ABSTRACT
Acute lung injury (ALI) is a pulmonary disease that acts as a severe acute inflammatory response with no specific drugs. iNOS, a catalyst of the excessive production of NO, has been demonstrated to participate in the inflammatory process, and targeting iNOS may be a promising therapeutic pathway to alleviate ALI. In our research, eighteen new disubstituted benzoxazolone derivatives were synthesized, characterized, and evaluated for activity against NO production in an LPS-induced RAW264.7 cell. The results showed that these compounds could obviously inhibit the over-generation of NO and disubstitution at the 4, N-position of the benzoxazolone ring, presenting better potency than substitution only at the 4-position. Among the analogues generated, compounds 2c, 2d, and 3d showed NO inhibitory activity with IC50 values of 16.43, 14.72, and 13.44 µM and iNOS inhibitory activity with IC50 values of 4.605, 3.342, and 9.733 µM, respectively. Meanwhile, compounds 2c, 2d, and 3d could also inhibit the release of IL-6, IL-1ß in vitro and suppress xylene-induced ear edema in vivo to realize anti-inflammatory activity. Furthermore, compound 2d could significantly protect the LPS-induced ALI, presenting as decreased inflammatory cytokines and obvious pathological changes. Immunohistochemistry and molecular modeling demonstrated that compound 2d significantly inhibited the expression of iNOS in vivo and interacted with iNOS through two hydrogen bindings with the MET368 and ILE195 residues of the iNOS protein. These results demonstrated that compound 2d could be a promising lead structure for iNOS inhibitors, with anti-inflammatory activity to treat LPS-induced acute lung injury.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Benzoxazoles/chemistry , Drug Design , Nitric Oxide Synthase Type II/antagonists & inhibitors , Acute Lung Injury/drug therapy , Acute Lung Injury/etiology , Animals , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Benzoxazoles/metabolism , Benzoxazoles/pharmacology , Benzoxazoles/therapeutic use , Disease Models, Animal , Edema/chemically induced , Edema/drug therapy , Gene Expression Regulation/drug effects , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Lipopolysaccharides/pharmacology , Lung/metabolism , Lung/pathology , Macrophages/cytology , Macrophages/drug effects , Macrophages/metabolism , Mice , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Peroxidase/metabolism , RAW 264.7 CellsABSTRACT
<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) hydrogel in wound healing in patients with deep partial thickness burn.</p><p><b>METHODS</b>The study was a multicenter, randomized, double-blind, placebo-controlled parallel clinical trial. Three hundred and twenty-one patients (302 cases finally fulfilled the protocol) with deep partial thickness burn were divided into A group (n = 200, with treatment of rhGM-CSF hydrogel, 100 microg/10 g/100 cm2/d), C group (n = 102,with treatment of placebo). Side-effect, systemic condition, wound healing time, wound healing rate, and total effective rate at different time points were observed.</p><p><b>RESULTS</b>There were no obvious differences in vital signs, wound secretion, wound edge reaction, blood and urine routine, liver and kidney function between two groups (P > 0.05). No side-effect was observed. The median wound healing time was 17 days in A group, which was obviously shorter than that in C group (20 days, P < 0.01). The mean wound healing rate in A group was 24.5%, 70.5%, 95.3%, 99.6% respectively on 8th, 14th, 20th, 28th day after treatment, which were obviously higher than that in C group (15.1%, 51.4%, 84.6%, 97.1%, respectively, P < 0.01). The total effective rates in A group on 8th, 14th, 20th day after treatment were also higher than that in C group (P < 0.01).</p><p><b>CONCLUSION</b>rhGM-CSF hydrogel can significantly accelerate wound healing in patients with deep partial thickness burn with certain safety.</p>
Subject(s)
Female , Humans , Male , Burns , Drug Therapy , Double-Blind Method , Granulocyte-Macrophage Colony-Stimulating Factor , Therapeutic Uses , Hydrogels , Therapeutic Uses , Placebos , Recombinant Proteins , Wound HealingABSTRACT
Nordy is a synthesized chrial compound. To investigate the effects of nordy (25 - 100 micromol x L(-1)) on the function of formylpeptide receptor (FPR) of malignant human glioma cells, human glioblastoma cell line U87 was used to detect its proliferation, migration, calcium mobilization, vascular endothelial growth factor (VEGF) mRNA and protein levels after activation of FPR by its agonist N-formyl-methionyl-leucyl-phenylalanine (fMLF). Cell proliferation, migration ability, VEGF mRNA, VEGF protein and calcium mobilization were evaluated by cell counting, chemotaxis assay, RT-PCR, ELISA and spectrometry. Nordy (50 - 100 micromol x L(-1)) potently inhibited the proliferation, migration and calcium mobilization of U87 cells induced by fMLF (P < 0.05). Moreover, 100 micromol x L(-1) nordy showed a significantly impaired VEGF mRNA expression and protein secretion induced by fMLF (P < 0.05). Nordy could inhibit FPR functioning in glioma cell proliferation, migration and angiogenesis, which might be a possible mechanism of its anti-cancer effects.
