Natural Xanthine Oxidase Inhibitor 5-O-Caffeoylshikimic Acid Ameliorates Kidney Injury Caused by Hyperuricemia in Mice.

Xanthine oxidase (XOD) inhibition has long been considered an effective anti-hyperuricemia strategy. To identify effective natural XOD inhibitors with little side effects, we performed a XOD inhibitory assay-coupled isolation of compounds from Smilacis Glabrae Rhizoma (SGR), a traditional Chinese medicine frequently prescribed as anti-hyperuricemia agent for centuries. Through the in vitro XOD inhibitory assay, we obtained a novel XOD inhibitor, 5-O-caffeoylshikimic acid (#1, 5OCSA) with IC50 of 13.96 µM, as well as two known XOD inhibitors, quercetin (#3) and astilbin (#6). Meanwhile, we performed in silico molecular docking and found 5OCSA could interact with the active sites of XOD (PDB ID: 3NVY) with a binding energy of -8.6 kcal/mol, suggesting 5OCSA inhibits XOD by binding with its active site. To evaluate the in vivo effects on XOD, we generated a hyperuricemia mice model by intraperitoneal injection of potassium oxonate (300 mg/kg) and oral gavage of hypoxanthine (500 mg/kg) for 7 days. 5OCSA could inhibit both hepatic and serum XOD in vivo, together with an improvement of histological and multiple serological parameters in kidney injury and HUA. Collectively, our results suggested that 5OCSA may be developed into a safe and effective XOD inhibitor based on in vitro, in silico and in vivo evidence.

Shikimic acid inhibits LPS-induced cellular pro-inflammatory cytokines and attenuates mechanical hyperalgesia in mice.

BACKGROUND AND AIMS: Shikimic acid (SA) is present in a wide variety of plants and microorganisms used in traditional and folk medicine and also is an essential starting material for the synthesis of the antiviral drug Oseltamivir (Tamiflu®). Some pharmacological actions observed in SA-enriched products include antioxidant and anti-inflammatory activities. Here, we investigated the anti-inflammatory and antinociceptive actions of isolated SA. METHODS: RAW 264.7 macrophage cells were treated with bacterial LPS (1µg/mL) and the effect of SA on the modulation of cell viability, nitric oxide (NO) production, TNF-α, and IL-1ß content and MAPK (ERK1/2 and p38) activation was evaluated. Besides, the anti-hyperalgesic actions of SA on in vivo model of mechanical hyperalgesia induced by carrageenan (CG), dopamine (DA), TNF-α and prostaglandin (PGE2) were assessed. RESULTS: In RAW 264.7 cells, SA suppressed LPS-induced decrease in cell viability and nitrite accumulation to control values and inhibited up-regulation of TNF-α (65%) and IL-1ß (39%). These effects may be mediated at least in part by inhibition of LPS-induced ERK 1/2 (22%) and p38 (17%) phosphorylation. In mice, SA at 50, 100, and 200mg/kg decreased formalin-induced nociceptive behavior (around 50%) and inhibited the inflammatory nociception induced by TNF-α and PGE2 (50 to 75% each). Moreover, SA (100 and 200mg/kg) significantly attenuated the mechanical hyperalgesia induced by CG and DA (25 to 40% each). CONCLUSIONS: These results indicate that SA presents anti-inflammatory actions with potential for development of drugs to treat pro-inflammatory and painful conditions.

Antinociceptive activity of aqueous extract and isolated compounds of Lithrea molleoides.

ETHNOPHARMACOLOGICAL RELEVANCE: Lithrea molleoides (Vell.) Engl. (Anacardiaceae) is a medicinal plant commonly used in traditional medicine in South America. AIM OF THE STUDY: In the present study, the in vivo antinociceptive effect of L. molleoides' aqueous extract and its isolated compounds has been investigated. MATERIALS AND METHODS: Antinociceptive activity was evaluated through writhing, formalin and hot plate tests in mice. The phytochemical analysis was performed. RESULTS: The extract produced significant inhibition on nociception induced by acetic acid (ED50: 8.7 mg/kg, i.p.) and formalin (ED50: 7.7 mg/kg, i.p.) administered intraperitoneally and also orally. Yohimbine diminished the activity of the extract in the acetic acid test meanwhile haloperidol enhanced its effect. Two majority compounds, shikimic and vanillic acid were active in chemical nociceptive models used in this work, producing the highest inhibition of the writhing response at a dose of 30 mg/kg i.p. (55.4% and 57.1%, respectively) meanwhile at 100 mg/kg p.o. produced a slight response (23.3% and 23.9%, respectively). CONCLUSIONS: These results suggest that L. molleoides' aqueous extract produced antinociception possibly related to the presence of shikimic and vanillic acid. The adrenergic and dopaminergic systems seem to be involved in the mechanism of antinociception of the extract.

Protective effects of 3,4-oxo-isopropylidene-shikimic acid on experimental colitis induced by trinitrobenzenesulfonic acid in rats.

