Therapeutic potency of pharmacological adenosine receptors agonist/antagonist on cancer cell apoptosis in tumor microenvironment,current status,and perspectives

The hypoxic niche of tumor leads to a tremendous increase in the extracellular adenosine concentration through alteration of adenosine metabolism in the tumor microenvironment (TME). This consequently affects cancer progression, local immune responses, and apoptosis of tumor cells. Regulatory effect of adenosine on apoptosis in TME depends on the cancer cell type, pharmacological characteristics of adenosine receptor subtypes, and the adenosine concentration in the tumor niche. Exploiting specific pharmacological adenosine receptor agonist and antagonist inducing apoptosis in cancer cells can be considered as a proper procedure to control cancer progression. This review summarizes the regulatory role of adenosine in cancer cell apoptosis for a better understanding, and hence better management of the disease.     

Effect of Na+and K+Ions on the Luminescence of Intact Vibrio harveyiCells at Different pH Values

The bioluminescent activity of intact Vibrio harveyicells loaded with different concentrations of NaCl and KCl at different pH values was studied. In the pH range of 6.5–8.5, the effect of Na⁺was significantly higher than that of K⁺at all concentrations studied. Maximum luminescent activity was observed in cells loaded with 0.68 M NaCl. When Na⁺was nonuniformly distributed on the plasma membrane, the cell luminescence kinetics was nonstationary in the 20-min range: during incubation, the luminescence intensity increased at pH 6.5 and decreased at pH 8.5. The activation and damping rate constants depended on the Na⁺gradient value. The maximum of luminescent activity shifted during incubation from pH 8.5 to 6.5–7.0. The luminescence kinetics in the systems with KCl was stationary; the maximum level of luminescence was observed in the pH range of 7.0–7.5. Under Na⁺-controlled conditions, the cell respiration and luminescence changed in synchronism. The protonophore CCP at a concentration of 20 M completely inhibited luminescence at pH 6.5 and was ineffective at pH 8.5.     

Intracellular H+ regulates the alpha -subunit of ENaC, the epithelial Na+ channel

Protons regulateelectrogenic sodium absorption in a variety of epithelia, including thecortical collecting duct, frog skin, and urinary bladder. Recently,three subunits (, , ) coding for the epithelial sodium channel(ENaC) were cloned. However, it is not known whether pH regulatesNa⁺ channels directly byinteracting with one of the three ENaC subunits or indirectly byinteracting with a regulatory protein. As a first step to identifyingthe molecular mechanisms of proton-mediated regulation of apicalmembrane Na⁺ permeability inepithelia, we examined the effect of pH on the biophysical propertiesof ENaC. To this end, we expressed various combinations of -, -,and -subunits of ENaC in Xenopusoocytes and studied ENaC currents by the two-electrode voltage-clampand patch-clamp techniques. In addition, the effect of pH on the-ENaC subunit was examined in planar lipid bilayers. We report that ,,-ENaC currents were regulated by changes in intracellular pH(pH_i) but not by changes inextracellular pH (pH_o).Acidification reduced and alkalization increased channel activity by avoltage-independent mechanism. Moreover, a reduction ofpH_i reduced single-channel openprobability, reduced single-channel open time, and increased single-channel closed time without altering single-channel conductance. Acidification of the cytoplasmic solution also inhibited ,-ENaC, ,-ENaC, and -ENaC currents. We conclude thatpH_i but notpH_o regulates ENaC and that the-ENaC subunit is regulated directly bypH_i.     

Lip reconstruction

Lip reconstruction remains challenging. Accurate analysis of the defect and a thorough understanding of the anatomy and options for reconstruction will maintain the functional and aesthetic quality of this sensitive area.     

Inhibitory effects of phenolic ecotoxicants on photobacteria at various pH values

Kinetic characteristics of light emission by intact cells of the photobacteria Photobacterium phosphoreum and Vibrio harveyi at pH 5.5, 7.0, and 8.0 were studied as well as specific features of inhibitory effects of 2,4-di- and 2,4,5-triphenoxyacetic acids (2,4-D and 2,4,5-T), pentachlorophenol (PCP), and 2,6-dimethylphenol (2,6-DMP) at the same pH values. Nonstationarity of emission kinetics was observed at all the pH values studied. Exponential luminescence decay in a 60-sec range was observed at pH 5.5; a 5-min luminescence activation, at pH 7.0 and 8.0. The cell respiratory activity drops by over one order of magnitude at pH 5.5 compared with the activities at pH 7.0 and 8.0. The inhibitory effects of 2,4-D, 2,4,5-T, and PCP differ by one-two orders of magnitude depending on pH. The maximal cell sensitivity to these compounds appears at pH 5.5; the minimal, at pH 8.0. The effect of 2,6-DMP is independent of pH. As is demonstrated, it is hydrophobicity of the molecule and pK values of the toxicants that determine the inhibitory effect. Characteristic of the substrate-starved photobacterial cells are higher sensitivity to chlorophenolic compounds compared with the cells provided with high energy supply at all the pH values.     

Mechanosensitivity of gramicidin A channels in semispherical bilayer membranes at constant tension

Mechanoelectrical transduction in gramicidin A channels was studied in macroscopic planar lipid bilayer membranes bulged at constant tension. We found a supralinear increase in the single channel activity, which was proportional to the square of membrane radius but could not be accounted for by the increase in membrane surface area or by recruitment of new channels. When being extrapolated to biological membranes, these observations may suggest that the activity of permeability of ion channels can be influenced simply by changing the shape of the membrane, with or without stretching.     

KCa1.1 potassium channels regulate key proinflammatory and invasive properties of fibroblast-like synoviocytes in rheumatoid arthritis

Fibroblast-like synoviocytes (FLS) play important roles in the pathogenesis of rheumatoid arthritis (RA). Potassium channels have regulatory roles in many cell functions. We have identified the calcium- and voltage-gated KCa1.1 channel (BK, Maxi-K, Slo1, KCNMA1) as the major potassium channel expressed at the plasma membrane of FLS isolated from patients with RA (RA-FLS). We further show that blocking this channel perturbs the calcium homeostasis of the cells and inhibits the proliferation, production of VEGF, IL-8, and pro-MMP-2, and migration and invasion of RA-FLS. Our findings indicate a regulatory role of KCa1.1 channels in RA-FLS function and suggest this channel as a potential target for the treatment of RA.