kaempferol-3-o-rhamnoside and Disease-Models--Animal

Neurodegenerative disorders are characterized by the decline of cognitive function and the progressive loss of memory. The dysfunctions of the cognitive and memory system are closely related to the decreases in brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) signalings. Ribes fasciculatum, a medicinal plant grown in diverse countries, has been reported to pharmacological effects for autoimmune diseases and aging recently. Here we found that afzelin is a major compound in Ribes fasciculatum. To further examine its neuroprotective effect, the afzelin (100 ng/µl, three times a week) was administered into the third ventricle of the hypothalamus of C57BL/6 mice for one month and scopolamine was injected (i.p.) to these mice to impair cognition and memory before each behavior experiment. The electrophysiology to measure long-term potentiation and behavior tests for cognitive and memory functions were performed followed by investigating related molecular signaling pathways. Chronic administration of afzelin into the brain ameliorated synaptic plasticity and cognitive/memory behaviors in mice given scopolamine. Studies of mice's hippocampi revealed that the response of afzelin was accountable for the restoration of the cholinergic systems and molecular signal transduction via CREB-BDNF pathways. In conclusion, the central administration of afzelin leads to improved neurocognitive and neuroprotective effects on synaptic plasticity and behaviors partly through the increase in CREB-BDNF signaling.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cognition; Cyclic AMP Response Element-Binding Protein; Dementia; Disease Models, Animal; Dose-Response Relationship, Drug; Hippocampus; Long-Term Potentiation; Male; Mannosides; Memory; Mice, Inbred C57BL; Neuroprotective Agents; Proanthocyanidins; Ribes; Scopolamine

Herpes simplex virus encephalitis (HSE) is an acute central nervous system infectious disease caused by herpes simplex virus (HSV). Currently, there is no effective treatment for HSE infection, which produces many pro-inflammatory factors. Kaempferol-3-O-rhamnoside (K-3-rh) is a plant flavonoid. This study was investigated the anti-inflammatory effect of K-3-rh on encephalitis induced by HSV-1.. HSV-1 was co-cultured with VERO cells. Cells were divided into four groups, including the control group, virus group, K-3-rh group, Astragalus polysaccharide (APS) group and dexamethasone group. Flow cytometry were utilized to determine cell apoptosis, respectively. Proteins and mRNAs were estimated by western blot and qRT-PCR, respectively.. After viral infection, the cytokines were significantly increased. After K-3-rh intervention, the expression of tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β), and nitric oxide (NO) in microglia were reduced contrast with those in the virus group, and the expression of interleukin-10 (IL-10) did not change. After viral infection, the apoptotic rate increased significantly, and K-3-rh could inhibit viral-induced apoptosis in the microglial cell line. The induction of microglia apoptosis was achieved by cytochrome c and caspase-9-mediated mitochondrial pathway. Also, the pathological changes of brain tissue in mice of each drug intervention group were alleviated.. In conclusion, K-3-rh had the potential to reduce HSV-1-induced brain injury by reducing the secretion of microglial pro-inflammatory factors, inducing apoptosis of microglia cells, and through cytochrome C and caspase-3 pathway.

Topics: Animals; Apoptosis; Caspase 3; Cell Line; Chlorocebus aethiops; Cytochromes c; Disease Models, Animal; Encephalitis, Herpes Simplex; Glycosides; Herpesvirus 1, Human; Humans; Kaempferols; Mice; Microglia; Vero Cells

