Cannabinoid pharmacology: the first 66 years.
Ontology highlight
ABSTRACT:
SUBMITTER: Pertwee RG
PROVIDER: S-EPMC1760722 | biostudies-other | 2006 Jan
REPOSITORIES: biostudies-other
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Project description:Cannabinoid pharmacology has been intensely studied because of cannabis' pervasive medicinal and non-medicinal uses as well as for the therapeutic potential of cannabinoid-based drugs for the treatment of pain, anxiety, substance abuse, obesity, cancer and neurodegenerative disorders. The identification of allosteric modulators of the cannabinoid receptor 1 (CB1) has given a new direction to the development of cannabinoid-based therapeutics due to the many advantages offered by targeting allosteric site(s). Allosteric receptor modulators hold potential to develop subtype-specific and pathway-specific therapeutics. Here we briefly discuss the first-generation of allosteric modulators of CB1 receptor, their structure-activity relationships, signaling pathways and the allosteric binding site(s) on the CB1 receptor. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".
| S-EPMC5540789 | biostudies-literature
Project description:Background: Early life epigenetic programming influences adult health outcomes. Moreover, DNA methylation levels have been found to change more rapidly during the first years of life. Our aim was the identification and characterization of the CpG sites that are modified with time during the first years of life. We hypothesize that these DNA methylation changes would lead to the detection of genes that might be epigenetically modulated by environmental factors during early childhood and which, if disturbed, might contribute to susceptibility to diseases later in life. Methods: The study of the DNA methylation pattern of 485577 CpG sites was performed on 30 blood samples from 15 subjects, collected both at birth and at 5 years old, using Illumina® Infinium 450 k array. To identify differentially methylated CpG (dmCpG) sites, the methylation status of each probe was examined using linear models and the Empirical Bayes Moderated t test implemented in the limma package of R/Bioconductor. Surogate variable analysis was used to account for batch effects. Results: DNA methylation levels significantly changed from birth to 5 years of age in 6641 CpG sites. Of these, 36.79 % were hypermethylated and were associated with genes related mainly to developmental ontology terms, while 63.21 % were hypomethylated probes and associated with genes related to immune function. Conclusions: Our results suggest that DNA methylation alterations with age during the first years of life might play a significant role in development and the regulation of leukocyte-specific functions. This supports the idea that blood leukocytes experience genome remodeling related to their interaction with environmental factors, underlining the importance of environmental exposures during the first years of life and suggesting that new strategies should be take into consideration for disease prevention.
2016-06-15 | GSE83334 | GEO
Project description:Background: Early life epigenetic programming influences adult health outcomes. Moreover, DNA methylation levels have been found to change more rapidly during the first years of life. Our aim was the identification and characterization of the CpG sites that are modified with time during the first years of life. We hypothesize that these DNA methylation changes would lead to the detection of genes that might be epigenetically modulated by environmental factors during early childhood and which, if disturbed, might contribute to susceptibility to diseases later in life. Methods: The study of the DNA methylation pattern of 485577 CpG sites was performed on 30 blood samples from 15 subjects, collected both at birth and at 5 years old, using Illumina® Infinium 450 k array. To identify differentially methylated CpG (dmCpG) sites, the methylation status of each probe was examined using linear models and the Empirical Bayes Moderated t test implemented in the limma package of R/Bioconductor. Surogate variable analysis was used to account for batch effects. Results: DNA methylation levels significantly changed from birth to 5 years of age in 6641 CpG sites. Of these, 36.79 % were hypermethylated and were associated with genes related mainly to developmental ontology terms, while 63.21 % were hypomethylated probes and associated with genes related to immune function. Conclusions: Our results suggest that DNA methylation alterations with age during the first years of life might play a significant role in development and the regulation of leukocyte-specific functions. This supports the idea that blood leukocytes experience genome remodeling related to their interaction with environmental factors, underlining the importance of environmental exposures during the first years of life and suggesting that new strategies should be take into consideration for disease prevention. Longitudinal study including 15 samples
