Thrombin is a novel regulator of hexokinase activity in mesangial cells

Thrombin is a novel regulator of hexokinase activity in mesangial cells.BackgroundHexokinase (HK) activity is fundamentally important to cellular glucose uptake and metabolism. Phorbol esters increase both HK activity and glucose utilization in cultured mesangial cells via a protein kinase C (PKC)- and extracellular signal-regulated kinases 1 and 2 (ERK1/2)-dependent mechanism. In adult kidneys, increased HK activity has been reported in both glomerular injury and in diabetes, but the mechanisms responsible for these changes are unknown. Thrombin, a known activator of both PKC and ERK1/2, is increased in the settings of renal injury and diabetes. Thus, thrombin may contribute to the observed changes in HK activity in vivo.MethodsThrombin and thrombin receptor agonists were tested for the ability to increase HK activity and glucose metabolism in murine mesangial (SV40 MES 13) cells. ERK1/2 activation was also evaluated in parallel. Thrombin inhibition (hirudins), PKC depletion, Ser-Thr kinase inhibition (H-7), MEK1/2 inhibition (PD98059), pertussis toxin (PTX), and general inhibitors of transcription or translation were then tested for the ability to attenuate these effects.ResultsThrombin (≥0.01 U/mL) mimicked the effect of phorbol esters, increasing HK activity 50% within 12 to 24 hours (P < 0.05). This effect was inhibited by hirudins, mimicked by thrombin receptor agonists, and accompanied by increased Glc utilization. H-7, PD98059, and general inhibitors of transcription or translation—but not PTX—prevented thrombin-induced HK activity at 24 hours. PKC depletion and PD98059 also blocked the associated phosphorylation and activation of ERK1/2.ConclusionsThrombin increases mesangial cell HK activity via a PTX-insensitive mechanism involving thrombin receptor activation, PKC-dependent activation of ERK1/2, and both ongoing gene transcription and de novo protein synthesis. As such, thrombin is a novel regulator of HK activity in mesangial cells and may play a role in coupling renal injury to metabolism

A Brief View of Molecular Modeling Approaches to P2 Receptors

Purinergic receptors are a class of receptors distributed into two groups, P1 and P2. P1 receptors are activated by nucleosides, like adenosine, while nucleotides active P2 receptors. In turn, P2 receptors comprise two families, metabotropic P2Y and ionotropic P2X. P2Y receptors consist in eight members, namely, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14, described in mammals, while P2X includes seven members, numbered P2X1 to P2X7. These receptors have been described as expressed in practically all cells studied to date. In this context, P2 receptors are suggested as participating in certain diseases. The general approach applied in the discovery of new drugs is expensive and lengthy. Alternatively, in the last 20 years, molecular modeling has emerged as an exciting tool for the design of new drugs, in less time and at low costs. These tools allow for in silico testing of thousands of molecules against a target protein, as well as toxicity, absorption, distribution, metabolism, and constant affinity predictions of a given interaction. Thus, molecular modeling algorithms emerge as an increasingly important tool for the design of drugs targeting purinergic receptors as therapeutic targets of many diseases, including cancer, pain, inflammation, cardiovascular, and endocrine conditions

Thermodynamics of charged and rotating black strings

We study thermodynamics of cylindrically symmetric black holes. Uncharged as well as charged and rotating objects have been discussed. We derive surface gravity and hence the Hawking temperature and entropy for all these cases. We correct some results in the literature and present new ones. It is seen that thermodynamically these black configurations behave differently from spherically symmetric objects

Cissus Sicyoides: Pharmacological Mechanisms Involved In The Anti-inflammatory And Antidiarrheal Activities

