Nitration of Hsp90 induces cell death

Oxidative stress is a widely recognized cause of cell death associated with neurodegeneration, inflammation, and aging. Tyrosine nitration in these conditions has been reported extensively, but whether tyrosine nitration is a marker or plays a role in the cell-death processes was unknown. Here, we show that nitration of a single tyrosine residue on a small proportion of 90-kDa heat-shock protein (Hsp90), is sufficient to induce motor neuron death by the P2X7 receptor-dependent activation of the Fas pathway. Nitrotyrosine at position 33 or 56 stimulates a toxic gain of function that turns Hsp90 into a toxic protein. Using an antibody that recognizes the nitrated Hsp90, we found immunoreactivity in motor neurons of patients with amyotrophic lateral sclerosis, in an animal model of amyotrophic lateral sclerosis, and after experimental spinal cord injury. Our findings reveal that cell death can be triggered by nitration of a single protein and highlight nitrated Hsp90 as a potential target for the development of effective therapies for a large number of pathologies

Mutant profilin1 transgenic mice recapitulate cardinal features of motor neuron disease

The recent identification of profilin1 mutations in 25 familial ALS cases has linked altered function of this cytoskeletonregulating protein to the pathogenesis of motor neuron disease. To investigate the pathological role of mutant profilin1 in motor neuron disease, we generated transgenic lines of mice expressing human profilin1 with a mutation at position 118 (hPFN1G118V). One of the mouse lines expressing high levels of mutant human PFN1 protein in the brain and spinal cord exhibited many key clinical and pathological features consistent with human ALS disease. These include loss of lower (ventral horn) and upper motor neurons (corticospinal motor neurons in layer V), mutant profilin1 aggregation, abnormally ubiquitinated proteins, reduced choline acetyltransferase (ChAT) enzyme expression, fragmented mitochondria, glial cell activation, muscle atrophy, weight loss, and reduced survival. Our investigations of actin dynamics and axonal integrity suggest that mutant PFN1 protein is associated with an abnormally low filamentous/globular (F/G)-actin ratio that may be the underlying cause of severe damage to ventral root axons resulting in a Wallerian-like degeneration. These observations indicate that our novel profilin1 mutant mouse line may provide a new ALS model with the opportunity to gain unique perspectives into mechanisms of neurodegeneration that contribute to ALS pathogenesis

A systematic review of emerging technologies to enhance the treatment of ovarian cancer

The efficacy and safety of chemotherapy are two major challenges when it comes to treating ovarian cancer. The associated undesirable side effects of chemotherapy agents jeopardize the clinical intent and the efficiency of the therapy. Multiple studies have been published describing new developments and novel strategies utilizing the latest therapeutic and drug delivery technologies to address the efficacy and safety of chemotherapeutics in ovarian cancers. We have identified five novel technologies that are available and, if used, have the potential to mitigate the above-mentioned challenges. Nanocarriers in different forms (Nano-gel, Aptamer, peptide medicated formulations, Antibody-drug conjugation, surface charge, and nanovesicle technologies) are developed and available to be employed to target the cancerous tissue. These strategies are promising to improve clinical efficacy and reduce side effects. We have systematically searched and analyzed published data, as well as the authors intent for the described technology on each publication. We narrowed to 81 key articles and extracted their data to be discussed in this review. In summary, the selected articles investigated the pharmacokinetic properties of drugs combined with nanocarriers and found significant improvement in efficacy and safety by reducing the IC50 values and drug doses. These key papers described promising novel technologies in anti-cancer therapeutic approaches to enable sustained drug release and achieve prolonged drug performance near the tumor site or target tissue.</p