Pyrazolone compounds could inhibit CES1 and ameliorates fat accumulation during adipocyte differentiation.

Carboxylesterase 1 (CES1), a member of the serine hydrolase superfamily, is involved in a wide range of xenobiotic and endogenous substances metabolic reactions in mammals. The inhibition of CES1 could not only alter the metabolism and disposition of related drugs, but also be benefit for treatment of metabolic disorders, such as obesity and fatty liver disease. In the present study, we aim to develop potential inhibitors of CES1 and reveal the preferred inhibitor structure from a series of synthetic pyrazolones (compounds 1-27). By in vitro high-throughput screening method, we found compounds 25 and 27 had non-competitive inhibition on CES1-mediated N-alkylated d-luciferin methyl ester (NLMe) hydrolysis, while compound 26 competitively inhibited CES1-mediated NLMe hydrolysis. Additionally, Compounds 25, 26 and 27 can inhibit CES1-mediated fluorescent probe hydrolysis in live HepG2 cells with effect. Besides, compounds 25, 26 and 27 could effectively inhibit the accumulation of lipid droplets in mouse adipocytes cells. These data not only provided study basis for the design of newly CES1 inhibitors. The present study not only provided the basis for the development of lead compounds for novel CES1 inhibitors with better performance, but also offered a new direction for the explore of candidate compounds for the treatment of hyperlipidemia and related diseases.

A meta-analysis of randomized controlled trials of fixation versus nonfixation of mesh in laparoscopic total extraperitoneal inguinal hernia repair.

BACKGROUND: Mesh fixation during laparoscopic total extraperitoneal (TEP) inguinal hernia repair is still controversial. Although many surgeons considered it necessary to fix the mesh, some published studies supported elimination of mesh fixation. Therefore, a meta-analysis based on randomized controlled trials (RCTs) was conducted to compare the effectiveness and safety of fixation versus nonfixation of mesh in TEP. METHODS: RCTs were identified from PubMed, Embase, the Cochrane Library, SCI, and the Chinese Biomedical Literature Database (CBM). Two reviewers assessed the quality of the studies and extracted data independently. The methodological quality was evaluated according to the Cochrane Handbook 5.0.2. Statistical analysis was conducted using the Cochrane software RevMan 5.0.21. RESULTS: Six RCTs involving 772 patients were included. The nonfixation group had advantages in length of hospital stay [MD =-0.37, 95% CI (-0.57, -0.17), p = 0.0003], operative time [MD = -4.19, 95% CI (-7.77, -0.61), p = 0.02], and costs. However, there was no statistically significant difference in hernia recurrence [OR = 2.01, 95% CI (0.37, 11.03), p = 0.42], time to return to normal activities [MD = -0.13, 95% CI (-0.45, 0.19), p = 0.43], seroma [OR = 1.25, 95% CI (0.30, 5.18), p = 0.75], and postoperative pain on postoperative day 1 [MD = -0.21, 95% CI (-0.52, 0.10), p = 0.18] and day 7 [MD = -0.11, 95% CI (-0.42, 0.20), p = 0.47]. CONCLUSIONS: Without increasing the risk of early hernia recurrence, the nonfixation of mesh in TEP appears to be a safe alternative that is associated with less costs, shorter operative time, and hospital stay for the selected patients. Further adequately powered RCTs are required to clarify whether mesh fixation is necessary for the patients with different types of hernias and larger hernia defects.

A copper chaperone for superoxide dismutase that confers three types of copper/zinc superoxide dismutase activity in Arabidopsis.

The copper chaperone for superoxide dismutase (CCS) has been identified as a key factor integrating copper into copper/zinc superoxide dismutase (CuZnSOD) in yeast (Saccharomyces cerevisiae) and mammals. In Arabidopsis (Arabidopsis thaliana), only one putative CCS gene (AtCCS, At1g12520) has been identified. The predicted AtCCS polypeptide contains three distinct domains: a central domain, flanked by an ATX1-like domain, and a C-terminal domain. The ATX1-like and C-terminal domains contain putative copper-binding motifs. We have investigated the function of this putative AtCCS gene and shown that a cDNA encoding the open reading frame predicted by The Arabidopsis Information Resource complemented only the cytosolic and peroxisomal CuZnSOD activities in the Atccs knockout mutant, which has lost all CuZnSOD activities. However, a longer AtCCS cDNA, as predicted by the Munich Information Centre for Protein Sequences and encoding an extra 66 amino acids at the N terminus, could restore all three, including the chloroplastic CuZnSOD activities in the Atccs mutant. The extra 66 amino acids were shown to direct the import of AtCCS into chloroplasts. Our results indicated that one AtCCS gene was responsible for the activation of all three types of CuZnSOD activity. In addition, a truncated AtCCS, containing only the central and C-terminal domains without the ATX1-like domain failed to restore any CuZnSOD activity in the Atccs mutant. This result indicates that the ATX1-like domain is essential for the copper chaperone function of AtCCS in planta.

AtHVA22 gene family in Arabidopsis: phylogenetic relationship, ABA and stress regulation, and tissue-specific expression.

HVA22 is an ABA- and stress-inducible gene first isolated from barley (Hordeum vulgare L.). Homologues of HVA22 have been found in plants, animals, fungi and protozoa, but not in prokaryotes, suggesting that HVA22 plays a unique role in eukaryotes. Five HVA22 homologues, designated AtHVA22a, b, c, d and e, have been identified in Arabidopsis. These five AtHVA22 homologues can be separated into two subfamilies, with AtHVA22a, b and c grouped in one subfamily and AtHVA22d and e in the other. Phylogenetic analyses show that AtHVA22d and e are closer to barley HVA22 than to AtHVA22a, b and c, suggesting that the two subfamilies had diverged before the divergence of monocots and dicots. The distribution and size of exons of AtHVA22 homologues and barley HVA22 are similar, suggesting that these genes are descendents of a common ancestor. AtHVA22 homologues are differentially regulated by ABA, cold, dehydration and salt stresses. These four treatments enhance AtHVA22a, d and e expression, but have little or even suppressive effect on AtHVA22c expression. ABA and salt stress induce AtHVA22b expression, but cold stress suppresses ABA induction of this gene. Expression of AtHVA22d is the most tightly regulated by these four treatments among the five homologues. In general, AtHVA22 homologues are expressed at a higher level in flower buds and inflorescence stems than in rosette and cauline leaves. The expression level of these homologues in immature siliques is the lowest among all tissues analyzed. It is suggested that some of these AtHVA22 family members may play a role in stress tolerance, and others are involved in plant reproductive development.