The pulmonary vein has a unique electrophysiological property showing an autonomic electrical activity, and this phenomenon has been further focused on as a source of triggers of atrial fibrillation. The pulmonary vein cardiomyocytes have shorter action potential duration, less negative resting membrane potential, and smaller maximum upstroke velocity than those in the left atrium, whose underlying cellular mechanisms may generate arrhythmogenic substrates such as abnormal automaticity and triggered activity. In diseased conditions including sustained atrial tachycardia or chronic volume overload, its arrhythmogenic profile can be further modified through abbreviation of action potential duration of the pulmonary vein myocardium, which may become a cause of reentry. Recently, antiarrhythmic effects of various drugs have been extensively investigated in isolated pulmonary vein preparations. The present review article highlights the recent advances in our understanding of electrophysiological and pharmacological profiles of the pulmonary vein.
Neuroinflammation, inflammation of the brain, is strongly implicated in Alzheimer’s disease (AD), which can be enhanced by systemic inflammation. Therefore, the initiation and progression of AD are affected by systemic diseases such as cardiovascular disease and diabetes. This concept suggests a possible link between periodontitis and AD because periodontitis is a peripheral, chronic infection that elicits a significant systemic inflammatory response. There is now growing clinical evidence that chronic periodontitis is closely linked to the initiation and progression of AD. Recent studies have suggested that leptomeningeal cells play an important role in transducing systemic inflammatory signals to the brain-resident microglia, which in turn initiate neuroinflammation. Furthermore, it is apparent that senescent-type microglia respond in an exaggerated manner to systemic inflammation. It is estimated that a high percentage of adults are suffering from periodontitis, and the prevalence of periodontitis increases with age. Therefore, chronic periodontitis can be a significant source of covert systemic inflammation within the general population. The present review article highlights our current understanding of the link between periodontitis and AD.
l-3,4-Dihydroxyphenylalanine (DOPA) is the metabolic precursor of dopamine, and the single most effective agent in the treatment of Parkinson’s disease. One problem with DOPA therapy for Parkinson’s disease is its cardiovascular side effects including hypotension and syncope, the underlying mechanisms of which are largely unknown. We proposed that DOPA is a neurotransmitter in the central nervous system, but specific receptors for DOPA had not been identified. Recently, the gene product of ocular albinism 1 (OA1) was shown to possess DOPA-binding activity. It was unknown, however, whether or not OA1 is responsible for the actions of DOPA itself. Immunohistochemical examination revealed that OA1 was expressed in the nucleus tractus solitarii (NTS). OA1-positive cells adjacent to tyrosine hydroxylase–positive cell bodies and nerve fibers were detected in the depressor sites of the NTS. OA1 knockdown using oa1-specific shRNA-adenovirus vectors in the NTS reduced the expression levels of OA1 in the NTS. The prior injection of the shRNA against OA1 suppressed the depressor and bradycardic responses to DOPA but not to glutamate in the NTS of anesthetized rats. Thus OA-1 is a functional receptor of DOPA in the NTS, which warrants reexamination of the mechanisms for the therapeutic and untoward actions of DOPA.
Epithelial Na+ transport participates in control of various body functions and conditions: e.g., homeostasis of body fluid content influencing blood pressure, control of amounts of fluids covering the apical surface of alveolar epithelial cells at appropriate levels for normal gas exchange, and prevention of bacterial/viral infection. Epithelial Na+ transport via the transcellular pathway is mediated by the entry step of Na+ across the apical membrane via Epithelial Na+ Channel (ENaC) located at the apical membrane, and the extrusion step of Na+ across the basolateral membrane via the Na+,K+-ATPase located at the basolateral membrane. The rate-limiting step of the epithelial Na+ transport via the transcellular pathway is generally recognized to be the entry step of Na+ across the apical membrane via ENaC. Thus, up-/down-regulation of ENaC essentially participates in regulatory systems of blood pressure and normal gas exchange. Amount of ENaC-mediated Na+ transport is determined by the number of ENaCs located at the apical membrane, activity (open probability) of individual ENaC located at the apical membrane, single channel conductance of ENaC located at the apical membrane, and driving force for the Na+ entry via ENaCs across the apical membrane. In the present review article, I discuss the characteristics of ENaC and how these factors are regulated.
This study determined the regulatory effect of inositol 1,4,5-trisphosphate receptors (IP3Rs) on the basal Ca2+ transients in cardiomyocytes. In cultured neonatal rat ventricular myocytes (NRVMs) at different densities, we used confocal microscopy to assess the effect of IP3Rs on the endogenous spontaneous Ca2+ oscillations through specific activation of IP3Rs with myo-IP3 hexakis (butyryloxymethyl) ester (IP3BM), a membrane permeable IP3, and interference of IP3R expression with shRNA. We found that NRVMs at the monolayer state displayed coordinated Ca2+ transients with less rate, shorter duration, and higher amplitude compared to single NRVMs. In addition, monolayer NRVMs exhibited 4 or 10 times more increased Ca2+ transients in response to phenylephrine, an α-adrenergic receptor agonist, or IP3BM than single NRVMs did, while the transient pattern remained unaltered, suggesting that the sensitivity of intracellular Ca2+ response to IP3R activation is different between single and monolayer NRVMs. However, interference of IP3R expression with shRNA reduced the frequency and amplitude of the spontaneous Ca2+ fluctuates similarly in both densities of NRVMs, resembling the effects of ryanodine receptor inhibition by ryanodine or tetracaine. Our findings suggest that IP3Rs are involved, in part, in the regulation of native Ca2+ transients, in profiles of their initiation and Ca2+ release extent, in developing cardiomyocytes. In addition, caution should be paid in evaluating the behavior of Ca2+ signaling in primary cultured cardiomyocytes at different densities.
