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Objective To investigate the relationship between rs17525495 locus polymorphism of leukotriene A4 hydrolase (LTA4H) gene and the severity of tuberculous meningitis (TBM). Methods A total of 184 TBM patients from Department of Neurology, the Second Hospital of Hebei Medical University from January 2014 to October 2016 were selected as research subjects. According to the British Medical Research Council criteria, the severity of TBM patients was divided into three stages. The single nucleotide polymorphism rs17525495 of LTA4H gene was sequenced, and the general case data, clinical manifestations and results of lumbar puncture were analyzed. Results There were 91 cases (49.5％) of CC genotypes of rs17525495 locus in LTA4H gene of 184 cases, 75 cases (40.8％) of CT genotypes and 18 cases (9.8％) of TT genotypes. The frequency of allele C was 69.8％ and T was 30.2％. Patients with different genotypes were compared for their severity, clinical manifestations and lumbar puncture results. Among CC patients, the proportion of stage Ⅰ patients(54.9％, 50/91)was higher than that of stage Ⅱ(22.0％, 20/91)and Ⅲ(23.1％, 21/91). Among TT patients, the proportion of patients with stage Ⅱ(8/18)and Ⅲ(8/18)was higher than patients with stageⅠ(2/18)(χ2=15.898,P=0.003). The incidence of headache, fever, nausea and vomiting, neck stiffness, epilepsy and disturbance of consciousness was statistically analyzed. Compared with CC and CT patients, the incidence of fever(TT:13/18,CC:42/91,CT:50/75,χ2=8.932,P=0.011)and neck stiffness(TT:12/18,CC:38/91,CT:46/75,χ2=7.993,P=0.018)was higher in TT patients. Headache, nausea and vomiting, disturbance of consciousness, and the incidence of epilepsy showed no statistically significant difference. And there was no statistically significant difference in lumbar puncture pressure, chloride, protein and glucose between different genotypes. Conclusion TBM patients with mild illness frequently prompt LTA4H gene rs17525495 locus for the CC type;while patients with severe disease prompt TT type.
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Objective: To assess the effective components of Chaihu Shugan Powder in the treatment of post-stroke depression and its potential mechanisms. Methods: The chemical constituents and targets of Chaihu Shugan Powder were obtained from Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Common targets for stroke and depression were obtained from OMIM, TTD, and PharmGkb databases. Excel was used to filter molecules and targets, so as the Cytoscape software to establish the network between Chinese medicine molecules and target. The biological information annotation database was used to analyze gene function and metabolic pathway. Results: There were 122 Chinese medicine ingredients from databases mteracting with 42 target proteins of post-stroke depression. Finally, five targets including Estrogen receptor (ESR1), prostaglandin G/H synthase 2 (PTGS2), glycogen synthase kinase-3 beta (GSK3β), sodium-dependent dopamine transporter (SLC6A4), and leukotriene A-4 hydrolase (LTA4H) were selected as the action targets for treating post-stroke depression, involved the arachidonic acid metabolism, 5-serotonin ergic synaptic pathway, prolactin signaling pathway, and thyroid hormone signaling pathways, which can treat post-stroke depression by regulating inflammatory response, synapse synthesis, estrogen response, recollection, biosynthesis, drug reaction, and circadian rhythm.Conclusion: The network pharmacology study revealed the underlying mechanisms of Chaihu Shugan Powder for treating the post-stroke depression.
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5-lipoxygenase (5-LOX) and leukotriene A4 hydrolase (LTA4H), as the major targets of 5-LOX branch in the arachidonic acid (AA) metabolic pathway, play an important role in the treatment of inflammation. Rhei Radix et Rhizoma, Notopterygii Rhizoma et Radix and Genitana Macrophyllae Radix have clear anti-inflammation activities. In this paper, the targets of 5-LOX and LTA4H were used as the research carrier, and Hiphop module in DS4.0 (Discovery studio) was used to construct ingredients database for preliminary screening of three traditional Chinese medicines based on target inhibitor pharmacophore, so as to obtain 5-LOX and LTA4H potential active ingredients. The ingredients obtained in initial pharmacophore screening were further screened by using CDOCKER module, and the screening rules were established based on the score of initial compound and the key amino acids to obtain 12 potential 5-LOX inhibitors and 7 potential LTA4H inhibitors. To be more specific, the potential 5-LOX inhibitors included 6 ingredients in Rhei Radix et Rhizoma, such as procyanidins B2-3,3'-O-double gallate and revandchinone 2; four ingredients in notopterygium, such as dodecanoic acid and so on. On the other hand, potential LTA4H inhibitors included revandchinone 1, revandchinone 4 in Rhei Radix et Rhizoma, tridecanoic acid, tetracosanoic acid and methyl eicosanoate in Notopterygii Rhizoma et Radix, montanic acid methyl ester and N-docosanoyl-O-aminobenzoate in Genitana Macrophyllae Radix and so on. The molecular simulation methods were highly efficient and time-saving to obtain the potential inhibitors of 5-LOX and LTA4H, which could provide assistance for discovering the chemical quality indicators of anti-inflammatory efficacy of three Chinese herbs, and may be helpful to promote the whole-process quality control of three Chinese herbs.
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OBJECTIVE Leukotriene B4 (LTB4) biosynthesis and subsequently neutrophilic inflam?mation may provide a potential strategy for the treatment of acute lung injury (ALI) or idiopathic pulmonary fibrosis (IPF). To provide a potential strategy for the treatment of ALI or IPF, we identified potent inhibi?tors of Leukotriene A4 hydrolase (LTA4H), a key enzyme in the biosynthesis of LTB4. METHODS In this study, we identified two known histone deacetylase (HDAC) inhibitors, suberanilohydroxamic acid (SAHA) and its analogue 4-(dimethylamino)-N-〔7-(hydroxyamino)-7-oxoheptyl〕benzamide (M344), as effective inhibitors of LTA4H using enzymatic assay, thermofluor assay, and X- ray crystallographic investigation. We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay. A murine experimental model of ALI was induced by lipopolysaccharide(LPS) inhalation. Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA. We next examined mRNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using qRT- PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA. We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin (BLM)-induced IPF model. RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H, signif?icantly decrease LTB4 levels in neutrophil, and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose. CONCLUSION Collectively, SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.
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Objective To investigate the effects of some compounds,bestatin,tripdiolide,etc,on leukotriene A4hydrolase activity.Methods LTB4,product of leukotriene A4hydrolase,was determined by reverse phase high performance liquid chromatography(PR-HPLC).Bestatin,an inhibitor of LTA4hydrolase was used as a positive control.Results Tripdiolide could inhibit LTA4hydrolase activity in a dose-depen-dent pattern.The50%inhibitory concentration values(IC 50 )was2.58?10 -5 ?g/mL.The other compounds,an-thralin,cyclosporin A,tretinoin,calcipotriene,clobetasol propionate,methotrexate,and erythromycin,had no effects.Conclusions Tripdiolide possibly has anti-inflammatory effect through down-regulation of leukotriene A4hydrolase in psoriasis.