2016-06-15 | E-GEOD-83334 | biostudies-arrayexpress
Project description:BackgroundThere is lack of data on effect modification by age on the association between body mass index (BMI) or waist circumference (WC) and cardiovascular diseases (CVDs). We aimed to investigate the impact of BMI and WC on incident CVDs in individuals aged 40 and 66 years.MethodsOverall, 2 430 510 participants who underwent a national health screening for transitional ages provided by the Korean National Health Insurance Service between 2009 and 2012 were included. The adjusted hazard ratios and 95% confidence intervals for myocardial infarction (MI), ischaemic stroke and CVDs as a composite outcome of MI and ischaemic stroke were calculated using multivariable Cox proportional hazard regression analysis.ResultsDuring a mean follow-up of 7.7 years, 24 884 MI and 29 415 ischaemic stroke events occurred. Among participants aged 40 years, there was a J-shaped association of BMI with incident CVDs, MI and ischaemic stroke with nadir at BMI 18.5-22.9 kg/m2 (P for trend < 0.001 for all). Among those aged 66 years, there were significant U-shaped associations of BMI with CVDs and MI with nadir at a BMI of 23.0-24.9 kg/m2 (P for trend 0.013 and 0.017, respectively). WC was linearly associated with all study outcomes in both age groups (P for trend < 0.001). The impact of general and abdominal obesity on both study outcomes was more prominent in those aged 40 years than in those aged 66 years (P for interaction < 0.001).ConclusionsTo prevent cardiovascular risk, weight loss intervention should be cautiously implemented and individualized according to age. The maintenance of muscle mass may be essential in managing weight loss particularly in older population.
| S-EPMC9891979 | biostudies-literature
Project description:We have previously reported the development of CB-25 and CB-52, two ligands of CB1 and CB2 cannabinoid receptors. We assessed here their functional activity.The effect of the two compounds on forskolin-induced cAMP formation in intact cells or GTP-gamma-S binding to cell membranes, and their action on nociception in vivo was determined.CB-25 enhanced forskolin-induced cAMP formation in N18TG2 cells (EC50 approximately 20 nM, max. stimulation = 48%), behaving as an inverse CB1 agonist, but it stimulated GTP-gamma-S binding to mouse brain membranes, behaving as a partial CB1 agonist (EC50 =100 nM, max. stimulation = 48%). At human CB1 receptors, CB-25 inhibited cAMP formation in hCB1-CHO cells (EC50 = 1600 nM, max. inhibition = 68% of CP-55,940 effect). CB-52 inhibited forskolin-induced cAMP formation by N18TG2 cells (IC50 = 450 nM, max. inhibition = 40%) and hCB1-CHO cells (EC50 = 2600 nM, max. inhibition = 62% of CP-55,940 effect), and stimulated GTP-gamma-S binding to mouse brain membranes (EC50 = 11 nM, max. stimulation approximately 16%). Both CB-25 and CB-52 showed no activity in all assays of CB2-coupled functional activity and antagonized CP55940-induced stimulation of GTP-gamma-S binding to hCB2-CHO cell membranes. In vivo, both compounds, administered i.p., produced dose-dependent nociception in the plantar test carried out in healthy rats, and antagonised the anti-nociceptive effect of i.p. WIN55,212-2. In the formalin test in mice, however, the compounds counteracted both phases of formalin-induced nociception.CB-25 and CB-52 behave in vitro mostly as CB1 partial agonists and CB2 neutral antagonists, whereas their activity in vivo might depend on the tonic activity of cannabinoid receptors.
| S-EPMC1978428 | biostudies-other
Project description:All transcription factors are equal, but some are more equal than others. In the 25 yr since the gene encoding the microphthalmia-associated transcription factor (MITF) was first isolated, MITF has emerged as a key coordinator of many aspects of melanocyte and melanoma biology. Like all transcription factors, MITF binds to specific DNA sequences and up-regulates or down-regulates its target genes. What marks MITF as being remarkable among its peers is the sheer range of biological processes that it appears to coordinate. These include cell survival, differentiation, proliferation, invasion, senescence, metabolism, and DNA damage repair. In this article we present our current understanding of MITF's role and regulation in development and disease, as well as those of the MITF-related factors TFEB and TFE3, and highlight key areas where our knowledge of MITF regulation and function is limited.
