Pomegranate for Diabetes and its’ Complications Amelioration
Main Article Content
Abstract
Diabetes mellitus is a metabolic disease affecting various body organs and systemscausing several complications such ascardiovascular diseases, stroke, nephropathy, retinopathy, neuropathy, erectile dysfunction and diabetic foot ulcer development. Diabetic patients are under oxidative stress and inflammation that play crucial role in complications development.Pomegranate, containingvarious phytochemicals with antioxidant, anti-inflammatory, antihyperglycemic, antihyperlipidemic, antihypertensive, antiatherogenic, antimicrobial, cardioprotective, neuroprotective, regenerative, wound healing andimmuno modulatory bioactivities, at the same time is sufficiently treating diabetesand its’ complications without any side effects as safety tests have shown. Pomegranate treatment improves antioxidant status of the patients, reduces inflammation, ameliorates diabetes improving insulin sensitivity, increasing insulin production and secretion,reducing blood glucose levels, inhibiting hemoglobin glycosylation, protecting pancreas and is contributing to pancreatic islets regeneration and stimulation. It also ameliorates cardiovascular complications decreasing total cholesterol, triglycerides, LDL, lipid peroxidation, atherosclerosis, increasing the beneficial HDL. Pomegranate alsoenhances wound healing byreducing bacterial count, inhibiting quorum sensing and biofilm formation, increasing collagen production, upregulating the EGF, VEGF and TGF-β1 levelsand leading to excellent epithelialization and neovascularization. Besides, pomegranate treatment ameliorates nephropathy reducing serum creatinine, urine albumin, blood urea nitrogen, urine albumin to creatinine ratio,renal fibrosis, glomerular sclerosis, hypertrophyand interstitial hyperplasia. Pomegranate treatment is preventing or ameliorating neuropathy and alsoimproving erectile function by increasingintracavernosal blood flow and MICP/MAP percentage in patients with atherosclerosis. Moreover, pomegranate ameliorates retinopathy reducing the oxidative stress biomarker 8-OHdG, decreasing the levels of sialic acid, malondialdehyde, improving retina cell layers and delaying cataract onset. Is important to be mentioned that while in diabetic individuals the values of several biochemical parameters were significantly improved, at the same time there were not changes on thehealthy individuals’ biochemical parameters which were normal, indicatingexcept its’ excellent pharmaceutical properties alsoa regulatory role of pomegranate as it is acting only whenever it is needed for health achievement and maintenance.These results indicate that pomegranate can offer an alternative,safe, holistic treatment for diabetes and its’ complications, improving the general health and quality of life of the patient.
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References
I. Castillo-Armengol, J., Fajas, L., Lopez-Mejia, I. C. (2019). Inter-organ communication: a gatekeeper for metabolic health. EMBO Rep. 20(9):e47903. doi: 10.15252/embr.201947903.
II. Priest, C., Tontonoz, P. (2019). Inter-organ cross-talk in metabolic syndrome. Nat Metab 1:1177–1188. https://doi.org/10.1038/s42255-019-0145-5
III. DeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F.B., Kahn, R., Raz, I., Shulman G. I., Simonson, D. C., Testa, M. A., Weiss, R. (2015). Type 2 diabetes mellitus. Nature Reviews Disease Primers, 15019. doi:10.1038/nrdp.2015.19
IV. Khalil, E. A. M. (2004) Antidiabetic effect of an aqueous extract of Pomegranate (Punica granatum L.) peels in normal and alloxan diabetic rats,The Egyptian Journal of Hospital Medicine Vol., 16: 92 – 99
V. Tang, D., Liu, L., Ajiakber, D., Ye, J., Xu, J., Xin, X.,Aisa, HA (2018). Anti-diabetic Effect of Punica granatum Flower Polyphenols Extract in Type 2 Diabetic Rats: Activation of Akt/GSK-3β and Inhibition of IRE1α-XBP1 Pathways. Front. Endocrinol. 9:586. doi: 10.3389/fendo.2018.00586
VI. Ge, S., Duo, L., Wang, J.,Zhula, G., Yang, J., Li, Z., Tu, Y. (2021). A unique understanding of traditional medicine of pomegranate, Punica granatum L. and its current research status. J Ethnopharmacol. 10:271:113877. doi: 10.1016/j.jep.2021.113877.
VII. Shekokar, S., Thombare, C. (2019). A phytopharmacological review of Dadim – Punica Granatum Linn, Int. J. Ayur. Pharma Research, 7(4):21-31.
VIII. Kandylis, P.,Kokkinomagoulos, E., (2020). Food Applications and Potential Health Benefits of Pomegranate and its Derivatives. Foods. 9, 122; doi:10.3390/foods9020122.
