The use of Cannabis sativa by humans dates back to the third millennium BC, and it has been utilized in many forms for multiple purposes, including production of fibre and rope, as food and medicine, and (perhaps most notably) for its psychoactive properties for recreational use. The discovery of Δ9-tetrahydrocannabinol (Δ9-THC) as the main psychoactive phytocannabinoid contained in cannabis by Gaoni and Mechoulam in 1964 (J Am Chem Soc 86, 1646-1647), was the first major step in cannabis research; since then the identification of the chemicals (phytocannabinoids) present in cannabis, the classification of the pharmacological targets of these compounds and the discovery that the body has its own endocannabinoid system (ECS) have highlighted the potential value of cannabis-derived compounds in the treatment of many diseases, such as neurological disorders and cancers. Although the use of Δ9-THC as a therapeutic agent is constrained by its psychoactive properties, there is growing evidence that non-psychoactive phytocannabinoids, derived from both Cannabis sativa and other plant species, as well as non-cannabinoid compounds found in Cannabis sativa, have real potential as therapeutics. This chapter will focus on the possibilities for using these compounds in the prevention and treatment of cardiovascular disease and related metabolic disturbances.

ABSTRACTHeart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of heart failure cases globally, and this incidence is increasing due to extended lifespans and accumulating comorbidities. Emerging evidence suggests that Wnt signaling plays a role in cardiomyocyte hypertrophy and cardiac fibrosis, which are key features of HFpEF. Furthermore, Porcupine (PORCN) inhibitors, which negatively regulate Wnt signaling, have shown promising results in improving cardiac function and reducing cardiac hypertrophy and/or fibrosis. This study investigated whether acute oral administration of the PORCN inhibitor, Wnt‐c59, alters the maladaptive structural and/or functional features in a mouse model of HFpEF. Male mice were given a high‐fat diet and L‐NAME (0.5 g L−1) in drinking water for 5 weeks, followed by a 2‐week intervention of orally administered Wnt‐c59 (5 mg kg−1 day−1). HFpEF mice were characterized by hypertension, cardiac hypertrophy and fibrosis, and diastolic dysfunction, although there was no evidence of activation of Wnt signaling in the heart. Despite this, short‐term treatment of HFpEF mice with Wnt‐c59 ameliorated adverse cardiac remodeling by increasing the ratio of the more compliant collagen type 3 to that of the more tensile collagen type 1 in the heart. Furthermore, Wnt‐c59 also improved diastolic dysfunction, which was associated with the increased cardiac expression of brain natriuretic peptide, a known promoter of ventricular compliance. Our findings demonstrate that even short‐term administration of a PORCN inhibitor improves both the structural and functional features of experimental HFpEF.

Drug discovery from natural sources is going through a renaissance, having spent many decades in the shadow of synthetic molecule drug discovery, despite the fact that natural product-derived compounds occupy a much greater chemical space than those created through synthetic chemistry methods. With this new era comes new possibilities, not least the novel targets that have emerged in recent times and the development of state-of-the-art technologies that can be applied to drug discovery from natural sources. Although progress has been made with some immunomodulating drugs, there remains a pressing need for new agents that can be used to treat the wide variety of conditions that arise from disruption, or over-activation, of the immune system; natural products may therefore be key in filling this gap. Recognising that, at present, there is no authoritative article that details the current state-of-the-art of the immunomodulatory activity of natural products, this in-depth review has arisen from a joint effort between the International Union of Basic and Clinical Pharmacology (IUPHAR) Natural Products and Immunopharmacology Sections, with contributions from a number of world-leading researchers in the field of natural product drug discovery, to provide a "position statement" on what natural products has to offer in the search for new immunomodulatory argents. To this end, we provide a historical look at previous discoveries of naturally occurring immunomodulators, present a picture of the current status of the field and provide insight into the future opportunities and challenges for the discovery of new drugs to treat immune-related diseases.

