Battling the known unknowns: a synoptic review of aquatic plastics research from Australia, the United Kingdom and China.

Plastic pollution is a global environmental and human health issue, with plastics now ubiquitous in the environment and biota. Despite extensive international research, key knowledge gaps ("known unknowns") remain around ecosystem-scale and human health impacts of plastics in the environment, particularly in limnetic, coastal and marine systems. Here we review aquatic plastics research in three contrasting geographic and cultural settings, selected to present a gradient of heavily urbanised (and high population density) to less urbanised (and low population density) areas: China, the United Kingdom (UK), and Australia.

Characterization of cannabinoid receptors expressed in Ewing sarcoma TC-71 and A-673 cells as potential targets for anti-cancer drug development.

Aims: Characterizing cannabinoid receptors (CBRs) expressed in Ewing sarcoma (EWS) cell lines as potential targets for anti-cancer drug development.

Main Methods: CBR affinity and function were examined by competitive binding and G-protein activation, respectively. Cannabinoid-mediated cytotoxicity and cell viability were evaluated by LDH, and trypan blue assays, respectively.

Functional traits reveal the presence and nature of multiple processes in the assembly of marine fish communities.

Functional traits can be used to identify the importance of various community assembly mechanisms such as ecological drift, environmental filtering, and limiting similarity. These processes act in concert, not isolation, and different processes may act upon separate traits, potentially concealing the ecological signal of one or more of the mechanisms. Nine functional attributes of marine fish were used to identify changes in the importance of various mechanisms in the assembly of marine fish communities over a latitudinal gradient along the Western Australian coast.

Reduced Tolerance and Asymmetrical Crosstolerance to Effects of the Indole Quinuclidinone Analog PNR-4-20, a G Protein-Biased Cannabinoid 1 Receptor Agonist in Mice: Comparisons with Δ-Tetrahydrocannabinol and JWH-018.

Most cannabinoid 1 receptor (CBR) agonists will signal through both G protein-dependent and -independent pathways in an unbiased manner. Recruitment of -arrestin 2 desensitizes and internalizes receptors, producing tolerance that limits therapeutic utility of cannabinoids for chronic conditions. We developed the indole quinuclidinone (IQD) analog (Z)-2-((1-(4-fluorobenzyl)-1H-indol-3-yl)methylene)quinuclidin-3-one (PNR-4-20) as a novel G protein-biased agonist at CBRs, and the present studies determine if repeated administration of PNR-4-20 produces lesser tolerance to in vivo effects compared with unbiased CBR agonists Δ-tetrahydrocannabinol (Δ-THC) and 1-pentyl-3-(1-naphthoyl)indole (JWH-018).

Atypical Pharmacodynamic Properties and Metabolic Profile of the Abused Synthetic Cannabinoid AB-PINACA: Potential Contribution to Pronounced Adverse Effects Relative to Δ-THC.

Recreational use of marijuana is associated with few adverse effects, but abuse of synthetic cannabinoids (SCBs) can result in anxiety, psychosis, chest pain, seizures and death. To potentially explain higher toxicity associated with SCB use, we hypothesized that AB-PINACA, a common second generation SCB, exhibits atypical pharmacodynamic properties at CB1 cannabinoid receptors (CB1Rs) and/or a distinct metabolic profile when compared to Δ-tetrahydrocannabinol (Δ-THC), the principal psychoactive cannabinoid present in marijuana. Liquid chromatography tandem mass spectrometry (LC/MS) identified AB-PINACA and monohydroxy metabolite(s) as primary phase I metabolites (4OH-AB-PINACA and/or 5OH-AB-PINACA) in human urine and serum obtained from forensic samples.

The tamoxifen derivative ridaifen-B is a high affinity selective CB receptor inverse agonist exhibiting anti-inflammatory and anti-osteoclastogenic effects.

Selective estrogen receptor modulators (SERMs) target estrogen receptors (ERs) to treat breast cancer and osteoporosis. Several SERMs exhibit anti-cancer activity not related to ERs. To discover novel anti-cancer drugs acting via ER-independent mechanisms, derivatives of the SERM tamoxifen, known as the "ridaifen" compounds, have been developed that exhibit reduced or no ER affinity, while maintaining cytotoxicity.

Characterization of structurally novel G protein biased CB agonists: Implications for drug development.

The human cannabinoid subtype 1 receptor (hCBR) is highly expressed in the CNS and serves as a therapeutic target for endogenous ligands as well as plant-derived and synthetic cannabinoids. Unfortunately, acute use of hCBR agonists produces unwanted psychotropic effects and chronic administration results in development of tolerance and dependence, limiting the potential clinical use of these ligands. Studies in β-arrestin knockout mice suggest that interaction of certain GPCRs, including μ-, δ-, κ-opioid and hCBRs, with β-arrestins might be responsible for several adverse effects produced by agonists acting at these receptors.

Synthetic Pot: Not Your Grandfather's Marijuana.

In the early 2000s in Europe and shortly thereafter in the USA, it was reported that 'legal' forms of marijuana were being sold under the name K2 and/or Spice. Active ingredients in K2/Spice products were determined to be synthetic cannabinoids (SCBs), producing psychotropic actions via CB cannabinoid receptors, similar to those of Δ-tetrahydrocannabinol (Δ-THC), the primary active constituent in marijuana. Often abused by adolescents and military personnel to elude detection in drug tests due to their lack of structural similarity to Δ-THC, SCBs are falsely marketed as safe marijuana substitutes.

Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2 Selectivity.

Selective estrogen receptor modulators (SERMs) are used to treat estrogen receptor (ER)-positive breast cancer and osteoporosis. Interestingly, tamoxifen and newer classes of SERMs also exhibit cytotoxic effects in cancers devoid of ERs, indicating a non-estrogenic mechanism of action. Indicative of a potential ER-independent target, reports demonstrate that tamoxifen binds to cannabinoid receptors (CBRs) with affinity in the low μM range and acts as an inverse agonist.

Tamoxifen Isomers and Metabolites Exhibit Distinct Affinity and Activity at Cannabinoid Receptors: Potential Scaffold for Drug Development.

Tamoxifen (Tam) is a selective estrogen receptor (ER) modulator (SERM) that is an essential drug to treat ER-positive breast cancer. Aside from known actions at ERs, recent studies have suggested that some SERMs like Tam also exhibit novel activity at cannabinoid subtype 1 and 2 receptors (CB1R and CB2Rs). Interestingly, cis- (E-Tam) and trans- (Z-Tam) isomers of Tam exhibit over a 100-fold difference in affinity for ERs.

Antinociceptive effects of the 6-O-sulfate ester of morphine in normal and diabetic rats: Comparative role of mu- and delta-opioid receptors.

Unlabelled: This study determined the antinociceptive effects of morphine and morphine-6-O-sulfate (M6S) in both normal and diabetic rats, and evaluated the comparative role of mu-opioid receptors (mu-ORs) and delta-opioid receptors (delta-ORs) in the antinociceptive action of these opioids. In vitro characterization of mu-OR and delta-OR-mediated signaling by M6S and morphine in stably transfected Chinese hamster ovary (CHO-K1) cells showed that M6S exhibited a 6-fold higher affinity for delta-ORs and modulated G-protein and adenylyl cyclase activity via delta-ORs more potently than morphine. Interestingly, while morphine acted as a full agonist at delta-ORs in both functional assays examined, M6S exhibited either partial or full agonist activity for modulation of G-protein or adenylyl cyclase activity, respectively.

Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole quinuclidine analogs.

Our laboratory recently reported that a group of novel indole quinuclidine analogs bind with nanomolar affinity to cannabinoid type-1 and type-2 receptors. This study characterized the intrinsic activity of these compounds by determining whether they exhibit agonist, antagonist, or inverse agonist activity at cannabinoid type-1 and/or type-2 receptors. Cannabinoid receptors activate Gi/Go-proteins that then proceed to inhibit activity of the downstream intracellular effector adenylyl cyclase.

CB1 and CB2 receptors are novel molecular targets for Tamoxifen and 4OH-Tamoxifen.

Tamoxifen (Tam) is classified as a selective estrogen receptor modulator (SERM) and is used for treatment of patients with ER-positive breast cancer. However, it has been shown that Tam and its cytochrome P450-generated metabolite 4-hydroxy-Tam (4OH-Tam) also exhibit cytotoxic effects in ER-negative breast cancer cells. These observations suggest that Tam and 4OH-Tam can produce cytotoxicity via estrogen receptor (ER)-independent mechanism(s) of action.

Taxonomic, spatial and temporal patterns of bleaching in anemones inhabited by anemonefishes.

Background: Rising sea temperatures are causing significant destruction to coral reef ecosystems due to coral mortality from thermally-induced bleaching (loss of symbiotic algae and/or their photosynthetic pigments). Although bleaching has been intensively studied in corals, little is known about the causes and consequences of bleaching in other tropical symbiotic organisms.

Methodology/principal Findings: This study used underwater visual surveys to investigate bleaching in the 10 species of anemones that host anemonefishes.

Design, synthesis, and biological evaluation of aminoalkylindole derivatives as cannabinoid receptor ligands with potential for treatment of alcohol abuse.

Attenuation of increased endocannabinoid signaling with a CB1R neutral antagonist might offer a new therapeutic direction for treatment of alcohol abuse. We have recently reported that a monohydroxylated metabolite of the synthetic aminoalkylindole cannabinoid JHW-073 (3) exhibits neutral antagonist activity at CB1Rs and thus may serve as a promising lead for the development of novel alcohol abuse therapies. In the current study, we show that systematic modification of an aminoalkylindole scaffold identified two new compounds with dual CB1R antagonist/CB2R agonist activity.

Evaluation of (Z)-2-((1-benzyl-1H-indol-3-yl)methylene)-quinuclidin-3-one analogues as novel, high affinity ligands for CB1 and CB2 cannabinoid receptors.

A small library of N-benzyl indolequinuclidinone (IQD) analogs has been identified as a novel class of cannabinoid ligands. The affinity and selectivity of these IQDs for the two established cannabinoid receptor subtypes, CB1 and CB2, was evaluated. Compounds 8 (R=R(2)=H, R(1)=F) and 13 (R=COOCH3, R(1)=R(2)=H) exhibited high affinity for CB2 receptors with Ki values of 1.