IX. Deshmukh C. D., Jain, A. (2015). Diabetes Mellitus: A Review. Int. J. Pure App. Biosci. 3 (3): 224-230
X. Gisela Wilcox,(2005). Insulin and Insulin Resistance, Clin Biochem Rev 26: 19-39
XI. Tayde P. Types of diabetes: Two or five. J Mahatma Gandhi Inst Med Sci 2019;24:75-7
XII. Krzyśko, I., Przewoźniak, S., Skowrońska, B., Niechciał, E.,Gertig-Kolasa, A.,Fichna, P,(2015) Type 1 diabetes in children and adolescents – a need for multi-professional team intervention, Pediatr. Endocrinol.14.3.52.41-46.
XIII. Dekker, A. M., Amick, A. E., Scholcoff, C., Doobay-Persaud, A. (2017). A mixed-methods needs assessment of adult diabetes mellitus (type II) and hypertension care in Toledo, Belize. BMC Health Services Research, 17(1). doi:10.1186/s12913-017-2075-9
XIV. Maechler, P.,Jornot, L.,Wollheim, C. B., (1999) Hydrogen Peroxide Alters Mitochondrial Activation and InsulinSecretion in Pancreatic Beta Cells, The Journal of Biological Chemistry, 274(39):27905–27913
XV. Da Silva Xavier, G. (2018). The Cells of the Islets of Langerhans. Journal of Clinical Medicine, 7(3), 54. doi:10.3390/jcm7030054
XVI. Nekooeian, A.A., Eftekhari, M.H., Adibi, S., Rajaeifard, A. (2014). Effects of Pomegranate Seed Oil on Insulin Release in Rats with Type 2 Diabetes. Iran J Med Sci. 39(2):130-135.
XVII. Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K. B., Ostolaza, H., Martín, C. (2020). Pathophysiology of Type 2 Diabetes Mellitus. International Journal of Molecular Sciences, 21(17), 6275. doi:10.3390/ijms21176275
XVIII. Butler, A. E., Misselbrook, D. (2020). Distinguishing between type 1 and type 2 diabetes. BMJ, m2998. doi:10.1136/bmj.m2998
XIX. Wolosowicz, M., Lukaszuk, B., Chabowski, A. (2020). The Causes of Insulin Resistance in Type 1 Diabetes Mellitus: Is There a Place for Quaternary Prevention? International Journal of Environmental Research and Public Health, 17(22), 8651. doi:10.3390/ijerph17228651
XX. Muhas, C., Naseef, P. P. (2016). Areview article-Gestational Diabetes Mellitus. International Journal of Current Pharmaceutical Research, 9(1), 1.
XXI. Granados, A., Chan, C. L., Ode, K. L., Moheet, A., Moran, A., Holl, R. (2019). Cystic fibrosis related diabetes: Pathophysiology, screening and diagnosis. Journal of Cystic Fibrosis, 18, S3–S9. doi:10.1016/j.jcf.2019.08.016
XXII. Carmody, D., Støy, J., Greeley, S. A. W., Bell, G. I., Philipson, L. H. (2016). A Clinical Guide to Monogenic Diabetes. Genetic Diagnosis of Endocrine Disorders, 21–30. doi:10.1016/b978-0-12-800892-8.00002-6
XXIII. Mihai B, Mihai C, Cijevschi-Prelipcean C, Lăcătuşu C. (2012). Rare types of diabetes mellitus. Rev Med Chir Soc Med Nat Iasi. 2012;116(3):700-707.
XXIV. Omar, E.A, Antony Kam, A., Alqahtani, A., Li, K. M.,Razmovski-Naumovski, V., Nammi, S., Chan, K.,Roufogalis, B, D., Li, G.Q. (2010). Herbal Medicines and Nutraceuticals for Diabetic Vascular Complications: Mechanisms of Action and Bioactive Phytochemical, Current Pharmaceutical Design, 2010, 16, 3776-3807
XXV. Stefanou, V., Timbis, D.,Kanellou, A., Margari, D.,Trianti, M., Tsaknis, I., Azar Naka, A.,Lougovois, V (2021) Wound Healing Properties of Pomegranate. Archives of Microbiology and Immunology 5: 263-291. retrieved from http://www.medicaljournalshouse.com/index.php/Int-J-Microbiology-Immunology/article/view/476
XXVI. Yisimayili, Z., Abdulla, R., Tian, Q., Wang, Y., Chen, M., Sun, Z., Li, Z., Liu, F., Aisa, H, A, Huang, C. (2019). A comprehensive study of pomegranate flowers polyphenols and metabolites in rat biological samples by high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. Journal of Chromatography A, 460472. doi:10.1016/j.chroma.2019.460472
XXVII. Katz, S.R., Newman, R.A., Lansky, E.P. (2007) Punica granatum: Heuristic Treatment for Diabetes Mellitus, J Med Food, 10 (2) 2007, 213–217
XXVIII. Wang,R., Ding,Y.,Liu, R.,Xiang, L., Du, L., (2010). Pomegranate: Constituents, Bioactivities and Pharmacokinetics. Fruit, Vegetable and Cereal Science and Biotechnology 4(2):77-87
