|Year : 2020 | Volume
| Issue : 2 | Page : 69-74
The Role of Phloridzin and its Possible Potential Therapeutic Effect on Parkinson’s Disease
Preeja Prabhakar1, Abdul Bakrudeen Ali Ahmed2, Saravana Babu Chidambaram3
1 Department of Biochemistry, Centre for Research and Development, PRIST University, Thanjavur, Tamil Nadu, India
2 Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
3 Department of Pharmacology, JSS College of Pharmacy, Mysuru, Karnataka, India
|Date of Submission||16-Dec-2019|
|Date of Decision||16-Jan-2019|
|Date of Acceptance||02-Feb-2020|
|Date of Web Publication||10-Apr-2020|
Department of Biochemistry, Centre for Research and Development, PRIST University, Thanjavur, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Parkinson’s disease (PD) is the second commonest neuro-degenerative disorder in the world and is complex in terms of its etio-pathological mechanisms, symptomatology, diagnosis and progression. Research on animal models, epidemiology, human postmortem analysis and genetic studies suggest that oxidative stress, mitochondrial dysfunction, neuro-inflammation, and derangements in neurochemical pathways regulating protein folding and aggregation, have a role in the etio-pathogenesis and progression PD. However, till date, the treatment options for PD including medication and surgical-interventions are only of symptomatic relief. There is no definite preventive or neuro-protective or disease-modifying cure currently available. The relevance of antioxidant molecules is considered as part of a novel research avenue tackling potential therapeutic adjuncts in the treatment of PD. The beneficial effects of naturally occurring dietary polyphenols provide promising perspectives and are of value in the quest of developing a novel generation of therapeutic agents capable of reducing neuro-inflammation and neuro-degeneration, thereby possibly delaying or preventing or halting the progression of PD. Phloridzin is a dihydrochalcone primarily present in unripe-apples (Malus sp., Rosaceae). There are many proposed mechanisms by which phloridzin mitigates the onset and decrease of the progression of neurodegenerative disorders such as PD. These protective actions of phloridzin include its antioxidant anti-neuro-inflammatory (by reducing pro-inflammatory and pro-apoptotic mediators) and modulation of gene expression including mitochondrial directed flavono-therapy. It is anticipated that further evidence in the efficacy of diet derived phenolic products like phloridzin could lend a novel perspective of the role of nutritional therapeutics in preventing the occurrence of neurodegenerative conditions including PD during the early stages and mitigate its progression in susceptible individuals.
Keywords: Parkinson’, s disease, natural molecules, polyphenols, phloridzin
|How to cite this article:|
Prabhakar P, Ahmed AA, Chidambaram SB. The Role of Phloridzin and its Possible Potential Therapeutic Effect on Parkinson’s Disease. Int J Nutr Pharmacol Neurol Dis 2020;10:69-74
|How to cite this URL:|
Prabhakar P, Ahmed AA, Chidambaram SB. The Role of Phloridzin and its Possible Potential Therapeutic Effect on Parkinson’s Disease. Int J Nutr Pharmacol Neurol Dis [serial online] 2020 [cited 2020 Aug 12];10:69-74. Available from: http://www.ijnpnd.com/text.asp?2020/10/2/69/282291
| Introduction|| |
Parkinson’s disease (PD) has been regarded as the second most common progressive neurodegenerative disorder (NDD) affecting the human nervous system. It is characterized by a set of clinical features—both classical and atypical motor and non-motor—that can have functional impact on the patients living within various stages of PD. According to the UK Parkinson’s disease Society Brain Bank Diagnostic criteria, the three cardinal motor symptom-complex in PD patients include bradykinesia or akinesia (slowness or absence of movement) in combination with either tremor at rest and rigidity. These clinical features occur due to histopathological changes in the basal ganglia of the brain wherein there is a progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and accumulation of protein aggregates composed mainly of misfolded α–synuclein that form intra-cytoplasmic inclusions termed ‘Lewy bodies’. As of today, there are medications and surgical therapies available to relieve symptoms in these patients. However, definite preventive or neuro-protective or disease-modifying cure is the need of the hour. Hence, there is a real challenge in tackling NDDs like PD as the treatment modalities are mainly aimed at symptomatic relief, and unfortunately are not yet successful at delaying or preventing this disease in susceptible individuals.