BACKGROUND: 3,4-Oxo-isopropylidene-shikimic acid (ISA) is a derivative of shikimic acid (SA). SA is extracted from Illicium verum Hook.fil., which has been used in traditional Chinese medicine and used for treating vomiting, stomach aches, insomnia, skin inflammation, and rheumatic pain. AIMS: To investigate the effects and the protective mechanism of 3,4-oxo-isopropylidene-shikimic acid on experimental colitis model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats. METHODS: Colitis in rats was induced by colonic administration with TNBS. ISA (50, 100, and 200 mg/kg) was administered for 12 days to experimental colitis rats. The inflammatory degree was assessed by macroscopic damage score, colon weight/length ratios (mg/cm), and myeloperoxidase (MPO) activity. Malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) levels, and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), inducible nitric oxide synthase (iNOS) activities were measured with biochemical methods. RESULTS: ISA significantly ameliorated macroscopic damage, reduced colon weight/length ratios and the activity of MPO, depressed MDA and NO levels and iNOS activity, and enhanced GSH level, and GSH-Px and SOD activities in the colon tissues of experimental colitis in a dose-dependent manner. Moreover, the effect of ISA (200 mg/kg) was as effective as sulfasalazine (500 mg/kg). CONCLUSIONS: The findings of this study demonstrate the protective effect of ISA on experimental colitis, probably due to an antioxidant action.

Identification of hypoglycaemic compounds from berries of Juniperus oxycedrus subsp. oxycedrus through bioactivity guided isolation technique.

ETHNOPHARMACOLOGICAL RELEVANCE: Decoction of Juniperus oxycedrus subsp. oxycedrus L. (Cupressaceae) berries is used internally as tea and pounded fruits are consumed to lower blood glucose levels in Turkey. AIM OF THE STUDY: To evaluate hypoglycaemic and antidiabetic activity of J. oxycedrus subsp. oxycedrus berries and to identify active compounds through bioactivity guided isolation technique. MATERIAL AND METHODS: Hypoglycaemic effect of J. oxycedrus subsp. oxycedrus (Joso) berry extracts on oral administration was studied using in vivo models in normal, glucose-hyperglycaemic rats. Streptozotocin induced diabetic rats were used to examine antidiabetic activity of Joso extracts, subextracts, fractions, subfractions and shikimic acid (SA). RESULTS: Through in vivo bioactivity-guided fractionation processes, shikimic acid, 4-O-ß-d-glucopyranosyl ferulic acid and oleuropeic acid-8-O-ß-d-glucopyranoside were isolated from the n-butanol subextract by silica gel and reverse phase column chromatography as the main active ingredient of the active subfraction. After 8 days administration of the major compound shikimic acid, blood glucose levels (24%), malondialdehyde levels in kidney tissues (63-64%) and liver enzymes (AST, ALT, ALP) of diabetic rats were decreased. CONCLUSION: Results indicated that Joso berry extract and its active constituents might be beneficial for diabetes and its complications.

Illicium verum: a review on its botany, traditional use, chemistry and pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Illicium verum Hook. f. (Chinese star anise) has long been used in traditional Chinese medicine and food industry with the actions of dispelling cold, regulating the flow of Qi and relieving pain. MATERIALS AND METHODS: A bibliographic investigation was carried out by analyzing recognized books including Chinese herbal classic, and worldwide accepted scientific databases (Pubmed, SciFinder, Scopus and Web of Science) were searched for the available information on I. verum. RESULTS: I. verum is an aromatic evergreen tree of the family Illiciaceae. It is sometimes contaminated with highly toxic Japanese star anise (I. anisatum L.) and poisonous star anise (I. lanceolatum A. C. Smith), which contain several neurotoxic sesquiterpenes. Traditional uses of I. verum are recorded throughout Asia and Northern America, where it has been used for more than 10 types of disorders. Numerous compounds including volatiles, seco-prezizaane-type sesquiterpenes, phenylpropanoids, lignans, flavonoids and other constituents have been identified from I. verum. Modern pharmacology studies demonstrated that its crude extracts and active compounds possess wide pharmacological actions, especially in antimicrobial, antioxidant, insecticidal, analgesic, sedative and convulsive activities. In addition, it is the major source of shikimic acid, a primary ingredient in the antiflu drug (Tamiflu). AIM OF THE REVIEW: This review summarizes the up-to-date and comprehensive information concerning the botany, traditional use, phytochemistry and pharmacology of I. verum together with the toxicology, and discusses the possible trend and scope for future research of I. verum.

Natural products and their derivatives as cholinesterase inhibitors in the treatment of neurodegenerative disorders: an update.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorders. If more effective therapies than the ones currently available are not developed that either prevent AD or other neurodegenerative or block progression of the diseases in its very early stages, the economic and societal cost of caring for AD patients will be devastating. Besides the neuropathologic hallmarks of the diseases, namely neurofibrillary tangles and AD neuritic plaques, the disease is characterized neurochemically by a consistent deficit in cholinergic neurotransmission, particularly affecting cholinergic neurons in basal forebrain. AD and other forms of dementia could be treated by the use of agents which restore the level of acetylcholine through inhibition of both two major forms of cholinesterase: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Moreover, the inhibition of AChE holds a key role not only to enhance cholinergic transmission in the brain but also to reduce the aggregation of beta-amyloid and the formation of the neurotoxic fibrils in AD. Following this view, in recent years, an increased interest has emerged directed to finding drugs able to inhibit both of these events. This review summarizes and highlights recent advances in current knowledge on natural products as cholinesterase inhibitors and how these compounds have also served as the starting points for semi-synthetic analogs with improved properties.