus linearis). Phytomedicine, 20(10), 813-819.
• Mazibuko-Mbeje, S. E., Dludla, P. V., Roux, C., Johnson, R., Ghoor, S., Joubert, E., ... & Muller, C. J. (2019). Aspalathin-enriched green rooibos extract reduces hepatic insulin resistance by modulating PI3K/AKT and AMPK pathways. International journal of molecular sciences, 20(3), 633.
• McKay, D. L.,& Blumberg, J. B. (2007). A review of the bioactivity of South African herbal teas: rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia). Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives, 21(1), 1-16.
• Mendoza-Núñez, V. M., García-Martínez, B. I., Rosado-Pérez, J., Santiago-Osorio, E., Pedraza-Chaverri, J., & Hernández-Abad, V. J. (2019). The effect of 600 mg alpha-lipoic acid supplementation on oxidative stress, inflammation, and RAGE in older adults with type 2 diabetes mellitus. Oxidative medicine and cellular longevity, 2019.
• Metodiewa, D., Jaiswal, A. K., Cenas, N., Dickancaité, E., & Segura-Aguilar, J. (1999). Quercetin may act as a cytotoxic prooxidant after its metabolic activation to semiquinone and quinoidal product. Free radical biology and medicine, 26(1-2), 107-116.
• Minakawa, M., Kawano, A., Miura, Y., & Yagasaki, K. (2011). Hypoglycemic effect of resveratrol in type 2 diabetic model db/db mice and its actions in cultured L6 myotubes and RIN-5F pancreatic β-cells. Journal of clinical biochemistry and nutrition, 48(3), 237-244.
• Momcilovic, M., Hong, S. P., & Carlson, M. (2006). Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. Journal of Biological Chemistry, 281(35), 25336-25343.
• Moon, H. S. (2016). Chemopreventive effects of alpha lipoic acid on obesity-related cancers. Annals of Nutrition and Metabolism, 68(2), 137-144.
• Muller, C. J. F., Joubert, E., De Beer, D., Sanderson, M., Malherbe, C. J., Fey, S. J., & Louw, J. (2012). Acute assessment of an aspalathin-enriched green rooibos (Aspalathus linearis) extract with hypoglycemic potential. Phytomedicine, 20(1), 32-39.
• Murase, T., Misawa, K., Haramizu, S., & Hase, T. (2009). Catechin-induced activation of the LKB1/AMP-activated protein kinase pathway. Biochemical pharmacology, 78(1), 78-84.
• Olcay, İ., Besler, H. T., Diyetisyeni, B. Ü. A. H. U., & Beslenme, H. Ü. (2012). Yeni doğanda beyin gelişimi ve Omega-3 yağ asitleri. Danone Enstitüsü Türkiye Derneği, Sağlık İçin Beslenme.
• Ong, C. S., Tran, E., Nguyen, T. T., Ong, C. K., Lee, S. K., Lee, J. J., ... & Huynh, H. (2004). Quercetin-induced growth inhibition and cell death in nasopharyngeal carcinoma cells are associated with increase in Bad and hypophosphorylated retinoblastoma expressions. Oncology reports, 11(3), 727-733.
• Park, D., Jeong, H., Lee, M. N., Koh, A., Kwon, O., Yang, Y. R., ... & Ryu, S. H. (2016). Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition. Scientific reports, 6(1), 1-11.
• Payton, F., Sandusky, P., & Alworth, W. L. (2007). NMR study of the solution structure of curcumin. Journal of natural products, 70(2), 143-146.
• Potdar, D., Hirwani, R. R., & Dhulap, S. (2012). Phyto-chemical and pharmacological applications of Berberis aristata. Fitoterapia, 83(5), 817-830.
• Reymond, P.,& Farmer, E. E. (1998). Jasmonate and salicylate as global signals for defense gene expression. Current opinion in plant biology, 1(5), 404-411.
• Ross, M. (2012). The ancient drug salicylate directly activates AMP-activated protein kinase. Kidney International, 82, 251-252.