XXIX. Kristiansen, O. P., Mandrup-Poulsen, T. (2005). Interleukin-6 and Diabetes: The Good, the Bad, or the Indifferent? Diabetes, 54(Supplement 2), S114–S124. doi:10.2337/diabetes.54.suppl_2.s114
XXX. Patel, S., Santani, D. (2009). Role of NF-κB in the pathogenesis of diabetes and its associated complications. Pharmacological Reports, 61(4): 595–603. doi:10.1016/s1734-1140(09)70111-2
XXXI. Stefanou, V., Papatheodorou, S., Tsakni, A., Lougovois, V., Talelli, A., Panourgias, G., Dariatos, A., Tsaknis,(2020). Anti-Inflammatory Properties of Pomegranate. Int J Adv Res MicroBiolImmunol : 2(1): 1-13. Retrieved from
http://www.medicaljournalshouse.com/index.php/Int-J-Microbiology-Immunology/article/view/430
XXXII. [32].Teresa Vanessa Fiorentino, T. V., Prioletta, A., PengouZuo, P.,Folli, F., (2013). Hyperglycemia-induced Oxidative Stress and its Role inDiabetes Mellitus Related Cardiovascular Diseases, Current Pharmaceutical Design, 2013, 19, 5695-5703
XXXIII. Slatter, D. A., Bolton, C. H., Bailey, A. J. (2000). The importance of lipid-derived malondialdehyde in diabetes mellitus. Diabetologia, 43(5): 550–557. doi:10.1007/s001250051342
XXXIV. Goth, L. (2008). Catalase Deficiency and Type 2 Diabetes. Diabetes Care, 31(12), e93–e93. doi:10.2337/dc08-1607
XXXV. Góth, L., Nagy, T. (2012). Acatalasemia and diabetes mellitus. Archives of Biochemistry and Biophysics, 525(2): 195–200. doi:10.1016/j.abb.2012.02.005
XXXVI. Niedernhofer, L. J., Daniels, J. S., Rouzer, C. A., Greene, R. E., &Marnett, L. J. (2003). Malondialdehyde, a Product of Lipid Peroxidation, Is Mutagenic in Human Cells. Journal of Biological Chemistry, 278(33): 31426–31433. doi:10.1074/jbc.m212549200
XXXVII. Ayala, A., Muñoz, M. F., Argüelles, S. (2014) Lipid Peroxidation: Production, Metabolism, and SignalingMechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal,Oxidative Medicine and Cellular Longevity, Volume 2014, Article ID 360438, 31 pages
XXXVIII. Wang, X., Lei, X. G., & Wang, J. (2014). Malondialdehyde regulates glucose-stimulated insulin secretion in murine islets via TCF7L2-dependent Wnt signaling pathway. Molecular and Cellular Endocrinology, 382(1), 8–16. doi:10.1016/j.mce.2013.09.003.
XXXIX. Dalleau, S., Baradat, M., Gue´raud, F., Huc. L. (2013) Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance. Cell Death and Differentiation (2013) 20, 1615–1630; doi:10.1038/cdd.2013.138
XL. Shoeb, M., Ansari N. H., Srivastava, S. K., Ramana K. V. (2014). 4-hydroxynonenal in the pathogenesis and progression of human diseases. Curr Med Chem. 2014 ; 21(2): 230–237.
XLI. Basu, A., Newman, E. D., Bryant, A. L., Lyons, T. J., Betts, N. M. (2013). Pomegranate Polyphenols Lower Lipid Peroxidation in Adults with Type 2 Diabetes but Have No Effects in Healthy Volunteers: A Pilot Study. Journal of Nutrition and Metabolism, 2013, 1–7. doi:10.1155/2013/708381
XLII. Bassuk A, S., Rifai, N., Ridker, P. (2004). High-sensitivity C-reactive proteinClinical importance. Current Problems in Cardiology, 29(8): 439–493. doi:10.1016/s0146-2806(04)00074-x
XLIII. Zarezadeh M., Saedisomeolia, A., Hosseini, B., Emam M. R. (2019). The Effect of Punica granatum (Pomegranate) Extract on Inflammatory Biomarkers, Lipid Profile, and Glycemic Indices in Patients with Overweight and Obesity: Randomized Clinical Trial, Qom Univ Med Sci J13(8):14-25
XLIV. Sohrab, G., Nasrollahzadeh, J., Zand, H., Amiri, Z., Tohidi, M., Kimiagar, M. (2014). Effects of pomegranate juice consumption on inflammatory markers in patients with type 2 diabetes: A randomized, placebo-controlled trial. J Res Med Sci 2014;19:215-20
XLV. Bermúdez, V., Finol, F., Parra, N., Parra, M., Pérez, A., Peñaranda, L.,Vı´lchez, D., Rojas, J., Arra´iz, N., Velasco, M. (2010). PPAR-γ Agonists and Their Role in Type 2 Diabetes Mellitus Management. American Journal of Therapeutics, 17(3): 274–283. doi:10.1097/mjt.0b013e3181c08081
XLVI. Afzal, N., Hassan, M., Fatima, S., Tariq, S., Qayum, I. (2016) Expression of peroxisome-proliferator activated receptors-γin diabretics, obese and normal subjects. J Ayub Med Coll Abbottabad. 28(1):130-134.
