**Background**
Inflammatory diseases, such as rheumatoid arthritis (RA) and allergic airway inflammation, are characterized by chronic immune activation and tissue damage, posing significant challenges to clinical management. Simultaneously, metabolic disorders involving glucose transport and adipogenesis are closely linked to systemic inflammation. Sodium/glucose cotransporters (SGLT1 and SGLT2) and glucose transporters (GLUT1) play critical roles in maintaining glucose homeostasis in the intestine, kidney, and erythrocytes. Targeting these transporters and the associated inflammatory pathways provides a promising strategy for treating both metabolic and autoimmune conditions. In this context, we will introduce a flavonoid with potent anti-inflammatory and glucose-inhibiting properties – Phloretin.
**Definition**
Phloretin is a flavonoid extracted from Malus pumila Mill. that acts as a competitive inhibitor of SGLT1 and SGLT2, as well as an inhibitor of GLUT1 with IC50 values of 49 μM (yeast-made) and 61 μM (human erythrocyte).
**In Vitro and In Vivo Studies**
According to the Phloretin description, this compound exhibits diverse biological activities across various cell lines and animal models. In terms of Phloretin in vitro activity, it demonstrates significant cytotoxicity against BEL-7402 cells with an IC50 of 89.23 μM. Treatment with 40-160 μM Phloretin for 24 hours induces apoptosis in BEL-7402 cells via the mitochondrial pathway, characterized by nuclear chromatin condensation and the sequential activation of caspase-9 (peak at 12 h), caspase-6 (18 h), and caspase-3 (24 h). Furthermore, in differentiated 3T3-L1 adipocytes, Phloretin (0-100 μM; 24 hours) inhibits adipogenesis by decreasing the expression of PPAR-γ, C/EBPα, and C/EBPβ in a dose-dependent manner, while upregulating the phosphorylation of AMPK and its substrate ACC-1. Additionally, it inhibits NF-kappaB transactivation in TNF-alpha-stimulated human K562 cells with an IC50 of 41 μM.
Regarding Phloretin in vivo efficacy, studies using Collagen-Induced Arthritis (CIA) mice showed that oral administration of Phloretin (50 or 100 mg/kg; once daily) mitigated clinical symptoms of RA and reduced hind-limb inflammation. This effect was associated with decreased oxidative stress, diminished levels of malondialdehyde (MDA) and hydrogen peroxide in paw tissue, and reduced production of anti-collagen antibodies in serum. In conclusion, Phloretin is a multi-target flavonoid that holds potential for the treatment of rheumatoid arthritis, metabolic disorders, and certain cancer cell lines.
Keywords
Phloretin, 60-82-2, NSC 407292, RJC 02792, NSC407292, NSC-407292, RJC02792, RJC-02792, SGLT, Endogenous Metabolite, GLUT, Sodium-dependent glucose cotransporters, Glucose transporter, Inhibitor, inhibitor, inhibit
References
[1] Kasahara T, Kasahara M. Expression of the rat GLUT1 glucose transporter in the yeast Saccharomyces cerevisiae. Biochem J. 1996 Apr 1;315 ( Pt 1):177-82.
[2] Luo H, et al. Phloretin induces apoptosis of BEL-7402 cells in vitro. Nan Fang Yi Ke Da Xue Xue Bao. 2008 Jul;28(7):1249-51.
[3] Huang WC, et al. Phloretin and phlorizin promote lipolysis and inhibit inflammation in mouse 3T3-L1 cells and in macrophage-adipocyte co-cultures.Mol Nutr Food Res. 2013 Oct;57(10):1803-13.
[4] Wang SP, et al. Potent Antiarthritic Properties of Phloretin in Murine Collagen-Induced Arthritis.Evid Based Complement Alternat Med. 2016;2016:9831263.