The rewarding effects of μ-receptor agonists can be suppressed under several pain conditions. We recently showed that clinically used μ-receptor agonists possess efficacies for relieving the neuropathic pain induced by chemotherapeutic drug in rats; however, it is possible that the use of μ-receptor agonists may trigger the rewarding effects even under chemotherapeutic drug–induced neuropathic pain. Nevertheless, no information is available regarding whether μ-receptor agonists produce psychological dependence under chemotherapeutic drug–induced neuropathic pain. Therefore, we examined the effects of neuropathy induced by chemotherapeutic drugs on the rewarding effects of morphine, oxycodone, and fentanyl in rats. Repeated treatment with oxaliplatin or paclitaxel produced neuropathy as measured by the von Frey test. Rewarding effects produced by antinociceptive doses of μ-receptor agonists were not suppressed under oxaliplatin- or paclitaxel-induced neuropathy. Furthermore, the morphine-induced increase in the release of dopamine from the nucleus accumbens, which is a critical step in the rewarding effects of μ-receptor agonists, was not altered in paclitaxel-treated rats. These results suggest that the rewarding effects of μ-receptor agonists can still be established under oxaliplatin- or paclitaxel-induced neuropathic pain. Therefore, patients should be carefully monitored for psychological dependence on μ-receptor agonists when they are used to control chemotherapeutic drug-induced neuropathic pain.
IAP antagonists increased the antitumor efficacy of X-irradiation in some types of cancers, but their effects on hypoxic cancer cells remain unclarified. We aims to investigate the radiosensitizing effect of an IAP inhibitor AT-406 on cervical cancer cell lines under both normoxia and hypoxia conditions. Hela and Siha cells were treated to investigate the effects of drug administration on cell proliferation, apoptosis, and radiosensitivity. Western blot analysis was used to determine the role of AT-406 in inhibition of IAPs. The pathway of apoptosis was characterized by caspases activity assay. AT-406 potently sensitized Hela cells but not Siha cells to radiation under normoxia. Notably, the radiosensitizing effect of AT-406 on hypoxic cells was more evident than on normoxic cells in both cell lines. Further mechanism studies by western blot showed that under normoxia AT-406 decreased the level of cIAP1 in Hela cells in a dose-dependent manner; while additional downregulation of XIAP expression was induced by AT-406 treatment under hypoxia in both cell lines. Finally, AT-406 works on both extrinsic death receptor and intrinsic mitochondrial apoptosis pathways to activate apoptosis. Totally, AT-406 acts as a strong radiosensitizer in human cervical cancer cells, especially in hypoxic condition.
P-glycoprotein (P-gp)-induced drug resistance is a major road block for successful cancer chemotherapy. Through phenotypic screening, the compound 2-(2-chlorophenylimino)-5-(4-dimethylaminobenzylidene) thiazolidin-4-one (CDBT) was discovered to have potent anti-tumor activity in P-gp over-expressing drug-resistant non-small-cell lung cancer (NSCLC) H460TaxR cells. Here, we report mechanistic investigations of the P-gp–evading anti-tumor activity of CDBT. CDBT is evidently not a P-gp substrate and escapes the P-gp efflux pump. As a novel microtubule and heat shock protein 90 (HSP90) dual targeting inhibitor, CDBT causes the destabilization of microtubules and degradation of HSP90 client proteins CRAF-1 and ERBB2, resulting in cell cycle arrest at the G2/M phase and apoptosis. Furthermore, CDBT effectively inhibits tumor growth by 60.4% relative to the vehicle control after intraperitoneal administration at 30 mg/kg for 11 days and shows no toxicity in normal tissues in the NSCLC H460TaxR xenograft mouse model. Our data suggest a novel drug discovery strategy to combat P-gp over-expressing drug-resistant NSCLC cancer cells with a single therapeutic agent.
Esophageal carcinoma is one of the most virulent malignant diseases and a major cause of cancer-related deaths worldwide. Despite improvements in surgical techniques and perioperative management and surgery combined with chemotherapy and/or radiotherapy, the prognosis of esophageal squamous cell carcinoma (ESCC) at an advanced stage remains poor. ESCC shows a relatively high incidence of EGFR (50% – 70%), and the humanized monoclonal antibody (mAb) cetuximab against EGFR has been undergoing clinical development. However, all responding patients eventually developed acquired resistance to cetuximab. In the current study, we described a cetuximab-sensitive ESCC xeongraft model that developed resistance to cetuximab as a result of FGFR2 gene amplification and overexpression. Inhibition of FGFR2 signaling in this xenograft model restored its sensitivity to cetuximab. The antitumor effect may be induced by inhibition of AKT phosphorylation. These findings suggest that combination therapyincluding cetuximab and FGFR2 inhibition may be a promising strategy to treat ESCC.