Therapeutic Potential and Pharmaceutical Development of a Multitargeted Flavonoid Phloretin
Abstract
:1. Introduction
2. Extraction, Purification, and Characterization of Phloretin
3. Development of Analogs of Phloretin for the Improvement of Bioavailability
4. Pharmacokinetics of Phloretin
5. Physicochemical and Pharmaceutical Characteristics of Phloretin
6. Pharmacological Potentials and Molecular Mechanisms of Phloretin
6.1. Anticancer Activity
6.2. Antidiabetic Activity
6.3. Antiobesity Activity
6.4. Cardiovascular Protective Activity
6.5. Hepatoprotective Activity
6.6. Anti-Inflammatory and Antioxidant Activities
6.7. Neuroprotective Activity
6.8. Immunosuppressant Activity
6.9. Antimicrobial Activity
SN | Activity | Mechanism | Reference |
---|---|---|---|
1. | Anticancer | ||
| Reduced LC3B-II expression in low-glucose and glucose-free media; Reversed doxorubicin- and tamoxifen-induced cytoprotective autophagy; Downregulated mTOR/ULK1 signaling; Facilitated apoptosis through Bcl2 and Bax; Downregulated PI3K/Akt/mTOR signaling | [3,10] | |
| ROS mediated cell death; Arrested cell cycle in G0-G1 phase; Reduced expression of cyclin D1, CDK4, and CDK6 | [4] | |
| Arrested cell cycle in G2/M phase; Reduced p-JNK and p38 expression | [5] | |
| Arrested cell cycle in G0-G1 phase; Increased p27 expression; Decreased cdk2, cdk4, cdk6, cyclin D, and cyclin E expressions; Inhibited PI3K/AKT/mTOR signaling; Induced mitochondrial apoptosis pathways; Increased ROS production; Down-regulated Bcl-2; Up-regulated Bax, Bak, and c-PARP | [8] | |
| Increased activity of p53; Increased levels of Bax; Decreased levels of Bcl-2 | [6,125] | |
| Decreased Bcl-2 expression; Increased cleaved-caspase-3 and -9 protein expression; Deregulated MMP-2 and -9 gene expression and protein levels | [6,7] | |
| Increased HSP70 penetration efficacy; Potentiated antitumor activity of HSP70 | [6,126] | |
| Potentiated anticancer effect of paclitaxel | [6,127] | |
| Marked anticancer activity | [6,9,64] | |
2. | Antidiabetic | Inhibited intestinal SGLT1 and GLUT2 to reduce glucose absorption | [11,12] |
Inhibited renal SGLT2 to reduce renal tubular reabsorption of glucose, and thus increased urinary excretion of glucose | [13,14] | ||
Activated PI3K/AKT signaling cascade by GLUT4 translocation and expression to improve glucose consumption and tolerance in type 2 diabetes | [15] | ||
Inhibited production of AGEs and suppressed receptor expression for AGEs by Nrf2-dependant pathway and mitigated HFD-induced diabetes in C57BL/6 mice | [94] | ||
Preserved nephrin and podocin contents to protect podocytes in diabetic nephropathy | [16] | ||
3. | Antiobesity | Inhibited adipogenicity by stimulating beta-catenin and adipocytes apoptosis; Stimulated phloretin OPG gene expression and OPG/RANKL ratio in adipocytes | [99] |
Blocked weight gain induced by high-fat diet feeding; Reduced hepatic lipid accumulation; Reduced expression of macrophage markers and pro-inflammatory genes and increased adiponectin gene in white adipose tissue; Increased fatty acid oxidation genes expression and reduced expression of lipogenesis transcriptional factor | [96] | ||
4. | Cardioprotective | Reduced the activation of platelets and TNF-induced expression of endothelial adhesion molecules in HUVECs | [17] |
Protected against hydrogen peroxide-induced apoptosis in primary culture by inhibiting the chloride ion channels; Inhibited uric acid-induced pro-inflammatory factors, p-NF-κB/p-ERK levels, and nuclear translocation of NF-κΒ p65, and improved endothelial tube formation in TNF-treated HUVECs | [18,19] | ||
Protected myocardium against doxorubicin-triggered injury; Attenuated doxorubicin-produced oxidative stress and decreased nitric oxide contents in heart tissue; Prevented doxorubicin-triggered changes in hemodynamic parameters; Decreased pro-inflammatory cytokines, and plasma myocardial injury markers such as CK-MB, LDH, AST and ALT | [104] | ||