Aging, environmental toxins, genetic mutations, chronic oxidative stress and inflammation are said to be major contributing factors for the onset and progression of NDDs including PD., Among these factors, accumulated oxidative stress has largely been considered a major factor in causing PD. Physiologically, in the substantia nigra (SN) of the normal brain, the energy-metabolism ratio of dopaminergic neurons is high. Hence, dopaminergic neurons are usually at relatively high levels of basal oxidative stress. Neuronal cells are considered hypersensitive to oxidative stress and ROS-induced damage due to their high energy demand and their comparatively higher rate of oxygen consumption. Neuronal damage and death is further exacerbated due to their low regenerative capacity and post-mitotic nature. Even at rest, the brain utilizes about 20% of the total oxygen compared to that of total body consumption leading to the abundant generation of reactive oxygen species (ROS), and being low in antioxidants compared to other body parts, is more prone to oxidative stress. The oxidative damage in the brain increases with age. Aging factor adds on to it by inducing a chronic basal level of inflammatory state in the brain that leads to the activation of neuro-glial cells and finally resulting in enhanced production of pro-inflammatory cytokines. These cumulative factors lead to the onset and progression of neurodegeneration in PD.
The research-based approach to the etio-pathogenesis of PD has shown that genetic and environmental risk factors induce oxidative stress, disrupted mitochondrial dynamics and neuronal excitotoxicity in the brain leading to the degeneration of the dopaminergic system in the mid-brain, causing PD. The mitochondrial membrane potential gets disrupted by the generation of protein aggregates and causes abnormal calcium (Ca2+) influx, impaired membrane respiratory enzyme activities, decreased ATP generation and the accumulation of ROS. Damaged mitochondria abnormally releases cytochrome c which in turn triggers the activation of the signaling cascades for cell-apoptosis in the neurons and the release of enzymes like caspases, resulting in neuronal cell death. The generation of free radicals then results in further cell damage through nitrosylation, oxidation, and peroxidation, to cellular organelles and macromolecules, thus aggravating neuronal damage.
Treatment of NDDs including PD mainly aims to replenish depleted dopamine with dopaminergic medications and modulate the dysfunctional circuit. Discovered in the 1960s, levo-carbidopa forms part of the main stay drug along other treatment options for PD that include dopamine agonists, monoamine oxidase B inhibitors, catechol-O-methyl transferase inhibitors and anti-cholinergics. Surgical modality like deep brain stimulation procedure is also tried in patients meeting specific criteria. However, no neuro-protective treatments are available yet and PD patients usually have poor prognosis and decline. In light of these pathologies and limited clinical treatment options, alternative or preventive therapeutics which can control the incidence, prevalence and limit the progression of PD, are searched for.
Recently, some convincing research has been published regarding the use of plant products, derivatives or phytochemicals to delay the occurrence of neuro-degeneration. There have been reports that a plant-based diet and regular use of phytochemicals and their derivatives can delay the progression of these diseases in susceptible individuals by boosting antioxidant, anti-inflammatory activity and improving mental and physical performance thereby increasing neuronal cell survival. Fruits and vegetables and by-products formed through their processing are some of the richest sources of natural antioxidants, due to the abundance of phenolic compounds such as flavonoids. A promising approach to protect the neuronal functionality comes from the evidence regarding the benefits associated with an appropriate and adequate intake of plant-based food. Extensive studies have been done worldwide looking for a product or substance that is capable of altering the disease course in NDDs. In this regard, the apple is a rich source of bioactive phytochemicals that help improve health by preventing and/or curing many diseases. Apples (Malus sp., Rosaceae) are one of the most widely and abundantly cultivated and consumed fruits worldwide. They form a major part of human diet and are one of the top five fruits consumed in the world. Apples have been identified as an important dietetic source of polyphenols, though there is difference in concentration of these molecules between different apple varieties.
Apples are rich in phloridzin, a dihydrochalcone (bicylic flavonoid). Phloridzin has been widely studied and used in research for its hypoglycemic, antioxidant, anti-inflammatory and anti-cancerous activities in a wide array of preclinical studies. Phloridzin is also called phlorhizin, phlorizin, phlorrhizin, or phlorizoside. When hydrolyzed by the intestinal lactase phloridzin hydrolase, phloridzin forms its aglycone known as phloretin. Following this, it undergoes phase-II metabolism creating conjugates like glucuronides as their major derivatives.
