Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi Metallo-ß-lactamase-1.

New Delhi Metallo-ß-lactamase-1 (NDM-1), a Zn (II)-dependent enzyme, can catalyze the hydrolysis of almost all ß-lactam antibiotics including carbapenems, resulting in bacterial antibiotic resistance, which threatens public health globally. Based on our finding that H2dedpa is as an efficient NDM-1 inhibitor, a series of H2dedpa derivatives was systematically prepared. These compounds exhibited significant activity against NDM-1, with IC50 values 0.06-0.94 µM. In vitro, compounds 6k and 6n could restore the activity of meropenem against Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis possessing either NDM or IMP. In particular, the activity of meropenem against E. coli producing NDM-4 could be improved up to 5333 times when these two compounds were used. Time-kill cell-based assays showed that 99.9% of P. mirabilis were killed when treated with meropenem in combination with compound 6k or 6n. Furthermore, compounds 6k and 6n were nonhemolytic (HC50 > 1280 µg/mL) and showed low toxicity toward mammalian (HeLa) cells. Mechanistic studies indicated that compounds 6k and 6n inhibit NDM-1 by chelating the Zn2+ ion of the enzyme.

Effect of Irbesartan on Chemerin in the Renal Tissues of Diabetic Rats.

BACKGROUND/AIMS: Chemerin was introduced as a novel adipokine that plays a crucial role in insulin signaling and diabetic nephropathy. Serum chemerin levels are significantly elevated in type 2 diabetes patients with macroalbuminuria. However, the underlying mechanisms remain unclear. We conducted a preliminary investigation of the effects of the renin-angiotensin system (RAS) on chemerin expression in streptozotocin-induced diabetic rats. METHODS: Streptozotocin-induced diabetic rats were randomized into control, diabetic, and irbesartan-treated groups. Real-time polymerase chain reaction was used to detect mRNA expression of chemerin, angiotensin II type 1a receptor (AT1a), angiotensin II type 1b receptor (AT1b) and angiotensin II type 2 receptor (AT2). Immunohistochemical staining was used to detect chemerin in renal tissues. RESULTS: Expression levels of chemerin in renal tissues were significantly elevated in the diabetic group compared to the control group. In the irbesartan-treated group, chemerin expression levels and RAS-related protein levels (i.e. AT1a and AT1b) were markedly decreased compared to the diabetic group. Irbesartan treatment reduced chemerin overexpression and RAS-related protein levels in diabetic rats (i.e. AT1a and AT1b). CONCLUSION: Irbesartan may inhibit intrarenal RAS in diabetic rats, which may affect the expression of chemerin in the kidneys; however, the precise underlying mechanism remains to be determined.

Damage to vascular endothelial cells by high insulin levels is associated with increased expression of ChemR23, and attenuated by PPAR-gamma agonist, rosiglitazone.

OBJECTIVE: This study investigated the effect of different insulin concentrations on the activity of vascular endothelial cells (VECs), and the role of PPARγ activator rosiglitazone (RGZ) on the expression of the chemerin receptor, ChemR23, in insulin-treated human umbilical vein endothelial cells (HUVECs). METHODS: Cell viability was determined in HUVECs treated with different insulin concentrations. Immunofluorescence staining was used to detect ChemR23 expression in insulin-treated HUVECs. Western blot assays were used to evaluate ChemR23 and PPARγ protein expression in insulin-treated HUVECs after pretreatment with PPARγ activator (RGZ) or inhibitor (GW9662). RESULTS: High insulin concentrations significantly inhibited HUVEC cell viability compared to low insulin concentrations, and this inhibition was attenuated by pretreatment with RGZ. High concentrations of insulin caused a significant upregulation of ChemR23 and a significant downregulation of PPARγ. These effects were attenuated by RGZ pretreatment, while PPARγ antagonist, GW9662 reversed this attenuation. CONCLUSION: ChemR23 upregulation may play a role in VEC damage caused by high concentrations of insulin. The protective effect of PPARγ activation in VECs may be mediated via ChemR23 downregulation.

Phytoecdysteroids from Dianthus superbus L.: Structures and anti-neuroinflammatory evaluation.

