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Intracellular Processes (intracellular + process)
Selected AbstractsAutophagic pathways and metabolic stressDIABETES OBESITY & METABOLISM, Issue 2010S. Kaushik Autophagy is an essential intracellular process that mediates degradation of intracellular proteins and organelles in lysosomes. Autophagy was initially identified for its role as alternative source of energy when nutrients are scarce but, in recent years, a previously unknown role for this degradative pathway in the cellular response to stress has gained considerable attention. In this review, we focus on the novel findings linking autophagic function with metabolic stress resulting either from proteins or lipids. Proper autophagic activity is required in the cellular defense against proteotoxicity arising in the cytosol and also in the endoplasmic reticulum, where a vast amount of proteins are synthesized and folded. In addition, autophagy contributes to mobilization of intracellular lipid stores and may be central to lipid metabolism in certain cellular conditions. In this review, we focus on the interrelation between autophagy and different types of metabolic stress, specifically the stress resulting from the presence of misbehaving proteins within the cytosol or in the endoplasmic reticulum and the stress following a lipogenic challenge. We also comment on the consequences that chronic exposure to these metabolic stressors could have on autophagic function and on how this effect may underlie the basis of some common metabolic disorders. [source] Two Possible Mechanisms Underlying Nitrate Tolerance In Monkey Coronary ArteriesCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2001Tomoko Omura SUMMARY 1. Previous studies using isolated arteries have demonstrated cross-tolerance between nitric oxide (NO) donors such as nitroglycerin (NTG) and sodium nitroprusside (SNP). However, it remains unclear whether the vasorelaxing effect of atrial natriuretic peptide (ANP), an activator of particulate guanylate cyclase, is affected by treatment with NO donors. To investigate the cross-tolerance and interactions between NTG and ANP in coronary vasorelaxant responses, we used two models of monkey coronary arterial strips (Macaca fuscata). 2. In one model, which was induced by a 1 h treatment with 4.4 × 10,4 mol/L NTG followed by washout of the agent for 1 h, the vasorelaxing effects of subsequent NTG were markedly attenuated, whereas those of ANP and NO were not affected. These findings suggest that the development of NTG tolerance is associated with a biotransformation process from NTG to NO. In the other model, which did not include washout after exposure to 3 × 10,6 mol/L NTG, the vasorelaxant responses to 10,8 mol/L ANP (31.1±5.4 vs 5.1±2.1%, respectively; P < 0.001), 10,6 mol/L NO (61.5±2.4 vs 29.5±8.5%, respectively; P < 0.001) and 10,8 mol/L SNP (49.4±6.4 vs 8.0±2.0%, respectively; P < 0.001) were significantly attenuated. The concentration, response curve for 8-bromo-cGMP (8-Br-cGMP) was shifted to the right, whereas responses to papaverine and forskolin were unchanged. These findings suggest that an intracellular process that occurs after the synthesis of cGMP is responsible for this interaction. 3. As a mechanism of NTG tolerance, two possible processes may be impaired: (i) biotransformation from NTG to NO; and (ii) an intracellular process that occurs after the synthesis of cGMP. [source] Could chronic pain and spread of pain sensation be induced and maintained by glial activation?ACTA PHYSIOLOGICA, Issue 1-2 2006E. Hansson Abstract An injury often starts with acute physiological pain, which becomes inflammatory or neuropathic, and may sometimes become chronic. It has been proposed recently that activated glial cells, astrocytes and microglia within the central nervous system could maintain the pain sensation even after the original injury or inflammation has healed, and convert it into chronic by altering neuronal excitability. Glial cell activation has also been proposed to be involved in the phenomenon of spread of pain sensation ipsilaterally or to the contralateral side (i.e. mirror image pain). Substance P and calcitonin gene-related peptide, released due to an inflammatory process, interact with the endothelial cells of the blood,spinal cord and blood,brain barriers. The barriers open partially and substances may influence adjacent glial cells. Such substances are also released from neurones carrying the ,pain message' all the way from the injury