Phloretin is β-(4-hydroxyphenyl)-1-(2’,4’,6’-trihydroxypropiophenone and phloridzin is its glucoside phloretin-2-β-D-glucose [Figure 2] and [Figure 3].
|Figure 2 Chemical structures of phloretin (R=H) and phloridzin (R=D-glucose).|
Click here to view
|Figure 3 Chemical structures of phloretin and phloridzin (phloretin-2՛-O-glucose).|
Click here to view
Phloridzin was first isolated in 1835 from the apple tree bark by De Koninck. Phloridzin has been a compound of extensive research for its multitude of in-vitro and in-vivo effects. Various studies have discussed about the effects of phloridzin on diabetes mellitus mainly aiming at glucose metabolism including its absorption and excretion.,, Unpeeled apples are a richer source of phloridzin than skin peeled ones. The phloridzin content in apple peel is 12–418 mg/kg, whereas that in apple pulp is only 4–20 mg/kg. Also, previous apple cultivars contained relatively higher amounts of phloridzin than the newer ones. Phloridzin is also a novel avenue of research on its role as the precursor in a group of anti-diabetic drugs belonging to the SGLT 1, 2 (sodium-glucose co-transporter 1, 2) inhibitors category.,,,
The polyphenols in an apple are also hydrogen donors, reducing agents, free radical scavengers and singlet oxygen quenchers and they show antioxidant activity by acting as metal ion chelators. The antioxidant potential elicited by phloretin and phloridzin  offers an additional mechanism impeding the formation of advanced glycation end products (AGEs), thus ameliorating neuronal inflammation and its consequences. Human studies have measured an increase in antioxidant activity in human serum after apple consumption (300 mL apple juice—comparable to 5 apples—single dose), which could reflect the anti-oxidant effects of phloridzin and its derivatives detected in plasma. A study showed that phloretin and phloridzin also inhibit lipid peroxidation in isolated liver hepatocyte microsomes of rats. The antioxidant protection of omega-3 PUFA and fish oil by apple skin extracts containing phloretin and phloridzin in food chemistry has also been reported., Phloridzin not only possess free radical scavenging properties, dihydrochalcones are considered to have other biological effects too.
A study by Muthuswamy et al., 2004 demonstrated the antimicrobial effects of phloridzin against various pathogenic bacteria. Phloridzin was also utilized in cancer research wherein xenograft tumor growth in athymic nude mice implanted with a variety of human cancer cells had been studied. An additional mechanism by which phloridzin and phloretin can impede the formation of advanced glycosylation end products (AGEs) and decrease intestinal inflammation has also been shown.  Mechanistically, phloridzin can form phloretin and glucose. Phloretin is also a Ca2+ channel reducer that can inhibit transport of glucose and fatty acids. Phloretin reduces glucose, fatty acids and glycerol absorption in the small intestine. Hence, phloridzin can be ameliorative in managing the dyslipidemia and hyperglycemia which are very well associated risk factors for onset and poor prognosis in PD. ,,
Possible role of phloridzin on Parkinson’s disease like conditions
There has been considerable public and scientific interest in the use of phyto-constituents for neuro-protection or to prevent neurodegenerative diseases. The proposed mechanisms by which many polyphenols mitigate the onset and progression of neurodegenerative disorders like PD include suppression of lipid peroxidation, inhibition of neuro-inflammation by reducing pro-inflammatory and pro-apoptotic mediators and modulation of gene expression changes including mitochondrial directed flavonoid therapy.
Different polyphenols have been shown to exert neuro-protective action on in vivo and in vitro models of neurological disorders. It is widely known and accepted that polyphenols and their metabolites can exert modulatory actions on proteins/enzymes through direct interaction with receptors or enzymes playing significant roles in signal transduction. Few examples of these are those involved in the lipid kinase and protein kinase signaling pathways. The different neuro-chemical mechanisms explaining the protective effects of plant polyphenols have been described mainly due to their inhibition of neuro-pathological processes,, iron chelating properties, modulation of signaling pathways related to neuronal survival and differentiation, and regulation of mitochondrial function.,,
A recent review also discussed other benefiting effects of dietary polyphenols for better cognition and brain health. Phytochemicals like phloridzin have been considered to bring about anti-parkinsonian effects through several similar mechanisms. The mechanisms of action include diminishing loss of dopaminergic neuronal cells and the depletion of the neurotransmitter dopamine, suppressing apoptosis (via the reduction of caspase-3,8 and 9, Bax/Bcl-2 and α-synuclein accumulation), modulating nuclear and cellular inflammatory signaling, reducing the expression of pro-inflammatory cytokines (IL-6, IL-1β, and NF-κB), increasing the expression of neuro-trophic factors (NTFs) and antioxidant activities. Other mechanisms by which flavonoids can be neuro-protective include their improvement in circulatory status on peripheral and cerebrovascular blood flow thereby positively influencing synaptic plasticity processes and cognition.
