Nobiletin exerts anti-diabetic and anti-inflammatory effects in anin vitrohuman model andin vivomurine model of gestational diabetes

Abstract

Gestational diabetes mellitus (GDM) is a global health issue, whereby pregnant women are afflicted with carbohydrate intolerance with first onset during pregnancy. GDM is characterized by maternal peripheral insulin resistance, thought to be driven by low-grade maternal inflammation. Nobiletin, a polymethoxylated flavonoid, possesses potent glucose-sensitizing and anti-inflammatory properties; however, its effects in GDM have not been assessed. The present study aimed to determine the effects of nobiletin on glucose metabolism and inflammation associated with GDM in both in vitro human tissues and an in vivo animal model of GDM. In vitro, treatment with nobiletin significantly improved TNF-impaired glucose uptake in human skeletal muscle, and suppressed mRNA expression and protein secretion of pro-inflammatory cytokines and chemokines in human placenta and visceral adipose tissue (VAT). Mechanistically, nobiletin significantly inhibited Akt and Erk activation in placenta, and NF-κB activation in VAT. In vivo, GDM mice treated with 50 mg/kg nobiletin daily via oral gavage from gestational day (gd) 1-17 or via i.p. injections from gd 10-17 significantly improved glucose tolerance. Pregnant GDM mice treated with nobiletin from either gd 1-17 or gd 10-17 exhibited significantly suppressed mRNA expression of pro-inflammatory cytokines and chemokines in placenta, VAT and subcutaneous adipose tissue (SAT). Using a quantitative mass spectrometry approach, we identified differentially abundant proteins associated with the effect of nobiletin in vivo. Together, these studies demonstrate that nobiletin improves glucose metabolism and reduces inflammation associated with GDM and may be a novel therapeutic for the prevention of GDM.

Chemical Profile of Launaea nudicaulis Ethanolic Extract and Its Antidiabetic Effect in Streptozotocin-Induced Rats

“…Nobiletin, a hexamethoxyflavone, demonstrated antidiabetic and anti-inflammatory activities [82]. Moreover, tangeretin, a pentamethoxyflavone, improves secretion of insulin and decreases blood glucose via stimulating glucose uptake [83].…”

Nobiletin in Cancer Therapy: How This Plant Derived-Natural Compound Targets Various Oncogene and Onco-Suppressor Pathways

“…It is held that inflammatory factors participate in glucose uptake interference [59]. The administration of NOB (50 mg/kg) remarkably improves glucose resistance by inhibition of the NF-κB signaling pathway, as a factor involved in inflammation to suppress tumor necrosis factor (TNF)-mediated glucose uptake disruption [60]. Although iron is a vital element for physiological processes such as hemoglobin synthesis and DNA replication [61], increasing evidence shows that iron overload is associated with the elevated generation of reactive oxygen species (ROS) that, in turn, induce cell and tissue damages [62][63][64][65][66][67][68].…”

Beneficial Effects of Citrus-Derived Polymethoxylated Flavones for Central Nervous System Disorders

“…Because of their anti-inflammatory and antioxidant effects, these citrus-derived PMFs have the potential to prevent neurodegenerative and neurological disorders [ 21 , 22 , 23 , 24 , 25 , 26 ]. In addition, these PMFs have shown beneficial effects against hyperlipidemia [ 27 , 28 ], obesity [ 29 , 30 ], diabetes [ 31 , 32 ], cardiovascular dysfunction [ 33 , 34 ], and cancer [ 35 , 36 , 37 ]. In this study, we focus on the neuroprotective and ameliorative effects of citrus-derived PMFs, nobiletin, tangeretin, and HMF, against central nervous system dysfunction in several rat and murine models of central nervous system disorders and related diseases as well as their mechanisms of action.…”