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Purified plant nutraceuticals afzelin and quercetrin from an edible plant- Crotolaria tetragona was employed for the fabrication of silver nanoparticles (AgNPs) by a sunlight mediated process. From among a panel of strains tested, AgNPs displayed potent bacteriostatic and bactericidal effect against P. aeruginosa and S. Typhi. Time kill studies revealed green synthesized AgNPs displayed comparable bactericidal effect with chemically synthesized AgNPs against S. Typhi. Antibiofilm potential of AgNPs showed that they were highly effective at sub MIC concentrations in causing 50% biofilm inhibition against food borne pathogen S. Typhi implying that antibiofilm effect is independent of antibacterial effect, which was evidenced by fluorescent imaging and SEM imaging. Mechanistic studies revealed that reduced cell surface hydrophobicity, decreased surface adherence, loss of membrane potential contributed to antibiofilm potential of afzelin/quercetrin AgNPs. Green synthesized afzelin/quercetrin AgNPs were also relatively less toxic and more effective in curtailing bioburden of S. Typhi in infected zebrafish by > 3 log fold. Ability of sunlight reduced afzelin/quercetrin NPs to mitigate planktonic mode of growth in vitro and in vivo and curtail biofilm formation of S. Typhi in vitro demonstrates its potential to curtail food borne pathogen in planktonic and biofilm mode of growth.

Topics: Adhesins, Bacterial; Animals; Anti-Bacterial Agents; Bacteria; Biofilms; Dietary Supplements; Disease Models, Animal; Fabaceae; Foodborne Diseases; Green Chemistry Technology; Hydrophobic and Hydrophilic Interactions; Mannosides; Membrane Potentials; Metal Nanoparticles; Microbial Sensitivity Tests; Proanthocyanidins; Pseudomonas aeruginosa; Quercetin; Salmonella typhi; Silver; Toxicity Tests; Zebrafish

Topics: Animals; Antioxidants; Chromatography, High Pressure Liquid; Diabetes Mellitus; Disease Models, Animal; Glucuronides; Juglandaceae; Kaempferols; Male; Mannosides; Mice; Molecular Structure; Phenols; Plant Extracts; Plant Leaves; Proanthocyanidins; Quercetin; Superoxide Dismutase

Solidago chilensis Meyenmost (Asteraceae), popularly known as "Brazilian arnica" or "arnica-do-campo," is widely used in the folk medicine to treat gastric disorders. Based on this, the gastroprotective activity of S. chilensis methanolic extract was investigated. Besides, a phytochemical study allowed isolation of two flavonoids (quercitrin and afzelin). The gastroprotective effects were investigated in acute gastric ulcer models, and the antisecretory activity was assessed in vivo and in vitro. The adhered mucus levels, reduced glutathione (GSH) content and myeloperoxidase (MPO) activity were quantified in ulcerated tissues. The contribution of isolated compounds in extract effects was evaluated, and its doses were calculated according to its yield. To evaluate the in vivo healing properties of S. chilensis methanolic extract, a chronic gastric ulcer was induced in mice by 10 % acetic acid. Evaluation of tumor necrosis factor (TNF) levels was also performed at the site of the acetic acid-induced gastric ulcer. In parallel, effects on cell viability and cell proliferation of fibroblasts (L929 cells) were determined by in vitro trials. Firstly, the S. chilensis methanolic extract (100 or 300 mg/kg) reduced the ulcer area induced by ethanol/HCl in mice when compared to the vehicle group. Moreover, the S. chilensis extract (300 mg/kg) prevented the mucus depletion, the increase in MPO activity and the decrease in the GSH levels in the ulcerated gastric tissue. The S. chilensis extract also was able to decrease the indomethacin-induced gastric ulcer in rats at a dose of 100 mg/kg. The antisecretory effect of the extract (100 mg/kg, intraduodenal (i.d.)) was confirmed by the reduction in the volume and acidity in parallel to an increase in the pH of gastric content. In addition, quercitrin (1.38 mg/kg, but not 0.46 mg/kg) and afzelin (0.026 and 0.078 mg/kg) decreased the ethanol/HCl-induced gastric ulcer. In this model, quercitrin (1.38 mg/kg) prevented the depletion of gastric GSH content and both quercitrin (1.38 mg/kg) and afzelin (0.078 mg/kg) reduced the MPO activity. These compounds also inhibited the H(+),K(+)-ATPase activity at a concentration of 1-100 μg/ml. In addition, the participation of quercitrin and afzelin in these effects also was confirmed. Furthermore, after 4 days of the treatment, an oral administration of S. chilensis methanolic extract (100 mg/kg) reduced the area of the gastric ulcer induced by acetic acid and the regeneration of the