XLVII. Shibata, T.,Takeuchi, S., Yokota, S., Kakimoto, K.,Yonemori, F.,Wakitani, K.(2000). Effects of peroxisome proliferator-activated receptor-a and -gagonist, JTT-501, on diabetic complications in Zucker diabeticfatty rats,2000, British Journal of Pharmacology (2000) 130:195-504
XLVIII. Kume, S., Uzu, T.,Isshiki, K., Koya, D. (2008). Peroxisome Proliferator-Activated Receptors inDiabetic Nephropathy, PPAR Research, Volume 2008, Article ID 879523, 11 pages, doi:10.1155/2008/879523
XLIX. Huang, T., Peng, G., Kota, B., Li, G., Yamahara, J., Roufogalis, B., Li, Y. (2005). Anti-diabetic action of flower extract: Activation of PPAR-γ and identification of an active component. Toxicology and Applied Pharmacology, 207(2): 160–169. doi:10.1016/j.taap.2004.12.009
L. Huang, T. H. W., Yang, Q., Harada, M., Li, G. Q., Yamahara, J., Roufogalis, B. D., Li, Y. (2005). Pomegranate Flower Extract Diminishes Cardiac Fibrosis in Zucker Diabetic Fatty Rats. Journal of Cardiovascular Pharmacology, 46(6): 856–862. doi:10.1097/01.fjc.0000190489.85058.7e
LI. Hontecillas, R.,O'Shea, M, Einerhand, A.,DiguardoM., Bassaganya-Riera, J. (2009). Activation of PPAR γ and α by Punicic Acid Ameliorates Glucose Toleranceand Suppresses Obesity-Related Inflammation, Journal of the American College of Nutrition, 28(2), 184-195,doi:10.1080/07315724.2009.10719770
LII. Likidlilid, A., Patchanans, N., Poldee, S., Peerapatdit, T. (2007) Glutathione and glutathione peroxidase in type 1 diabetic patients. J Med Assoc Thai. 90(9):1759-67. PMID: 17957916.
LIII. Tugcu, B., Nacaroglu, S. A., Gedikbasi, A., Uhri, M., Acar, N., Ozdemir, H. (2017). Protective effect of pomegranate juice on retinal oxidative stress in streptozotocin-induced diabetic rats. Int J Ophthalmol.10(11):1662-1668. doi: 10.18240/ijo.2017.11.05.
LIV. Vroegrijk, I. O. C. M., van Diepen, J. A., van den Berg, S., Westbroek, I., Keizer, H., Gambelli, L., Hontecilas, R., Bassaganya-Riera, J., Zondag, G.C.M., Romijn. J. A.,Havekes, L.M.,Voshol, P. J. (2011). Pomegranate seed oil, a rich source of punicic acid, prevents diet-induced obesity and insulin resistance in mice. Food and Chemical Toxicology, 49(6), 1426–1430. doi:10.1016/j.fct.2011.03.037
LV. Das, S., Barman, S. (2012). Antidiabetic and antihyperlipidemic effects of ethanolic extract of leaves of Punica granatum in alloxan-induced non–insulin-dependent diabetes mellitus albino rats, Indian Journal of Pharmacology, 44(2):219-224
LVI. [56].Banihani, S. A., Fashtaky, R. A., Makahleh, S. M., El‐Akawi, Z. J., Khabour, O. F., Saadeh, N. A. (2019). Effect of fresh pomegranate juice on the level of melatonin, insulin, and fasting serum glucose in healthy individuals and people with impaired fasting glucose. Food Science & Nutrition, 8(1), 567–574. doi:10.1002/fsn3.1344
LVII. Liang, Y., Yang, X. M., Gu, Y. R., Tao, X., Zhong, Z. Z., Gong, J. J., Chen, X. H., Lv, X. B. (2015). Developmental changes in the expression of the GLUT2 and GLUT4 genes in the longissimus dorsi muscle of Yorkshire and Tibetan pigs. Genetics and Molecular Research, 14(1), 1287–1292. doi:10.4238/2015.february.13.7
LVIII. Thorens, B. (2014). GLUT2, glucose sensing and glucose homeostasis. Diabetologia, 58(2), 221–232. doi:10.1007/s00125-014-3451-1
LIX. Marette, A. (2003). Regulation of GLUT4 traffic and function by insulin and contraction in skeletal muscle. Frontiers in Bioscience, 8(4):1072–1084. doi:10.2741/1137
LX. [60].Alam, F., Islam, M.A., Khalil, M.I, Gan S.H. (2016) Metabolic Control of Type 2 Diabetes by Targeting the GLUT4 Glucose Transporter: Intervention Approaches. Curr Pharm Des. 22(20):3034-3049. doi:10.2174/1381612822666160307145801
LXI. [Gharib, E., Kouhsari, S. M. (2019) Study of the Antidiabetic Activity of Punica granatum L. Fruits Aqueous Extract on the Alloxan-Diabetic Wistar Rats, 2019, Iran J Pharm Res, 18(1): 358–368.