to the cerebral cortex. Pro-inflammatory cytokines may be released from the microglial cells, and astroglial Ca2+ -transients or oscillations may spread within the astroglial networks. One theory is that Ca2+ -oscillations could facilitate the formation of new synapses. These new synapses could establish neuronal contacts for maintaining and spreading the pain sensation. If this theory holds true, it is possible that Ca2+ waves, production of cytokines and growth factors could be modified by selective anti-inflammatory drugs to achieve a balance in the activities of the different intercellular and intracellular processes. This paper reviews current knowledge about glial mechanisms underlying the phenomena of chronic pain and spread of the pain sensation. [source] Epigenetic dysregulation in cognitive disordersEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2009Johannes Gräff Abstract Epigenetic mechanisms are not only essential for biological functions requiring stable molecular changes such as the establishment of cell identity and tissue formation, they also constitute dynamic intracellular processes for translating environmental stimuli into modifications in gene expression. Over the past decade it has become increasingly clear that both aspects of epigenetic mechanisms play a pivotal role in complex brain functions. Evidence from patients with neurodegenerative and neurodevelopmental disorders such as Alzheimer's disease and Rett syndrome indicated that epigenetic mechanisms and chromatin remodeling need to be tightly controlled for proper cognitive functions, and their dysregulation can have devastating consequences. However, because they are dynamic, epigenetic mechanisms are also potentially reversible and may provide powerful means for pharmacological intervention. This review outlines major cognitive disorders known to be associated with epigenetic dysregulation, and discusses the potential of ,epigenetic medicine' as a promising cure. [source] Surface Action Potential and Contractile Properties of the Human Triceps Surae Muscle: Effect of ,Dry' Water ImmersionEXPERIMENTAL PHYSIOLOGY, Issue 1 2002Yuri A. Koryak The effects of 7 days of ,dry' water immersion were investigated in six subjects. Changes in the contraction properties were studied in the triceps surae muscle. After immersion, the maximal voluntary contraction (MVC) was reduced by 18.9% (P < 0.01), and the electrically evoked (150 impulses s,1) maximal tension during tetanic contraction (Po) was reduced by 8.2% (P > 0.05). The difference between Po and MVC expressed as a percentage of Po and referred to as force deficiency was also calculated. The force deficiency increased by 44.1% (P < 0.001) after immersion. The decrease in Po was associated with increased maximal rates of tension development (7.2%) and relaxation. The twitch time-to-peak was not significantly changed, and half-relaxation and total contraction time were decreased by 5.3% and 2.8%, respectively, but the twitch tension (Pt) was not significantly changed and the Pt/Po ratio was decreased by 8.7%. The 60 s intermittent contractions (50 impulses s,1) decreased tetanic force to 57% (P < 0.05) of initial values, but force reduction was not significantly different in the two fatigue-inducing tests: fatigue index (the mean loss of force of the last five contractions, expressed as a percentage of the mean value of the first five contractions) was 36.2 ± 5.4% vs. 38.6 ± 2.8%, respectively (P > 0.05). While identical force reduction was present in the two fatigue-inducing tests, it would appear that concomitant electrical failure was considerably different. Comparison of the electrical and mechanical alterations recorded during voluntary contractions, and in contractions evoked by electrical stimulation of the motor nerve, suggests that immersion not only modifies the peripheral processes associated with contraction, but also changes central and/or neural command of the contraction. At peripheral sites, it is proposed that the intracellular processes of contraction play a role in the contractile impairment recorded during immersion. [source] Conformational stability and multistate unfolding of poly(A)-specific ribonucleaseFEBS JOURNAL, Issue 10 2009Guang-Jun He Poly(A)-specific ribonuclease (PARN) specifically catalyzes the degradation of the poly(A) tails of single-stranded mRNAs in a highly processive mode. PARN participates in diverse and important intracellular processes by acting as a regulator of mRNA stability and translational