The Chaperonopathies - Diseases with Defective Molecular Chaperones

In the mid 1950's the Nobel Prize Laureate Christian B. Anfinsen from his research on the folding of ribonuclease A, began to concentrate on the problem of the relationship between structure and function in enzymes. On the basis of studies on ribonuclease, he proposed that the information determining the tertiary structure of a protein resides in the chemistry of its amino acid sequence...

Clinical biomarkers in brain injury: a lesson from cardiac arrest.

Cardiac arrest (CA) is the primary cause of death in industrialized countries. Successful resuscitation rate is estimated of about 40%, but a good neurological outcome remains difficult to achieve. The majority of resuscitated victims suffers of a pathophysiological entity termed as "post resuscitation disease". Today's efforts are mainly pointed to the chain of survival, often devoting less attention to post-resuscitation care. Resuscitated patients are often victims of nihilistic therapeutic approach, with clinicians failing to promptly institute strategies that mitigate the ischemia-reperfusion injury to vital organs. Only after 72 hours prognostication can be realistically attempted. Neurological evaluation relies on a combination of clinical, instrumental and laboratoristic parameters, since no one alone holds a specificity of 100%. Biochemical markers, such as neuron specific enolase and S-100b, may contribute to predict prognosis after CA. To the contrary, when used individually the necessary precision remains poorly characterized. Biochemical studies suffer from substantial methodological differences hampering attempts to summarize their findings. We review the information available on biochemical markers of brain damage for neurological prognostication after CA

Heme oxygenase-1 in central nervous system malignancies

Central nervous system tumors are the most common pediatric solid tumors and account for 20%-25% of all childhood malignancies. Several lines of evidence suggest that brain tumors show altered redox homeostasis that triggers the activation of various survival pathways, leading to disease progression and chemoresistance. Among these pathways, heme oxygenase-1 (HO-1) plays an important role. HO-1 catalyzes the enzymatic degradation of heme with the simultaneous release of carbon monoxide (CO), ferrous iron (Fe2+), and biliverdin. The biological effects of HO-1 in tumor cells have been shown to be cell-specific since, in some tumors, its upregulation promotes cell cycle arrest and cellular death, whereas, in other neoplasms, it is associated with tumor survival and progression. This review focuses on the role of HO-1 in central nervous system malignancies and the possibility of exploiting such a target to improve the outcome of well-established therapeutic regimens. Finally, several studies show that HO-1 overexpression is involved in the development and resistance of brain tumors to chemotherapy and radiotherapy, suggesting the use of HO-1 as an innovative therapeutic target to overcome drug resistance. The following keywords were used to search the literature related to this topic: nuclear factor erythroid 2 p45-related factor 2, heme oxygenase, neuroblastoma, medulloblastoma, meningioma, astrocytoma, oligodendroglioma, glioblastoma multiforme, and gliomas

Pentraxin-3 in late-preterm newborns with hypoxic respiratory failure.

The aim of this study was: echocardiographical assessment of cardiac alterations in late-preterm newborns with hypoxic respiratory failure (HRF), and, study serum pentraxin-3 (PTX-3) in relation to the severity of respiratory impairment and to some echocardiographic parameters (i.e. ejection fraction (EF), stroke volume (SV) and cardiac output (CO). We enrolled in this study 40 newborn infants whose 22 (group I) with moderate HRF and 18 (group II) with severe HRF. In group I the mean values of EF, SV and CO were significantly higher than in the group II. Our results showed a significant increase of PTX-3 in group II patients at 24h of life when compared to group I. Taking patients all together (n=40), we found a significant (R=-73) reverse correlation between EF and serum values of PTX-3. PTX-3 in our patients with HRF is affected by the severity of the hypoxic insult and correlate with the cardio-vascular impairment

The Role of Neutrophils in Corneal Wound Healing in HO-2 Null Mice

Our studies demonstrated that Heme oxygenase (HO), in particular, the constitutive HO-2, is critical for a self-resolving inflammatory and repair response in the cornea. Epithelial injury in HO-2 null mice leads to impaired wound closure and chronic inflammation in the cornea. This study was undertaken to examine the possible relationship between HO-2 and the recruitment of neutrophils following a corneal surface injury in wild type (WT) and HO-2 knockout (HO-2−/−) mice treated with Gr-1 monoclonal antibody to deplete peripheral neutrophils. Epithelial injury was performed by removing the entire corneal epithelium. Infiltration of inflammatory cell into the cornea in response to injury was higher in HO-2−/− than in WT. However, the rate of corneal wound closure following neutrophil depletion was markedly inhibited in both WT and HO-2−/− mice by 60% and 85%, respectively. Neutropenia induced HO-1 expression in WT but not in HO-2−/− mice. Moreover, endothelial cells lacking HO-2 expressed higher levels of the Midkine and VE-cadherin and displayed strong adhesion to neutrophils suggesting that perturbation in endothelial cell function caused by HO-2 depletion underlies the increased infiltration of neutrophils into the HO-2−/− cornea. Moreover, the fact that neutropenia worsened epithelial healing of the injured cornea in both WT and HO-2−/− mice suggest that cells other than neutrophils contribute to the exaggerated inflammation and impaired wound healing seen in the HO-2 null cornea

Role of Adrenomedullin in LPS-mediated lung injury

Acute Respiratory Distress Syndrome is a life-threatening disease characterized by diffuse lung injury that leads to respiratory failure and death. Among various endogenous protective peptides, adrenomedullin (AM) has been demonstrated to play a major role. The aim of our study was to assess the significance of AM in the complex pathophysiological cascade underlying lipopolysaccharide (LPS) mediated inflammatory response. In the first set of our experiments we showed that LPS induced a significant increase in the activation of the mitogen-activated protein kinase (MAPK) transduction signals in epithelial respiratory cells. In particular, our results showed a time and dose dependent activation of ERK and JNK pathways. No significant changes were observed for p38MAPK phosphorylation. Luminex analysis further confirmed the significant increase of IL-6 release along with a significant increase of MCP-1 , VEGF and IL-8. Pre-treatment of cells with AM (0.5 and 1 ng/ml) showed that AM was able to prevent JNK and ERK phosphorylation. Such effect turned into a significant reduction of IL-6 and TNF- gene transcription and induction of heme oxygenase-1 (Hsp32). Taken all together our data suggest that AM may play a major role in reducing LPS mediated inflammatory response by reducing the activation of MAPK signal transduction pathway

Biochemical and clinical relevance of alpha lipoic acid: antioxidant and anti-inflammatory activity, molecular pathways and therapeutic potential

The molecular nature of lipoic acid (LA) clarifies its capability of taking part to a variety of biochemical reactions where redox state is meaningful. The pivotal action of LA is the antioxidant activity due to its ability to scavenge and inactivate free radicals. Furthermore, LA has been shown to chelate toxic metals both directly and indirectly by its capability to enhance intracellular glutathione (GSH) levels. This last property is due to its ability to interact with GSH and recycle endogenous GSH. LA exhibits significant antioxidant activity protecting against oxidative damage in several diseases, including neurodegenerative disorders. Interestingly, LA is unique among natural antioxidants for its capability to satisfy a lot of requirements, making it a potentially highly effective therapeutic agent for many conditions related with oxidative damage. In particular, there are evidences showing that LA has therapeutic activity in lowering glucose levels in diabetic conditions. Similarly, LA supplementation has multiple beneficial effects on the regression of the mitochondrial function and on oxidative stress associated with several diseases and aging