LXII. Das, A. K., Mandal, S. C., Banerjee, S. K., Sinha, S., Saha, B. P., Pal, M. (2001). Studies on the hypoglycaemic activity of Punica granatum seed in streptozotocin induced diabetic rats. Phytotherapy Research, 15(7): 628–629. doi:10.1002/ptr.740
LXIII. Shankaraiah, P., Reddy, Y.N. (2011). α-amylase Expressions in Indian Type-2 Diabetic Patients, J. Med. Sci, 11(7): 280-284
LXIV. Sani, S.B.,Nair, S. S. (2017).Studies on in vitro evaluation of antidiabetic potentials of watermelon and pomegranate peels. Bayero Journal of Pure and Applied Sciences, 10(1): 32 – 35
LXV. Hashemi, S., M., Namiranian, N., Tavahen, H., Dehghanpour, A., Rad, M. H., Jam-Ashkezari, S., Emtiazy, M., Hashempur, M. H. (2020). Efficacy of Pomegranate Seed Powder on Glucose and Lipid Metabolism in Patients with Type 2 Diabetes: A Prospective Randomized Double-Blind Placebo-Controlled Clinical Trial. Complementary Medicine Research, 1–8. doi:10.1159/000510986
LXVI. Raafat, K., Samy, W. (2014). Amelioration of Diabetes and Painful Diabetic Neuropathy byPunicagranatumL. Extract and Its Spray Dried Biopolymeric Dispersions. Evidence-Based Complementary and Alternative Medicine, 2014, 1–12. doi:10.1155/2014/180495
LXVII. Stefanou, V., Papatheodorou, S., Vougiouklaki, D.,Antonopoulos, D., Lougovois, V., Tsaknis, I. Houhoula. D.(2020). Medicinal Properties of Antioxidant Pomegranatein Cardiovascular Health. Int J Preven Cardio 1(1):10-19. Retrieved from http://www.medicaljournalshouse.com/index.php/IntJ-PreventiveCardiology/article/view/356
LXVIII. Kowalczyk, A., Kleniewska, P., Kolodziejczyk, M., Skibska, B., &Goraca, A. (2014). The Role of Endothelin-1 and Endothelin Receptor Antagonists in Inflammatory Response and Sepsis. Archivum Immunologiae et TherapiaeExperimentalis, 63(1):41–52. doi:10.1007/s00005-014-0310-1
LXIX. Yung, J.H.M., Giacca, A. (2020). Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes. Cells. 9(3):706. https://doi.org/10.3390/cells9030706
LXX. Gamble, C., McIntosh, K., Scott, R., Ho, K. H., Plevin, R., Paul, A. (2012). Inhibitory kappa B kinases as targets for pharmacological regulation. British Journal of Pharmacology, 165(4): 802–819. doi:10.1111/j.1476-5381.2011.01608.x
LXXI. Huang, T. H., Peng, G., Kota, B. P., Li G. Q., Yamahara J, Roufogalis, B. D., Li, Y. (2005). Pomegranate flower improves cardiac lipid metabolism in a diabetic rat model: role of lowering circulating lipids. Br J Pharmacol, 145(6):767-774. doi: 10.1038/sj.bjp.0706245.
LXXII. González-Ortiz, M., Martínez-Abundis, E., Espinel-Bermúdez, M. C., Pérez-Rubio, K. G. (2011). Effect of Pomegranate Juice on Insulin Secretion and Sensitivity in Patients with Obesity. Annals of Nutrition and Metabolism, 58(3): 220–223. doi:10.1159/000330116
LXXIII. Saad, E., Hassanien, M., El-Hagrasy, M., Radwan, K., (2015). Antidiabetic, hypolipidemic and antioxidant activities and protective effects of Punica Granatum peels powder against pancreatic and hepatic tissues injuries in streptozotocin induced IDDM in rats, Int J Pharm Pharm Sci, Vol 7, Issue 7, 397-402.
LXXIV. Odiba, A. S.,Onosakponome, I, Iroha, O. K., Ukegbu, C Y., Omeje,K. O. (2014). Transaminase [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] Activity of HIVFemale Patients on Drugs and Female Patients Not on Drugs, Journal of Pharmacy and Biological Sciences, 9(2): 60-65.