• Salas, J., López, J. M., Jansen, S., Zambrana, J. L., Castro, P., Paniagua, J. A., ... & Pérez, F. J. (1999). The diet rich in monounsaturated fat modifies in a beneficial way carbohydrate metabolism and arterial pressure. Medicina clinica, 113(20), 765-769.
• Schrör, K. (2016). Acetylsalicylic acid. John Wiley & Sons, 263-446.
• Semwal, R. B., Semwal, D. K., Combrinck, S., & Viljoen, A. M. (2015). Gingerols and shogaols: Important nutraceutical principles from ginger. Phytochemistry, 117, 554-568.
• Sharmila, G., Bhat, F. A., Arunkumar, R., Elumalai, P., Singh, P. R., Senthilkumar, K., & Arunakaran, J. (2014). Chemopreventive effect of quercetin, a natural dietary flavonoid on prostate cancer in in vivo model. Clinical nutrition, 33(4), 718-726.
• Sheena, A., Mohan, S. S., Haridas, N. P. A., & Anilkumar, G. (2011). Elucidation of the glucose transport pathway in glucose transporter 4 via steered molecular dynamics simulations. PLoS One, 6(10).
• Shen, L., Xiong, Y., Wang, D. Q., Howles, P., Basford, J. E., Wang, J., ... & Liu, M. (2013). Ginsenoside Rb1 reduces fatty liver by activating AMP-activated protein kinase in obese rats. Journal of lipid research, 54(5), 1430-1438.
• Shirakawa, K., Wang, L., Man, N., Maksimoska, J., Sorum, A. W., Lim, H. W., ... & Ott, M. (2016). Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. Elife, 5, e11156.
• Singh S and Aggarwal BB (1995) Activation of transcription factor NF-kB is suppressed by curcumin (diferuloylmethane) [corrected]. J Biol Chem 270:24995– 25000
• Singh, A., Bajpai, V., Srivastava, M., Arya, K. R., & Kumar, B. (2015). Rapid screening and distribution of bioactive compounds in different parts of Berberis petiolaris using direct analysis in real time mass spectrometry. Journal of pharmaceutical analysis, 5(5), 332-335.
• Smith, B. K., Marcinko, K., Desjardins, E. M., Lally, J. S., Ford, R. J., & Steinberg, G. R. (2016). Treatment of nonalcoholic fatty liver disease: role of AMPK. American Journal of Physiology-Endocrinology and Metabolism, 311(4), E730-E740.
• Smith, C.,& Swart, A. (2018). Aspalathus linearis (Rooibos)–a functional food targeting cardiovascular disease. Food & function, 9(10), 5041-5058.
• Sofi, F., Cesari, F., Abbate, R., Gensini, G. F., & Casini, A. (2008). Adherence to Mediterranean diet and health status: meta-analysis. Bmj, 337, a1344.
• Son, M. J., Minakawa, M., Miura, Y., & Yagasaki, K. (2013). Aspalathin improves hyperglycemia and glucose intolerance in obese diabetic ob/ob mice. European journal of nutrition, 52(6), 1607-1619.
• Suau, R., Rico, R., López-Romero, J. M., Nájera, F., & Cuevas, A. (1998). Isoquinoline alkaloids from Berberis vulgaris subsp. australis. Phytochemistry, 49(8), 2545-2549.
• Sun, G. Z., Meng, F. J., Cai, H. Q., Diao, X. B., Zhang, B., & Bai, X. P. (2020). Ginsenoside Rg3 protects heart against isoproterenol-induced myocardial infarction by activating AMPK mediated autophagy. Cardiovascular diagnosis and therapy, 10(2), 153–160.
• Tabeshpour, J., Imenshahidi, M., & Hosseinzadeh, H. (2017). A review of the effects of Berberis vulgaris and its major component, berberine, in metabolic syndrome. Iranian journal of basic medical sciences, 20(5), 557.