Protected against hyperglycemia-triggered injury in diabetic cardiomyopathy by reducing fibrosis via restoring sirtuin 1 expression | [20] | ||
Decreased hyperglycemia by inhibiting SGLT2 in the kidney and consequently prevented the development of hypertension | [14] | ||
5. | Hepatoprotective | Protected against acetaminophen, CCl4, and D-galactosamine-induced acute liver damage; Decreased levels of ALT, AST, GGT, ALP, and total bilirubin levels; Alleviated oxidative stress and lipid peroxidation in liver tissue | [21,22,23] |
6. | Anti-inflammatory | Activated Nrf2 signaling to decrease the release of IL-8 triggered by LPS and thereby produced anti-inflammatory effect in retinal pigment epithelium (ARPE-19 cells); Inhibited the glucose uptake in ARPE-19 cells | [28] |
Suppressed neuroinflammation in experimental autoimmune encephalomyelitis model via activation of Nrf2 signaling in macrophages, attributed to AMPK-dependent activation of autophagy and consequent degradation of Keap1 | [24] | ||
Reduced levels of BUN, UACR, tubular necrosis, ECM deposition, and interstitial fibroblasts in mice with hyperuricemia-induced renal dysfunction; Reduced renal inflammatory cells infiltration, cytokines (NLRP3 and IL-1β), mitochondrial ROS, and morphological lesions; Inhibited renal GLUT9 and promoted urinary uric acid excretion | [111] | ||
Inhibited Propionibacterium acnes-induced TLR2-mediated inflammatory signaling in human keratinocytes | [25] | ||
Improved histopathological changes in the colon of mice with dextran sulfate sodium-induced ulcerative colitis; Inhibited TNF-α, IL-1β, IL-12 IL-17A and IFN-γ levels; Activation of NF-κB pathway, increased TLR4 expression, and reduced PPARγ expression in ulcerative colitis were restored; Escherichia coli and Lactobacillus levels were re-balanced | [2] | ||
Reduced inflammation, eosinophil infiltration, Th2 cytokine production, and oxidative stress in ovalbumin-induced asthmatic mice | [26] | ||
Reduced formation of inflammatory cytokines (TNF, IL-6, IL-1, and IL-17) in collagen-induced arthritic mice | [27] | ||
7. | Antioxidant | Antioxidant action in DPPH and ABTS assay | [29] |
Reduced the matrix MMP-1, tyrosinase, and elastase activity due to its dihydrochalcone structure | [30,31] | ||
Augmented antioxidant defense mechanisms by phlorizin (glycone of phloretin) to ameliorate LPS-induced cognitive deficit, and diabetes-induced depression, memory impairment, delayed wound healing, and peripheral neuropathy | [32,33,34,35] | ||
8. | Neuroprotective | ||
a. Alzheimer’s disease | Improved learning and memory performance of animals with Alzheimer’s disease-like condition induced by scopolamine and amyloid β; Inhibited activity of acetylcholinesterase; Increased BDNF levels;Decreased oxidative stress by enhancing activities of GSH, SOD and CAT, and decreasing levels of MDA; Decreased TNF-α-triggered neuroinflammation; Reduced accumulation of amyloid-β in the CA1 hippocampal region and number of pyknotic nuclei in the hippocampal DG;Exhibited protective effect on the synaptophysin; Increased count of Ki67- and doublecortin in the DG; No change in PSD-95 levels | [120,121,122] | |
b. Parkinson’s disease | Improved motor performance of animals with Parkinson’s disease-like condition induced by MPTP; Increased dopamine levels and tyrosine hydroxylase enzyme expression; Suppressed neuroinflammation: reduced expression of GFAP, iba1, iNOS and COX2; Reduced levels of proinflammatory cytokines (IL-β, IL-6, and TNF-α) | [123] | |
9. | Immunosuppressant | Suppressed proliferation of T lymphocytes and expression of CD69 and CD25, and arrested cell cycle in G0/G1 phase | [36] |
10. | Antimicrobial | Suppressed production of Escherichia coli O157:H7 biofilm and reduced colon inflammation without causing harm to the beneficial commensal Escherichia coli biofilms | [37] |
Inhibited Mycobacterium tuberculosis by reducing the expression of inflammatory molecules such as ILs and TNF-α | [38] | ||