LXXV. Dekker, A. M., Amick, A. E., Scholcoff, C., Doobay-Persaud, A. (2017). A mixed-methods needs assessment of adult diabetes mellitus (type II) and hypertension care in Toledo, Belize. BMC Health Services Research, 17(1). doi:10.1186/s12913-017-2075-9
LXXVI. Tayde P. (2019). Types of diabetes: Two or five. J Mahatma Gandhi Inst Med Sci 2019;24:75-7
LXXVII. Chei, C.-L., Yamagishi, K., Kitamura, A., Kiyama, M., Sankai, T.,Okada T., Imano, H., Ohira T, Cui, R., Umesawa, M., Muraki, I., Tanigawa T., Sato, S., Iso, H., T. (2018). Serum Fatty Acid and Risk of Coronary Artery Disease ― Circulatory Risk in Communities Study (CIRCS) ―. Circulation Journal. doi:10.1253/circj.cj-18-0240
LXXVIII. Tallima, H., & El Ridi, R. (2018). Arachidonic acid: Physiological roles and potential health benefits – A review. Journal of Advanced Research, 11, 33–41. doi:10.1016/j.jare.2017.11.004
LXXIX. Prasetyastuti, Mochammad Willy Pratama Anthony, NubaAuliaRachman, Ngadikun and Sunarti, 2014, Hypoglycemic and Antioxidative Effects of Pomegranate (Punica Granatum L.) Juice in Streptozotocin Induced Diabetic Rats, Pakistan Journal of Nutrition 13(10): 567-572.
LXXX. Amri, Z., Ben Khedher, M. R., Zaibi, M. S., Kharroubi, W., Turki, M., Ayadi, F., Hammami, M. (2020). Anti-diabetic effects of pomegranate extracts in long-term high fructose-fat fed rats. Clinical Phytoscience, 6(1). doi:10.1186/s40816-020-00202-y
LXXXI. Taskinen, M.R. (1987). Lipoprotein lipase in diabetes. Diabetes / Metabolism Reviews, 3(2): 551–570. doi:10.1002/dmr.5610030208
LXXXII. Mohan, M., Waghulde, H., Kasture, S. (2009). Effect of pomegranate juice on Angiotensin II-induced hypertension in diabetic wistar rats. Phytotherapy Research, 24(S2), S196–S203. doi:10.1002/ptr.3090
LXXXIII. Fang, L., Geng, M., Liu, C., Wang, J., Min, W., Liu, J. (2019). Structural and molecular basis of angiotensin-converting enzyme by computational modeling: Insights into the mechanisms of different inhibitors. PLOS ONE, 14(4), e0215609. doi:10.1371/journal.pone.0215609
LXXXIV. Reid, I. A., Morris, B. J., Ganong, W. F. (1978). The Renin-Angiotensin System. Annual Review of Physiology, 40(1): 377–410. doi:10.1146/annurev.ph.40.030178
LXXXV. De Leon A. D., J., Borges, C. R. (2020). Evaluation of Oxidative Stress in Biological Samples Using the Thiobarbituric Acid Reactive Substances Assay. Journal of Visualized Experiments, (159). doi:10.3791/61122
LXXXVI. Bagri, P., Ali, M., Aeri, V., Bhowmik, M., Sultana, S. (2009). Antidiabetic effect of Punica granatum flowers: Effect on hyperlipidemia, pancreatic cells lipid peroxidation and antioxidant enzymes in experimental diabetes. Food and Chemical Toxicology, 47(1): 50–54. doi:10.1016/j.fct.2008.09.058
LXXXVII. Sanajou, D., GhorbaniHaghjo, A., Argani, H., Aslani, S. (2018). AGE-RAGE axis blockade in diabetic nephropathy: Current status and future directions. European Journal of Pharmacology, 833, 158–164. doi:10.1016/j.ejphar.2018.06.001
LXXXVIII. Huang, X., Liu, G., Guo, J., Su, Z. (2018). The PI3K/AKT pathway in obesity and type 2 diabetes. International Journal of Biological Sciences, 14(11): 1483–1496. doi:10.7150/ijbs.27173
LXXXIX. Gogg, S., Smith, U., Jansson, P.-A. (2009). Increased MAPK Activation and Impaired Insulin Signaling in Subcutaneous Microvascular Endothelial Cells in Type 2 Diabetes: The Role of Endothelin-1. Diabetes, 58(10): 2238–2245. doi:10.2337/db08-0961
XC. Patil, C., Tidke, P., Patil, K., Patil, S., Dubey, V., Kamble, S., Tidce, P., Patil, K., Maniya, P., Jadhav, R. (2013). Oleanolic acid prevents progression of streptozotocin induced diabetic nephropathy and protects renal microstructures in Sprague Dawley rats. Journal of Pharmacology and Pharmacotherapeutics, 4(1), 47. doi:10.4103/0976-500x.107678
XCI. [91].Sciarretta, S., Zhai, P., Shao, D., Zablocki, D., Nagarajan, N., Terada, LS., Volpe, M., Sadoshima, J. (2013) Activation of NADPH oxidase 4 in the endoplasmic reticulum promotes cardiomyocyte autophagy and survival during energy stress through the protein kinase RNA-activated-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/activating transcription factor 4 pathway. Circ Res.8:13(11):1253-1264.
doi: 10.1161/CIRCRESAHA.113.301787.
