In mouse the cannabinoid receptor 2 (CB2) agonists L768242 and (+)‐AM1241, at doses of 30 mg/kg i.p. and 1 and 3 mg/kg i.v., respectively, reduced the second phase of nocifensive behaviors elicited ...by formalin intraplantar injection. This effect was counteracted by the selective CB2 antagonist SR144528 (1 mg/kg i.p.). In rat (+)‐AM1241 (3 and 6 mg/kg i.v.) and L768242 (30 mg/kg i.p.) reduced allodynia elicited by L5–L6 spinal nerve ligation. SR144528 reverted these effects, supporting a CB2‐mediated action. To clarify the mechanisms underlying these effects we investigated CB2 gene expression and function in the nervous system. CB2 mRNA was expressed in spinal cord and dorsal root ganglia (DRG) of both sham and neuropathic rats and was up‐regulated in the ipsilateral spinal cord of neuropathic rats. Expression studies demonstrated the presence of CB2 mRNA in culture of spinal cord microglia. A biomarker, CGRP, was used to investigate modulation of DRG primary afferents by CB2 agonists. Both L768242 and (+)‐AM1241 dose dependently (EC50 of 3.6 and 4.5 nm, respectively) reduced capsaicin‐induced calcitonin gene‐related peptide (CGRP) release. Coadministration of SR144528 resulted in a rightforward shift (pKB 8.1 and 8.2 for (+)‐AM1241 and L768242, respectively) of the dose–response curve. Experiments on capsaicin‐induced CGRP release in tissue from CB1–/– mice ruled out a CB1‐mediated effect. These results confirm that CB2 is present in the central nervous system and suggest that CB2 agonists may elicit their analgesic effect by acting not only at non‐neuronal peripheral sites but also at neural level, making CB2 an attractive target for chronic pain treatment.
REV-ERBα and REV-ERBβ nuclear receptors regulate several physiological processes, including circadian rhythm and metabolism. A previous study reported the REV-ERBα gene to be co-overexpressed with ...ERBB2 in breast cancer cell lines. Surprisingly, we found that several tumor types, including a number of breast cancer cell lines, predominantly express the REV-ERBβ variant. This pattern was independent of ERBB2 and ER status, and opposite to that of non-cancer mammary epithelial HMEC cells, in which REV-ERBα was the major variant. Consistent with this molecular profile, REV-ERB target genes in both circadian and metabolic pathways were derepressed upon silencing of REV-ERBβ, but not REV-ERBα. Strikingly, we found that REV-ERBβ is a determinant of sensitivity to chloroquine, a clinically relevant lysosomotropic agent that suppresses autophagy. The cytoprotective function of REV-ERBβ appears to operate downstream of autophagy blockade. Through compound screening, we identified ARN5187, a novel lysosomotropic REV-ERBβ ligand with a dual inhibitory activity toward REV-ERB-mediated transcriptional regulation and autophagy. Remarkably, although ARN5187 and chloroquine share similar lysosomotropic potency and have a similar effect on autophagy inhibition, ARN5187 is significantly more cytotoxic. Collectively, our results reveal that dual inhibition of REV-ERBβ and autophagy is an effective strategy for eliciting cytotoxicity in cancer cells. Furthermore, our discovery of a novel inhibitor compound of both REV-ERB and autophagy may provide a scaffold for the discovery of new multifunctional anticancer agents.
This paper proposes a general conceptual framework which aims to integrate the concept of network resilience within that of transport security.
In particular, methodological reflections on the role ...of resilience vs vulnerability in connectivity network structures, such as scale-free networks, are highlighted. Operational measures of resilience are also outlined in order to enhance resilience in transport and communication networks.
Current policy strategies which focus on resilience show the relevance of this issue and the need for continuing research on the links between complex transport networks and resilience, mostly by exploring this relationship at different scale levels and its impact on the whole network.
In silico research in drug discovery Terstappen, G C; Reggiani, A
Trends in pharmacological sciences (Regular ed.)
22, Številka:
1
Journal Article
Recenzirano
Target and lead discovery constitute the main components of today's early pharmaceutical research. The aim of target discovery is the identification and validation of suitable drug targets for ...therapeutic intervention, whereas lead discovery identifies novel chemical molecules that act on those targets. With the near completion of the human genome sequencing, bioinformatics has established itself as an essential tool in target discovery and the in silico analysis of gene expression and gene function are now an integral part of it, facilitating the selection of the most relevant targets for a disease under study. In lead discovery, advances in chemoinformatics have led to the design of compound libraries in silico that can be screened virtually. Moreover, computational methods are being developed to predict the drug-likeness of compounds. Thus, drug discovery is already on the road towards electronic R&D.
BACKGROUND AND PURPOSE
URB937 is a peripherally restricted inhibitor of the anandamide‐deactivating enzyme fatty‐acid amide hydrolase (FAAH). Despite its limited access to the CNS, URB937 produces ...marked antinociceptive effects in rodents. URB937 is actively extruded from the CNS by the ATP‐binding cassette (ABC) membrane transporter, Abcg2. Tissue Abcg2 levels are markedly different between males and females, and this transporter is known to limit the access of xenobiotics to the fetoplacental unit in gestating female rodents. In the present study, we investigated the tissue distribution and antinociceptive properties of URB937 in female mice and rats.
