Review of the effects of vitexin in oxidative stress‐related diseases

Abstract Vitexin is an apigenin flavone glycoside found in food and medicinal plants. It has a variety of pharmacological effects, including antioxidant, anti‐inflammatory, anticancer, antinociceptive, and neuroprotective effects. This review study summarizes all the protective effects of vitexin as an antioxidant against reactive oxygen species, lipid peroxidation, and other oxidative damages in a variety of oxidative stress‐related diseases, including seizure, memory impairment, cerebral ischemia, neurotoxicity, myocardial and respiratory injury, and metabolic dysfunction, with possible molecular and cellular mechanisms. This review describes any activation or inhibition of the signaling pathways that depend on the antioxidant activity of vitexin. More basic research is needed on the antioxidative effects of vitexin in vivo, and carrying out clinical trials for the treatment of oxidative stress‐related diseases is also recommended.

found as a major polyphenol in food sources such as mung beans (Hou et al., 2019).
Vitexin is poorly absorbed in the gastrointestinal tract. It is rapidly removed from the blood, and its absolute oral bioavailability is very low. Vitexin is probably deglycosylated as the first step and converted to 3-(4-hydroxyphenyl) propionic acid in the end. The first-pass effects of vitexin are almost intestinal (approximately 94%) and less gastric (30%) and hepatic (5%), which contribute to its low bioavailability.
Vitexin is rapidly and widely distributed into various tissues. Vitexin is excreted most in the urine and bile (Ninfali & Angelino, 2013;Xue et al., 2014).
Recently, the nanoparticles of vitexin have increased its rate of dissolution despite the low aqueous solubility of the raw drug (Gu et al., 2017). In recent years, an increasing attention has been paid to the search for natural antioxidants, and vitexin has received great attention due to its antioxidant activities. This review study thus summarizes the antioxidant effects of vitexin and its derivatives on oxidative stress-related diseases ( Figure 2).

| ME THODS
All the major in vivo or in vitro studies conducted over the past decade about the effects of vitexin as an antioxidant on oxidative stress were selected for this review study. All the studies related to herbal medicines in which vitexin plays a major role as an antioxidant were also selected. Scopus, PubMed, and Web of Science were used as the data-
Vitexin (10-30 mg/kg, i.p.) also reduced the immobility time in both the tail-suspension test and the modified forced swimming test in mice, which is attributed to its antidepressant-like effects. The antidepressant effects of vitexin may be related to increasing catecholamine in synaptic cleft, activating serotonergic 5-HT 1A , noradrenergic α 2 , and dopaminergic D 1 , D 2 , and D 3 receptors (Can et al., 2013).
Vitexin (100 µM) showed significant cholinesterase inhibitory effects for both acetylcholinesterase and butyrylcholinesterase activity (Sheeja Malar et al., 2017). As an antioxidant, vitexin (40 mg/kg) increased the total antioxidant capacity, superoxide dismutase, catalase, and glutathione peroxidase activities in the serum and also the levels of superoxide dismutase, catalase, glutathione peroxidase, Na + -K + -ATP enzyme, and Ca 2+ -Mg 2+ -ATP enzyme in the liver, brain, and kidneys in D-galactose model of aging in mice. Vitexin also reduced MDA levels in the liver, brain, and kidney and lipofuscin levels in the brain too. In addition, the TA B L E 1 Effect of vitexin on oxidative stress in some neurotoxicity models

| Antinociceptive and antiinflammatory activities
Vitexin (10 mg/kg, i.p., 30 min before stimulus with phenyl-p-benzoquinone, 1,890 μg/kg) inhibits inflammation-associated pain and can also inhibit 91% of the acetic acid-induced writhing response and pain-like behavior induced by phenyl-p-benzoquinone, complete Freund's adjuvant, capsaicin (an agonist of transient receptor potential vanilloid 1, TRPV1), and both phases of the formalin test.
As the possible mechanism, vitexin could prevent the reduction of glutathione levels, the ferric-reducing ability potential, and the free-radical scavenger ability, inhibit the production of hyperalgesic cytokines, such as TNF-α, IL-1β, IL-6, and IL-33, and upregulate antihyperalgesic cytokine IL-10 levels (Borghi et al., 2013). Figure 3 also shows the role of vitexin in the activity of peripheral cytokines in the peripheral system.

Vitexin and isovitexin, as major antioxidant components in various cultivars of mung bean, may be involved in DPPH and ABTS ˚+
radicals' scavenging abilities, and FRAP (ferric reducing antioxidant power) in MBS (Table 3). Nonetheless, this effect was greater in the MBS of cv. Huang and cv. Mao than cv. Ming (Li, Cao, Yi, Cao, & Jiang, 2012).

| C AN CER
As previously described, vitexin inhibits apoptosis in noncancerous cells and acts as antioxidant. On the other hand, it has different effect on apoptosis in tumor cells. Vitexin has shown anticancer effects in the cancer cell line by inducing apoptosis in several studies (Ninfali et al., 2017;He et al., 2016).
The effective concentration of each derivative of vitexin with molecular target and mechanism in different cancers has been summarized by Ninfali et al. (2017). For example, vitexin-2-O-xyloside has a dose-response anticancer effect (IC 50 of 8.8 ± 0.8 μM, at 72 hr) and activated intrinsic pathway of apoptosis in T24 bladder cancer cells (Scarpa et al., 2016). An interesting issue is that vitexin had no toxicity against normal human bronchial epithelial 16HBE cells.

| CON CLUS ION
Vitexin is found in food sources and is used as an active component with herbal supplement. The present review study summarized all the protective effects of vitexin as an antioxidant against ROS, lipid peroxidation, and other oxidative damages with changes in oxidative and defense biomarkers in the nervous system, heart, and respiratory systems with possible mechanism on molecular and cellular signaling. Any activation (AMPK, Nrf-2, and mTOR) or inhibition (JNK and BACE1) of the signaling pathways that depend on the antioxidant activity of vitexin in noncancer cells was also described. The diversity of the mechanisms of effect of vitexin against different oxidative stress models is the one of the most important points to consider regarding vitexin. Clinical studies are needed to further examine the protective effects of vitexin against oxidative stress-related diseases, and as formerly noted, nanoparticles of it have been developed for increasing the bioavailability of vitexin.

CO N FLI C T O F I NTE R E S T
The authors declare that there is no conflict of interest.

E TH I C A L A PPROVA L
The study did not involve any human or animal testing.