Trends of the Global Burden of Disease Attributable to Cannabis Use Disorder in 204 Countries and Territories, 1990-2019: Results from the Disease Burden Study 2019.

Cannabis is the fourth psychoactive substance to be legalized which are of far-reaching significance to the world. We analyzed data from the 2019 Global Burden of Disease Study (GBD) to estimate the incidence and prevalence of cannabis use disorder (CUD) and calculated the disease burden of CUD in 204 countries and territories and 21 regions over the past three decades. We reported disease burden due to CUD in terms of disability-adjusted life years (DALYs), age-standardized rate (ASR), estimated annual percentage change (EAPC), and analyzed associations between the burden of CUD and sociodemographic index (SDI) quintiles. Globally, the number of incidence cases of CUD was estimated to be increasing by 32.3% from 1990 to 2019 and males are nearly double higher than that of female. DALYs increase 38.6% from 1990. Young people aged 20-24 years old with cannabis use disorder have the highest DALYs in 2019, followed by those younger than 20 years old. India, Canada, USA, Qatar, Kenya, and high SDI quintile areas showed a high burden of disease. Nearly 200 million individuals are cannabis users worldwide, and CUD is a notable condition of GBD. The global cultivation of cannabis, rooted in different cultures, diversified access to cannabis, legalization in controversy, the promotion of medical cannabis, and many other factors promote the global cannabis industry is constantly updated and upgraded. It deserves more discussion in the future in terms of pathophysiological mechanisms, socioeconomics, law, and policy improvement. Supplementary Information: The online version contains supplementary material available at 10.1007/s11469-022-00999-4.

Biphasic modulation of chemerin peptide-induced calcium flux and ERK phosphorylation by amyloid beta peptide / 中国药理学与毒理学杂志

OBJECTIVE The chemokine-like receptor 1 (CMKLR1, ChemR23) is a functional receptor for chemerin, the chemerin-derived nonapeptide (C9), and the amyloid β peptide 1-42 (Aβ42). Because these peptides share little sequence homology, studies were conducted to investigate their pharmaco?logical properties and regulation at CMKLR1. METHODS Cells expressing CMKLR1 were incubated with Aβ42 before stimulation with a strong agonist, the C9 peptide. Calcium mobilization, cAMP inhibition and MAP kinase activation were measured. Intramolecular FRET were determined using CMKLR1 constructs with an ECFP attached to the C- terminus and a FlAsH binding motif embedded in the first intracellular loop (IL1). RESULTS Binding of both Aβ42 and the C9 peptide induced CMKLR1 internal?ization, but only the Aβ42-induced receptor internalization involved clathrin-coated pits. Likewise, Aβ42 but not C9 stimulated β-arrestin 2 translocation to plasma membranes. A robust Ca2+ flux was observed following C9 stimulation, whereas Aβ42 was ineffective even at micromolar concentrations. Despite its low potency in calcium mobilization assay, Aβ42 was able to alter C9 -induced Ca2+ flux in dose-dependent manner: a potentiation effect at 100 pmol·L-1 of Aβ42 was followed by a suppression at 10 nmol·L-1 and further potentiation at 1 μmol·L-1. This unusual and biphasic modulatory effect was also seen in the C9-induced ERK phosphorylation but the dose curve was opposite to that of Ca2+ flux and cAMP inhibition, suggesting a reciprocal regulatory mechanism. Intramolecular FRET assay confirmed that Aβ42 modulates CMKLR1 rather than its downstream signaling pathways. CONCLUSION These findings suggest Aβ42 as an allosteric modulator that can both positively and negatively regulate the activation state of CMKLR1 in a manner that differs from existing allosteric modulatory mechanisms.

Functionally diverse ligands modulate different activation states of the formyl peptide receptor 2, a G protein-coupled receptor / 中国药理学与毒理学杂志

OBJECTIVE To identify the mechanisms by which the formyl peptide receptor 2 (FPR2) mediates both inflammatory and anti-inflammatory signaling in an agonist-dependent manner. METHODS Cells expressing FPR2 were incubated with weak agonists, Aβ42 and Ac2-26, before stimulation with a strong agonist, WKYMVm. Calcium mobilization, cAMP inhibition and MAP kinase activation were measured. Intramolecular FRET were determined using FPR2 constructs with an ECFP attached to the C- terminus and a FlAsH binding motif embedded in the first or third intracellular loop (IL1 or IL3, respectively). RESULTS Aβ42 did not induce significant Ca2 + mobilization, but positively modulated WKYMVm-induced Ca2 + mobilization and cAMP reduction in a dose-variable manner within a narrow range of ligand concentrations. Treating FPR2-expressing cells with Ac2-26, a peptide with anti-inflam?matory activity, negatively modulated WKYMVm-induced Ca2 + mobilization and cAMP reduction. Intra?molecular FRET assay showed that stimulation of the receptor constructs with Aβ42 brought the C-terminal domain closer to IL1 but away from IL3. An opposite conformational change was induced by Ac2-26. The FPR2 conformation induced by Aβ42 corresponded to enhanced ERK phosphorylation and attenuated p38 MAPK phosphorylation, whereas Ac2-26 induced FPR2 conformational change corresponding to elevated p38 MAPK phosphorylation and reduced ERK phosphorylation. CONCLUSION Aβ42 and Ac2-26 induce different conformational changes in FPR2. These findings provide a structural basis for FPR2 mediation of inflammatory vs anti-inflammatory functions and identify a type of receptor modulation that differs from the classic positive and negative allosteric modulation.

Small changes huge impact: the role of thioredoxin 1 in the regulation of apoptosis by S-nitrosylation.

Nitric oxide (NO) is a bioregulator of apoptosis, which has both antiapoptotic and proapoptotic functions. However, the molecular mechanisms responsible for its opposite biological effects are not fully understood. Recent advances in the study of protein S-nitrosylation may provide novel insights into the regulation of apoptotic signaling by NO. S-nitrosylation of some proteins, such as glyceraldehyde-3-phosphate dehydrogenase and Fas, stimulates apoptosis whereas S-nitrosylation of other proteins, such as caspases and Bcl-2, inhibits apoptosis, implying the complexity of the biological function of this post-translational modification. Moreover, the nitrosylation and denitrosylation can be regulated by the thioredoxin 1 (Trx1) system. Studies have shown that Trx1 either transnitrosylates or denitrosylates specific proteins, depending on the redox status of different cysteine residues in Trx1. The Cys73 of S-nitrosylated Trx1 is responsible for its transnitrosylating activity whereas the free thiol in Cys32 of Trx1 for its denitrosylating activity. In this minireview, we provide an overview in the understanding of the interactions between Trx1 and the NO targets, and discuss the role of Trx1-mediated S-nitrosylation and denitrosylation of specific proteins in regulating apoptosis.