Topics: Animals; Anti-Inflammatory Agents; Anti-Ulcer Agents; Cell Line; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fibroblasts; Gastric Mucosa; Glutathione; H(+)-K(+)-Exchanging ATPase; Hydrogen-Ion Concentration; Mannosides; Methanol; Mice; Phytotherapy; Plant Extracts; Plant Leaves; Plants, Medicinal; Proanthocyanidins; Proton Pump Inhibitors; Quercetin; Rabbits; Rats, Wistar; Solidago; Solvents; Stomach Ulcer; Tumor Necrosis Factor-alpha; Wound Healing

The modification of natural flavonoid by glycosylation alters their physicochemical and pharmacokinetic properties, such as increased water solubility and stability, reduced toxicity, and sometimes enhanced or even new pharmacological activities. Kaempferol (KF), a plant flavonoid, and its glycosylated derivative, kaempferol-3-O-rhamnoside (K-3-rh), were evaluated and compared for their anti-inflammatory, anti-oxidant, and anti-asthmatic effects in an asthma model mouse. The results showed that K-3-rh fully maintained its anti-inflammatory and anti-asthmatic effects compared with KF in an asthma model mouse. Both KF and K-3-rh significantly reduced the elevated inflammatory cell numbers in the bronchoalveolar lavage fluid (BALF). KF and K-3-rh also significantly inhibited the increase in Th2 cytokines (IL-4, IL-5, and IL-13) and TNF-α protein levels through inhibition of the phosphorylation Akt and effectively suppressed eosinophilia in a mouse model of allergic asthma. The total immunoglobulin (Ig) E levels in the serum and BALF were also blocked by KF and K-3-rh to similar extents. K-3-rh exerts similar or even slightly higher inhibitory effects on Th2 cytokines and IgE production compared with KF, whereas K-3-rh was less effective at DPPH radical scavenging and the inhibition of ROS generation in inflammatory cells compared with KF. These results suggested that the K-3-rh, as well as KF, may also be a promising candidate for the development of health beneficial foods or therapeutic agents that can prevent or treat allergic asthma.

Topics: Alanine Transaminase; Allergens; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Aspartate Aminotransferases; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Female; Glycosides; Immunoglobulin E; Kaempferols; Lung; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Ovalbumin; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species

Asthma is a serious health problem causing significant mortality and morbidity globally. Persistent airway inflammation, airway hyperresponsiveness, increased immunoglobulin E (IgE) levels and mucus hypersecretion are key characteristics of the condition. Asthma is mediated via a dominant T-helper 2 (Th2) immune response, causing enhanced expression of Th2 cytokines. These cytokines are responsible for the various pathological changes associated with allergic asthma. To investigate the anti-asthmatic potential of afzelin, as well as the underlying mechanisms involved, its anti-asthmatic potential were investigated in a murine model of asthma. In the present study, BALB/c mice were systemically sensitized using ovalbumin (OVA) followed by aerosol allergen challenges. The effect of afzelin on airway hyperresponsiveness, eosinophilic infiltration, Th2 cytokine and OVA‑specific IgE production in a mouse model of asthma were investigated. It was found that afzelin‑treated groups suppressed eosinophil infiltration, allergic airway inflammation, airway hyperresponsiveness, OVA-specific IgE and Th2 cytokine secretion. The results of the present study suggested that the therapeutic mechanism by which afzelin effectively treats asthma is based on reduction of Th2 cytokine via inhibition of GATA-binding protein 3 transcription factor, which is the master regulator of Th2 cytokine differentiation and production.

Topics: Allergens; Animals; Asthma; Bronchial Hyperreactivity; Cytokines; Disease Models, Animal; Eosinophils; GATA3 Transcription Factor; Gene Expression Regulation; Humans; Immunoglobulin E; Mannosides; Mice; Ovalbumin; Proanthocyanidins; Th2 Cells