• Terra, X., Montagut, G., Bustos, M., Llopiz, N., Ardèvol, A., Bladé, C., ... & Blay, M. (2009). Grape-seed procyanidins prevent low-grade inflammation by modulating cytokine expression in rats fed a high-fat diet. The Journal of nutritional biochemistry, 20(3), 210-218.
• Tibullo, D., Volti, G. L., Giallongo, C., Grasso, S., Tomassoni, D., Anfuso, C. D., ... & Bramanti, V. (2017). Biochemical and clinical relevance of alpha lipoic acid: antioxidant and anti-inflammatory activity, molecular pathways and therapeutic potential. Inflammation Research, 66(11), 947-959.
• Timmers, S., de Vogel-van den Bosch, J., Towler, M. C., Schaart, G., Moonen-Kornips, E., Mensink, R. P., Hesselink, M. K., Hardie, D. G., & Schrauwen, P. (2010). Prevention of high-fat diet-induced muscular lipid accumulation in rats by alpha lipoic acid is not mediated by AMPK activation. Journal of lipid research, 51(2), 352–359.
• Timmers, S., Konings, E., Bilet, L., Houtkooper, R. H., van de Weijer, T., Goossens, G. H., ... & Moonen-Kornips, E. (2011). Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell metabolism, 14(5), 612-622.
• Turner, N., Li, J. Y., Gosby, A., To, S. W., Cheng, Z., Miyoshi, H., ... & Hu, L. H. (2008). Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes, 57(5), 1414-1418.
• Valls, J., Millán, S., Martí, M. P., Borràs, E., & Arola, L. (2009). Advanced separation methods of food anthocyanins, isoflavones and flavanols. Journal of Chromatography A, 1216(43), 7143-7172.
• Van Aller, G. S., Carson, J. D., Tang, W., Peng, H., Zhao, L., Copeland, R. A., ... & Luo, L. (2011). Epigallocatechin gallate (EGCG), a major component of green tea, is a dual phosphoinositide-3-kinase/mTOR inhibitor. Biochemical and biophysical research communications, 406(2), 194-199.
• Van Wyk, B. E.,& Gorelik, B. (2017). The history and ethnobotany of Cape herbal teas. South African Journal of Botany, 110, 18-38.
• Vessby, B., Uusitupa, M., Hermansen, K., Riccardi, G., Rivellese, A. A., Tapsell, L. C., ... & Calvert, G. D. (2001). Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study. Diabetologia, 44(3), 312-319.
• Viollet, B., Guigas, B., Leclerc, J., Hébrard, S., Lantier, L., Mounier, R., ... & Foretz, M. (2009). AMP‐activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta physiologica, 196(1), 81-98.
• Wang, H., Zhu, C., Ying, Y., Luo, L., Huang, D., & Luo, Z. (2018). Metformin and berberine, two versatile drugs in treatment of common metabolic diseases. Oncotarget, 9(11), 10135.
• Wang, J., Zhang, L., Dong, L., Hu, X., Feng, F., & Chen, F. (2019). 6-Gingerol, a Functional Polyphenol of Ginger, Promotes Browning through an AMPK-Dependent Pathway in 3T3-L1 Adipocytes. Journal of Agricultural and Food Chemistry, 67(51), 14056-14065.
• Wang, X. H., Zhu, L., Hong, X., Wang, Y. T., Wang, F., Bao, J. P., Xie, X. H., Liu, L., & Wu, X. T. (2016). Resveratrol attenuated TNF-α-induced MMP-3 expression in human nucleus pulposus cells by activating autophagy via AMPK/SIRT1 signaling pathway. Experimental biology and medicine (Maywood, N.J.), 241(8), 848–853.
• Wang, Y., Li, X., Guo, Y., Chan, L., & Guan, X. (2010). alpha-Lipoic acid increases energy expenditure by enhancing adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor-gamma coactivator-1alpha signaling in the skeletal muscle of aged mice. Metabolism: clinical and experimental, 59(7), 967–976.
• Warner, T. D., Giuliano, F., Vojnovic, I., Bukasa, A., Mitchell, J. A., & Vane, J. R. (1999). Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proceedings of the National Academy of Sciences, 96(13), 7563-7568.
