Field Test for Repellency of Cedarwood Oil and Cedrol to Little Fire Ants

Eastern redcedars (Juniperus virginiana L.) are an abundant renew- able resource and represent a potential source of valuable natural products that may serve as natural biocides. The aromatic wood can be extracted to obtain cedarwood oil (CWO) and critical carbon dioxide (CO2) extraction of eastern redcedars gives both high yields and high quality CWO. In this study, CO2-derived CWO and cedrol, the most abundant component of CWO, were field-tested for repellency against the little fire ant (LFA), Wasmannia auropunctata Roger, in a Hawaiian macadamia orchard. Field tests were conducted using chopsticks baited with peanut-butter placed in established LFA trails on macadamia tree trunks and branches. The chopsticks and any ants present were collected after ca. 24 hours and the number of ants determined by visual counting. Four treatments were compared: Hexane only control; mineral oil; CWO; and cedrol. Control chopsticks and chopsticks treated with mineral oil had very high numbers of ants and were statistically equivalent. The CWO-treated chopsticks had significantly fewer LFAs than all the other treatments. Chopsticks treated with cedrol had fewer ants than the control chopsticks but more than the chopsticks treated with CWO. This research suggests that CWO extracts from J. virginianna may provide a renewable source of a natural ant repellent and could help manage this invasive pest

Activation of type-2 cannabinoid receptor inhibits neuroprotective and antiinflammatory actions of glucocorticoid receptor α: when one is better than two.

Endocannabinoids (eCBs) and glucocorticoids (GCs) are two distinct classes of signaling lipids that exert both neuroprotective and immunosuppressive effects; however, the possibility of an actual interaction of their receptors [i.e., type-2 cannabinoid (CB2) and glucocorticoid receptor α (GRα), respectively] remains unexplored. Here, we demonstrate that the concomitant activation of CB2 and GRα abolishes the neuroprotective effects induced by each receptor on central neurons and on glial cells in animal models of remote cell death. We also show that the ability of eCBs and GCs, used individually, to inhibit tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) production from activated human T lymphocytes is lost when CB2 and GRα are activated simultaneously. In addition, signal transduction pathways triggered by concomitant activation of both receptors led to increased levels of GRβ, heat-shock proteins-70 and -90, and p-JNK, as well as to reduced levels of p-STAT6. These effects were reversed only by selectively antagonizing CB2, but not GRα. Overall, our study demonstrates for the first time the existence of a CB2-driven negative cross-talk between eCB and GC signaling in both rats and humans, thus paving the way to the possible therapeutic exploitation of CB2 as a new target for chronic inflammatory and neurodegenerative diseases

Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474

A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomic methods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system.Bio-organic SynthesisMolecular Physiolog

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474

A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomicmethods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system

Dopamine-dependent CB(1) receptor dysfunction at corticostriatal synapses in homozygous PINK1 knockout mice

Recessive mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause early-onset Parkinson's disease (PD). We investigated the interaction between endocannabinoid (eCB) and dopaminergic transmission at corticostriatal synapses in PINK1 deficient mice. Whole-cell patch-clamp and conventional recordings of striatal medium spiny neurons (MSNs) were made from slices of PINK1-/-, heterozygous PINK1+/- mice and wild-type littermates (PINK1+/+). In PINK1+/+ mice, CB1 receptor (CB1R) activation reduced spontaneous excitatory postsynaptic currents (sEPSCs). Likewise, CB1R agonists (ACEA, WIN55,212-3 and HU210) induced a dose-dependent reduction of cortically-evoked excitatory postsynaptic potential (eEPSP) amplitude. While CB1R agonists retained their inhibitory effect in heterozygous PINK1+/- mice, conversely, in PINK1-/- mice they failed to modulate sEPSC amplitude. Similarly, CB1R activation failed to reduce eEPSP amplitude in PINK1-/- mice. Parallel biochemical measurements revealed no significant difference in the levels of the two main eCBs, 2-arachidonoylglycerol (2-AG) and anandamide (AEA) in PINK1-/- striata. Similarly, no change was observed in the enzymatic activity of both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), responsible for eCB hydrolysis. Instead, a significant reduction of binding ability of CB1R agonists was found in PINK1-/- mice. Notably, the CB1R-dependent inhibition of synaptic activity was restored either by amphetamine or after chronic treatment with the D2 dopamine receptor agonist quinpirole. Additionally, CB1R binding activity returned to control levels after chronic pretreatment with quinpirole. Consistent with the hypothesis of a close interplay with dopaminergic neurotransmission, our findings show a CB1R dysfunction at corticostriatal synapses in PINK1-/-, but not in PINK1+/- mice, and provide a mechanistic link to the distinct plasticity deficits observed in both genotypes

Ultrafast photoresponse organic phototransistors based on pyrimido[4,5-g] quinazoline-4,9-dione polymer

We report the photoresponse characteristics of a pyrimido[4,5-g]quinazoline-4,9-dione (PQ) based polymer, PPQ2T-BT-24, which served as an active channel layer in organic phototransistors (OPTs). OPTs using this polymer showed very short rise time of 3 ms and fall time of 59 ms, photoresponsivity (R) of 0.24 and external quantum efficiency (EQE) of 50%. When PC61BM was incorporated into PPQ2T-BT-24, a significantly shortened fall time of 8 ms along with a much-improved rise time of 1 ms were realized. These response times are among the best values reported for OPTs. The R and EQE of the devices using this polymer blend also increased to 0.88 A W-1 and 189%, respectively