Emerging evidence suggests that G protein coupled receptor 55 (GPR55) may influence adrenoceptor function/activity in the cardiovascular system. Whether this reflects direct interaction (dimerization) between receptors or signalling crosstalk has not been investigated. This study explored the interaction between GPR55 and the alpha 1A-adrenoceptor (α1A-AR) in the cardiovascular system and the potential to influence function/signalling activities. GPR55 and α1A-AR mediated changes in both cardiac and vascular function was assessed in male wild-type (WT) and GPR55 homozygous knockout (GPR55-/-) mice by pressure volume loop analysis and isolated vessel myography, respectively. Dimerization of GPR55 with the α1A-AR was examined in transfected Chinese hamster ovary-K1 (CHO-K1) cells via Bioluminescence Resonance Energy Transfer (BRET). GPR55 and α1A-AR mediated signalling (extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation) was investigated in neonatal rat ventricular cardiomyocytes using AlphaScreen proximity assays. GPR55-/- mice exhibited both enhanced pressor and inotropic responses to A61603 (α1A-AR agonist), while in isolated vessels, A61603 induced vasoconstriction was attenuated by a GPR55-dependent mechanism. Conversely, GPR55-mediated vasorelaxation was not altered by pharmacological blockade of α1A-ARs with tamsulosin. While cellular studies demonstrated that GPR55 and α1A-AR failed to dimerize, pharmacological blockade of GPR55 altered α1A-AR mediated signalling and reduced ERK1/2 phosphorylation. Taken together, this study provides evidence that GPR55 and α1A-AR do not dimerize to form heteromers, but do interact at the signalling level to modulate the function of α1A-AR in the cardiovascular system.

There is epidemiological evidence that dietary intake of seaweeds is associated with a lower prevalence of chronic diseases. While seaweeds are of high nutritious value, due to their high content of fiber, polyunsaturated fatty acids and minerals, they also contain an abundance of bioactive compounds. There is a growing body of scientific data that these bioactive moieties exert effects that could correct the metabolic dysregulation that is present in obesity and Type 2 diabetes (T2D). In this review we describe how the molecular mechanisms, specific to different tissues, that underly obesity and T2D are influenced by both seaweed extracts and seaweed-derived bioactive molecules. In obesity, modulation of antioxidant capacity and reduction of intracellular ROS levels within tissues, and regulation of signaling pathways involved in enhancing browning of white adipose tissue, have been highlighted as key mechanism and identified as a potential target for optimal energy metabolism. In T2D, management of post-prandial blood glucose by modulating α-glucosidase or α-amylase activities, modulation of the AMPK signaling pathway, and similarly to obesity, reduction of ROS and NO production with subsequent increased expression of antioxidant enzymes have been shown to play a key role in glucose metabolism and insulin signaling. Future studies aimed at discovering new therapeutic drugs from marine natural products should, therefore, focus on bioactive compounds from seaweed that exert antioxidant activity and regulate the expression of key signaling pathways involved in glucose homeostasis, mechanisms that are common to both obesity and T2D management. In addition, more data is required to provide evidence of clinical benefit.

Zn plays an important role in maintaining the anti-oxidant status within the heart and helps to counter the acute redox stress that occurs during myocardial ischaemia and reperfusion. Individuals with low Zn levels are at greater risk of developing an acute myocardial infarction; however, the impact of this on the extent of myocardial injury is unknown. The present study aimed to compare the effects of dietary Zn depletion with in vitro removal of Zn (N,N,N,N-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN)) on the outcome of acute myocardial infarction and vascular function. Male Sprague-Dawley rats were fed either a Zn-adequate (35 mg Zn/kg diet) or Zn-deficient (<1 mg Zn/kg diet) diet for 2 weeks before heart isolation. Perfused hearts were subjected to a 30 min ischaemia/2 h reperfusion (I/R) protocol, during which time ventricular arrhythmias were recorded and after which infarct size was measured, along with markers of anti-oxidant status. In separate experiments, hearts were challenged with the Zn chelator TPEN (10 mu m) before ischaemia onset. Both dietary and TPEN-induced Zn depletion significantly extended infarct size; dietary Zn depletion was associated with reduced total cardiac glutathione (GSH) levels, while TPEN decreased cardiac superoxide dismutase 1 levels. TPEN, but not dietary Zn depletion, also suppressed ventricular arrhythmias and depressed vascular responses to nitric oxide. These findings demonstrate that both modes of Zn depletion worsen the outcome from I/R but through different mechanisms. Dietary Zn deficiency, resulting in reduced cardiac GSH, is the most appropriate model for determining the role of endogenous Zn in I/R injury.