• Waterman, E.,& Lockwood, B. (2007). Active components and clinical applications of olive oil. Alternative medicine review, 12(4).
• Weiskirchen, S.,& Weiskirchen, R. (2016). Resveratrol: how much wine do you have to drink to stay healthy?. Advances in Nutrition, 7(4), 706-718.
• Woods, A., Johnstone, S. R., Dickerson, K., Leiper, F. C., Fryer, L. G., Neumann, D., ... & Carling, D. (2003). LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Current biology, 13(22), 2004-2008.
• Wu, N., Zheng, B., Shaywitz, A., Dagon, Y., Tower, C., Bellinger, G., ... & Kahn, B. B. (2013). AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Molecular cell, 49(6), 1167-1175.
• Wu, Z., Shen, S., Jiang, J., Tan, D., Jiang, D., Bai, B., ... & Fu, S. (2015). Protective effects of grape seed extract fractions with different degrees of polymerisation on blood glucose, lipids and hepatic oxidative stress in diabetic rats. Natural product research, 29(10), 988-992.
• Xiao, N., Mei, F., Sun, Y., Pan, G., Liu, B., & Liu, K. (2014). Quercetin, luteolin, and epigallocatechin gallate promote glucose disposal in adipocytes with regulation of AMP-activated kinase and/or sirtuin 1 activity. Planta medica, 80(12), 993-1000.
• Yagasaki, K. (2014). Anti-diabetic phytochemicals that promote GLUT4 translocation via AMPK signaling in muscle cells. Nutrition and Aging, 2(1), 35-44.
• Yalçın, A. S., Yılmaz, A. M., AltunDAğ, E. M., & KOçtürK, S. (2017). Kurkumin, kuersetin ve çay kateşinlerinin anti-kanser etkileri.
• Yamashita, Y., Okabe, M., Natsume, M., & Ashida, H. (2012). Cacao liquor procyanidin extract suppresses hyperglycemia by enhancing glucose transporter 4 translocation and glucose uptake in skeletal muscle. J Nutr Sci, 1, 1-9.
• Yamashita, Y., Okabe, M., Natsume, M., & Ashida, H. (2012). Prevention mechanisms of glucose intolerance and obesity by cacao liquor procyanidin extract in high-fat diet-fed C57BL/6 mice. Archives of biochemistry and biophysics, 527(2), 95-104.
• Yamashita, Y., Wang, L., Nanba, F., Ito, C., Toda, T., & Ashida, H. (2016). Procyanidin promotes translocation of glucose transporter 4 in muscle of mice through activation of insulin and AMPK signaling pathways. PLoS One, 11(9).
• Yang, B. Y., Zhang, X. Y., Guan, S. W., & Hua, Z. C. (2015). Protective effect of procyanidin B2 against CCl4-induced acute liver injury in mice. Molecules, 20(7), 12250-12265.
• Yin, J., Hu, R., Chen, M., Tang, J., Li, F., Yang, Y., & Chen, J. (2002). Effects of berberine on glucose metabolism in vitro. Metabolism-Clinical and Experimental, 51(11), 1439-1443.
• Zamora-Ros, R., Urpi-Sarda, M., Lamuela-Raventós, R. M., Martínez-González, M. Á., Salas-Salvadó, J., Arós, F., ... & PREDIMED Study Investigators. (2012). High urinary levels of resveratrol metabolites are associated with a reduction in the prevalence of cardiovascular risk factors in high-risk patients. Pharmacological research, 65(6), 615-620.
• Zang, M., Xu, S., Maitland-Toolan, K. A., Zuccollo, A., Hou, X., Jiang, B., ... & Cohen, R. A. (2006). Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor–deficient mice. Diabetes, 55(8), 2180-2191.
• Zhang, D. W., Fu, M., Gao, S. H., & Liu, J. L. (2013). Curcumin and diabetes: a systematic review. Evidence-Based Complementary and Alternative Medicine, 2013.