efficiency. In this article, the equilibrium unfolding of PARN was studied using both guanidine hydrochloride and urea as chemical denaturants. The unfolding of PARN was characterized as a multistate process, but involving dissimilar equilibrium intermediates when denatured by the two denaturants. A comparison of the spectral characteristics of these intermediates indicated that the conformational changes at low concentrations of the chemical denaturants were more likely to be rearrangements of the tertiary and quaternary structures. In particular, an inactive molten globule-like intermediate was identified to exist as soluble non-native oligomers, and the formation of the oligomers was modulated by electrostatic interactions. An active dimeric intermediate unique to urea-induced unfolding was characterized to have increased regular secondary structures and modified tertiary structures, implying that additional regular structures could be induced by environmental stresses. The dissimilarity in the unfolding pathways induced by guanidine hydrochloride and urea suggest that electrostatic interactions play an important role in PARN stability and regulation. The appearance of multiple intermediates with distinct properties provides the structural basis for the multilevel regulation of PARN by conformational changes. [source] Vasomotion dynamics following calcium spiking depend on both cell signalling and limited constriction velocity in rat mesenteric small arteriesJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2008Ed VanBavel Abstract Vascular smooth muscle cell contraction depends on intracellular calcium. However, calcium-contraction coupling involves a complex array of intracellular processes. Quantitating the dynamical relation between calcium perturbations and resulting changes in tone may help identifying these processes. We hypothesized that in small arteries accurate quantitation can be achieved during rhythmic vasomotion, and questioned whether these dynamics depend on intracellular signalling or physical vasoconstriction. We studied calcium-constriction dynamics in cannulated and pressurized rat mesenteric small arteries (,300 ,m in diameter). Combined application of tetra-ethyl ammonium (TEA) and BayK8644 induced rhythmicity, consisting of regular and irregular calcium spiking and superposition of spikes. Calcium spikes induced delayed vasomotion cycles. Their dynamic relation could be fitted by a linear second-order model. The dirac impulse response of this model had an amplitude that was strongly reduced with increasing perfusion pressure between 17 and 98 mmHg, while time to peak and relaxation time were the largest at an intermediate pressure (57 mmHg: respectively 0.9 and 2.3 sec). To address to what extent these dynamics reside in intracellular signalling or vasoconstriction, we applied rhythmic increases in pressure counteracting the vasoconstriction. This revealed that calcium-activation coupling became faster when vasoconstriction was counteracted. During such compensation, a calcium impulse response remained that lasted 0.5 sec to peak activation, followed by a 1.0 sec relaxation time, attributable to signalling dynamics. In conclusion, this study demonstrates the feasibility of quantitating calcium-activation dynamics in vasomoting small arteries. These dynamics relate to both intracellular sig-nalling and actual vasoconstriction. Performing such analyses during pharmacological intervention and in genetic models provides a tool for unravelling calcium-contraction coupling in small arteries. [source] Water spin dynamics during apoptotic cell death in glioma gene therapy probed by T1, and T2,MAGNETIC RESONANCE IN MEDICINE, Issue 6 2008A. Sierra Abstract Longitudinal and transverse relaxations in the rotating frame, with characteristic time constants T1, and T2,, respectively, have potential to provide unique MRI contrast in vivo. On-resonance spin-lock T1, with different spin-lock field strengths and adiabatic T2, with different radiofrequency-modulation functions were measured in BT4C gliomas treated with Herpes Simplex Virus thymidine kinase (HVS-tk) gene therapy causing apoptotic cell death. These NMR tools were able to discriminate different treatment responses in tumor tissue from day 4 onward. An equilibrium two-site exchange model was used to calculate intrinsic parameters describing changes in water dynamics. Observed changes included increased correlation time of water associated with macromolecules and a decreased fractional population