| S-EPMC6672050 | biostudies-literature
Project description:ImportanceA frailty index has been proposed as a measure of aging among older individuals. However, few studies have examined whether a frailty index measured at the same chronologic age at younger ages could forecast the development of new age-related conditions.ObjectiveTo examine the association of the frailty index at 66 years of age with incident age-related diseases, disability, and death over 10 years.Design, setting, and participantsThis retrospective nationwide cohort study used the Korean National Health Insurance database to identify 968 885 Korean individuals who attended the National Screening Program for Transitional Ages at 66 years of age between January 1, 2007, and December 31, 2017. Data were analyzed from October 1, 2020, to January 2022.ExposuresFrailty was defined using a 39-item frailty index ranging from 0 to 1.00 as robust (<0.15), prefrail (0.15-0.24), mildly frail (0.25-0.34), and moderately to severely frail (≥0.35).Main outcomes and measuresThe primary outcome was all-cause death. Secondary outcomes were 8 age-related chronic diseases (congestive heart failure, coronary artery disease, stroke, type 2 diabetes, cancer, dementia, fall, and fracture) and disability qualifying for long-term care services. Cox proportional hazards regression and cause-specific and subdistribution hazards regression were used to examine hazard ratios (HRs) and 95% CIs for the outcomes until the earliest of date of death, the occurrence of relevant age-related conditions, 10 years from the screening examination, or December 31, 2019.ResultsAmong the 968 885 participants included in the analysis (517 052 women [53.4%]), the majority were classified as robust (65.2%) or prefrail (28.2%); only a small fraction were classified as mildly frail (5.7%) or moderately to severely frail (1.0%). The mean frailty index was 0.13 (SD, 0.07), and 64 415 (6.6%) were frail. Compared with the robust group, those in the moderately to severely frail group were more likely to be women (47.8% vs 61.7%), receiving medical aid insurance for low income (2.1% vs 18.9%), and less active (median, 657 [IQR, 219-1133] vs 319 [IQR, 0-693] metabolic equivalent task [min/wk]). After adjusting for sociodemographic and lifestyle characteristics, moderate to severe frailty was associated with increased rates of death (HR, 4.43 [95% CI, 4.24-4.64]) and new diagnosis of all chronic diseases, including congestive heart failure (adjusted cause-specific HR, 2.90 [95% CI, 2.67-3.15]), coronary artery disease (adjusted cause-specific HR, 1.98 [95% CI, 1.85-2.12]), stroke (adjusted cause-specific HR, 2.22 [95% CI, 2.10-2.34]), diabetes (adjusted cause-specific HR, 2.34 [95% CI, 2.21-2.47]), cancer (adjusted cause-specific HR, 1.10 [95% CI, 1.03-1.18]), dementia (adjusted cause-specific HR, 3.59 [95% CI, 3.42-3.77]), fall (adjusted cause-specific HR, 2.76 [95% CI, 2.29-3.32]), fracture (adjusted cause-specific HR, 1.54 [95% CI, 1.48-1.62]), and disability (adjusted cause-specific HR, 10.85 [95% CI, 10.00-11.70]). Frailty was associated with increased 10-year incidence of all the outcomes, except for cancer (moderate to severe frailty adjusted subdistribution HR, 0.99 [95% CI, 0.92-1.06]). Frailty at 66 years of age was associated with greater acquisition of age-related conditions (mean [SD] conditions per year for the robust group, 0.14 [0.32]; for the moderately to severely frail group, 0.45 [0.87]) in the next 10 years.Conclusions and relevanceThe findings of this cohort study suggest that a frailty index measured at 66 years of age was associated with accelerated acquisition of age-related conditions, disability, and death over the next 10 years. Measuring frailty at this age may offer opportunities to prevent age-related health decline.
| S-EPMC9982694 | biostudies-literature
Project description:There are at least two types of cannabinoid receptors (CB(1) and CB(2)). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ(9)-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB(1), non-CB(2) established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB(1) and/or CB(2) receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel "CB(3)" cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB(1), non-CB(2) pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB(3) receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB(1) receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB(1)/CB(2) receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB(1), non-CB(2) cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.
