ABSTRACT
Hesperetin has been known to exert several activities such as anti-oxidant, antitumor and anti-inflammatory. To find hesperetin derivatives showing better activity, sixteen novel hesperetin derivatives were designed and synthesized. The new obtained compounds were investigated for their anti-inflammatory activity by inhibiting interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and production of nitric oxide (NO) in mouse RAW264.7 macrophages, and the structure-activity relationship of them was discussed. Among them, the compound 1l, 2c demonstrated more effective inhibitory activity of IL-1ß and IL-6, meanwhile, the compound 1l showed the best inhibition of NO production. The results of NO inhibition study were basically accord with the molecular docking results of inducible nitric oxide synthase (iNOS). Furthermore, the expression of LPS-induced iNOS and components of NF-κB signaling pathway were reduced by compound 1l. Our results suggest that the inhibitory effect of compound 1l on LPS-stimulated inflammatory mediator production in RAW 264.7 cells is associated with the suppression of NF-κB signaling pathway and inhibition of iNOS protein and iNOS activity. From in vivo study, it was also observed that compound 1l had hepato-protective and anti-inflammatory effects in CCl4-induced acute liver injury mouse models.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Chemical and Drug Induced Liver Injury/drug therapy , Hesperidin/pharmacology , Inflammation/drug therapy , Macrophages/drug effects , Animals , Anti-Inflammatory Agents/chemical synthesis , Carbon Tetrachloride , Disease Models, Animal , Hesperidin/chemical synthesis , Humans , Inflammation/chemically induced , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Lipopolysaccharides/immunology , Macrophages/physiology , Mice , Mice, Inbred Strains , NF-kappa B/metabolism , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , RAW 264.7 Cells , Signal Transduction , Structure-Activity RelationshipABSTRACT
A flavonoid hesperetin is reported to have a variety of biological activities, including anticancer, antiviral, antioxidant, neuroprotective and anti-inflammatory properties. Thirty-one novel hesperetin derivatives were designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells and CCl4-induced acute liver injury model. Among these compounds, 5b displayed the excellent anti-inflammatory activity on decreasing NO, IL-6 and TNF-α both in vitro and vivo. In addition, 5b could also reduce the release of NO, IL-6 and TNF-α production by LPS stimulated RAW 264.7 cell through MAPK and NF-κB signaling pathway in a concentration dependent manner. From in vivo study, it was also observed that 5b attenuated liver histopathologic changes in mouse models.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Chemical and Drug Induced Liver Injury/drug therapy , Hesperidin/pharmacology , Animals , Anti-Inflammatory Agents/chemical synthesis , Hesperidin/chemical synthesis , Interleukin-6/metabolism , Liver/drug effects , MAP Kinase Signaling System/drug effects , Macrophages/drug effects , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Nitric Oxide/metabolism , RAW 264.7 Cells , Tumor Necrosis Factor-alpha/metabolismABSTRACT
In this study we designed and synthesized a series of new hesperetin derivatives on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of the novel derivatives was also evaluated. Results showed that the synthesized hesperetin derivatives displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (selectivity index values from 68 to 305). The Lineweaver-Burk plot and molecular docking study showed that these compounds targeted both the peripheral anionic site (PAS) and catalytic active site (CAS) of AChE. The derivatives also showed a potent self-induced ß-amyloid (Aß) aggregation inhibition and a peroxyl radical absorbance activity. Moreover, compound 4f significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Cytotoxicity assay showed that the low concentration of the derivatives does not affect the viability of the SH-SY5Y neurons. Thus, these hesperetin derivatives are potential multifunctional agents for further development for the treatment of Alzheimer's disease.
Subject(s)
Amyloid beta-Peptides/drug effects , Antioxidants/chemical synthesis , Hesperidin/chemical synthesis , Neuroprotective Agents/chemical synthesis , Acetylcholinesterase , Amyloid beta-Peptides/chemistry , Animals , Antioxidants/chemistry , Antioxidants/pharmacology , Catalytic Domain , Cell Line , Drug Design , GPI-Linked Proteins/antagonists & inhibitors , Hesperidin/chemistry , Hesperidin/pharmacology , Humans , Hydrogen Peroxide/adverse effects , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , PC12 Cells , Protein Aggregates/drug effects , Rats , Structure-Activity RelationshipABSTRACT
Hesperetin is a flavanone glycoside compound naturally occurring in the fruit peel of Citrusaurantium L. (Rutaceae). Previous studies revealed that hesperetin possesses various pharmacological effects, including anti-inflammation, anti-tumor, anti-oxidant and neuroprotective properties. Hesperetin derivative-14 (HD-14) is a derivative of hesperetin improved in water solubility and bioavailability. In this study, we indicated that HD-14 (2µM) significantly attenuated inflammation in LPS-treated RAW264.7 cells, besides, HD-14 (100mg/kg) exhibited hepato-protective effects and anti-inflammatory effects on C57BL/6J mice with CCl4-induced acute liver injury. In addition, it was demonstrated that HD-14 dramatically up-regulated the expression of PPAR-γ in vivo and in vitro. Interestingly, over-expression of PPAR-γ had anti-inflammatory effects on the expressions of TNF-α, IL-6, and IL-1ß, whereas, knockdown of PPAR-γ with small interfering RNA had pro-inflammatory effects in LPS-treated RAW264.7 cells. Thus, our findings demonstrated that HD-14 alleviated inflammation by activating PPAR-γ expression at least in part. Further studies founded that HD-14 remarkably inhibited the expression of p-JAK1 and p-STAT1 through up-regulating PPAR-γ. Together, these results suggested that HD-14 served as an activator of PPAR-γ and the JAK1/STAT1 signaling pathway may be involved in the progress of inflammation. Collectively, HD-14 may be utilized as a potential anti-inflammation monomeric compound in the treatment of acute liver injury.