The phospholipid l-α-lysophosphatidylinositol (LPI), an endogenous ligand for GPR55, is elevated in patients with acute coronary syndrome, and a GPR55 antagonist cannabidiol (CBD) reduces experimental ischemia/reperfusion (I/R) injury. While LPI activates multiple signaling pathways, little is known about which ones are important in cardiomyocytes. In this study we explored whether activation of the Rho kinase/ROCK/p38 MAPK pathway is responsible for LPI-induced extension of I/R injury. Using a high-throughput screening method (dynamic mass redistribution; DMR), mouse- and human-induced pluripotent stem cell (iPSC) cardiomyocytes exposed to LPI were shown to exhibit a rapid, sustained, and concentration-dependent (1 nmol L-1-30 μmol L-1) cellular response. Y-27632 (ROCK inhibitor; 10 & 50 μmol L-1) and CBD (1 μmol L-1) both abolished the DMR response to LPI (10 μmol L-1). In murine iPSC cardiomyocytes, LPI-induced ROCK and p38 MAPK phosphorylation, both of which were prevented by Y-27632 and CBD, but did not induce JNK activation or cleavage of caspase-3. In hearts isolated from wild type (WT) mice subjected to 30 minutes global I/R, LPI (10 μmol L-1) administered via the coronary circulation increased infarct size when applied prior to ischemia onset, but not when given at the time of reperfusion. The exacerbation of tissue injury by LPI was not seen in hearts from GPR55-/- mice or in the presence of Y-27632, confirming that injury is mediated via the GPR55/ROCK/p38 MAPK pathway. These findings suggest that raised levels of LPI in the vicinity of a developing infarct may worsen the outcome of AMI.

The 2017 China (Lianyungang) International Medical Technology Conference was held in Lianyungang,Jiangsu Province during November 15-17,2017.During this conference,the Division for Traditional Chinese Medicine and Natural Products Pharmacology of Chinese Pharmacological Society (CNPHARS) and Jiangsu Kanion Pharmaceutical Co. Ltd.jointly held the Forum on R&D and Interna-tionalization of New Drugs and Health Products of Traditional Chinese Medicine.The forum was co-chaired by Professor ZHANG Yong-xiang, President of CNPHARS, Chair of Division for Traditional Chinese Medicine and Natural Products Pharmacology of CNPHARS,and Chair of the Natural Product Section of Inter-national Union of Basic&Clinical Pharmacology(IUPHAR), Professor DU Guan-hua,former President of CNPHARS and Vice-Chair of Division for Traditional Chinese Medicine and Natural Products Pharmacology of CNPHARS,and Dr.XIAO Wei,Chairman of the Board of Jiangsu Kanion Pharmaceutical Co. Ltd. And Vice-Chair of Division for Traditional Chinese Medicine and Natural Products Pharmacology of CNPHARS. More than 70 scholars attended the forum, including four foreign experts [Michael SPEDDING, Secretary-General of IUPHAR; Professor Valérie B. SCHINI-KERTH, Vice-Chair of the Natural Product Section of IUPHAR; Professor Cherry WAINWRGHT, Director of Centre for Natural Product Drugs of Robert Gordon University; Professor InKyeom KIM, Director of the Korean Society of Pharmacology], members of the Division for Traditional Chinese Medicine and Natural Products Pharmacology of CNPHARS and leading researchers at Jiangsu Kanion Pharmaceutical Co.,Ltd.GU Jin-hui,Director of the Division of National Science and Technology Major Project for Drug Innovation,Department of Health Science,Technology and Education,National Health and Family Planning Commission of the People's Republic of China was also invited to attend the forum. Representatives discussed the R&D and internationalization of new drugs and health products of traditional Chinese medicine.The summary of views and advice of some experts was published here for the purpose of promoting domestic and overseas academic exchange, and playing an active role in improving the level of R&D and internationalization of new drugs and health products of traditional Chinese medicine in China.

Emerging evidence indicates that G-protein coupled receptor 55 (GPR55), a nonclassic receptor of the endocannabinoid system that is activated by L-α-lysophosphatidylinositol and various cannabinoid ligands, may regulate endocrine function and energy metabolism. We examined how GPR55 deficiency and modulation affects insulin signaling in skeletal muscle, adipose tissue, and liver alongside expression analysis of proteins implicated in insulin action and energy metabolism. We show that GPR55-null mice display decreased insulin sensitivity in these tissues, as evidenced by reduced phosphorylation of PKB/Akt and its downstream targets, concomitant with increased adiposity and reduced physical activity relative to wild-type counterparts. Impaired tissue insulin sensitivity coincided with reduced insulin receptor substrate-1 abundance in skeletal muscle, whereas in liver and epididymal fat it was associated with increased expression of the 3-phosphoinoistide lipid phosphatase, phosphatase and tensin homolog. In contrast, GPR55 activation enhanced insulin signaling in cultured skeletal muscle cells, adipocytes, and hepatocytes; this response was negated by receptor antagonists and GPR55 gene silencing in L6 myotubes. Sustained GPR55 antagonism in 3T3-L1 adipocytes enhanced expression of proteins implicated in lipogenesis and promoted triglyceride accumulation. Our findings identify GPR55 as a positive regulator of insulin action and adipogenesis and as a potential therapeutic target for countering obesity-induced metabolic dysfunction and insulin resistance.-Lipina, C., Walsh, S. K., Mitchell, S. E., Speakman, J. R., Wainwright, C. L., Hundal, H. S. GPR55 deficiency is associated with increased adiposity and impaired insulin signaling in peripheral metabolic tissues.

