neoisoliquiritin and Disease-Models--Animal

Ischemic stroke is a multifactorial disease contributing to mortality and neurological dysfunction. Isoliquiritin (ISL) has been reported to possess a series of pharmacological activities including antioxidant, anti-inflammatory, antifungal, anti-depression, anti-neurotoxicity and pro-angiogenesis activities but whether it can be used for ischemic stroke treatment remains unknown.. The goal of this study is to explore its therapeutic effect on ischemic stroke and demonstrated the potential mechanism of ISL in zebrafish model.. Using the photothrombotic-induced adult zebrafish model of ischemic stroke, we visualized the telencephalon (Tel) and optic tectum (OT) infarction injury at 24 h post-light exposure for 30 min by TTC and H&E staining. The effect of ISL on neurological deficits was analyzed during open tank swimming by video tracking. The antioxidant activity against ischemia injury was quantified by SOD, GSH-Px and MDA assay. Transcriptome analysis of zebrafish Tel revealed how ISL regulating gene expression to exert protective effect, which were also been validated by real-time quantitative PCR assays.. We found for the first time that the Tel tissue was the first damaged site of the whole brain and it showed more sensitivity to the brain ischemic damage compared to the OT. ISL reduced the rate of Tel injury, ameliorated neurological deficits as well as counteracted oxidative damages by increasing SOD, GSH-Px and decreasing MDA activity. GO enrichment demonstrated that ISL protected membrane and membrane function as well as initiate immune regulation in the stress response after ischemia. KEGG pathway analysis pointed out that immune-related pathways, apoptosis as well as necroptosis pathways were more involved in the protective mechanism of ISL. Furthermore, the log2 fold change in expression pattern of 25 genes detected by qRT-PCR was consistent with that by RNA-seq.. Tel was highly sensitive to the brain ischemia injury in zebrafish model of ischemic stroke. ISL significantly exerted protective effect on Tel injury, neurological deficits and oxidative damages. ISL could regulate a variety of genes related to immune, apoptosis and necrosis pathways against complex cascade reaction after ischemia. These findings enriched the study of ISL, making it a novel multi-target agent for ischemic stroke treatment.

Topics: Animals; Antioxidants; Apoptosis; Brain Ischemia; Chalcone; Disease Models, Animal; Enzymes; Female; Glucosides; Ischemic Stroke; Male; Oxidative Stress; Protective Agents; Signal Transduction; Telencephalon; Zebrafish; Zebrafish Proteins

Chronic neuropathic pain poses a significant health problem worldwide, for which effective treatment is lacking. The current work aimed to investigate the potential analgesic effect of isoliquiritin, a flavonoid from Glycyrrhiza uralensis, against neuropathic pain and elucidate mechanisms. Male C57BL/6J mice were subjected to chronic constriction injury (CCI) by loose ligation of their sciatic nerves. Following CCI surgery, the neuropathic mice developed pain-like behaviors, as shown by thermal (heat) hyperalgesia in the Hargreaves test and tactile allodynia in the von Frey test. Repetitive treatment of CCI mice with isoliquiritin (p.o., twice per day for two weeks) ameliorated behavioral hyperalgesia to thermal (heat) stimuli and allodynia to tactile stimuli in a dose-dependent fashion (5, 15 and 45 mg/kg). The isoliquiritin-triggered analgesia seems serotonergically dependent, since its antihyperalgesic and antiallodynic actions were totally abolished by chemical depletion of spinal serotonin by p-chlorophenylalanine, whereas potentiated by 5-HTP (a precursor of 5-HT). Consistently, isoliquiritin-treated neuropathic mice showed escalated levels of spinal monoamines especially 5-HT, with depressed monoamine oxidase activity. Moreover, isoliquiritin-evoked antihyperalgesia and antiallodynia were preferentially counteracted by the 5-HT

Topics: Analgesics; Animals; Behavior, Animal; Brain; Chalcone; Disease Models, Animal; Glucosides; Hyperalgesia; Male; Mice, Inbred C57BL; Neuralgia; Pain Threshold; Receptor, Serotonin, 5-HT1A; Serotonin; Serotonin 5-HT1 Receptor Agonists; Spinal Cord

