Antioxidant and Antineuroinflammatory Mechanisms of Kaempferol-3-O-β-d-Glucuronate on Lipopolysaccharide-Stimulated BV2 Microglial Cells through the Nrf2/HO-1 Signaling Cascade and MAPK/NF-κB Pathway

Abstract

Aglycone-and glycoside-derived forms of flavonoids exist broadly in plants and foods such as fruits, vegetables, and peanuts. However, most studies focus on the bioavailability of flavonoid aglycone rather than its glycosylated form. Kaempferol-3-O-β-D-glucuronate (K3G) is a natural flavonoid glycoside obtained from various plants that have several biological activities, including antioxidant and anti-inflammatory effects. However, the molecular mechanism related to the antioxidant and antineuroinflammatory activity of K3G has not yet been demonstrated. The present study was designed to demonstrate the antioxidant and antineuroinflammatory effect of K3G against lipopolysaccharide (LPS)stimulated BV2 microglial cells and to evaluate the underlying mechanism. Cell viability was determined by MTT assay. The inhibition rate of reactive oxygen species (ROS) and the production of pro-inflammatory mediators and cytokines were measured by DCF-DA assay, Griess assay, enzyme-linked immunosorbent assay (ELISA), and western blotting. K3G inhibited the LPS-induced release of nitric oxide, interleukin (IL)-6, and tumor necrosis factor-α (TNF-α) as well as the expression of prostaglandin E synthase 2. Additionally, K3G reduced the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor-kappa B (NF-κB) related proteins. Mechanistic studies found that K3G downregulated phosphorylated mitogen-activated protein kinases (MAPKs) and upregulated the Nrf2/HO-1 signaling cascade. In this study, we demonstrated the effects of K3G on antineuroinflammation by inactivating phosphorylation of MPAKs and on antioxidants by upregulating the Nrf2/HO-1 signaling pathway through decreasing ROS in LPS-stimulated BV2 cells.

Antioxidant, anti-inflammatory, and anti-reprotoxic effects of kaempferol and vitamin E on lead acetate-induced testicular toxicity in male rats

“…Importantly, the impacts of kaempferol have not yet been completely identified on the reproductive system. Current results revealed that the administration of kaempferol following exposure to lead caused elevation in the levels of CAT, GPx, and SOD, whereas MDA and NO were reduced relative to their levels in rats treated with vitamin E and/or lead only; this may be attributed to the antioxidant ability of kaempferol to suppress the activities of pro-oxidant enzymes such as xanthine oxidase that responsible for generating ROS ( Lim et al , 2023 ). Kaempferol, like other flavonoids, can chelate with cuprous or ferrous ions in Fenton’s reaction, ultimately leading to prevent lipid peroxidation of cytomembrane, as well as; kaempferol increases the expression and activity of CAT, GPx, and SOD, as found by ( Lim et al , 2023 ).…”

“…Current results revealed that the administration of kaempferol following exposure to lead caused elevation in the levels of CAT, GPx, and SOD, whereas MDA and NO were reduced relative to their levels in rats treated with vitamin E and/or lead only; this may be attributed to the antioxidant ability of kaempferol to suppress the activities of pro-oxidant enzymes such as xanthine oxidase that responsible for generating ROS ( Lim et al , 2023 ). Kaempferol, like other flavonoids, can chelate with cuprous or ferrous ions in Fenton’s reaction, ultimately leading to prevent lipid peroxidation of cytomembrane, as well as; kaempferol increases the expression and activity of CAT, GPx, and SOD, as found by ( Lim et al , 2023 ). Furthermore, kaempferol possesses a double bond at C3-C2 and hydroxyl groups at C5, C3, and C4, and an oxo group at C4 which might explain its powerful antioxidant properties ( Imran et al , 2019 ); the current results consistent with ( Albrakati et al , 2021 ) who concluded that kaempferol can suppress lipid peroxidation and NO production with increase generation of antioxidants in neurotoxic rats.…”

“…Kaempferol, ″3,5,7-trihydroxy-2-(4-hydroxyphenyl) -4H- chromen-4-one″ is a type of flavonoids, a polyphenol and lipophilic, also known as kaempferol flavonol, kaempferide, kaempferol-3 ( Jin et al , 2023 ), it can be extracted from tea and many vegetables and fruits such as green cabbage, broccoli, olive oil, apple, chives, cucumber, strawberries, lettuce, onion, grapes, spinach, tomatoes, horseradish, and cowpea ( Alam et al , 2020 ). Studies in vivo and in vitro reported that kaempferol possesses therapeutic effects in neurodegenerative disease, colitis, and in acute and chronic inflammatory disease, including acute lung injury and postmenopausal bone loss ( Ren et al , 2019 , Liu et al , 2022 , Lim et al , 2023 ), as well as, kaempferol has a protective role in liver injury and prevents metabolic disorders, furthermore, anticancer role in breast cancer, and hepatocellular carcinoma ( Wang et al , 2019 , Sharma et al , 2021 , Fan et al , 2023 ).…”

Current understanding and future directions of cruciferous vegetables and their phytochemicals to combat neurological diseases

“…Moreover, Kaempeferitin a derivative of KPF delayed the onset of myoclonic seizures, generalized seizures, and decreased mortality in Swiss Webster mice and Wistar rats (González‐Trujano et al, 2017). Further, the synthetic KPF analogs have been reported to ameliorate the phosphorylation of NF‐kB, reduction in COX‐2, iNOS, and promote the AMPK/NRF2/HO‐1 pathway in epilepsy conditions (Lim et al, 2023; Velagapudi et al, 2019). Altogether, these findings indicate that KPF could be a promising antiepileptic agent.…”

An Update of Kaempferol Protection against Brain Damage Induced by Ischemia-Reperfusion and by 3-Nitropropionic Acid

“…Brain inflammation has been shown to play a causal role in the neurodegeneration in ischemia-reperfusion injury ( Section 2 ) and in NPA intoxication ( Section 3 ), and recent reviews have highlighted the molecular mechanisms of action of flavonoids as anti-inflammatory molecules, see, for example [ 199 , 200 ]. The anti-inflammatory actions of kaempferol are well recognized [ 201 , 202 ], and it is to be noted that recently it has been shown with lipopolysaccharide-stimulated BV2 microglial cells that its derived glucuronate metabolite also displays cellular antioxidant and anti-neuroinflammatory activity [ 203 ]. Kaempferol administration has been shown to inhibit astrogliosis and/or microglia activation in the brain of animal models of MCAO [ 41 , 76 , 78 , 79 ] and of NPA-induced neurological dysfunction [ 43 , 48 , 139 , 140 , 141 ].…”