Role of nitric oxide on the electrophysiological properties of isolated rabbit atrioventricular node by extracellular field potential during atrial fibrillation

Introduction: The aim of the present study was to determine direct effects of NO modulation on protective electrophysiological properties of atrioventricular node (AV node) in the experimental model of AF in rabbit. Methods: Isolated perfused rabbit AV nodal preparations were used in two groups. In the first group (N=7), LNAME (50μM) was applied. In the second group (N=12), different concentrations of L - argenine (250 μM - 5000 μM) were added to the solution. Programmed stimulation protocols were used to quantify AV nodal conduction time, refractoriness and zone of concealment. AF protocol was executed by software with coupling intervals (ranging from 75–125 msec). Results: L-NAME had depressive effects on basic AV nodal properties. L-Arginine (250μM) had direct inhibitory effects on nodal conduction time, Wenckebach and refractoriness. Significant increases in the number of concealed beats were induced by L-Arginine (500 μM). Number of concealed beats were increased from 700.7±33.7 to 763±21 msec (P<0.05). Trend of zone of concealment prolongation in a frequency-dependent model was abrogated by Larginine (250, 5000 μM). Conclusion: NO at low concentration (in the presence of L-NAME) had facilitatory role on AV nodal properties, but at high concentration (in the presence of L-arginine) enhanced protective role of AV node during AF. Biphasic modulatory role of NO may affect protective behavior of AV node during AF. © 2011, Iranian Society of Physiology and Pharmacology. All rights reserved

Elucidating role of reactive oxygen species (Ros) in cisplatin chemotherapy: A focus on molecular pathways and possible therapeutic strategies

The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Impact of alternative solid state forms and specific surface area of high-dose, hydrophilic active pharmaceutical ingredients on tabletability

YesIn order to investigate the effect of using different solid state forms and specific surface area (TBET) of active pharmaceutical ingredients on tabletability and dissolution performance, the mono- and dihydrated crystalline forms of chlorothiazide sodium and chlorothiazide potassium (CTZK) salts were compared to alternative anhydrous and amorphous forms, as well as to amorphous microparticles of chlorothiazide sodium and potassium which were produced by spray drying and had a large specific surface area. The tablet hardness and tensile strength, porosity, and specific surface area of single-component, convex tablets prepared at different compression pressures were characterized. Results confirmed the complexity of the compressibility mechanisms. In general it may be concluded that factors such as solid-state form (crystalline vs amorphous), type of hydration (presence of interstitial molecules of water, dehydrates), or specific surface area of the material have a direct impact on the tabletability of the powder. It was observed that, for powders of the same solid state form, those with a larger specific surface area compacted well, and better than powders of a lower surface area, even at relatively low compression pressures. Compacts prepared at lower compression pressures from high surface area porous microparticles presented the shortest times to dissolve, when compared with compacts made of equivalent materials, which had to be compressed at higher compression pressures in order to obtain satisfactory compacts. Therefore, materials composed of nanoparticulate microparticles (NPMPs) may be considered as suitable for direct compaction and possibly for inclusion in tablet formulations as bulking agents, APIs, carriers, or binders due to their good compactibility performanceSolid State Pharmaceutical Cluster (SSPC), supported by Science Foundation Ireland under Grant No. 07/SRC/B1158

"Lymph node revealing solution: A prospective study on 35 patients with colorectal carcinomas "

Lymph node dissection is of prime importance for accurate staging of colorectal carcinomas. Since a great number of small lymph nodes are missed in the traditional method, several fat clearing solutions have been introduced for easier detection of smaller lymph nodes. In this study we evaluated the efficacy of a new fat clearing solution so-called lymph node revealing solution (LNRS) in colectomy specimens of patients with colorectal carcinoma from year 2000 till 2002, thirty five colectomy specimens with less than 4 metastatic lymph nodes received in the pathology department of IKMC, were selected and re-evaluated using the LNRS. By using this solution 456 additional lymph nodes and 16 more metastatic lymph nodes were detected resulting in upstaging of 3 patients from Duke’s B to C. In all patients categorized as Nx (regional lymph nodes not assessed) by the traditional method, lymph nodes were detected after employment of LNRS. The mean diameter of dissected lymph nodes was significantly smaller than the traditional method (0.268 versus 0.429, P&lt;0.000001). LNRS in comparison with previous solutions is inexpensive, rapid and easy to use. We propose use of this solution in all Duke’s B and patients with no lymph node detection by traditional method

Geochronology of early human settlements in Java: What is at stake?