Membranous glomerulonephritis (MGN) is a nephrotic syndrome which shows the symptoms of heavy proteinuria and immune complex deposition in glomerular sub-epithelial space and finally leads to chronic kidney disease. Isoliquiritin (ILQ) is a flavonoid with a wide range of pharmacological properties, including antioxidant and anti-inflammatory activity. The present study was undertaken to investigate the possible mechanisms by which ILQ ameliorates cationic bovine serum albumin (C-BSA) induced MGN in rat model.. The MGN condition was confirmed by the 24 hr proteinuria and ILQ (10 mg/kg/bw/day) or TPCA-1 (10 mg/kg/bw/day; IKKβ inhibitor) was administered to successfully induce rats for 4 weeks.. The present study revealed that MGN rats treated with ILQ showed significantly ameliorated kidney dysfunction and histopathological changes in kidneys. ILQ treated MGN rats alleviated the oxidative stress and were presented with increased anti-oxidative status in kidneys. Furthermore, ILQ treatment to MGN rats showed anti-oxidative effects through the prominent stimulation of Nrf2 signaling pathway and inhibition of Keap1, which consequently increases the Nrf2 nuclear translocation and thereby induces expression of NQO1 and HO-1. In addition, ILQ-treated MGN rats demonstrated anti-inflammatory effects by inhibiting NF-κB signaling pathway through decreased mRNA and protein expressions of NF-κB p65, IKKβ, COX-2, iNOS, p38-MAPK, p-p38-MAPK, TNF-α, IL-1β, IL-8, ICAM-1, E-selectin and VCAM-1 and reduced the nuclear translocation of NF-κB p65.. The protective effect of ILQ on MGN can be explained by its anti-oxidative and anti-inflammatory activities, which in turn due to the activation of Nrf2 and downregulation of NF-κB pathway.

Topics: Animals; Biomarkers; Cations; Chalcone; Disease Models, Animal; Dose-Response Relationship, Drug; Glomerulonephritis, Membranous; Glucosides; Inflammation; Injections, Intravenous; Male; Molecular Structure; Oxidative Stress; Protective Agents; Rats; Rats, Sprague-Dawley; Serum Albumin, Bovine; Structure-Activity Relationship

Screening active constituents of traditional Chinese medicines (TCMs) is vital for lead compound discovery. Sini decoction (SND) is a well-known TCM formula for relieving myocardial ischemia (MI) in clinic. Due to complex nature, the effective compounds of SND are still unknown. In this study, a novel "system to system" strategy based on the correlation of drug-related and drug-induced ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOFMS) serum metabolomic profiles was developed to discover bioactive compounds of SND against isoproterenol-induced MI. Thirteen SND-induced metabolites and 19 SND-related metabolites were identified by UHPLC-Q-TOFMS coupled with S-plot and SUS-plot of orthogonal projection to latent structure-discriminant analysis (OPLS-DA) models, respectively. Canonical correlation analysis between the SND-induced and SND-related metabolites revealed that 12 compounds had strongly correlated relationship with the protective effect of SND on MI, and these compounds include isotalatizidine, songorine, fuziline, neoline, talatizamine, 14-acetyltalatizamine, liquiritigenin, benzoylmesaconitine, isoliquiritin, benzoylaconitne, benzoylhypaconitine and 6-gingerol. Combination functional enrichment analysis and network topology analysis revealed that the targeted metabolic pathways of these correlated compounds were involved in valine, leucine and isoleucine biosyntheses, tryptophan metabolism, glycerophospholipid metabolism and sphingolipid metabolism. The results demonstrated that the "system to system" strategy may be a high-throughput method to discover potentially effective compounds from TCMs.

Topics: Aconitine; Alkaloids; Animals; Aspartate Aminotransferases; Catechols; Chalcone; Chromatography, High Pressure Liquid; Creatine Kinase; Disease Models, Animal; Drugs, Chinese Herbal; Fatty Alcohols; Flavanones; Glucosides; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Malondialdehyde; Mass Spectrometry; Metabolome; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Superoxide Dismutase