A cannabinoid anticancer para-quinone, HU-331, which was synthesized by our group five decades ago, was shown to have very high efficacy against human cancer cell lines in-vitro and against in-vivo ...grafts of human tumors in nude mice. The main mechanism was topoisomerase IIα catalytic inhibition. Later, several groups synthesized related compounds. In the present presentation, we review the publications on compounds synthesized on the basis of HU-331, summarize their published activities and mechanisms of action and report the synthesis and action of novel quinones, thus expanding the structure-activity relationship in these series.
BACKGROUNDChronic pain is a debilitating illness with currently limited therapy, in part due to difficulties in translating treatments derived from animal models to patients. The transient receptor ...potential vanilloid 1 (TRPV1) channel is associated with noxious heat detection and inflammatory pain, and reports of adverse effects in human trials have hindered extensive efforts in the clinical development of TRPV1 antagonists as novel pain relievers.METHODSWe examined 2 affected individuals (A1 and A2) carrying a homozygous missense mutation in TRPV1, rendering the channel nonfunctional. Biochemical and functional assays were used to analyze the mutant channel. To identify possible phenotypes of the affected individuals, we performed psychophysical and medical examinations.RESULTSWe demonstrated that diverse TRPV1 activators, acting at different sites of the channel protein, were unable to open the cloned mutant channel. This finding was not a consequence of impairment in the expression, cellular trafficking, or assembly of protein subunits. The affected individuals were insensitive to application of capsaicin to the mouth and skin and did not demonstrate aversive behavior toward capsaicin. Furthermore, quantitative sensory testing of A1 revealed an elevated heat-pain threshold but also, surprisingly, an elevated cold-pain threshold and extensive neurogenic inflammatory, flare, and pain responses following application of the TRPA1 channel activator mustard oil.CONCLUSIONOur study provides direct evidence in humans for pain-related functional changes linked to TRPV1, which is a prime target in the development of pain relievers.FUNDINGSupported by the Israel Science Foundation (368/19); Teva's National Network of Excellence in Neuroscience grant (no. 0394886) and Teva's National Network of Excellence in Neuroscience postdoctoral fellowship.
Physiological activation by light of the
TRP and TRP-like (TRPL) channels requires the activation of phospholipase Cβ (PLC). The hydrolysis of phosphatidylinositol 4,5, bisphosphate (PIP
) by PLC is ...a crucial step in the still-unclear light activation, while the generation of Diacylglycerol (DAG) by PLC seems to be involved. In this study, we re-examined the ability of a DAG analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG) to activate the TRPL channels expressed in HEK cells. Unlike previous studies, we added OAG into the cytosol via a patch-clamp pipette and observed robust activation of the expressed TRPL channels. However, TRPL channel activation was much slower than the physiologically activated TRPL by light. Therefore, we used a picosecond-fast optically activated DAG analogue, OptoDArG. Inactive OptoDArG was added into the intracellular solution with the patch-clamp pipette, and it slowly accumulated on the surface membrane of the recorded HEK cell in the dark. A fast application of intense UV light to the recorded cell resulted in a robust and relatively fast TRPL-dependent current that was greatly accelerated by the constitutively active TRPL
pore-region mutation. However, this current of the mutant channel was still considerably slower than the native light-induced TRPL current, suggesting that DAG alone is not sufficient for TRPL channel activation under physiological conditions.