IUPHAR brings together two different worlds by creating synergies between them, rather than independent research, and increasing mechanistic research of NPs: Natural/traditional products (NPs): Plant, Microbial, Animal, Marine-based Sometimes Mixtures Chinese, Indian, African-based research Benefits from centuries of natural practice Natural, biological synthesis. New Molecular Chemical Entities (NMEs): Synthetic chemistry-based Frequently multiple metabolites USA and European-based research Benefits from molecular research Synthesis often with lipid/aqueous separation. There is insufficient clinical evidence for NP efficacy or if/how they work. Agents such as curcumin have been claimed to have multiple beneficial effects (>9000 PubMed references), yet Nelson et al. [1] propose that curcumin is a PAIN (pan-assay interference compound): unstable, reactive and non-bioavailable 1. WHO have issued guidelines for the use/research of natural products and traditional medicines. However, both disease and drug targets need defining, because both NMEs and NPs need re-evaluating based on recent genetic data. IUIS (immunology) and IUPHAR are collaborating on inflammation and immune system research as immunopharmacological drug targets are crucial for new drug discovery, particularly in cancer, but immunological targets and protocols are poorly defined for NPs. Scientific education to the developing (and developed) world via our publicly available web sites backed up by expert subcommittees (example: www.guidetopharmacology.org for all drug targets is supported by >90 subcommittees of scientists) will help in a unique cooperative international initiative. We are also establishing industry and clinical priorities to help progress.

This special issue of Biochemical Pharmacology contains proceedings of a joint conference sponsored by the Natural Products Section of the International Union of Basic and Clinical Pharmacology (IUPHAR) and the International Conference on the Mechanism of Action of Nutraceuticals (ICMAN), an organization dedicated to defining actions and clinical benefits of pharmaceuticals and nutraceuticals. Entitled “From Nutraceuticals to Pharmaceuticals: Common Challenges and Approaches”, the conference was held in Aberdeen UK in September 2017. The aim of this gathering was to identify the challenges that must be overcome to identify and characterize novel therapeutics from natural products. Contained in this issue are reviews prepared by conference participants as well as abstracts describing oral and poster presentations.

Magnolol is a biologically active compound isolated from Magnolia officinalis, which has been used as a traditional medicine for the treatment of stroke and myocardial infarction, and exerts vasodilator and anti-platelet activity [1]. We undertook a study to determine whether leaf and bark extracts from a different member of the Magnolia family (Magnolia poasana; MP) not used in traditional medicine, possess similar biological activity. In rat isolated mesenteric arteries pre-contracted with U46619, magnolol induced a concentration-dependent relaxation (Emax 98.8 ± 3.4%; EC50 4.4x10−5 M) that was resistant to L-NAME (10−3 M) demonstrating a mechanism independent of nitric oxide. MP bark extract (0.1–50 μg ml−1) induced a 66.9 ± 11.9% relaxation, which was similarly L-NAME resistant, while the leaf extract induced a smaller relaxation (38.9 ± 3.9%; 50 μg ml−1) that was reduced in the presence of L-NAME (27.8 ± 1.7%; P < 0.05). In rat whole blood, collagen-induced aggregation was modestly reduced by magnolol at 3 & 10 μM (81 ± 9 and 77 ± 13% of control area under the aggregation curve; P = ns) with no effect on maximum aggregation. In contrast, 50 μg ml−1 extracts from both the leaf and the bark of MP caused modest increases in maximum aggregation (128 ± 17% and 113 ± 19% of control) with no significant effect on area under the aggregation curve (117 ± 24% and 79 ± 6% of control; P = 0.05). This is the first demonstration that extracts from Magnolia posana possess biological activity suggesting that, like Magnolia officinalis, it may yield novel biologically active compounds.

Zinc (Zn) supplementation in acute myocardial ischaemia and reperfusion (I/R) is cardioprotective, however the effect of dietary Zn deficiency on I/R outcomes is unknown. Furthermore, Zn deficiency leads to VSMC apoptosis, but its effect on vascular function has not been determined. The aims of this study were therefore to determine the effect of a Zn deficient diet in rats on the outcome of I/R and ex vivo vascular function. Male rats were allocated to one of three groups: 1) Zn adequate (ZA) diet (35mg Zn/kg) fed ad libitum; 2) Zn deficient (ZD) diet (