TRPM8 and dyspnea: from the frigid and fascinating past to the cool future?

The transient receptor potential melastatin 8 (TRPM8) ion channel is gated by cool and noxious cold temperatures. The activation threshold is in the range of ≈25-28°C, which aligns well with the discharge of airway afferents. TRPM8 is widely expressed across species and evolutionary changes in the TRPM8 amino acid sequence may tune the temperatures at which it is gated. The discovery of TRPM8 and its molecular/biophysical characterization provides a robust candidate for airway afferents responding to cool/cold temperatures. TRPM8 may provide a mechanistic link for the manipulation of respiratory sensations such as dyspnea or mechanisms leading to cold-induced asthma and cough.     

Hydrogen sulphide--a novel mediator of inflammation?

Hydrogen sulphide (H2S) is a naturally occurring gas synthesized from cysteine. It exhibits vasodilator activity (most probably by opening vascular smooth muscle K(ATP) channels), influences leucocyte chemotaxis and promotes vascular smooth muscle cell apoptosis. Increased biosynthesis of H2S has been demonstrated in animal models of septic/endotoxic and haemorrhagic shock, pancreatitis and carrageenan-evoked hindpaw oedema in the rat. In each case, pharmacological inhibition of H2S biosynthesis is anti-inflammatory.     

Psychoneurendocrinology: a science of the past or a new pathway for the future?

Psychoneuroendocrinology is a branch of neuroscience that developed in the beginning of the last century, which investigates the possibility of a cause-effect link between endocrinopathies and mental disorders - with these studies ending in negative results. Psychoneuroendocrinology was then used as a methodological approach for the investigation of neurotransmitter function, on the basis of the observation that neurotransmitters regulate neurohormone and peripheral hormone secretions. Data were obtained for hypothalamic noradrenergic, serotoninergic, dopaminergic, gabaergic and acetylcholinergic functions, which could not be automatically extended to higher brain centers whose impairments might be etiopathogenetically involved in the development of mental disorders. Future studies should focus on new methodological approaches to brain biochemistry, on investigation of genetic, molecular biology, brain imaging, psychoneuroimmunoendocrinology, neuropeptide and neurosteroid secretion in relation to brain endocrine function in mental diseases.     

Ketolides: the future of the macrolides?

The prevalence of antibiotic resistance in bacterial pathogens associated with community-acquired respiratory tract infections is increasing. Ketolides, semi-synthetic derivatives of erythromycin, overcome the macrolide resistance mechanisms found in Streptococcus pneumoniae and Streptococcus pyogenes, two key pathogens. They also have improved potency and longer post-antibiotic effects, while maintaining the antibacterial spectrum of the macrolide class. The new ketolides cethromycin (ABT-773) and telithromycin have overall antibacterial properties that suggest they will be clinically useful new antibiotics and are undergoing clinical development and regulatory review.     

Hydrogen sulfide in inflammation: friend or foe?

Hydrogen sulfide (H(2)S), the gaseous mediator produced by various cells in our body, was recently discovered to play a major role in human physiology despite its toxic nature known for centuries. In addition to its pathophysiological relevance in cardiovascular and neuronal disorders, there is considerable interest in the significance of H(2)S in inflammation. A number of preclinical studies in our laboratory as well as by others, using H(2)S donors and inhibitors of its endogenous synthesis, have provided evidence for both pro- and anti-inflammatory character of H(2)S. But so far, there is a significant lack of support from relevant clinical studies. One of the major contentious issues being variable dose and sampling time, controversies exist on the precise friend or foe nature of this gaseous transmitter. However, it is well accepted that once a clearer picture of the whole story of H(2)S in inflammation emerges, potential for therapeutic manipulations in this field are immense. This review focuses on the intriguing effects of H(2)S in some of the inflammatory conditions such as acute pancreatitis, sepsis, burn injuries and local inflammation of the joints. Active research projects have been undertaken to elucidate the mechanisms of action of H(2)S in inflammation, including neurogenic inflammation and interaction with other biological mediators and pathways. The early and fragmentary evidence obtained holds promise for a successful drug intervention for these inflammatory diseases.     

Depletion of blood neutrophils from patients with sepsis: treatment for the future?

Organ failure arising from severe sepsis accounts for nearly 6 million deaths worldwide per annum. At present there are no specific pharmacological agents available for its treatment and identifying a suitable therapeutic target is urgently needed. Neutrophils appear to be contributing directly to pulmonary damage in severe forms of lung injury and indirectly to the failure of other organs. Blood neutrophils from patients with sepsis possess a phenotype that is indicative of activation and our results show that neutrophils isolated from patients with sepsis exhibit a supranormal adherence to endothelial monolayers treated with pro-inflammatory cytokines. Additional studies reveal that the patients' cells are highly efficient at releasing IL-8. We also demonstrate that organ function is improved upon removing neutrophils from the circulation. In this article we propose that in severe sepsis there is a subpopulation of neutrophils which is actively engaged in pathological insult. The phenotypic characterisation of this subset may provide a novel therapeutic strategy for sepsis that could lead to patient benefit.     

Gut hormones: the future of obesity treatment?

Obesity is a major worldwide health problem. The treatment options are severely limited. The development of novel anti-obesity drugs is fraught with efficacy and safety issues. Consequently, several investigational anti-obesity drugs have failed to gain marketing approval in recent years. Anorectic gut hormones offer a potentially safe and viable option for the treatment of obesity. The prospective utility of gut hormones has improved drastically in recent years with the development of longer acting analogues. Additionally, specific combinations of gut hormones have been demonstrated to have additive anorectic effects. This article reviews the current stage of anti-obesity drugs in development, focusing on gut hormone-based therapies.     

Squalamine: a polyvalent drug of the future?

The purpose of this mini-review is to summarize and highlight the different advances in our understanding of the antimicrobial and antiangiogenic activity of squalamine, a cationic steroid isolated in 1993 from the dogfish shark Squalus Acanthias. Indeed, squalamine has shown to be useful for the treatment of important diseases such as cancers (lung, ovarian, brain and others), age-related macular degeneration (AMD) and the control of body weight in man. All these results led to a question: could we consider squalamine as a polyvalent drug of the future?