Magnetic particle hyperthermia is an approved cancer treatment that harnesses thermal energy generated by magnetic nanoparticles when they are exposed to an alternating magnetic field (AMF). Thermal ...stress is either directly cytotoxic or increases the susceptibility of cancer cells to standard therapies, such as radiation. As with other thermal therapies, the challenge with nanoparticle hyperthermia is controlling energy delivery. Here, we describe the design and implementation of a prototype pre-clinical device, called HYPER, that achieves spatially confined nanoparticle heating within a user-selected volume and location.PURPOSEMagnetic particle hyperthermia is an approved cancer treatment that harnesses thermal energy generated by magnetic nanoparticles when they are exposed to an alternating magnetic field (AMF). Thermal stress is either directly cytotoxic or increases the susceptibility of cancer cells to standard therapies, such as radiation. As with other thermal therapies, the challenge with nanoparticle hyperthermia is controlling energy delivery. Here, we describe the design and implementation of a prototype pre-clinical device, called HYPER, that achieves spatially confined nanoparticle heating within a user-selected volume and location.Spatial control of nanoparticle heating was achieved by placing an AMF generating coil (340 kHz, 0-15 mT), between two opposing permanent magnets. The relative positions between the magnets determined the magnetic field gradient (0.7 T/m-2.3 T/m), which in turn governed the volume of the field free region (FFR) between them (0.8-35 cm3). Both the gradient value and position of the FFR within the AMF (-14, 14x, -18, 18y, -30, 30z) mm are values selected by the user via the graphical user interface (GUI). The software then controls linear actuators that move the static magnets to adjust the position of the FFR in 3D space based on user input. Within the FFR, the nanoparticles generate hysteresis heating; however, outside the FFR where the static field is non-negligible, the nanoparticles are unable to generate hysteresis loss power.DESIGNSpatial control of nanoparticle heating was achieved by placing an AMF generating coil (340 kHz, 0-15 mT), between two opposing permanent magnets. The relative positions between the magnets determined the magnetic field gradient (0.7 T/m-2.3 T/m), which in turn governed the volume of the field free region (FFR) between them (0.8-35 cm3). Both the gradient value and position of the FFR within the AMF (-14, 14x, -18, 18y, -30, 30z) mm are values selected by the user via the graphical user interface (GUI). The software then controls linear actuators that move the static magnets to adjust the position of the FFR in 3D space based on user input. Within the FFR, the nanoparticles generate hysteresis heating; however, outside the FFR where the static field is non-negligible, the nanoparticles are unable to generate hysteresis loss power.We verified the performance of the HYPER to design specifications by independently heating two nanoparticle-rich areas of a phantom placed within the volume occupied by the AMF heating coil.VERIFICATIONWe verified the performance of the HYPER to design specifications by independently heating two nanoparticle-rich areas of a phantom placed within the volume occupied by the AMF heating coil.
The goal of this study was to estimate the prevalence of spirometry testing among patients with asthma and chronic obstructive pulmonary disease (COPD) in general practices (GPs) in Germany. This ...retrospective cross-sectional study was based on data from the Disease Analyzer database (IQVIA), This retrospective cross-sectional study included all patients with at least one confirmed asthma or COPD diagnosis in one of those 50 general practices in Germany between January 2020, and January 2021, as well as at least one visit to these general practices between January 2021, and January 2022. The main outcomes of the study aimed to ascertain the proportion of spirometry testing among asthma and COPD patients between January 2021, and January 2022, overall, and separately, in men, women, six age groups (≤30, 31−40, 41−50, 51−60, 61, 70, >70), and patients who received at least one prescription of anti-asthma or anti-COPD drugs. This study included 8835 patients with asthma only, 5597 with COPD only, and 1897 with both asthma and COPD diagnoses. Of these, 27.2% of COPD patients, 7% of asthma patients, and 54.7% of asthma + COPD patients, received spirometry testing during the study period. Among COPD and asthma + COPD patients, the prevalence of spirometry testing was much higher in women than in men (COPD: 31.6% vs. 23.2%; asthma + COPD: 59.6% vs. 46.3%) and much higher in treated than in non-treated patients (COPD: 31.7% vs. 15.0%; asthma + COPD: 57.5% vs. 27.8%). The prevalence of spirometry testing was relatively low among COPD and asthma patients followed in GP practices, but usually higher in female patients, treated patients, and patients suffering from both asthma and COPD.
The aim of this review is to present some of the recent publications on cannabidiol (CBD; 2), a major non‐psychoactive constituent of Cannabis, and to give a general overview. Special emphasis is ...laid on biochemical and pharmacological advances, and on novel mechanisms recently put forward, to shed light on some of the pharmacological effects that can possibly be rationalized through these mechanisms. The plethora of positive pharmacological effects observed with CBD make this compound a highly attractive therapeutic entity.
