The endocannabinoid system (ECS) is a major lipid signalling network that plays important pro‐homeostatic (allostatic) roles not only in the nervous system but also in peripheral organs. There is ...increasing evidence that there is a dietary component in the modulation of the ECS. Cannabinoid receptors in hominids co‐evolved with diet, and the ECS constitutes a feedback loop for food selection and energy metabolism. Here, it is postulated that the mismatch of ancient lipid genes of hunter‐gatherers and pastoralists with the high‐carbohydrate diet introduced by agriculture could be compensated for via dietary modulation of the ECS. In addition to the fatty acid precursors of endocannabinoids, the potential role of dietary cannabimimetic phytochemicals in agriculturist nutrition is discussed. Dietary secondary metabolites from vegetables and spices able to enhance the activity of cannabinoid‐type 2 (CB2) receptors may provide adaptive metabolic advantages and counteract inflammation. In contrast, chronic CB1 receptor activation in hedonic obese individuals may enhance pathophysiological processes related to hyperlipidaemia, diabetes, hepatorenal inflammation and cardiometabolic risk. Food able to modulate the CB1/CB2 receptor activation ratio may thus play a role in the nutrition transition of Western high‐calorie diets. In this review, the interplay between diet and the ECS is highlighted from an evolutionary perspective. The emerging potential of cannabimimetic food as a nutraceutical strategy is critically discussed.
Linked Articles
This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc
This commentary is based on a general concern regarding the low level of self-criticism (-evaluation) in the interpretation of molecular pharmacological data published in ethnopharmacology-related ...journals. Reports on potentially new lead structures or pharmacological effects of medicinal plant extracts are mushrooming. At the same time, nonsense in bioassays is an increasing phenomenon in herbal medicine research. Only because a dataset is reproducible does not imply that it is meaningful. Currently, there are thousands of claims of pharmacological effects of medicinal plants and natural products. It is argued that claims to knowledge in ethnopharmacology, as in the exact sciences, should be rationally criticized if they have empirical content as it is the case with biochemical and pharmacological analyses. Here the major problem is the misemployment of the concentration–effect paradigm and the overinterpretation of data obtained
in vitro. Given the almost exponential increase of scientific papers published it may be the moment to adapt to a falsificationist methodology.
For centuries the science of pharmacognosy has dominated rational drug development until it was gradually substituted by target-based drug discovery in the last fifty years. Pharmacognosy stems from ...the different systems of traditional herbal medicine and its “reverse pharmacology” approach has led to the discovery of numerous pharmacologically active molecules and drug leads for humankind. But do botanical drugs also provide effective mixtures? Nature has evolved distinct strategies to modulate biological processes, either by selectively targeting biological macromolecules or by creating molecular promiscuity or polypharmacology (one molecule binds to different targets). Widely claimed to be superior over monosubstances, mixtures of bioactive compounds in botanical drugs allegedly exert synergistic therapeutic effects. Despite evolutionary clues to molecular synergism in nature, sound experimental data are still widely lacking to support this assumption. In this short review, the emerging concept of network pharmacology is highlighted, and the importance of studying ligand-target networks for botanical drugs is emphasized. Furthermore, problems associated with studying mixtures of molecules with distinctly different pharmacodynamic properties are addressed. It is concluded that a better understanding of the polypharmacology and potential network pharmacology of botanical drugs is fundamental in the ongoing rationalization of phytotherapy.
Chemical probes that irreversibly inhibit protein function may be used across species to discover proteins. Combining phenotypic screening and activity-based protein profiling, a new study uncovers a ...discrete lipid signaling pathway regulating lifespan in the worm Caenorhabditis elegans.
Humans can ingest gram amounts of plant secondary metabolites daily through diet. Many of these phytochemicals are bioactive beyond our current understanding because they act through weak negative ...biological feedback mechanisms, undetectable in vitro. Homeostatic-type assessments shed light on the evolutionary implications of the human diet from plants, giving rise to the metabolic plant feedback hypothesis. The hypothesis states that ancient diets rich in carbohydrates coincide with bulk dietary phytochemicals that act as nonspecific inhibitors of metabolic and inflammatory processes. Consequently, food-derived phytochemicals are likely to be equally effective as herbal medicines for these indications. In addition to the ubiquitous flavonoids, terpenoids, and fatty acids in the diet, the likely impact of chronic chlorophyll ingestion on human health is discussed, and data on its modulation of blood glucose levels are presented. A major deduction of this hypothesis is that starchy diets lacking plant secondary metabolites are associated with multimorbidity (lifestyle diseases) including obesity, type 2 diabetes, and cardiovascular disease. It is proposed that the intake of leafy vegetables, spices, and herbal remedies rich in phytochemicals matches the transition and genetic adaptation to early agriculture, playing a compensatory role in the mismatch of old genes and new diets.
