Strategies for blocking the fibrogenic actions of connective tissue growth factor (CCN2): From pharmacological inhibition in vitro to targeted siRNA therapy in vivo

Connective tissue growth factor (CCN2) is a major pro-fibrotic factor that frequently acts downstream of transforming growth factor beta (TGF-β)-mediated fibrogenic pathways. Much of our knowledge of CCN2 in fibrosis has come from studies in which its production or activity have been experimentally attenuated. These studies, performed both in vitro and in animal models, have demonstrated the utility of pharmacological inhibitors (e.g. tumor necrosis factor alpha (TNF-α), prostaglandins, peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists, statins, kinase inhibitors), neutralizing antibodies, antisense oligonucleotides, or small interfering RNA (siRNA) to probe the role of CCN2 in fibrogenic pathways. These investigations have allowed the mechanisms regulating CCN2 production to be more clearly defined, have shown that CCN2 is a rational anti-fibrotic target, and have established a framework for developing effective modalities of therapeutic intervention in vivo

Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury

Kruppel-like factor 6 (KLF6) is a transcription factor and tumor suppressor. We previously identified KLF6 as mediator of hepatocyte glucose and lipid homeostasis. The loss or reduction of KLF6 is linked to the progression of hepatocellular carcinoma, but its contribution to liver regeneration and repair in acute liver injury are lacking so far. Here we explore the role of KLF6 in acute liver injury models in mice, and in patients with acute liver failure (ALF). KLF6 was induced in hepatocytes in ALF, and in both acetaminophen (APAP)- and carbon tetrachloride (CCl4)- treated mice. In mice with hepatocytespecific Klf6 knockout (DeltaKlf6), cell proliferation following partial hepatectomy (PHx) was increased compared to controls. Interestingly, key autophagic markers and mediators LC3-II, Atg7 and Beclin1 were reduced in DeltaKlf6 mice livers. Using luciferase assay and ChIP, KLF6 was established as a direct transcriptional activator of ATG7 and BECLIN1, but was dependent on the presence of p53. Here we show, that KLF6 expression is induced in ALF and in the regenerating liver, where it activates autophagy by transcriptional induction of ATG7 and BECLIN1 in a p53-dependent manner. These findings couple the activity of an important growth inhibitor in liver to the induction of autophagy in hepatocytes

Spin-lattice relaxation rates and water content of freeze-dried articular cartilage.

Objective: Nuclear magnetic resonance (NMR) spin-lattice relaxation rates were measured in bovine and porcine articular cartilage as a function of water content. Methods: Water content was varied by freeze-drying samples for short periods of time (up to 15. min). The samples were weighed at all stages of drying so that water content could be quantified. Spin-lattice relaxation rates were measured using magnetic resonance imaging (MRI). Results: Linear correlations were observed between relaxation rate and two measures of inverse water content: (1) solid-to-water ratio (ρ), expressed as a ratio of the mass of the solid component of the cartilage (m s) and the mass of water at each freeze-drying time point (m w), and (2) a ratio of the total mass of the fully-hydrated cartilage and m w (1/w). These correlations did not appear significantly different for the bovine and porcine data. However, fitting the data to a piecewise-linear model revealed differences between these two species. We interpret the first two segments of the piecewise model as the depletion of different water phases but conjecture that the third segment is partially caused by changes in relaxation rates as a result of a reduction in macromolecular mobilities. Conclusions: Whilst we can produce linear correlations which broadly describe the dependence of the measured spin-lattice relaxation rate on (inverse) water content, the linear model seems to obscure a more complicated relationship which potentially provides us with more information about the structure of articular cartilage and its extracellular water

"Adaptive response" - some underlying mechanisms and open questions

Organisms are affected by different DNA damaging agents naturally present in the environment or released as a result of human activity. Many defense mechanisms have evolved in organisms to minimize genotoxic damage. One of them is induced radioresistance or adaptive response. The adaptive response could be considered as a nonspecific phenomenon in which exposure to minimal stress could result in increased resistance to higher levels of the same or to other types of stress some hours later. A better understanding of the molecular mechanism underlying the adaptive response may lead to an improvement of cancer treatment, risk assessment and risk management strategies, radiation protection, e. g. of astronauts during long-term space flights. In this mini-review we discuss some open questions and the probable underlying mechanisms involved in adaptive response: the transcription of many genes and the activation of numerous signaling pathways that trigger cell defenses - DNA repair systems, induction of proteins synthesis, enhanced detoxification of free radicals and antioxidant production.Publisher PDFPeer reviewe