Experimental and epidemiological studies have clearly suggested that dietary polyphenols such as phloridzin can activate Nrf2/HO1 antioxidant pathways and down regulate PPAR, NFκB, HIF- 1, MMPs and STAT pathways. They can also act as immune response modulators by inhibiting pro-inflammatory biomarkers like, CXCL(9, 10, 11), CCR1, CCR2, CCL22, CCL17, IL(1β, 6, 17A,22), MIP1α, MIP 1β, IFN-γ and TNF- α. All of these mechanisms are put in use to combat the main pathogenic mechanisms in neurodegenerative disorders, i.e. oxidative damage, neuronal inflammation and mitochondrial damage leading to apoptosis and neuronal death [Figure 3] and [Figure 4].
Results from a population-based study suggested that patients suffering from diabetes are at 23% higher risk of PD after adjusting for the different confounding factors like age, gender, occupation, co-morbidities, drug history and associated morbidities and complications. Blood glucose levels during the post prandial state can be lowered by inhibition of digestion and decreasing the absorption of carbohydrates in the small intestine. Carbohydrate digestion in the small intestine can be reduced by inhibition of alpha-amylase and also by blocking carbohydrate absorption via SGLT1 and SGLT2 transporters, the sodium dependent sugar transporter systems., Studies have showcased the properties of phloridzin including the inhibitory effects of SGLT1 (sodium-glucose transport protein 1) and SGLT2 (sodium-glucose transport protein 2).,, Hence, phloridzin shows a promising role in improving, to a great extent, the morbidities associated with the diabetic state along with the higher risk for PD like conditions.
Aging remains the biggest risk factor for developing idiopathic PD. Studies have shown that the phloridzin in yeast has anti-aging effects. Mechanism studies revealed that phloridzin mediates life span extension in yeast via the SIR2 signaling pathways and SOD gene and an increase in SIRT1 activity, thus providing supportive evidence for future research on the anti-aging effects of phloridzin on mammalian cells and in experimental animals.
| Conclusion|| |
Current scientific research and its evidences suggest that neuro-degenerative diseases such as PD are accompanied by the accumulation of ROS and oxidative stress, neuro-inflammation and mitochondrial functional derangements. The prevention and treatment of this second most common NDD, with complex etio-pathologic mechanisms, requires novel therapeutic strategies targeting varied etio-pathologies and mechanisms involving multiple genes and proteins. Polyphenol flavanoids such as phloridzin are naturally occurring plant derivatives from apple with secondary metabolites which exhibit remarkable multi-potent ability to reduce oxidative stress and ROS, metal toxicity, inflammatory markers, apoptosis, signal transduction, modulate ion channels, and neurotransmitters. Studies showing significant anti-diabetic and anti-aging effects of phloridzin give promise to the potential role of this flavanoid polyphenol in mitigating the onset and progression of PD.
However, future research on this novel therapeutic agent combating PD needs to aim towards clinical acceptance directed at pre-clinical, in vitro and in vivo models. It would also be essential for research to focus on human clinical trials of this potent polyphenol and its derivatives in PD should be carried out after finding out the effect on pre-clinical studies. Furthermore, phloridzin must be investigated for risk assessment and safety evaluation to observe any undesirable effects. Aside from this, research in this field would still remain incomplete without studying the pharmacological interactions between anti- parkinsonian drugs and flavonoid supplements. Hence, many questions remain unanswered, especially regarding the translation of findings from in-vitro studies to in-vivo application in order to clearly associate phloridzin with improvements in neurological well-being and health.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Wirdefeldt K, Adami H-O, Cole P et al.
1.Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol 2011;6:S1-58.
Hughes AJ, Daniel SE, Kilford L LA. UK Parkinson’s disease society Brain Bank Clinical Diagnostic criteria Accuracy of clinical diagnosis of idiopathic Parkinson’s disease. A clinico-pathological study of 100 cases. JNNP 1992;55181-4.
