Myricetin Attenuated Diabetes-Associated Kidney Injuries and Dysfunction via Regulating Nuclear Factor (Erythroid Derived 2)-Like 2 and Nuclear Factor-κB Signaling

Abstract

Background/Aims: Previous studies have suggested that myricetin (Myr) could promote the expression and nuclear translocation of nuclear factor (erythroid-derived 2)-like (Nrf2). This study aimed to investigate whether Myr could attenuate diabetes-associated kidney injuries and dysfunction in wild-type (WT) and Nrf2 knockdown (Nrf2-KD) mice. Methods: Lentivirus-mediated Nrf2-KD and WT mice were used to establish type 1 diabetes mellitus (DM) by streptozotocin (STZ) injection. WT and Nrf2-KD mice were then randomly allocated into four groups: control (CON), Myr, STZ, and STZ + Myr. Myr (100 mg/kg/day) or vehicle was administered for 6 months. Kidneys were harvested and weighed at the end of the experiment. Hematoxylin and eosin staining and Masson’s trichrome staining were used to assess the morphology and fibrosis of the kidneys, respectively. Urinary albumin-to-creatinine ratio was used to test renal function. Western blotting was performed to determine oxidative-stress- or inflammation-associated signaling pathways. Real-time polymerase chain reaction (RT-PCR) was performed to detect the expression of fibrosis or inflammatory cytokines at the message Ribonucleic Acid (mRNA) level. Results: In WT mice, Myr alleviated DM-induced renal dysfunction, fibrosis, and oxidative damage and enhanced the expression of Nrf2 and its downstream genes. After knockdown of Nrf2, Myr treatment partially but significantly mitigated DM-induced renal dysfunction and fibrosis, which might be associated with inhibition of the I-kappa-B (IκB)/nuclear factor-κB (NF-κB) (P65) signaling pathway. Conclusions: This study showed that Myr prevented DM-associated decreased expression of Nrf2 and inhibited IκB/NF-κB (P65) signaling pathway. Moreover, inhibition of IκB/NF-κB (P65) signaling pathway is independent of the regulation of Nrf2. Thus, Myr could be a potential treatment for preventing the development and progression of DM-associated kidney injuries and dysfunction.

Myricetin Modulates Macrophage Polarization and Mitigates Liver Inflammation and Fibrosis in a Murine Model of Nonalcoholic Steatohepatitis

“…Of note, our results further revealed that myricetin led to inhibiting LPS-induced TREM-1-mediated inflammatory response via downregulation of NF-κB activation and reducing the phosphorylation of STAT3 and JNK expression as shown by our western blotting (Figure 8). These findings were consistent with previous studies exhibiting that myricetin attenuated inflammatory response in LPS-induced macrophages in vitro and in streptozotocin-induced diabetic nephropathy by inhibiting NF-κB signaling pathways (28,37).…”

“…Group B or C: mice were fed CDAHFD with orally administration myricetin at 100 mg/kg per day or vehicle ( Figure 1B). The doses of myricetin were chosen based on previous studies in mice (28,32,37). At the end of treatment period, mice were euthanized using ketamine/xylazine, blood samples were collected via cardiac puncture to detect biochemical biomarkers.…”

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

“…Treatment with Nrf2 activators, tert-butylhydroquinone (TBHQ) [293], bardoxolone methyl analog [294], or sulforaphane [295], reduced expression of proinflammatory cytokines and macrophage infiltration in preclinical models of DN. Furthermore, other compounds with the ability to promote Nrf2 translocation, such as omentin-1, and natural flavonoids (myricetin, hesperetin, and curcumin), improve renal function and reduces proinflammatory cytokine production in DN [296][297][298][299]. Particularly, dietary supplementation with curcumin increased the antioxidant capacity, reduced microalbuminuria and plasma MDA levels of patients with DN [300,301].…”

Myricetin bioactive effects: moving from preclinical evidence to potential clinical applications

“…Myricetin exhibited antioxidant properties and free radical-scavenging effects [19]. These activities seem to support a wide range of beneficial outcomes including, anti-platelet aggregation, antihypertensive, immunomodulatory, anti-inflammatory, anti-allergic, analgesic, anticancer actions and so on [6,[20][21][22][23][24][25]. The main goal of the present review is to provide new insights on myricetin preclinical pharmacological activities, and its role in selected clinical trials.…”