The objective of this study was to evaluate the pharmacological mechanisms involved in anti-inflammatory and antidiarrheal actions of hydroalcoholic extract obtained from the leaves of Cissus sicyoides (HECS). The anti-inflammatory effect was evaluated by oral administration of HECS against acute model of edema induced by xylene, and the mechanisms of action were analysed by involvement of arachidonic acid (AA) and prostaglandin E2 (PGE2). The antidiarrheal effect of HECS was observed and we analyzed the motility and accumulation of intestinal fluid. We also analyzed the antidiarrheal mechanisms of action of HECS by evaluating the role of the opioid receptor, α2 adrenergic receptor, muscarinic receptor, nitric oxide (NO) and PGE2. The oral administration of HECS inhibited the edema induced by xylene and AA and was also able to significantly decrease the levels of PGE2. The extract also exhibited significant anti-diarrheal activity by reducing motility and intestinal fluid accumulation. This extract significantly reduced intestinal transit stimulated by muscarinic agonist and intestinal secretion induced by PGE2. Our data demonstrate that the mechanism of action involved in the anti-inflammatory effect of HECS is related to PGE2. The antidiarrheal effect of this extract may be mediated by inhibition of contraction by acting on the intestinal smoothmuscle and/or intestinal transit. © 2016 by the authors; licensee MDPI, Basel, Switzerland.17

Measurement of the tensor analyzing power T20 in the dd->^3Hen and dd->^3Hp at intermediate energies and at zero degree

The data on the tensor analyzing power T20 in the dd->^3Hen and dd-> ^3Hp reactions at 140, 200 and 270 MeV of the deuteron kinetic energy and at zero degree obtained at RIKEN Accelerator Research Facility are presented. The observed positive sign of T20 clearly demonstrates the sensitivity to the D/S wave ratios in the ^3He and ^3H in the energy domain of the measurements. The T20 data for the ^3He-n and ^3H-p channels are in agreement within experimental accuracy.Comment: 9 pages, 3 figures, submitted in Phys.Lett.

The Deuteron Spin-dependent Structure Function g1d and its First Moment

We present a measurement of the deuteron spin-dependent structure function g1d based on the data collected by the COMPASS experiment at CERN during the years 2002-2004. The data provide an accurate evaluation for Gamma_1^d, the first moment of g1d(x), and for the matrix element of the singlet axial current, a0. The results of QCD fits in the next to leading order (NLO) on all g1 deep inelastic scattering data are also presented. They provide two solutions with the gluon spin distribution function Delta G positive or negative, which describe the data equally well. In both cases, at Q^2 = 3 (GeV/c)^2 the first moment of Delta G is found to be of the order of 0.2 - 0.3 in absolute value.Comment: fits redone using MRST2004 instead of MRSV1998 for G(x), correlation matrix adde

A new measurement of the Collins and Sivers asymmetries on a transversely polarised deuteron target

New high precision measurements of the Collins and Sivers asymmetries of charged hadrons produced in deep-inelastic scattering of muons on a transversely polarised 6LiD target are presented. The data were taken in 2003 and 2004 with the COMPASS spectrometer using the muon beam of the CERN SPS at 160 GeV/c. Both the Collins and Sivers asymmetries turn out to be compatible with zero, within the present statistical errors, which are more than a factor of 2 smaller than those of the published COMPASS results from the 2002 data. The final results from the 2002, 2003 and 2004 runs are compared with naive expectations and with existing model calculations.Comment: 40 pages, 28 figure

The COMPASS Experiment at CERN

The COMPASS experiment makes use of the CERN SPS high-intensitymuon and hadron beams for the investigation of the nucleon spin structure and the spectroscopy of hadrons. One or more outgoing particles are detected in coincidence with the incoming muon or hadron. A large polarized target inside a superconducting solenoid is used for the measurements with the muon beam. Outgoing particles are detected by a two-stage, large angle and large momentum range spectrometer. The setup is built using several types of tracking detectors, according to the expected incident rate, required space resolution and the solid angle to be covered. Particle identification is achieved using a RICH counter and both hadron and electromagnetic calorimeters. The setup has been successfully operated from 2002 onwards using a muon beam. Data with a hadron beam were also collected in 2004. This article describes the main features and performances of the spectrometer in 2004; a short summary of the 2006 upgrade is also given.Comment: 84 papes, 74 figure

Search for a Higgs Boson Decaying to Weak Boson Pairs at LEP

A Higgs particle produced in association with a Z boson and decaying into weak boson pairs is searched for in 336.4 1/pb of data collected by the L3 experiment at LEP at centre-of-mass energies from 200 to 209 GeV. Limits on the branching fraction of the Higgs boson decay into two weak bosons as a function of the Higgs mass are derived. These results are combined with the L3 search for a Higgs boson decaying to photon pairs. A Higgs produced with a Standard Model e+e- --> Zh cross section and decaying only into electroweak boson pairs is excluded at 95% CL for a mass below 107 GeV