ThermoTRP Channels in Nociceptors: Taking a Lead from Capsaicin Receptor TRPV1

Nociceptors with peripheral and central projections express temperature sensitive transient receptor potential (TRP) ion channels, also called thermoTRP’s. Chemosensitivity of thermoTRP’s to certain natural compounds eliciting pain or exhibiting thermal properties has proven to be a good tool in characterizing these receptors. Capsaicin, a pungent chemical in hot peppers, has assisted in the cloning of the first thermoTRP, TRPV1. This discovery initiated the search for other receptors encoding the response to a wide range of temperatures encountered by the body. Of these, TRPV1 and TRPV2 encode unique modalities of thermal pain when exposed to noxious heat. The ability of TRPA1 to encode noxious cold is presently being debated. The role of TRPV1 in peripheral inflammatory pain and central sensitization during chronic pain is well known. In addition to endogenous agonists, a wide variety of chemical agonists and antagonists have been discovered to activate and inhibit TRPV1. Efforts are underway to determine conditions under which agonist-mediated desensitization of TRPV1 or inhibition by antagonists can produce analgesia. Also, identification of specific second messenger molecules that regulate phosphorylation of TRPV1 has been the focus of intense research, to exploit a broader approach to pain treatment. The search for a role of TRPV2 in pain remains dormant due to the lack of suitable experimental models. However, progress into TRPA1’s role in pain has received much attention recently. Another thermoTRP, TRPM8, encoding for the cool sensation and also expressed in nociceptors, has recently been shown to reduce pain via a central mechanism, thus opening a novel strategy for achieving analgesia. The role of other thermoTRP’s (TRPV3 and TRPV4) encoding for detection of warm temperatures and expressed in nociceptors cannot be excluded. This review will discuss current knowledge on the role of nociceptor thermoTRPs in pain and therapy and describes the activator and inhibitor molecules known to interact with them and modulate their activity

Pharmacology of Traditional Herbal Medicines and Their Active Principles Used in the Treatment of Peptic Ulcer, Diarrhoea and Inflammatory Bowel Disease

The endocrine, exocrine and paracrine secretions of the gastrointestinal (GI) tract play a pivotal role in the digestion and absorption of food and orally administered drugs. The secretion of mucus by mucus-secreting cells protects the erosion of the gastric mucosa from the highly acidic gastric juice. The secretion of hydrochloric acid from parietal cells is regulated by acetylcholine, histamine and gastrin. Disturbances in secretory functions of the gastrointestinal tract can lead to several GI complications. Conventional therapies employ a range of drugs that have been pharmacologically well characterised. While these drug molecules are proven to be beneficial, the adverse effects and drug-drug interactions highlight the need for better treatment modalities for GI tract disorders

Impact of phytochemicals on PPAR receptors : implications for disease treatments

Peroxisome proliferator-activated receptors (PPARs) are members of the ligand-dependent nuclear receptor family. PPARs have attracted wide attention as pharmacologic mediators to manage multiple diseases and their underlying signaling targets. They mediate a broad range of specific biological activities and multiple organ toxicity, including cellular differentiation, metabolic syndrome, cancer, atherosclerosis, neurodegeneration, cardiovascular diseases, and inflammation related to their up/downstream signaling pathways. Consequently, several types of selective PPAR ligands, such as fibrates and thiazolidinediones (TZDs), have been approved as their pharmacological agonists. Despite these advances, the use of PPAR agonists is known to cause adverse effects in various systems. Conversely, some naturally occurring PPAR agonists, including polyunsaturated fatty acids and natural endogenous PPAR agonists curcumin and resveratrol, have been introduced as safe agonists as a result of their clinical evidence or preclinical experiments. This review focuses on research on plant-derived active ingredients (natural phytochemicals) as potential safe and promising PPAR agonists. Moreover, it provides a comprehensive review and critique of the role of phytochemicals in PPARs-related diseases and provides an understanding of phytochemical-mediated PPAR-dependent and -independent cascades. The findings of this research will help to define the functions of phytochemicals as potent PPAR pharmacological agonists in underlying disease mechanisms and their related complications

Challenges in integrating herbal medicine in healthcare systems

In this perspective some of the challenges facing the integration of herbal medicine in the healthcare system are described. Such challenges include the need to understand the chemical nature of complex herbal products and their formulation for human therapeutic use, the importance of translation of basic scientific research to human clinical safety and efficacy, provision of a framework for obtaining the evidence required for validation of traditional herbal medicinal products and defining a regulatory system which allows adequate research funding and protection of resulting intellectual property. Requirements for developing standard operating procedures for clinical trials on herbal medicines are described

Organisation of mitochondria in living sensory neurons

AbstractIn this work, we have examined the mitochondrial organisation in living cultured primary dorsal root ganglion (DRG) neurons. Confocal microscopy and the mitochondrial potential-sensitive fluorescent dye 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolo carbocyanine iodide (JC-1) were used to visualise intracellular structures with a high and low membrane potential. Three-dimensional reconstruction revealed a mitochondrial organisation featuring separate highly polarised mitochondria, clusters of mitochondria located mainly at the base of neurite hillocks and filamentous mitochondrial structures. Filamentous mitochondria were distributed along the cell body, especially between neurites. A functional integration between mitochondrial structures is proposed

Light-to-moderate ethanol feeding augments AMPK-α phosphorylation and attenuates SREBP-1 expression in the liver of rats

Purpose: Fatty liver disease, a hepatic manifestation of metabolic syndrome, is one of the major causes of chronic liver diseases. Epidemiological studies suggest that regular light-to-moderate ethanol consumption lowers the risk of developing metabolic disorders including dislipidemia, insulin resistance, type 2 diabetes and fatty liver disease. However, the mechanism(s) of the protective effect of light-to-moderate ethanol consumption on the liver remains unknown. Methods: In the present study, we investigated the effects of light (6%, 0.94 g/kg/day) and moderate (12%, 1.88 g/kg/day) ethanol feeding in rats for 3 weeks on the circulating and hepatic biochemical profiles and on the hepatic protein expression and phosphorylation status of adenosine monophosphate-activated protein kinase-α (AMPK-α) and other down-stream targets of this enzyme including sterol regulatory element-binding protein-1 (SREBP-1), SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase). Results: Despite no significant difference in food-intake among the groups, light ethanol treatment significantly increased the body weight compared to control rats. Serum glucose, insulin, total cholesterol, triglycerides, phospholipids and hepatic cholesterol and triglycerides were not significantly different among the groups. However, serum free fatty acids were significantly reduced with light ethanol treatment. Both light and moderate ethanol treatment significantly increased the hepatic levels of phosphorylated AMPK-α protein and this was associated with significant reduction of SREBP-1 protein expression, suggesting an enhanced fatty acid oxidation. In addition, light ethanol treatment significantly decreased the SCAP protein expression in the liver. However, liver HMG-CoA protein expression was not significantly different with ethanol consumption. Conclusion: Chronic light-to-moderate ethanol consumption increased AMPK activation which was associated with decreased expression of SREBP-1 and SCAP in the liver. Thus, our studies provide mechanistic evidence for the earlier epidemiological studies that indicate light-to-moderate ethanol intake lowers the risk of development of fatty liver disease and other metabolic disorders. Our studies demonstrate that the protective effects of light-to-moderate ethanol arise at least in part by increased phosphorylation of AMPK-α and decreased SREBP-1 expression in the liver. Further studies are warranted to determine the effects of light-to-moderate ethanol on intracellular up-stream and down-stream targets of AMPK and also on the implications of light-to-moderate ethanol in protecting non-alcoholic fatty liver disease