Biomass distribution pattern and stoichiometric characteristics in main shrub ecosystems in Central Yunnan, China.

Background: With the exacerbating effects of the global climate change and the more and more attention to the study of plant carbon sink, an increasing number of researches on plant carbon sinks has grown. Although many studies exist on shrub vegetation, soil and litters, most studies focus on the community structure, biomass, surface soil of single plant and shrub layer vegetation, and lack the studies which included the potential relationships between climate change and ecological stoichiometric elements, comprehensive research on main species, even herb and litter layer. In order to provide relevant theoretical basis and data support, it is necessary to take the main terrestrial shrub ecosystem in Central Yunnan as the starting point to analyze and explore its carbon sink distribution characteristics, formation causes, the correlation between climatic factors (temperature and precipitation) and stoichiometric elements, which from community and species levels.

Novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines as potent and selective agonists of the 5-HT receptor.

A series of novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines were identified as potent and selective agonists of the 5-HT receptor. Optimizations performed on a previously reported series of racemic tetrahydroquinoline-based tricyclic amines, delivered an advanced drug lead, (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine, which displayed excellent in vitro and in vivo pharmacological profiles.

Responses of short-chain fatty acids production to the addition of various biocarriers to sludge anaerobic fermentation.

This study aimed to evaluate the effects and explore the mechanisms of polyethylene (PE), polyurethane sponge (PUS), and granule activated carbon (GAC) on short-chain fatty acids (SCFAs) production from sludge anaerobic fermentation. Results showed that no matter the biocarrier type, addition of biocarriers increased the diversity of SCFAs. In contrast with GAC, addition of PE and PUS considerably facilitated the accumulation of the total SCFAs.

Discovery of a lead series of potent benzodiazepine 5-HT receptor agonists with high selectivity in functional and binding assays.

A series of potential new 5-HT receptor scaffolds based on a simplification of the clinically studied, 5-HTR agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.

Chrysin induces cell growth arrest, apoptosis, and ER stress and inhibits the activation of STAT3 through the generation of ROS in bladder cancer cells.

Chrysin is a natural flavone that has various biological activities, including antitumor effects. However, the effect of chrysin on bladder cancer cells remains elusive. The present study investigated the effects of chrysin on bladder cancer cells and its underlying mechanisms.

Discovery of APD371: Identification of a Highly Potent and Selective CB Agonist for the Treatment of Chronic Pain.

The discovery of a novel, selective and fully efficacious CB agonist with satisfactory pharmacokinetic and pharmaceutical properties is described. Compound was efficacious in a rat model of osteoarthritis pain following oral administration and, in contrast to morphine, maintained its analgesic effect throughout a 5-day subchronic treatment paradigm. These data were consistent with our hypothesis that full agonist efficacy is required for efficient internalization and recycling of the CB receptor to avoid tachyphylaxis.

An increase in long non-coding RNA PANDAR is associated with poor prognosis in clear cell renal cell carcinoma.

Background: Nearly 30% of clear cell renal cell carcinoma (ccRCC) patients present with metastasis at the time of diagnosis, and the prognosis for these patients is poor. Therefore, novel potential prognostic biomarkers and therapeutic targets for ccRCC could be helpful. Emerging evidence indicates that lncRNAs play important roles in cancer tumorigenesis and could be used as potential biomarkers or therapeutic targets.

Anti-proliferative effects of paeonol on human prostate cancer cell lines DU145 and PC-3.

Paeonol (Pae) is the main active ingredient from the root bark of Paeonia moutan and the grass of Radix Cynanchi Paniculati. Numerous reports indicate that Pae effectively inhibits several types of cancer lines. In this study, we report that Pae hinders prostate cancer growth both in vivo and in vitro.

Expression and functional role of miR-29b in renal cell carcinoma.

Objectives: microRNAs (miRNAs) play essential roles in many tumors, including renal cell carcinoma (RCC). The aim of the present study was to investigate the expression and functional role of miR-29b in RCC and to identify its target genes.

Methods: We determined the expression of miR-29b in clear cell RCC (ccRCC) tissues and RCC cell lines (786-O, A498, and SN12-PM6) using quantitative real-time PCR (qRT-PCR).

Discovery of a novel trans-1,4-dioxycyclohexane GPR119 agonist series.

The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models.

Design and synthesis of new tricyclic indoles as potent modulators of the S1P1 receptor.

Modulators of S1P1 have proven utility for the treatment of autoimmune disease and efforts to identify new agents with improved safety and pharmacokinetic parameters are ongoing. Several new S1P1 chemotypes were designed and optimized for potency and oral bioavailability. These new agents are characterized by a 'tricyclic fused indole array' and are highly potent agonists of the S1P1 receptor.

(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acids as S1P1 Functional Antagonists.

S1P1 is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acids as potent, centrally available, direct acting S1P1 functional antagonists, with favorable pharmacokinetic and safety properties.

Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor.

APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.

Discovery of 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamides as potent and selective CB2 receptor agonists.

The design and synthesis of novel 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamide CB2 selective ligands for the potential treatment of pain is described. Compound (R,R)-25 has good balance between CB2 agonist potency and selectivity over CB1, and possesses overall favorable pharmaceutical properties. It also demonstrated robust in vivo efficacy mediated via CB2 activation in the rodent models of inflammatory and osteoarthritis pain after oral administration.