Inhibited Staphylococcus aureus, Listeria monocytogenes, methicillin-resistant Staphylococcus aureus clinical strains, and Salmonella typhimurium | [39] | ||
Inhibited Listeria monocytogenes | [40,41] | ||
Decreased Salmonella typhimurium bacterial load of infected mice | [42] | ||
Inhibited Candida albicans without inducing any tissue necrosis in mouse model of oral candidiasis | [124] | ||
Inhibited plant pathogenic fungi Phytophthora capsici, Alternaria panax, Sclerotinia sclerotiorum, Rhizoctonia solani AG4, and Magnaporthe grisea on rice and tomato seedlings | [62] |
7. Safety and Adverse Effects of Phloretin
8. Pharmaceutical Development of Phloretin
9. Conclusion and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Plant Part | Extraction Method | Extraction Solvent | Analytical Technique | Reference |
---|---|---|---|---|
Apple fruits | Solvent extraction | Methanol, n-hexane, CHCl3, ethyl acetate | HPLC-NMR | [62] |
Apple leaves | Homogenization, centrifugation | Methanol, acetone | HPLC | [63] |
Apple leaves | Solvent extraction | Ethanol, water | HPLC | [64] |
Apple leaves | Ultrasound | Ethanol, water | LCMS | [65] |
Apple leaves, bark, and buds | Centrifugation and sonication | Methanol, formic acid | HPLC-DAD | [66] |
Apple peel, flesh, and leaves | Solvent extraction | Methanol, water | UPLC-DAD-HESI-MS | [67] |
Apple pomace | Solvent extraction | Acetone, methanol, ethanol, ethyl acetate | RP-HPLC-DAD | [68] |
Apple pomace | Solvent extraction | Acetone, methanol, ethanol, CHCl3, ethyl acetate | HPLC-DAD | [69] |
Apple pulp and peel | Solvent extraction | Methanol | HPLC-NMR-MS | [70] |
Apple pulp and peel | Solvent extraction and sonication | Methanol (1% HCl) | HPLC | [71] |
Apple tree bark | Solvent extraction | Ethanol, ethyl acetate | HSCCC | [72] |
Strawberry fruits | Homogenization, solvent extraction | Acetone, ethyl acetate, methanol | HPLC−PDA−MS/MS and NMR | [73] |
Strawberry fruits | Centrifugation, solvent extraction | Methanol (HCl:Water, 50:50) | UPLC−PDA−MS/MS and NMR | [74] |
Strawberry fruits | Solvent extraction | Acetone, water | UPLC−MS/MS | [75] |
Strawberry pomace | Solvent extraction | Water, ethanol | HPLC-DAD | [76] |
Particulars | Data | Reference |
---|---|---|
Molecular structure and other details | [77] | |
Molecular formula: C15H14O5 | ||
Synonyms: dihydronaringenin, phloretol | ||
Color: pearl white powder | ||
Melting point: 263.5 °C | ||
Molecular weight: 274.27 | ||
Solubility: slightly soluble in water, sparingly soluble in methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, butan-2-ol, pentan-1-ol, hexan-1-ol, ethyl acetate, butyl acetate, and 1,4-dioxane and DMSO | [78] | |
Spectroscopic analysis | UV-Visible: λ = 225, 282.8, 369 | [67,68] |
1H NMR: δ: 2.86 (2H, t, J = 7.6 Hz, H-β), 3.20 (2H, t, J = 7.6 Hz, H-α), 5.80 (2H, s, H-3′, 5′), 6.65 (2H, d, J = 8.5 Hz, H-3, 5), 7.00 (2H, d, J = 8.5 Hz, H-2,6) | [62,64] | |
13C NMR: 132.6, 128.93, 114.7, 155.03, 114.7, 128.93, 103.91, 164.74, 94.34, 164.44, 94.34, 164.74, 45.93, 30.09, 205 | [64] |
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Nakhate, K.T.; Badwaik, H.; Choudhary, R.; Sakure, K.; Agrawal, Y.O.; Sharma, C.; Ojha, S.; Goyal, S.N. Therapeutic Potential and Pharmaceutical Development of a Multitargeted Flavonoid Phloretin. Nutrients 2022, 14, 3638. https://doi.org/10.3390/nu14173638
Nakhate KT, Badwaik H, Choudhary R, Sakure K, Agrawal YO, Sharma C, Ojha S, Goyal SN. Therapeutic Potential and Pharmaceutical Development of a Multitargeted Flavonoid Phloretin. Nutrients. 2022; 14(17):3638. https://doi.org/10.3390/nu14173638
Chicago/Turabian StyleNakhate, Kartik T., Hemant Badwaik, Rajesh Choudhary, Kalyani Sakure, Yogeeta O. Agrawal, Charu Sharma, Shreesh Ojha, and Sameer N. Goyal. 2022. "Therapeutic Potential and Pharmaceutical Development of a Multitargeted Flavonoid Phloretin" Nutrients 14, no. 17: 3638. https://doi.org/10.3390/nu14173638