of this pool. These results are consistent with destructive intracellular processes associated with cell death and the increase of extracellular space during the treatment. Furthermore, association between longer exchange correlation time and decreased pH during apoptosis is discussed. In this study, we demonstrated that T1, and T2, MR imaging are useful tools to quantify early changes in water dynamics reflecting treatment response during gene therapy. Magn Reson Med 59:1311,1319, 2008. © 2008 Wiley-Liss, Inc. [source] Bayesian Inference for Stochastic Kinetic Models Using a Diffusion ApproximationBIOMETRICS, Issue 3 2005A. Golightly Summary This article is concerned with the Bayesian estimation of stochastic rate constants in the context of dynamic models of intracellular processes. The underlying discrete stochastic kinetic model is replaced by a diffusion approximation (or stochastic differential equation approach) where a white noise term models stochastic behavior and the model is identified using equispaced time course data. The estimation framework involves the introduction of m, 1 latent data points between every pair of observations. MCMC methods are then used to sample the posterior distribution of the latent process and the model parameters. The methodology is applied to the estimation of parameters in a prokaryotic autoregulatory gene network. [source] Simplified Synthetic TMC-95A/B Analogues Retain the Potency of Proteasome Inhibitory ActivityCHEMBIOCHEM, Issue 6 2003Zhi-Qiang Yang Dr. Abstract The proteasome regulates diverse intracellular processes, including cell-cycle progression, antigen presentation, and inflammatory response. Selective inhibitors of the proteasome have great therapeutic potential for the treatment of cancer and inflammatory disorders. Natural cyclic peptides TMC-95A and B represent a new class of noncovalent, selective proteasome inhibitors. To explore the structure,activity relationship of this class of proteasome inhibitors, a series of TMC-95A/B analogues were prepared and analyzed. We found that the unique enamide functionality at the C8 position of TMC-95s can be replaced with a simple allylamide. The asymmetric center at C36 that distinguishes TMC-95A from TMC-95B but which necessitates a complicated separation of the two compounds can be eliminated. Therefore, these findings could lead to the development of more accessible simple analogues as potential therapeutic agents. [source] Traditional therapies: glucocorticoids, azathioprine, methotrexate, hydroxyureaCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 7 2002G. Belgi Summary The ,old favourites' used for treatment of inflammatory diseases, and hence, the original immunomodulators, include the glucocorticoids, azathioprine, methotrexate and hydroxyurea. Glucocorticoids are still one of the most effective anti-inflammatory agents because they work on several different intracellular processes and hence, block many components that contribute to inflammatory and immune responses. They bind to intracellular glucocorticoid receptors which transport them into the nucleus. Here the receptor/steroid complex may bind to many genes that interact with transcription factors including NF,B and AP-1, to inhibit their activation, thereby preventing activation of many genes encoding immune effector and pro-inflammatory cytokines. Also, protein kinases involved in intracellular signalling, are directly activated resulting in phosphorylation of various targets of which Annexin (AXA)-1 is critical in inhibiting biosynthesis of both purines and DNA. This results in reduced proliferation of B and T lymphocytes, reduced immune effector mechanisms and reduced recruitment of mononuclear cells including monocytes into sites of immune inflammation. Methotrexate also blocks DNA synthesis and hence cellular proliferation but also induces release of adenosine. This inhibits chemotaxis of polymorph neutrophils and release of critical cytokines such as TNF-, and Interleukins 6 and 8. Hydroxyurea also inhibits DNA synthesis with inhibitory effects on proliferation of lymphocytes and possibly kerationcytes. Even though many new agents with much greater selectivity are coming through into clinical use, this group of old agents still have an absolutely central position in the therapeutic armamentarium. Their value lies in the fact that they are not ,clean' drugs with narrow effects but they inhibit a wide range of mechanisms involved in immune and inflammatory processes. [source] | ||||||||||||||||