EXPERIMENTAL APPROACH
We studied the systemic disposition of URB937 in female mice and the antinociceptive effects of this compound in models of visceral (acetic acid‐induced writhing) and inflammatory nociception (carrageenan‐induced hyperalgesia) in female mice and rats. Furthermore, we evaluated the interaction of URB937 with the blood‐placenta barrier in gestating mice and rats.
KEY RESULTS
Abcg2 restricted the access of URB937 to the CNS of female mice and rats. Nevertheless, URB937 produced a high degree of antinociception in female mice and rats in models of visceral and inflammatory pain. Moreover, the compound displayed a restricted access to placental and fetal tissues in pregnant mice and rats.
CONCLUSIONS AND IMPLICATIONS
Peripheral FAAH blockade with URB937 reduces nociception in female mice and rats, as previously shown for males of the same species. In female mice and rats, Abcg2 limits the access of URB937, not only to the CNS, but also to the fetoplacental unit.
LINKED ARTICLES This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue‐8
•Unique review of resilience and vulnerability in transportation science.•Resilience and vulnerability are seen from a connectivity and accessibility angle.•Both concepts are related to robustness, ...reliability and friability.
This paper aims to adopt a critical stance on the relevance and interpretation of the recently emerging concepts of resilience and vulnerability in transportation studies. It makes a clear distinction between engineering and ecological interpretations of these concepts and offers a systematic typology of various studies in this field. A core element in the study is the linkage between the aforementioned concepts and connectivity/accessibility in transport networks. The methodological findings in the study are put in perspective by addressing also such concepts as robustness, reliability and friability of transport systems.
Background and purpose: Cannabinoid‐2 (CB2) receptor‐selective agonists have shown anti‐nociceptive activity in models of neuropathic and inflammatory pain, and the two agonists most widely used, ...(+/−)AM1241 (2‐iodo‐5‐nitrophenyl)‐1‐(1‐methylpiperidin‐2‐ylmethyl)‐1H‐indol‐3‐yl‐methanone and L768242 (2,3‐dichloro‐phenyl)‐5‐methoxy‐2‐methyl‐3‐(2‐morpholin‐4‐yl‐ethyl)‐indol‐1‐yl‐methanone (GW405833), have been suggested to be protean agonists. Here we investigated the role of the constitutive activity of CB2 receptors in (+)AM1241 and L768242 protean agonism.
Experimental approach: Pharmacological profiles of CB2 receptor ligands were evaluated in Chinese hamster ovary cells expressing recombinant human (hCB2) or rat (rCB2) receptors, by measuring modulation of cAMP. To assess the influence of constitutive activity on pharmacological profile, constitutive activity was abolished by pretreatment with AM630 (6‐iodo‐2‐methyl‐1‐2‐(4‐morpholinyl)ethyl‐1H‐indol‐3‐yl(4‐methoxyphenyl) methanone), followed by extensive washing.
Key results: In cell lines expressing either hCB2 or rCB2 receptors, (+)AM1241 did not reverse forskolin stimulation of cAMP levels. Conversely, L768242 was an inverse agonist at both hCB2 and rCB2 receptors. Abolition of constitutive activity disclosed (+)AM1241 and L768242 agonist activity, while activity of CP55940 5‐(1,1‐dimethylheptyl)‐2‐(1R,2R,5R)‐5‐hydroxy‐2‐(3‐hydroxy‐propyl)‐cyclohexyl‐phenol was unaffected and AM630 became a neutral antagonist. In presence of constitutively active CB2 receptors, (+)AM1241 antagonized CP55940, but when constitutive activity was abolished, it acted as a partial agonist with additive or antagonistic behaviour, depending on concentration.
Conclusions and implications: These results show that (+)AM1241 and L768242 are protean agonists at both hCB2 and rCB2 receptors. Abolition of constitutive activity reveals the agonist activity of these compounds. Thus, differences between in vivo and in vitro profiles of CB2 receptor agonists could be due to different levels of constitutive activity in recombinant versus native CB2 receptors.
•Quartz composites swarfs are used as aggregate in geopolymer based-mortars.•High-waste content samples show very good mechanical performances.•Geopolymer materials are suitable to increase building ...sector sustainability.
The possibility to use quartz-composite industrial swarfs as aggregate component in geopolymer-based mortars, to produce materials for upcycling applications, was evaluated. Two different composites (A-type: 90 wt.% quartz, 10 wt.% unsaturated polyester resin; B-type: 60 wt.% quartz, 40 wt.% acrylic resin) were ground to the grainsize < 2 mm, then mixed with metakaolin and potassium silicate (K2SiO3), with the aim to obtain samples with high waste content. The samples produced, with 60–70–80 wt.% waste, show low water absorption, isolated porosity, and good textural relations among components. Mechanical tests indicated very good results at 7 and 28 days, with best data obtained for A-type 70 wt.% waste-bearing sample showing values of 7.5 MPa for flexural strength and 62.5 MPa for compressive strength. The study revealed that quartz-composite waste, usually destined to landfill, could be effectively recycled using geopolymeric binders, postponing therefore their end-of-life. The new materials are very promising for applications in the building sector, e.g., as tiles, slabs or even structural panels and bricks.
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