Activation of Hypoxia Inducible Factor 1 Is a General Phenomenon in Infections with Human Pathogens

Background: Hypoxia inducible factor (HIF)-1 is the key transcriptional factor involved in the adaptation process of cells and organisms to hypoxia. Recent findings suggest that HIF-1 plays also a crucial role in inflammatory and infectious diseases. Methodology/Principal Findings: Using patient skin biopsies, cell culture and murine infection models, HIF-1 activation was determined by immunohistochemistry, immunoblotting and reporter gene assays and was linked to cellular oxygen consumption. The course of a S. aureus peritonitis was determined upon pharmacological HIF-1 inhibition. Activation of HIF-1 was detectable (i) in all ex vivo in biopsies of patients suffering from skin infections, (ii) in vitro using cell culture infection models and (iii) in vivo using murine intravenous and peritoneal S. aureus infection models. HIF-1 activation by human pathogens was induced by oxygen-dependent mechanisms. Small colony variants (SCVs) of S. aureus known to cause chronic infections did not result in cellular hypoxia nor in HIF-1 activation. Pharmaceutical inhibition of HIF-1 activation resulted in increased survival rates of mice suffering from a S. aureus peritonitis. Conclusions/Significance: Activation of HIF-1 is a general phenomenon in infections with human pathogenic bacteria, viruses, fungi and protozoa. HIF-1-regulated pathways might be an attractive target to modulate the course of life-threatening infections

Lung injury-induced skeletal muscle wasting in aged mice is linked to alterations in long chain fatty acid metabolism

INTRODUCTION: Older patients are more likely to acquire and die from acute respiratory distress syndrome (ARDS) and muscle weakness may be more clinically significant in older persons. Recent data implicate muscle ring finger protein 1 (MuRF1) in lung injury-induced skeletal muscle atrophy in young mice and identify an alternative role for MuRF1 in cardiac metabolism regulation through inhibition of fatty acid oxidation. OBJECTIVES: To develop a model of lung injury-induced muscle wasting in old mice and to evaluate the skeletal muscle metabolomic profile of adult and old acute lung injury (ALI) mice. METHODS: Young (2 month), adult (6 month) and old (20 month) male C57Bl6J mice underwent Sham (intratracheal H(2)O) or ALI [intratracheal E. coli lipopolysaccharide (i.t. LPS)] conditions and muscle functional testing. Metabolomic analysis on gastrocnemius muscle was performed using gas chromatography-mass spectrometry (GC-MS). RESULTS: Old ALI mice had increased mortality and failed to recover skeletal muscle function compared to adult ALI mice. Muscle MuRF1 expression was increased in old ALI mice at day 3. Non-targeted muscle metabolomics revealed alterations in amino acid biosynthesis and fatty acid metabolism in old ALI mice. Targeted metabolomics of fatty acid intermediates (acyl-carnitines) and amino acids revealed a reduction in long chain acyl-carnitines in old ALI mice. CONCLUSION: This study demonstrates age-associated susceptibility to ALI-induced muscle wasting which parallels a metabolomic profile suggestive of altered muscle fatty acid metabolism. MuRF1 activation may contribute to both atrophy and impaired fatty acid oxidation, which may synergistically impair muscle function in old ALI mice

Resveratrol: biological activities and potential use in health and disease

Resveratrol (RV) is a polyphenol non-flavonoid compound present in strongly pigmented vegetables and fresh fruits as well as dried nuts such as peanuts. High concentrations of this natural compound were found, in the modern occidental world, in the peel of the berries of the red grape Vitis vinifera, but usage of this natural drug in popular medicine has been documented much earlier. Resveratrol exhibits diverse biological activities such as antitumor, antioxidant, antiviral, and phytoestrogenic. In particular, as the work reported from our laboratories, the compound shows an inhibitory effect on murine polyomavirus DNA replication, while at higher concentrations, RV shows a significant cytotoxic effect. This complex dose-dependent behavior is not intrinsic to the drug. Other natural substances behave in a similar way, curcumin and a semi-purified fraction of the whole neem oil being two different examples. Most likely, the administration of RV to cultured cells alters the permeability and fluidity of the cell membrane. Also, data presented in literature ascribe to RV an antiproliferative action, thus rendering this drug a good candidate for the control of neoplastic growth. The potential usage of RV both in human and veterinary medicine is also examined in this review