This article reviews the development of our knowledge of the actions of histamine which have taken place during the course of the 20th century. Histamine has been shown to have a key physiological role in the control of gastric acid secretion and a pathophysiological role in a range of allergic disorders. The synthesis of, and pharmacological studies on, selective agonists and antagonists has established the existence of four types of histamine receptor and histamine receptor antagonists have found very important therapeutic applications. Thus, in the 1940s, H 1 -receptor antagonists ('the antihistamines') yielded and still provide valuable treatment for allergic conditions such as hay fever and rhinitis. In the late 1970s and 1980s, H 2 -receptor antagonists (in the discovery of which the two authors were personally involved) revolutionised the treatment of peptic ulcer and other gastric acid-related diseases. The H 3 -receptor antagonists, although available since 1987, have been slower to find a therapeutic role. However, the discovery of nonimidazole derivatives such as brain-penetrating H 3 antagonists has provided drugs that are in early-phase clinical trials, possibly for application in obesity, and a variety of central nervous system disorders, such as memory, learning deficits and epilepsy. Finally, the most recently (1999) discovered H 4 receptor promises the potential to provide drugs acting on the immunological system with possible applications in asthma and inflammation.

The WNT signaling pathway is a critical regulator of development and adult tissue homeostasis and becomes dysregulated in many cancer types. Although hyperactivation of WNT signaling is common, the type and frequency of genetic WNT pathway alterations can vary dramatically between different cancers, highlighting possible cancer-specific mechanisms for WNT-driven disease. In this review, we discuss how WNT pathway disruption contributes to tumorigenesis in different organs and how WNT affects the tumor cell and immune microenvironment. Finally, we describe recent and ongoing efforts to target oncogenic WNT signaling as a therapeutic strategy. Significance: WNT signaling is a fundamental regulator of tissue homeostasis and oncogenic driver in many cancer types. In this review, we highlight recent advances in our understanding of WNT signaling in cancer, particularly the complexities of WNT activation in distinct cancer types, its role in immune evasion, and the challenge of targeting the WNT pathway as a therapeutic strategy.

Background and purpose:Cannabis is taken as self-medication by patients with inflammatory bowel disease for symptomatic relief. Cannabinoid receptor agonists decrease inflammation in animal models of colitis, but their effects on the disturbed motility is not known. (-)-Cannabidiol (CBD) has been shown to interact with D 9-tetrahydrocannabinol (THC) in behavioural studies, but it remains to be established if these cannabinoids interact in vivo in inflammatory disorders. Therefore the effects of CBD and THC alone and in combination were investigated in a model of colitis. Experimental approach: The 2,4,6-trinitrobenzene sulphonic acid (TNBS) model of acute colitis in rats was used to assess damage, inflammation (myeloperoxidase activity) and in vitro colonic motility. Sulphasalazine was used as an active control drug. Key results: Sulphasalazine, THC and CBD proved beneficial in this model of colitis with the dose-response relationship for the phytocannabinoids showing a bell-shaped pattern on the majority of parameters (optimal THC and CBD dose, 10 mg·kg -1 ). THC was the most effective drug. The effects of these phytocannabinoids were additive, and CBD increased some effects of an ineffective THC dose to the level of an effective one. THC alone and in combination with CBD protected cholinergic nerves whereas sulphasalazine did not. Conclusions and implications:In this model of colitis, THC and CBD not only reduced inflammation but also lowered the occurrence of functional disturbances. Moreover the combination of CBD and THC could be beneficial therapeutically, via additive or potentiating effects.

In view of the evidence for a role for extracellular ATP in both pancreatic endocrine and exocrine functions, we have investigated the expression of P2X and P2Y receptors in this tissue in neonate and aged rat and mouse. Using immunohistochemistry it was shown that P2X(1), P2X(4), P2X(7), P2Y(1) and P2Y(2) receptors were present in different regions of the rat and mouse pancreas; P2X(3) and P2X(6) receptors were not found, and P2X(5) immunolabelling was only found in some nerves. The pancreatic vasculature of both rat and mouse expressed P2X(1), P2X(2), P2Y(1) and P2Y(2) receptors in the smooth muscle. P2X(1) and P2X(4) receptors were absent in the islets of the neonate pancreas, but were progressively upregulated with age after birth. In contrast, the greatest expression of P2Y(1) in cells from the duct system was in neonate pancreas, while there was no P2Y(1) expression in aged rat pancreas. P2X(7) receptors had a consistent pattern of distribution in all of the groups examined, being located in the outer periphery of the islet. Using antibodies raised against insulin, somatostatin and glucagon, double-labelling immunofluorescence was used to identify P2X(7)-positive cells in different islet of Langerhans cell populations. Our results demonstrated a clear immunoreaction to P2X(7) receptors in islet alpha cells, while no P2X(7) was expressed in beta and delta cells. The significance of the differential expression of P2 receptors in the pancreas during development and ageing, and a possible role for the proliferation and death of the islet cell population are discussed.