Thomas B. Parkinson’s disease: from molecular pathways in disease to therapeutic approaches. Antioxid Redox Signal 2009;11:2077-82.
Rizek P, Kumar N. An update on the diagnosis and treatment of Parkinson disease. C 2016 DOI101503 /cmaj15117. 2016;188(16):1157-65.
Belarbi K, Cuvelier E, Destée A, Gressier B, Chartier-Harlin MC. NADPH oxidases in Parkinson’s disease: a systematic review. Mol Neurodegener 2017;12:1-18.
Jin H, Kanthasamy A, Ghosh A, Anantharam V, Kalyanaraman B, Kanthasamy AG. of Parkinson’s Disease: preclinical and clinical. Biochim Biophys Acta 2014;1842:1282-94.
Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Current Neuropharmacology 2009;7:65-74. doi:10.2174/157015909787602823
Nilsson MI, Tarnopolsky MA. Mitochondria and aging—the role of exercise as a countermeasure. Biology (Basel) 2019;8:40.
Barreto GE, Iarkov A, Moran VE. Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson’s disease. Front Aging Neurosci 2015;7:1-13.
Magalingam KB, Radhakrishnan AK, Haleagrahara N. Protective mechanisms of flavonoids in Parkinson’s Disease. Oxid Med Cell Longev 2015;2015:1-14.
Figueira I, Menezes R, Macedo D, Costa I, dos Santos CN. Polyphenols beyond barriers: a glimpse into the brain. Curr Neuropharmacol 2016;15:562-94.
Barreto GE, Guedes RCA. Polyphenols and neurodegenerative diseases. Nutr Neurosci 2012;15:92-3.
Zielinska D, Laparra-Llopis JM, Zielinski H, Szawara-Nowak D, Giménez-Bastida JA. Role of apple phytochemicals, phloretin and phloridzin, in modulating processes related to intestinal inflammation. Nutrients 2019;11:1173. Available from: https://www.mdpi.com/2072-6643/11/5/1173
Hertog MG, Hollman PCH, Katan MB. Content of potentially anticarcinogenic flavonoids of 28 vegetables and 9 fruits commonly consumed in the Netherlands. J Agric Food Chem 1992;12:2379-83.
Rupasinghe HPV, Yasmin A. Inhibition of oxidation of aqueous emulsions of Omega-3 fatty acids and fish oil by phloretin and phloridzin. Molecules 2010;15:251-7.
Gosch C, Halbwirth H, Stich K. Phloridzin: biosynthesis, distribution and physiological relevance in plants. Phytochemistry 2010;71:838-43.
Ehrenkranz JRL, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev 2005;21:31-8.
Masumoto S, Akimoto Y, Oike H, Kobori M. Dietary phloridzin reduces blood glucose levels and reverses Sglt1 expression in the small intestine in streptozotocin-induced diabetic mice. J Agric Food Chem 2009;57:4651-6.
Kschonsek J, Wolfram T, Stöckl A, Böhm V. Polyphenolic compounds analysis of old and new apple cultivars and contribution of polyphenolic profile to the in vitro antioxidant capacity. Antioxidants 2018;7.
Choi CI. Sodium-glucose cotransporter 2 (SGLT2) inhibitors from natural products: discovery of next-generation antihyperglycemic agents. Molecules 2016;21:1136.
Gulcin I. Antioxidant activity of food constituents: an overview. Arch Toxicol 2012;86:345-91.
Li X, Chen B, Xie H, He Y, Zhong D, Chen D. Antioxidant structure(−)activity relationship analysis of five dihydrochalcones. Molecules 2018;23:1162.
Vieira FGK, Di Pietro PF, da Silva EL, Borges GSC, Nunes EC, Fett R. Improvement of serum antioxidant status in humans after the acute intake of apple juices. Nutr Res 2012;32:229-32.
De Oliveira MR. Phloretin-induced cytoprotective effects on mammalian cells: a mechanistic view and future directions. Biofactors 2016;42:13-40.
Rezk BM, Haenen RMM, Vijgh WJF, Bast A. The antioxidant activity of phloretin; the disclosure of a new antioxidant pharmacophore in flavonoids. Biochem Biophys Res Comun 2002;295:9-13.