XCII. Manna, K., Mishra, S., Saha, M., Mahapatra, S., Saha, C., Yenge, G., Gaikwad, N., Pal, R., Oulkar, D., Banerjee, K., Das Saha, K. (2019).Amelioration of diabetic nephropathy using pomegranate peel extract-stabilized gold nanoparticles: assessment of NF-κB and Nrf2 signaling system. International Journal of Nanomedicine, Volume 14: 1753–1777. doi:10.2147/ijn.s176013
XCIII. Ahmed, A.T.G., Belal, S. K. M., Salem A. G. E., (2014). Protective Effect of Pomegranate Peel Extract against Diabetic-Induced Renal Histo-pathological Changes in Albino Rats, Journal of Dental and Medical Sciences, 13(10): 94-105
XCIV. Bansal, P.,Bansal, P., Verma, R., (2021). Association of serum sialic acid concentration with diabetic complications and cardiovascular risk factors in an Indian population, Arch Med Sci Atheroscler Dis 2021; 6: e14–e17, doi: https://doi.org/10.5114/amsad.2021.105142
XCV. Odetti, P., Garibaldi, S., Noberasco, G., Aragno, I., Valentini, S., Traverso, N., &Marinari, U. M. (1999). Levels of carbonyl groups in plasma proteins of type 2 diabetes mellitus subjects. Acta Diabetologica, 36(4): 179–183. doi:10.1007/s005920050164
XCVI. Çukurova,Z.,Hergunsel, O.,Eren, G., Gedikbasi, A., Uhri, M., Demir, G., Tekdos, Y, (2012).The Effect of Pomegranate Juice onDiabetes-Related Oxidative Stress inRat Lung,TurkiyeKlinikleri J Med Sci 2012;32(2):444-452, doi:10.5336/medsci.2011-24472.
XCVII. An, X., Zhang, Y., Cao, Y., Chen, J., Qin, H., Yang, L. (2020) Punicalagin Protects Diabetic Nephropathy by Inhibiting Pyroptosis Based on TXNIP/NLRP3 Pathway. Nutrients.12(5):1516. doi: 10.3390/nu12051516. PMID: 32456088; PMCID: PMC7284711.
XCVIII. Mollazadeh, H.Sadeghnia, HR.,Hoseini, A.,Farzadnia, M.,Boroushaki, MT. (2016). Effects of pomegranate seed oil on oxidative stress markers, serum biochemical parameters and pathological findings in kidney and heart of streptozotocin-induced diabetic rats. Ren Fail. 38(8):1256-1266
XCIX. Meyer, J. S. (1996). Diabetes and Wound Healing. Critical Care Nursing Clinics of North America, 8(2): 195–201. doi:10.1016/s0899-5885(18)30335-6
C. Sharp, A. Clark, J., 2011, Diabetes and its impact on wound healing, Nursing Standard. 25, 45, 41-47.
CI. Bowler, P. G., Duerden, B. I., Armstrong, D. G. (2001) Wound Microbiology and Associated Approaches to Wound Management, American Society for Microbiology, Clinical Microbiology Reviews, 14(2):244-269
CII. Shaheen,M. M. A.,Al Dahab, S., Abu Fada, M., Idieis, R.(2021).Isolation and characterization of bacteria from diabetic foot ulcer: amputation, antibiotic resistance and mortality rate, International Journal of Diabetes in Developing Countries,https://doi.org/10.1007/s13410-021-00997-7
CIII. .Rodrigues, J., Mitt, N. (2011). Diabetic Foot and Gangrene. Gangrene - Current Concepts and Management Options. doi:10.5772/23994.
