Biochimica et biophysica acta
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Biochim. Biophys. Acta · Oct 2011
ReviewFibrosis and progression of autosomal dominant polycystic kidney disease (ADPKD).
The age on onset of decline in renal function and end-stage renal disease (ESRD) in autosomal polycystic kidney disease (ADPKD) is highly variable and there are currently no prognostic tools to identify patients who will progress rapidly to ESRD. In ADPKD, expansion of cysts and loss of renal function are associated with progressive fibrosis. Similar to the correlation between tubulointerstitial fibrosis and progression of chronic kidney disease (CKD), in ADPKD, fibrosis has been identified as the most significant manifestation associated with an increased rate of progression to ESRD. ⋯ Since fibrosis is a major component of ADPKD it follows that preventing or slowing fibrosis should retard disease progression with obvious therapeutic benefits. The development of effective anti-fibrotic strategies in ADPKD is dependent on understanding the precise mechanisms underlying initiation and progression of fibrosis in ADPKD and the role of the intrinsic genetic defect in these processes. This article is part of a Special Issue entitled: Polycystic Kidney Disease.
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Biochim. Biophys. Acta · May 2011
ReviewThe pro- and anti-inflammatory properties of the cytokine interleukin-6.
Interleukin-6 is a cytokine not only involved in inflammation and infection responses but also in the regulation of metabolic, regenerative, and neural processes. In classic signaling, interleukin-6 stimulates target cells via a membrane bound interleukin-6 receptor, which upon ligand binding associates with the signaling receptor protein gp130. Gp130 dimerizes, leading to the activation of Janus kinases and subsequent phosphorylation of tyrosine residues within the cytoplasmic portion of gp130. ⋯ It turns out that regenerative or anti-inflammatory activities of interleukin-6 are mediated by classic signaling whereas pro-inflammatory responses of interleukin-6 are rather mediated by trans-signaling. This is important since therapeutic blockade of interleukin-6 by the neutralizing anti-interleukin-6 receptor monoclonal antibody tocilizumab has recently been approved for the treatment of inflammatory diseases. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
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Biochim. Biophys. Acta · May 2011
P2X(7) receptor antagonists display agonist-like effects on cell signaling proteins.
The activation of various P2 receptors (P2R) by extracellular nucleotides promotes diverse cellular events, including the stimulation of cell signaling protein and increases in [Ca(2+)](i). We report that some agents that can block P2X(7)R receptors also promote diverse P2X(7)R-independent effects on cell signaling. ⋯ Some compounds used to block P2 receptors have complicated effects that may confound their use in blocking receptor activation and other biological processes for which they are employed, including their use as blockers of various ion transport proteins.
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Pain is a complex biological phenomenon that encompasses intricate neurophysiological, behavioural, psychosocial and affective components. Protracted or chronic pain alerts an individual to a possible pathological abnormality and is the main reason why patients visit a primary care physician. ⋯ This review spotlights a number of promising targets for peripheral pain control including the transient receptor potential (TRP) family of neuronal ion channels, the family of proteinase activated receptors (PARs), cannabinoids, and opioids. A critical appraisal of these targets in preclinical models of disease is given and their suitability as future peripheral analgesics is discussed.
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Biochim. Biophys. Acta · Mar 2011
A novel approach for the purification and proteomic analysis of pathogenic immunoglobulin free light chains from serum.
An excess of circulating monoclonal free immunoglobulin light chains (FLC) is common in plasma cell disorders. A subset of FLC, as amyloidogenic ones, possess intrinsic pathogenicity. Because of their complex purification, little is known on the biochemical features of serum FLC, possibly related to their pathogenic spectrum. ⋯ The nature of eluted FLC and coincidence with the LC sequence from the bone marrow clone was confirmed by MS, which also detected post-translational modifications, including truncation, tryptophan oxidation, cysteinylation, peptide dimerization. Serum FLC were purified in soluble form and adequate amounts for proteomics, which allowed studying primary sequence and detecting post-translational modifications. This method is a novel instrument for studying the molecular bases of FLC pathogenicity, allowing for the first time the punctual biochemical description of the circulating forms.