Abstract Transient receptor potential (TRP) channels are essential components of biological sensors that detect changes in the environment in response to a myriad of stimuli. A major difficulty in ...the study of TRP channels is the lack of pharmacological agents that modulate most members of the TRP superfamily. Notable exceptions are the thermoTRPs, which respond to either cold or hot temperatures and are modulated by a relatively large number of chemical agents. In the present study we demonstrate by patch clamp whole cell recordings from Schneider 2 and Drosophila photoreceptor cells that carvacrol, a known activator of the thermoTRPs, TRPV3 and TRPA1 is an inhibitor of the Drosophila TRPL channels, which belongs to the TRPC subfamily. We also show that additional activators of TRPV3, thymol, eugenol, cinnamaldehyde and menthol are all inhibitors of the TRPL channel. Furthermore, carvacrol also inhibits the mammalian TRPM7 heterologously expressed in HEK cells and ectopically expressed in a primary culture of CA3–CA1 hippocampal brain neurons. This study, thus, identifies a novel inhibitor of TRPC and TRPM channels. Our finding that the activity of the non-thermoTRPs, TRPL and TRPM7 channels is modulated by the same compound as thermoTRPs, suggests that common mechanisms of channel modulation characterize TRP channels.
Changes of cholesterol level in the plasma membrane of cells have been shown to modulate ion channel function. The proposed mechanisms underlying these modulations include association of cholesterol ...to a single binding site at a single channel conformation, association to a highly flexible cholesterol binding site adopting multiple poses, and perturbation of lipid rafts. These perturbations have been shown to induce reversible targeting of mammalian transient receptor potential C (TRPC) channels to the cholesterol-rich membrane environment of lipid rafts. Thus, the observed inhibition of TRPC channels by methyl-β-cyclodextrin (MβCD), which induces cholesterol efflux from the plasma membrane, may result from disruption of lipid rafts. This perturbation was also shown to disrupt multimolecular signaling complexes containing TRPC channels. The
TRP and TRP-like (TRPL) channels belong to the TRPC channel subfamily. When the
TRPL channel was expressed in S2 or HEK293 cells and perfused with MβCD, the TRPL current was abolished in less than 100 s, fitting well the fast kinetic phase of cholesterol sequestration experiments in cells. It was thus suggested that the fast kinetics of TRPL channel suppression by MβCD arise from disruption of lipid rafts. Accordingly, lipid raft perturbation by cholesterol sequestration could give clues to the function of lipid environment in TRPC channel activity and its mechanism.
Background: Inflammatory bowel disease (IBD) is of high medical and socioeconomic relevance. Moderate and severe disease courses often require treatment with biologics. The aim of this study was to ...evaluate machine learning (ML)-based methods for the prediction of biologic therapy in IBD patients using a large prescription database. Methods: The present retrospective cohort study utilized a longitudinal prescription database (LRx). Patients with at least one prescription for an intestinal anti-inflammatory agent from a gastroenterologist between January 2015 and July 2021 were included. Patients who had received an initial biologic therapy prescription (infliximab, adalimumab, golimumab, vedolizumab, or ustekinumab) were categorized as the “biologic group”. The potential predictors included in the machine learning-based models were age, sex, and the 100 most frequently prescribed drugs within 12 months prior to the index date. Six machine learning-based methods were used for the prediction of biologic therapy. Results: A total of 122,089 patients were included in this study. Of these, 15,824 (13.0%) received at least one prescription for a biologic drug. The Light Gradient Boosting Machine had the best performance (accuracy = 74%) and was able to correctly identify 78.5% of the biologics patients and 72.6% of the non-biologics patients in the testing dataset. The most important variable was prednisolone, followed by lower age, mesalazine, budesonide, and ferric iron. Conclusions: In summary, this study reveals the advantages of ML-based models in predicting biologic therapy in IBD patients based on pre-treatment and demographic variables. There is a need for further studies in this regard that take into account individual patient characteristics, i.e., genetics and gut microbiota, to adequately address the challenges of finding optimal treatment strategies for patients with IBD.
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