Rupasinghe HPV, Erkan N, Yasmin A. Antioxidant protection of eicosapentaenoic acid and fish oil oxidation by polyphenolic-enriched apple skin extract. 2010. J Agric Food Chem 2010
Mathiesen L, Malterud KE, Sund RB. Hydrogen bond formation as basis for radical scavenging activity: a structure-activity study of C-methylated dihydrochalcones from Myrica gale and structurally related acetophenones. Free Rad Biol 1997;22:307-11.
Calliste C, Bail JL, Trouillas P, Pouget C, Habrioux G, Chulia A, Duroux J. Chalcones: structural requirements for antioxidant estrogenic and antiproliferative activities. Anticancer Res 2001;21.
Muthuswamy S, Rupasinghe HPV. Fruit phenolics as natural antimicrobial agents: Selective antimicrobial activity of catechin, chlorogenic acid and phloridzin. J Food Agric Environ 2007;5.
Lu L, Fu DL, Li HQ, Liu AJ, Li JH, Zheng GQ. Diabetes and risk of Parkinson’s disease: an updated meta-analysis of case-control studies. PLoS One 2014;9.
Huang X, Auinger P, Eberly S, Oakes D, Schwarzschild M, Ascherio A et al.
Serum cholesterol and the progression of Parkinson’s disease: results from DATATOP. PLoS One 2011;6.
Riaz N, Wolden SL, Gelblum DY, Eric J. HHS Public Access 2016;118:6072-8.
Bhullar KS, Rupasinghe HPV. Polyphenols: multipotent therapeutic agents in neurodegenerative diseases. Oxid Med Cell Longev 2013;2013:1-18.
Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med 2004;36:838-49.
Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, Ehrhart J, Townsend K, Zeng J, Morgan D, Hardy J, Town T, Tan J. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci 2005;25:8807-14.
Wang J, Ho L, Zhao W, Ono K, Rosensweig C, Chen L, Humala N, Teplow DB, Pasinetti GM. Grape-derived polyphenolics prevent Abeta oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimers disease. J Neurosci 2008;28. Available from: http://dx.doi.org/10.1523/JNEUROSCI
. 0364-08.2008] [PMID: 18562609
Griffioen G, Duhamel H, Van Damme N, Pellens K, Zabrocki P, Pannecouque C, van Leuven F, Winderickx J, Wera S. A yeast-based model of α-synucleinopathy identifies compounds with therapeutic potential. Biochim Biophys Acta 2006;1762:312-8.
Spencer JP. Beyond antioxidants: the cellular and molecular interactions of flavonoids and how these underpin their actions on the brain. Proc Nutr Soc 2010;69:244-60.
Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF- kappa B activation. Mutat Res 2001;480-481:243-68.
Skupień K, Oszmiański J, Kostrzewa-Nowak D, Tarasiuk J. In vitro antileukaemic activity of extracts from berry plant leaves against sensitive and multidrug resistant HL60 cells. Cancer Lett 2006;236:282-91. Available from: http://dx.doi.org/10.1016/j.canlet.2005.%0A05.018
] [PMID: 16039042
Yang YW, Hsieh TF, Li CI, Liu CS, Lin WY, Chiang JH et al.
Increased risk of Parkinson disease with diabetes mellitus in a population-based study. Med (United States) 2017;96.
Najafian M, Ebrahim-Habibi A, Hezareh N et al.
Trans-chalcone: a novel small molecule inhibitor of mammalian alpha-amylase. Mol Biol Rep 2011;38:1717. Available from: https://doi.org/10.1007/s11033-010-0271-3
Lo Piparo E, Scheib H, Frei N, Williamson G, Grigorov M CC. Flavonoids for controlling starch digestion: structural requirements for inhibiting human a-amylase. J Med Chem 2008;51:3555-61.
Pajor AM, Randolph KM, Kerner SA SC. Inhibitor binding in the human renal low- and high-affinity Na?/glucose cotransporters. J Pharmacol Exp Ther 2008;324:985-91.
Tyagi NK, Kumar A, Goyal P, Pandey D, Siess W KR. D-Glucose recognition and phlorizin-binding sites in human sodium/D-glucose cotransporter 1 (hSGLT1): a tryptophan scanning study. Biochemistry 2007;46:13616-28.
Xiang l, Sun K, Lu J, Weng Y, Taoka A Sakagami. Anti-aging effects of phloridzin, an Apple Polyphenol, on Yeast via the SOD and Sir2 Genes. Biosci Biotechnol Biochem 2011;75:854-8.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]