International audienceDespite the fact Java Island is a volcanic area, it has been challenging to build a chronological framework of its early human settlements, from the oldest Lower Pleistocene Homo erectus up to the dispersals that followed the Last Glacial Maximum (LGM). Various dating methods are implemented on volcanic effluents, sedimentary deposits, speleothems and also on fossils (including direct analyses on human remains), thanks to radiometric and palaeodosimetric grounded techniques as well as to magnetostratigraphy. However, a number of results must be considered with caution, in order to identify specific bias originating from reworking of volcanic effluents or post-depositional geochemical evolution. Such bias might well explain apparent contradictions between absolute dating results and other chronologically significant proxies (e.g. biostratigraphy). Converging age estimates resulting from the implementation of several dating methods, though being sometimes less precise, seem to have a higher reliability

Acute direct effects of cyclosporine on extracellular field potential of isolated rabbit AV node during experimental atrial fibrillation

Introduction: Previous studies have indicated a relationship between MPTP pore and AV nodal rate-dependent properties. The aim of present study was to determine acute direct effects of cyclosporine on extracellular field potential of isolated rabbit AV node during experimental atrial fibrillation. Methods: In one group of male New Zealand rabbits (1.5-2.5 kg) cumulative concentrations of cyclosporine (0.5 -10 μm) were applied on isolated perfused atrio-nodal preparation (n=7). Extracellular field potential recording was sampled during specific stimulation protocols (recovery, zone of concealment and atrial fibrillation) in the presence of drug on electrophysiological properties of AV-node. Results: Cyclosporine significantly decreased the ventricular rate (HH mean) from 231.8 ± 5.7 to 277.4 ± 14.6 msec and functional refractory period during AF (AF FRP) from 138.3 ± 7.5 to 161.2 ± 10.31 msec in control and treated groups, respectively. Effective refractory period during AF (AF ERP) was significantly decreased by cyclosporine 10 mM compared to control group (p<0.05). Conclusion: Cyclosporine-evoked slowing ventricular heart rate during AF was induced by increasing functional refractoy period and ZOC. A possible mechanism can be through blocking of MPT pores

Broad-spectrum preclinical antitumor activity of chrysin: Current trends and future perspectives

10.3390/biom10101374Biomolecules1010Jan-4

Regulation of the epithelial Na+ channel by Nedd4 and ubiquitination.

The epithelial Na+ channel (ENaC) is comprised of three subunits, alpha, beta and gamma, and plays an essential role in Na+ and fluid absorption in the kidney, colon and lung. We had identified proline-rich sequences at the C termini of alpha beta gamma ENaC, which include the sequence PPxY, the PY motif. This sequence in beta or gamma ENaC is deleted or mutated in Liddle's syndrome, a hereditary form of arterial hypertension. Our previous work demonstrated that these PY motifs bind to the WW domains of Nedd4, a ubiquitin protein ligase containing a C2 domain, three or four WW domains and a ubiquitin protein ligase Hect domain. Accordingly, we have recently demonstrated that Nedd4 regulates ENaC function by controlling the number of channels at the cell surface, that this regulation is impaired in ENaC bearing Liddle's syndrome mutations, and that ENaC stability and function are regulated by ubiquitination. The C2 domain is responsible for localizing Nedd4 to the plasma membrane in a Ca(2+)-dependent manner, and in polarized epithelial MDCK cells this localization is primarily apical. In accordance, electrophysiological characterization of ENaC expressed in MDCK cells revealed inhibition of channel activity by elevated intracellular Ca2+ levels. Thus, in response to Ca2+, Nedd4 may be mobilized to the apical membrane via its C2 domain, where it binds ENaC via Nedd4-WW:ENaC-PY motifs' interactions, leading to ubiquitination of the channel by the Nedd4-Hect domain and subsequent channel endocytosis and lysosomal degradation. This process may be at least partially impaired in Liddle's syndrome due to reduced Nedd4 binding, leading to increased retention of ENaC at the cell surface

PTEN, a barrier for proliferation and metastasis of gastric cancer cells: From molecular pathways to targeting and regulation

10.3390/BIOMEDICINES8080264Biomedicines8826

Polychemotherapy with curcumin and doxorubicin via biological nanoplatforms: Enhancing antitumor activity

10.3390/pharmaceutics12111084Pharmaceutics12111-3