| S-EPMC2993256 | biostudies-literature
Project description:BackgroundIn the United States, anal squamous cell carcinoma rates have increased rapidly, particularly among women 50 or older than 66 years of age. As immunosuppression is associated with increased risk, autoimmune conditions may be associated with greater risk of anal squamous cell carcinoma.MethodsWe conducted a population-based, case-control study using Surveillance, Epidemiology, and End Results-Medicare data (2000-2017). Anal squamous cell carcinoma cases (n = 4505) were matched to 200 000 cancer-free controls. Using multivariable logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between 47 autoimmune conditions diagnosed before selection, identified using Medicare claims, and anal squamous cell carcinoma. The Bonferroni threshold was used to correct for multiple comparisons. Population attributable fractions were calculated for conditions nominally associated with anal squamous cell carcinoma.ResultsIn total, 18% of anal squamous cell carcinoma cases and 15% of cancer-free controls had a diagnosed autoimmune condition. Any autoimmune condition was associated with an increased risk of anal squamous cell carcinoma (OR = 1.11, 95% CI = 1.02 to 1.21; population attributable fraction = 1.8%). Anal squamous cell carcinoma was associated with systemic lupus erythematosus (OR = 1.79, 95% CI = 1.32 to 2.42; population attributable fraction = 0.4%) and nominally associated (P < .05) with sarcoidosis (OR = 2.09, 95% CI = 1.30 to 3.37; population-attributable fraction = 0.2%) and psoriasis (OR = 1.28, 95% CI = 1.06 to 1.56; population attributable fraction = 0.5%). Stratified by sex, only women showed statistically significant associations for systemic lupus erythematosus (OR = 1.97, 95% CI = 1.46 to 2.68). Statistically significant interaction was observed by sex for psoriasis (men vs women: OR = 1.68 [95% CI = 1.03 to 4.28] vs OR = 1.12 [95% CI = 0.88 to 1.43]) and polymyalgia rheumatica (OR = 0.33 [95% CI = 0.12 to 0.89] vs OR = 0.99 [95% CI = 0.75 to 1.30]).ConclusionSystemic lupus erythematosus, sarcoidosis, and psoriasis were associated with a moderately increased risk of anal squamous cell carcinoma. Given these conditions' rarity and moderate associations with anal squamous cell carcinoma, autoimmune diseases cannot explain the rising trend in this disease.
| S-EPMC10852610 | biostudies-literature
Project description:Background and purposeWe sought to understand why (-)-cannabidiol (CBD) and (-)-cannabidiol-dimethylheptyl (CBD-DMH) exhibit distinct pharmacology, despite near identical structures.Experimental approachHEK293A cells expressing either human type 1 cannabinoid (CB1 ) receptors or CB2 receptors were treated with CBD or CBD-DMH with or without the CB1 and CB2 receptor agonist CP55,940, CB1 receptor allosteric modulator Org27569 or CB2 receptor inverse agonist SR144528. Ligand binding, cAMP levels and βarrestin1 recruitment were measured. CBD and CBD-DMH binding was simulated with models of human CB1 or CB2 receptors, based on the recently published crystal structures of agonist-bound (5XRA) or antagonist-bound (5TGZ) human CB1 receptors.Key resultsAt CB1 receptors, CBD was a negative allosteric modulator (NAM), and CBD-DMH was a mixed agonist/positive allosteric modulator. CBD and Org27569 shared multiple interacting residues in the antagonist-bound model of CB1 receptors (5TGZ) but shared a binding site with CP55,940 in the agonist-bound model of CB1 receptors (5XRA). The binding site for CBD-DMH in the CB1 receptor models overlapped with CP55,940 and Org27569. At CB2 receptors, CBD was a partial agonist, and CBD-DMH was a positive allosteric modulator of cAMP modulation but a NAM of βarrestin1 recruitment. CBD, CP55,940 and SR144528 shared a binding site in the CB2 receptor models that was separate from CBD-DMH.Conclusion and implicationsThe pharmacological activity of CBD and CBD-DMH in HEK293A cells and their modelled binding sites at CB1 and CB2 receptors may explain their in vivo effects and illuminates the difficulties associated with the development of allosteric modulators for CB1 and CB2 receptors.Linked articlesThis article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.
| S-EPMC6487556 | biostudies-literature