Fused tricyclic indoles as S1P₁ agonists with robust efficacy in animal models of autoimmune disease.

Two series of fused tricyclic indoles were identified as potent and selective S1P(1) agonists. In vivo these agonists produced a significant reduction in circulating lymphocytes which translated into robust efficacy in several rodent models of autoimmune disease. Importantly, these agonists were devoid of any activity at the S1P(3) receptor in vitro, and correspondingly did not produce S1P(3) mediated bradycardia in telemeterized rat.

[Reverse island flap of digital artery parallel for repairing degloved injuries of fingertip].

Objective: To investigate the effectiveness of reverse island flaps of digital artery parallel for repairing degloved injuries of the fingertip.

Methods: Between June 2008 and January 2010, 13 cases of degloved injuries of the fingertip were treated. There were 8 males and 5 females with an average age of 34 years (range, 19-62 years).

Revealing a core signaling regulatory mechanism for pluripotent stem cell survival and self-renewal by small molecules.

Using a high-throughput chemical screen, we identified two small molecules that enhance the survival of human embryonic stem cells (hESCs). By characterizing their mechanisms of action, we discovered an essential role of E-cadherin signaling for ESC survival. Specifically, we showed that the primary cause of hESC death following enzymatic dissociation comes from an irreparable disruption of E-cadherin signaling, which then leads to a fatal perturbation of integrin signaling.

A short Nur77-derived peptide converts Bcl-2 from a protector to a killer.

Bcl-2 can be converted into a proapoptotic molecule by nuclear receptor Nur77. However, the development of Bcl-2 converters as anticancer therapeutics has not been explored. Here we report the identification of a Nur77-derived Bcl-2-converting peptide with 9 amino acids (NuBCP-9) and its enantiomer, which induce apoptosis of cancer cells in vitro and in animals.

LMP1 protein from the Epstein-Barr virus is a structural CD40 decoy in B lymphocytes for binding to TRAF3.

Epstein-Barr virus is a human herpesvirus that causes infectious mononucleosis and lymphoproliferative malignancies. LMP1 (latent membrane protein-1), which is encoded by this virus and which is essential for transformation of B lymphocytes, acts as a constitutively active mimic of the tumor necrosis factor receptor (TNFR) CD40. LMP1 is an integral membrane protein containing six transmembrane segments and a cytoplasmic domain at the C terminus that binds to intracellular TNFR-associated factors (TRAFs).

Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak.

Recently, we discovered that Humanin (HN), a small endogenous peptide of 24 amino acids, binds to and inhibits the proapoptotic protein Bax. We show here that HN also interacts with the BH3-only Bcl-2/Bax family protein, Bid, as well as a truncated form of Bid (tBid) associated with protease-mediated activation of this proapoptotic protein. Synthetic HN peptide binds purified Bid and tBid in vitro and blocks tBid-induced release of cytochrome c and SMAC from isolated mitochondria, whereas mutant peptides that fail to bind Bid or tBid lack this activity.

Cytoprotective peptide humanin binds and inhibits proapoptotic Bcl-2/Bax family protein BimEL.

Humanin (HN) is a recently identified endogenous peptide that protects cells against cytotoxicity induced by various stimuli. Recently, we showed that HN binds to and inhibits Bax, a proapoptotic Bcl-2 family protein, suggesting a mechanism for HN action. In this study, we identified Bim, a Bcl-2 homology 3-only member of the Bcl-2/Bax family, as an additional HN target protein.

Key molecular contacts promote recognition of the BAFF receptor by TNF receptor-associated factor 3: implications for intracellular signaling regulation.

B cell-activating factor belonging to the TNF family receptor (BAFF-R), a member of the TNFR superfamily, plays a role in autoimmunity after ligation with BAFF ligand (also called TALL-1, BLyS, THANK, or zTNF4). BAFF/BAFF-R interactions are critical for B cell regulation, and signaling from this ligand-receptor complex results in NF-kappaB activation. Most TNFRs transmit signals intracellularly by recruitment of adaptor proteins called TNFR-associated factors (TRAFs).

Enzymatic synthesis of an indole diterpene by an oxidosqualene cyclase: mechanistic, biosynthetic, and phylogenetic implications.

Petromindole (1) is an unusual indole diterpene that bears a triterpene-like carbon skeleton, suggesting biogenesis from 3-(omega-oxido-geranylgeranyl)indole (4). We found that lupeol synthase (LUP1) from Arabidopsis thaliana cyclizes 4 to 1. Chiral HPLC comparisons of racemic 1 (from biomimetic cyclization of N-pivaloyl-4) with the LUP1 product and authentic 1 established the absolute stereochemistry of petromindole (3S) as that of cyclic triterpenes.

Total synthesis of debromoflustramine B via biomimetic alkylative cyclization.

[reaction: see text] The hexahydropyrrolo[2,3-b]indoline skeleton is readily accessed by the zinc triflate-mediated alkylation of tryptamine derivatives. The methodology was employed in a three-step total synthesis of debromoflustramine B.