CIV. Stefanou, V., Tsakni, A., Timbis, D., Vougiouka, PA, Doumi, I., Maronikolaki, I., Siatras, N., Lougovois, V (2020). Pomegranate as anAntibacterial Agent against Pathogens and at the same Time Advantageous to Beneficial Bacteria: AReview. Int J Adv Res MicroBiol Immunol 2(2): 1-13 Retrieved from http://www.medicaljournalshouse.com/index.php/Int-J-Microbiology-Immunology/article/view/476
CV. Baothman, O. A., Zamzami, M. A., Taher, I., Abubaker, J., Abu-Farha, M. (2016). The role of Gut Microbiota in the development of obesity and Diabetes. Lipids in Health and Disease, 15(1):1-8, doi:10.1186/s12944-016-0278-4
CVI. Bilgili, S., Ozaydin-Yavuz, G., Yavuz, I., Bilgili, M., Karadag, A. (2019). Cutaneous reactions caused by nitrofurazone. Advances in Dermatology and Allergology, 36(4): 398–402. doi:10.5114/ada.2019.87444
CVII. Aslam, M. N., Lansky, E. P., Varani, J. (2006). Pomegranate as a cosmeceutical source: Pomegranate fractions promote proliferation and procollagen synthesis and inhibit matrix metalloproteinase-1 production in human skin cells. Journal of Ethnopharmacology, 103(3): 311–318. doi:10.1016/j.jep.2005.07.027
CVIII. .Stefanou, V., Timbis, D., Antonopoulos, D., Papatheodorou, S., Panourgias, G., Gouti, A. M., Makri, M., Andreou, A., Lougovois, V. (2021). Pomegranate as an Anti-Viral Agent and Immune System Stimulant. Int J Adv Res MicroBiol Immunol. 3(1):1-12. Retrieved from http://www.medicaljournalshouse.com/index.php/Int-J-Microbiology-Immunology/article/view/616
CIX. Akash, M. S. H., Rehman, K., Fiayyaz, F., Sabir, S., Khurshid, M. (2020). Diabetes-associated infections: development of antimicrobial resistance and possible treatment strategies. Archives of Microbiology. doi:10.1007/s00203-020-01818-x
CX. Wu, Y., Zhu, C., Zhang, Y., Li, Y., & Sun, J. (2019). Immunomodulatory and antioxidant effects of pomegranate peel polysaccharides on immunosuppressed mice. International Journal of Biological Macromolecules. doi:10.1016/j.ijbiomac.2019.06.139
CXI. Mahmoud, S., Mahmoud, R. M., Ashoush, I. S., Attia M.Y. (2015). Immunomodulatory and Antioxidant Activity ofPomegranate Juice Incorporated with Spirulina and Echinacea Extracts Sweetened by Stevioside. Journal of Agricultural and Veterinary Sciences, 8(2): 161-174.
CXII. Aharoni S, Lati Y, Aviram M, Fuhrman B. (2015). Pomegranate juice polyphenols induce a phenotypic switch in macrophage polarization favoring a M2 anti-inflammatory state. Biofactors, 41(1):44-51. doi: 10.1002/biof.1199.
CXIII. Thorve, V. S., Kshirsagar, A. D., Vyawahare, N. S., Joshi, V. S., Ingale, K. G., Mohite, R. J. (2011). Diabetes-induced erectile dysfunction: epidemiology, pathophysiology and management. Journal of Diabetes and Its Complications, 25(2): 129–136. doi:10.1016/j.jdiacomp.2010.03.0
CXIV. Zhang, Q., Radisavljevic, Z. M., Siroky, M. B., Azadzoi, K. M. (2010). Dietary antioxidants improve arteriogenic erectile dysfunction. International Journal of Andrology, 34(3):225–235. doi:10.1111/j.1365-2605.2010.01083.x
CXV. Onal, E., Yilmaz, D., Kaya, E., Bastaskın, T., Bayatlı, N., Gur, S. (2016). Pomegranate juice causes a partial improvement through lowering oxidative stress for erectile dysfunction in streptozotocin-diabetic rat. International Journal of Impotence Research, 28(6): 234–240. doi:10.1038/ijir.2016.34
CXVI. Wu, L. L., Chiou, C. C., Chang, P. Y., Wu, J. T. (2004). Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. Clin Chim Acta. 339(1-2):1-9. doi: 10.1016/j.cccn.2003.09.010.
CXVII. Belal, S. K. M., Al Ghamdi, A.(2021).Protective effect of pomegranate peel extract on diabetic ocular structural changes in experimental diabetic rats: A histological, immunohistochemical and clinical study, Adv Med Plant Res, 9(1): 11-21, doi: 10.30918/AMPR.91.20.042
CXVIII. https://www.medicalnewstoday.com/articles/323387#Insulin-delivery-devices
CXX. https://www.rxlist.com/diabinese-drug.htm#indications
CXXI. https://www.drugs.com/sfx/metformin-side-effects.html
CXXIII. https://www.medicalnewstoday.com/articles/drugs-glipizide-oral-tablets#about
CXXIV. https://nurseslabs.com/antihyperlipidemic-drugs/
CXXVI. https://www.drugs.com/rosuvastatin.html
CXXVII. Jardine, M. J., Mahaffey, K. W., Neal, B., Agarwal, R., Bakris, G. L.,Brenner, B. M., Bull, S.,Cannon, C. P., Charytan, D. M., de Zeeuw, D., Edwards, R., Greene, T.,Heerspink, H. L. D., Levin, A., Pollock, C. P., Wheeler, D. C., Xie, J., Zhang, H., Zinman, B., Desai, M., Perkovic, V.(2017). The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics. American Journal of Nephrology, 46(6):462–472. doi:10.1159/000484633
CXXVIII. https://www.medicalnewstoday.com/articles/losartan-oral-tablet#side-effects
CXXIX. https://www.drugs.com/sfx/telmisartan-side-effects.html
CXXX. Zhou, L., Liu, L., Yang, J., Li, Y., Bai, W., Liu, N., Li, W., Gao, Y., Xu, L., Liu, Z., Han, R. (2016). LDL acts as an opsonin enhancing the phagocytosis of group A Streptococcus by monocyte and whole human blood. Med Microbiol Immunol., 205(2):155-62. doi: 10.1007/s00430-015-0436-8.