Microinjection of Adenosine into the Hypothalamic Ventrolateral Preoptic Area Enhances Wakefulness via the A1 Receptor in Rats

Adenosine (AD) is a nucleic acid component that is critical for energy metabolism in the body. AD modulates numerous neural functions in the central nervous system, including the sleep-wake cycle. Previous studies have indicated that the A₁ receptor (A₁R) or A_2A receptor (A_2AR) may mediate the effects of AD on the sleep-wake cycle. The hypothalamic ventrolateral preoptic area (VLPO) initiates and maintains normal sleep. Histological studies have shown A₁R are widely expressed in brain tissue, whereas A_2AR expression is limited in the brain and undetectable in the VLPO. We hypothesize therefore, that AD modulates the sleep-wake cycle through A₁R in the VLPO. In the present study, bilateral microinjection of AD or an AD transporter inhibitor (s-(4-nitrobenzyl)-6-thioinosine) into the VLPO of rats decreased non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. An A₁R agonist (N₆-cyclohexyladenosine) produced similar effects in the VLPO. Microinjection of an A₁R antagonist (8-cyclopentyl-1,3-dimethylxanthine) into the VLPO enhanced NREM sleep and diminished AD-induced wakefulness. These data indicate that AD enhances wakefulness in the VLPO via A₁R in rats.     

The Antitumor Activity of the Novel Compound Jesridonin on Human Esophageal Carcinoma Cells

Jesridonin, a small molecule obtained through the structural modification of Oridonin, has extensive antitumor activity. In this study, we evaluated both its in vitro activity in the cancer cell line EC109 and its in vivo effect on tumor xenografts in nude mice. Apoptosis induced by Jesridonin was determined using an MTT assay, Annexin-V FITC assay and Hoechest 33258 staining. Apoptosis via mitochondrial and death receptor pathways were confirmed by detecting the regulation of MDM2, p53, and Bcl-2 family members and by activation of caspase-3/-8/-9. In addition, vena caudalis injection of Jesridonin showed significant inhibition of tumor growth in the xenograft model, and Jesridonin-induced cell apoptosis in tumor tissues was determined using TUNEL. Biochemical serum analysis of alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), total protein (TP) and albumin (ALB) indicated no obvious effects on liver function. Histopathological examination of the liver, kidney, lung, heart and spleen revealed no signs of JD-induced toxicity. Taken together, these results demonstrated that Jesridonin exhibits antitumor activity in human esophageal carcinomas EC109 cells both in vitro and in vivo and demonstrated no adverse effects on major organs in nude mice. These studies provide support for new drug development.     

Estimation of above-ground biomass of reed (Phragmites communis) based on in situ hyperspectral data in Beijing Hanshiqiao Wetland,China

Wetlands Ecology and Management - Accurate estimates of reed (Phragmites communis) biomass are critical for efficient reed swamp monitoring and management. This study compared the accuracy of...     

Is oral microbiome of children able to maintain resistance and functional stability in response to short-term interference of ingesta?

Dear Editor, A series of studies had focused on the ecological stability of human microbiome (Lozupone et al.,2012;Faith et al.,2013;Moya and Ferrer,2016).Despite the continuous perturbation and the highly personalized composition within the human microbiome (Human Microbiome Project,2012),healthy adults stably maintain their microbial communities in terms of space and time (Faith et al.,2013;Moya and Ferrer,2016;Oh et al.,2016).This stability is proved to be critical for the well-being of human body (Lozupone et al.,2012).On the contrary,major shifts in microbial community composition are often related to diseases (Lynch and Pedersen,2016).     

Sampling and energy evaluation challenges in ligand binding protein design

The steroid hormone 17α‐hydroxylprogesterone (17‐OHP) is a biomarker for congenital adrenal hyperplasia and hence there is considerable interest in development of sensors for this compound. We used computational protein design to generate protein models with binding sites for 17‐OHP containing an extended, nonpolar, shape‐complementary binding pocket for the four‐ring core of the compound, and hydrogen bonding residues at the base of the pocket to interact with carbonyl and hydroxyl groups at the more polar end of the ligand. Eight of 16 designed proteins experimentally tested bind 17‐OHP with micromolar affinity. A co‐crystal structure of one of the designs revealed that 17‐OHP is rotated 180° around a pseudo‐two‐fold axis in the compound and displays multiple binding modes within the pocket, while still interacting with all of the designed residues in the engineered site. Subsequent rounds of mutagenesis and binding selection improved the ligand affinity to nanomolar range, while appearing to constrain the ligand to a single bound conformation that maintains the same “flipped” orientation relative to the original design. We trace the discrepancy in the design calculations to two sources: first, a failure to model subtle backbone changes which alter the distribution of sidechain rotameric states and second, an underestimation of the energetic cost of desolvating the carbonyl and hydroxyl groups of the ligand. The difference between design model and crystal structure thus arises from both sampling limitations and energy function inaccuracies that are exacerbated by the near two‐fold symmetry of the molecule.     

Staphylococcal protein A promotes osteoclastogenesis through MAPK signaling during bone infection

Bone infection is a common and serious complication in the orthopedics field, which often leads to excessive bone destruction and non‐union. Osteoclast is the only type of cells which have the function of bone resorption. Its over activation is closely related to excessive bone loss. Staphylococcus aureus (S. aureus) is a major pathogen causing bone infection, which can produce a large number of strong pathogenic substances staphylococcal protein A (SPA). However, few studies were reported about the effects of SPA on osteoclastogenesis. In our study, we observed that S. aureus activated osteoclasts and promoted bone loss in bone infection specimens. Then, we investigated the effects of SPA on RANKL‐induced osteoclastogenesis in vitro, the results revealed that SPA promoted osteoclastic differentiation and fusion, and enhanced osteoclastic bone resorption. In addition, we also showed that SPA upregulated the expression of NFATc1 and c‐FOS through the activation of MAPK signaling to promote osteoclastogenesis. Our findings might help us better understand the pathogenic role of S. aureus in bone infection and develop new therapeutic strategies for infectious bone diseases.     

Discovery of novel inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 by docking and pharmacophore modeling

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is a potential target for treatment of diabetes and metabolic syndrome. Docking and pharmacophore modeling have been used to discover novel inhibitors of 11beta-HSD1. Several compounds, with large structural diversity and good potency against 11beta-HSD1, have been found and their potency was determined by the enzyme assay. New scaffolds of 11beta-HSD1 inhibitors are also reported.