Six undescribed C27-phytoecdysteroid derivatives, named superecdysones A-F, and ten known analogs were extracted from the whole plant of Dianthus superbus L. Their structures were identified by extensive spectroscopy, mass spectrometric methods, chemical transformations, chiral HPLC analysis, and the single-crystal X-ray diffraction analysis. Superecdysones A and B possess a tetrahydrofuran ring in the side chain and superecdysones C-E are rare phytoecdysones containing a (R)-lactic acid moiety, whereas superecdysone F is an uncommon B-ring-modified ecdysone. Notably, based on the variable temperature (from 333 K to 253 K) NMR experiments of superecdysone C, the missing carbon signals were visible at 253 K and assigned. The neuroinflammatory bioassay of all compounds were evaluated, and 22-acetyl-2-deoxyecdysone, 2-deoxy-20-hydroxyecdysone, 20-hydroxyecdysone, ecdysterone-22-O-benzoate, 20-hydroxyecdysone-20,22-O-R-ethylidene, and acetonide derivative 20-hydroxyecdysterone-20, 22-acetonide significantly suppressed the LPS-induced nitric oxide generation in microglia cells (BV-2), with IC50 values ranging from 6.9 to 23.0 µM. Structure-activity relationships were also discussed. Molecular docking simulations of the active compounds confirmed the possible mechanism of action against neuroinflammations. Furthermore, none compounds showed cytotoxicity against HepG2 and MCF-7. It is the first report about the occurrence and anti-neuroinflammatory activity of the phytoecdysteroids in the genus Dianthus. Our findings demonstrated that ecdysteroids may be used as potential anti-inflammatory drugs.

Neonatal Cri du chat syndrome with atypical facial appearance: A case report.

BACKGROUND: Cri du chat syndrome (CdCS), also known as 5p deletion syndrome (5p-) is a syndrome caused by partial deletion of the 5p chromosome in human beings. The incidence accounts for 1/50000 and the cause of CdCS is related to partial deletion of chromosome 5 short arm (p). CdCS is a sporadic event. Only one case of CdCS was detected by chromosome screening in 125 and 170 pregnant Iranian women[1]. The most prominent clinical manifestations of CdCS are typical high-pitched cat calls, severe mental retardation or mental retardation and is most harmful to both language and growth retardation[2]. CdCS is a chromosome mutation disease which occurs during embryonic development and the symptoms of some cases are extremely atypical. It is difficult to make an early diagnosis and screening in clinic. We can suspect the disease from its atypical manifestations in the weak crying of cats, and chromosome karyotype analysis can find some questionable gene deletion fragments to assist the clinical diagnosis and prognosis of CdCS. CASE SUMMARY: A 2-d-old male child who was admitted to our hospital with a poor postnatal reaction and poor milk intake. The baby's crying and sucking is weak, reaction and feeding time is poor and the baby has nausea and vomiting. Karyotype analysis showed that the chromosomes were 46, XY, deletion (5) p15. Whole genome microarray analysis (named ISCN2013) showed that the chromosomes of the child were male karyotypes and contained three chromosomal abnormalities. Among them, loss of 5p15.2pter (113576-13464559) was associated with cat call syndrome. After 3 mo of follow-up, the child still vomited repeatedly, had poor milk intake, did not return to normal growth, had developmental retardation and a poor directional response. CONCLUSION: Therefore, when cat crying and laryngeal sounds occur in the neonatal period, it should be considered that they are related to CdCS. Chromosome karyotype and genome analysis are helpful for the diagnosis of CdCS.

Soluble epoxide hydrolase inhibitory and anti-inflammatory components from the leaves of Eucommia ulmoides Oliver (duzhong).

Eucommia ulmoides leaves have been used as a functional food and drink in China. The purpose of this study was to identify the bioactive constituents with soluble epoxide hydrolase (sEH) inhibitory activity and anti-inflammatory properties. Twenty-seven known compounds (1-27) were isolated from the leaves of E. ulmoides Oliver, and their structures were identified by NMR and ESIMS analysis; three of these, 2,5-dimethoxy-3-glucopyranosyl cinnamic alcohol (11), foliasalacioside E2 (26), and icariside F2 (27), were obtained from this plant for the first time. Compounds 1-7 exhibited soluble epoxide hydrolase (sEH) inhibitory activity at 100 µM; among them, quercetin (1) and kaempferol (5) displayed potential activities with IC50 values of 22.5 ± 0.9 and 31.3 ± 2.6 µM, respectively, with noncompetitive inhibition mode. Nuclear factor kappa B (NF-κB) inhibitory activity of the isolated compounds was evaluated by the NF-κB liciferase assay in HepG2 cells. Compounds 1, 9, 20, and 27 displayed potent NF-κB inhibitory effects, with IC50 values of 15.14 ± 2.29, 15.23 ± 2.34, 16.88 ± 2.17, and 16.25 ± 2.19 µM, respectively, whereas other compounds showed weak inhibition of NF-κB transcriptional activity ranging from 17.54 to 92.6 µM. A structure-activity relationship of flavonoids 1-9 was also discussed. The results obtained in this work might contribute to the understanding of pharmacological activities of E. ulmoides leaves and further investigation on its potential application values for food and drug.