Blocking Plasmodium falciparum Development via Dual Inhibition of Hemoglobin Degradation and the Ubiquitin Proteasome System by MG132

Among key potential drug target proteolytic systems in the malaria parasite Plasmodium falciparum are falcipains, a family of hemoglobin-degrading cysteine proteases, and the ubiquitin proteasomal system (UPS), which has fundamental importance in cellular protein turnover. Inhibition of falcipains blocks parasite development, primarily due to inhibition of hemoglobin degradation that serves as a source of amino acids for parasite growth. Falcipains prefer P2 leucine in substrates and peptides, and their peptidyl inhibitors with leucine at the P2 position show potent antimalarial activity. The peptidyl inhibitor MG132 (Z-Leu-Leu-Leu-CHO) is a widely used proteasome inhibitor, which also has P2 leucine, and has also been shown to inhibit parasite development. However, the antimalarial targets of MG132 are unclear. We investigated whether MG132 blocks malaria parasite development by inhibiting hemoglobin degradation and/or by targeting the UPS. P. falciparum was cultured with inhibitors of the UPS (MG132, epoxomicin, and lactacystin) or falcipains (E64), and parasites were assessed for morphologies, extent of hemoglobin degradation, and accumulation of ubiquitinated proteins. MG132, like E64 and unlike epoxomicin or lactacystin, blocked parasite development, with enlargement of the food vacuole and accumulation of undegraded hemoglobin, indicating inhibition of hemoglobin degradation by MG132, most likely due to inhibition of hemoglobin-degrading falcipain cysteine proteases. Parasites cultured with epoxomicin or MG132 accumulated ubiquitinated proteins to a significantly greater extent than untreated or E64-treated parasites, indicating that MG132 inhibits the parasite UPS as well. Consistent with these findings, MG132 inhibited both cysteine protease and UPS activities present in soluble parasite extracts, and it strongly inhibited recombinant falcipains. MG132 was highly selective for inhibition of P. falciparum (IC(50) 0.0476 µM) compared to human peripheral blood mononuclear cells (IC(50) 10.8 µM). Thus, MG132 inhibits two distinct proteolytic systems in P. falciparum, and it may serve as a lead molecule for development of dual-target inhibitors of malaria parasites

Rewiring of human lung cell lineage and mitotic networks in lung adenocarcinomas

Analysis of gene expression patterns in normal tissues and their perturbations in tumors can help to identify the functional roles of oncogenes or tumor suppressors and identify potential new therapeutic targets. Here, gene expression correlation networks were derived from 92 normal human lung samples and patient-matched adenocarcinomas. The networks from normal lung show that NKX2-1 is linked to the alveolar type 2 lineage, and identify PEBP4 as a novel marker expressed in alveolar type 2 cells. Differential correlation analysis shows that the NKX2-1 network in tumors includes pathways associated with glutamate metabolism, and identifies Vaccinia-related kinase (VRK1) as a potential drug target in a tumor-specific mitotic network. We show that VRK1 inhibition cooperates with inhibition of PARP signaling to inhibit growth of lung tumor cells. Targeting of genes that are recruited into tumor mitotic networks may provide a wider therapeutic window than that seen by inhibition of known mitotic genes

Body integrity identity disorder: deranged body processing, right fronto-parietal dysfunction, and phenomenological experience of body incongruity

Body integrity identity disorder (BIID) is characterised by profound experience of incongruity between the biological and desired body structure. The condition manifests in "non-belonging" of body parts, and the subsequent desire to amputate, paralyse or disable a limb. Little is known about BIID; however, a neuropsychological model implicating right fronto-parietal and insular networks is emerging, with potential disruption to body representation. We argue that, as there is scant systematic research on BIID published to date and much of the research is methodologically weak, it is premature to assume that the only process underlying bodily experience that is compromised is body representation. The present review systematically investigates which aspects of neurological processing of the body, and sense of self, may be compromised in BIID. We argue that the disorder most likely reflects dysregulation in multiple levels of body processing. That is, the disunity between self and the body could arguably come about through congenital and/or developmental disruption of body representations, which, together with altered multisensory integration, may preclude the experience of self-attribution and embodiment of affected body parts. Ulimately, there is a need for official diagnostic criteria to facilitate epidemiological characterisation of BIID, and for further research to systematically investigate which aspects of body representation and processing are truly compromised in the disorder