Excessive manganese exposure is toxic, but a comprehensive biochemical picture of this assault is poorly understood. Whether oxidative stress or reduced energy metabolism under manganese exposure causes toxicity is still a debate. To address this, we chose Δmnt P Escherichia coli, a highly manganese-sensitive strain, in this study. Combining microarray, proteomics, and biochemical analyses, we show that the chronic manganese exposure rewires diverse regulatory and metabolic pathways. Manganese stress affects protein and other macromolecular stability, and envelope biogenesis. Most importantly, manganese exposure disrupts both iron-sulfur cluster and heme-enzyme biogenesis by depleting cellular iron level. Therefore, the compromised function of the iron-dependent enzymes in the tricarboxylic acid cycle, and electron transport chain impede ATP synthesis, leading to severe energy deficiency. Manganese stress also evokes reactive oxygen species, inducing oxidative stress. However, suppressing oxidative stress does not improve oxidative phosphorylation and cell growth. On the contrary, iron supplementation resumed cell growth stimulating oxidative phosphorylation. Therefore, we hypothesize that affected energy metabolism is the primal cause of manganese toxicity.

ParaPep is a repository of antiparasitic peptides, which provides comprehensive information related to experimentally validated antiparasitic peptide sequences and their structures. The data were collected and compiled from published research papers, patents and from various databases. The current release of ParaPep holds 863 entries among which 519 are unique peptides. In addition to peptides having natural amino acids, ParaPep also consists of peptides having d-amino acids and chemically modified residues. In ParaPep, most of the peptides have been evaluated for growth inhibition of various species of Plasmodium, Leishmania and Trypanosoma. We have provided comprehensive information about these peptides that include peptide sequence, chemical modifications, stereochemistry, antiparasitic activity, origin, nature of peptide, assay types, type of parasite, mode of action and hemolytic activity. Structures of peptides consisting of natural, as well as modified amino acids have been determined using state-of-the-art software, PEPstr. To facilitate users, various user-friendly web tools, for data fetching, analysis and browsing, have been integrated. We hope that ParaPep will be advantageous in designing therapeutic peptides against parasitic diseases.Database URL: http://crdd.osdd.net/raghava/parapep/

Radioprotection Gamma irradiationIsoflavone Antioxidant A B S T R A C T The in vitro antioxidant potential and in vivo radioprotective ability of soy isoflavones was studied. Male Wistar rats were orally administered with soybean isoflavones (60 mg/kg) for 21 days followed by gamma irradiation exposure. Survival studies in rats exposed at 10 Gy and endogenous spleen colony forming unit assay (CFU) at 6.0 Gy were performed in order to find radioprotective and immunomodulatory nature of the compound. The rat liver post mitochondrial supernatant and erythrocytes were used to measure lipid peroxidation (LPO) and glutathione (GSH) content along with various antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) after gamma irradiation exposure at 2.0 Gy. Pretreatment with soy isoflavone, prior to gamma irradiation resulted in the increased survival rate of the animals as compared to irradiated group. CFU counts in the isoflavone treated group followed by gamma irradiation at 6 Gy were significantly high as compared to control and the irradiated group, showing immunomodulatory nature of the isoflavones. Pretreatment with isoflavones also significantly reduced the LPO, enhanced the activity of antioxidant enzymes and improved haematological and histological parameters. The present study suggests that supplementation with isoflavone has potent antioxidant activity and act as probable radioprotector against gamma radiation induced oxidative damage.

Manganese is a micronutrient required for activities of several important enzymes under conditions of oxidative stress and iron starvation. In Escherichia coli, the manganese homeostasis network primarily constitutes a manganese importer (MntH) and an exporter (MntP), which are regulated by the MntR dual regulator. In this study, we find that deletion of E. coli hflX, which encodes a ribosome-associated GTPase with unknown function, renders extreme manganese sensitivity characterized by arrested cell growth, filamentation, lower rate of replication, and DNA damage. We demonstrate that perturbation by manganese induces unprecedented influx of manganese in ⌬hflX cells compared to that in the wild-type E. coli strain. Interestingly, our study indicates that the imbalance in manganese homeostasis in the ⌬hflX strain is independent of the MntR regulon. Moreover, the influx of manganese leads to a simultaneous influx of zinc and inhibition of iron import in ⌬hflX cells. In order to review a possible link of HflX with the phage life cycle, we performed a lysis-lysogeny assay to show that the Mn-perturbed ⌬hflX strain reduces the frequency of lysogenization of the phage. This observation raises the possibility that the induced zinc influx in the manganese-perturbed ⌬hflX strain stimulates the activity of the zinc-metalloprotease HflB, the key determinant of the lysis-lysogeny switch. Finally, we propose that manganese-mediated autophosphorylation of HflX plays a central role in manganese, zinc, and iron homeostasis in E. coli cells.

The oxidative stress that evolves under cobalt and nickel exposure is thought to exert toxicity, though the exact routes of such metal poisoning remain ambiguous. We revisited the metal toxicity in Escherichia coli to show that cobalt and nickel exposure at levels as low as 0.5 and 1 mM, respectively, visibly inhibits growth. We also observed that acidic conditions aggravated, while alkaline conditions alleviated the metal toxicity. Besides, 1 mM manganese, which is non-cytotoxic, as judged by the growth of E. coli, synergistically elevated cobalt and nickel stress. However, the metal toxicity did not lead to oxidative stress in E. coli. On the other hand, we show that cobalt and nickel, but not manganese, reduced the rate of DNA replication to 50% within 2 hours. Interestingly, the metal ions promoted DNA double-strand breaks but did not induce SOS repair pathways, indicating that the metal ions could block SOS induction. To test this, we show that cobalt and nickel, but not manganese, suppressed the nalidixic acid-induced SOS response. Finally, using an in vitro assay system, we demonstrated that cobalt and nickel inhibit RecBCD function, which is essential for SOS induction. Therefore, our data indicate that cobalt and nickel affect DNA replication, damage DNA, and inhibit the SOS repair pathway to exert toxicity.

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