Chagas disease remains a major public health risk in Bolivia, particularly among rural indigenous communities. Here we studied the cultural perception of the triatomine vectors and Chagas disease ...among selected rural and urban ethnic groups from different socio-economic and geographical milieus. We focused on the indigenous communities in the Bolivian Chaco where the disease is hyperendemic.
A cross-sectional study using field observations and structured interviews was carried out among 480 informants in five different regions of Bolivia. Additional semi-structured interviews were conducted. Statistical analyses were performed to determine the correlation of socio-economic variables and indigenous Chagas disease knowledge systems. A total of 170 domestic Triatoma infestans vectors were collected and infection with Trypanosoma cruzi was analyzed by real-time PCR.
Triatomine bugs were associated with Chagas disease in 70.2% (n = 480) of the responses (48.0% Ayoreo, 87.5% Chiquitano, 83.9% Guaraní, 72.2% Quechua, 46.1% La Paz citizens and 67.7% Santa Cruz citizens). Generally, indigenous informants have been educated on the association between triatomine bugs and Chagas disease by institutional anti-Chagas disease campaigns. While communities were largely aware of the vectors as a principal mode of disease transmission, rather unexpectedly, health campaigns had little influence on their prevention practices, apparently due to cultural constraints. Overall, 71.9% of the collected domestic vectors in the Chaco region were infected with T. cruzi, matching the high infection rates in the indigenous communities.
Among the Guaraní, Ayoreo and Quechua communities, the groups living in traditional houses have not integrated the scientific knowledge about Chagas disease transmission into their daily hygiene and continue to cohabit with T. infestans vectors hyperinfected with T. cruzi. An effective translation of Western disease concepts into traditional preventive measures is missing because asymptomatic infections are not generally perceived as threat by the communities. New participatory approaches involving existing ethnomedical knowledge systems could be a successful strategy in the control of T. cruzi infection.
Endocannabinoids are arachidonic acid-derived endogenous lipids that activate the endocannabinoid system which plays a major role in health and disease. The primary endocannabinoids are anandamide ...(AEA, N-arachidonoylethanolamine) and 2-arachidonoyl glycerol. While their biosynthesis and metabolism have been studied in detail, it remains unclear how endocannabinoids are transported across the cell membrane. In this review, we critically discuss the different models of endocannabinoid trafficking, focusing on AEA cellular uptake which is best studied. The evolution of the current knowledge obtained with different AEA transport inhibitors is reviewed and the confusions caused by the lack of their specificity discussed. A comparative summary of the most important AEA uptake inhibitors and the studies involving their use is provided. Based on a comprehensive literature analysis, we propose a model of facilitated AEA membrane transport followed by intracellular shuttling and sequestration. We conclude that novel and more specific probes will be essential to identify the missing targets involved in endocannabinoid membrane transport.
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly ...1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15542. Enzymes are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Abstract
The cannabinoid CB
2
receptor (CB
2
R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed ...and widely used to target CB
2
R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB
2
R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB
2
R agonists to study the role of CB
2
R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research.
Astrocytes orchestrate neural development by powerfully coordinating synapse formation and function and, as such, may be critically involved in the pathogenesis of neurodevelopmental abnormalities ...and cognitive deficits commonly observed in psychiatric disorders. Here, we report the identification of a subset of cortical astrocytes that are competent for regulating dopamine (DA) homeostasis during postnatal development of the prefrontal cortex (PFC), allowing for optimal DA-mediated maturation of excitatory circuits. Such control of DA homeostasis occurs through the coordinated activity of astroglial vesicular monoamine transporter 2 (VMAT2) together with organic cation transporter 3 and monoamine oxidase type B, two key proteins for DA uptake and metabolism. Conditional deletion of VMAT2 in astrocytes postnatally produces loss of PFC DA homeostasis, leading to defective synaptic transmission and plasticity as well as impaired executive functions. Our findings show a novel role for PFC astrocytes in the DA modulation of cognitive performances with relevance to psychiatric disorders.
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