Catechol-Amyloid Interactions.

This review introduces multifaceted mutual interactions between molecules containing a catechol moiety and aggregation-prone proteins. The complex relationships between these two molecular species have previously been elucidated primarily in a unidirectional manner, as demonstrated in cases involving the development of catechol-based inhibitors for amyloid aggregation and the elucidation of the role of functional amyloid fibers in melanin biosynthesis. This review aims to consolidate scattered clues pertaining to catechol-based amyloid inhibitors, functional amyloid scaffold of melanin biosynthesis, and chemically designed peptide fibers for providing chemical insights into the role of the local three-dimensional orientation of functional groups in manifesting such interactions. These orientations may play crucial, yet undiscovered, roles in various supramolecular structures.

Supramolecular Regulation of Polydopamine Formation by Amyloid Fibers.

Polydopamine (PD) and melanin species are chemically complex systems, the formation and properties of which are incompletely understood. Inspired by the role of functional amyloids in melanin biosynthesis, this paper examines the influences of the supramolecular structure of amyloids on oxidative polymerization of dopamine. Kinetic analyses on the formation of PD species in the presence of hen egg white lysozyme (HEWL) fibers or soluble HEWL revealed that both forms gave rise to the total quantity of PD species, but the rate of their formation could be accelerated only by the amyloid form. PD species formed with HEWL fibers showed a morphology of bundled fibers, whereas those with soluble HEWL had a mesh-like structure. Amyloid fibers of recombinant Pmel17 had properties similar to those of HEWL fibers in modulating PD formation. The results presented here suggest how nature designs functionality with an amyloid structure and can help understand and engineer chemistries of other functional amyloids.

Antibacterial nanoparticles: enhanced antibacterial efficiency of coral-like crystalline rhodium nanoplates.

This paper deals with the newly found antibacterial efficiency of coral-like crystalline Rh nanoplates. Rh nanoplates with rough surface morphology synthesized by inverse-directional galvanic replacement exhibited highly enhanced antibacterial efficiency compared to Rh3+ ion and Rh nanospheres. The observed antibacterial efficiency was comparable to Ag nanoplates, a well-known anticancer nano-agent. Results clearly demonstrate that the composition and morphology of a nanostructure play significant roles in antibacterial effects.

Zika preparedness and response in Viet Nam.

The findings and conclusions in this article are those of the authors and do not necessarily represent the official positions of the United States Centers for Disease Control and Prevention.

The dual personalities of matrix metalloproteinases in inflammation.

Collagen, gelatin, elastin, fibronectin, proteoglycans and vitronectin are just a few proteins which form the "mesh" that holds a multicellular organism together. The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade the extracellular matrix. Over several decades it has been clearly established that MMPs are the key molecules associated with matrix remodeling. The remodeling of this matrix is important for physiological and pathological processes such as pregnancy, wound repair, cancer and arthritis. The identification of new non-matrix MMP substrates involved in inflammation, highlights the diverse role of MMPs. These enzymes can enhance leukocyte invasion and regulate the inflammatory activity of serine proteases, cytokines and chemokines. Interestingly, the MMP family appears to have a "dual personality" in that several MMPs such as MMP-2 and -9 can favour either anti- or pro-inflammatory action, respectively. The extent of this dual functionality of MMPs is yet to be realized. Elucidating these processes may assist in the development of drugs for the treatment of inflammatory diseases such as arthritis, cancer and chronic wounds.

Targeting matrix metalloproteases to improve cutaneous wound healing.

Wound repair is a physiological event in which tissue injury initiates a repair process leading to restoration of structure and function of the tissue. Cutaneous wound repair can be divided into a series of overlapping phases including formation of fibrin clot, inflammatory response, granulation tissue formation incorporating re-epithelialisation and angiogenesis and finally, matrix formation and remodelling. Matrix metalloproteases (MMPs) are a family of neutral proteases that play a vital role throughout the entire wound healing process. They regulate inflammation, degrade the extracellular matrix (ECM) to facilitate the migration of cells and remodel the new ECM. However, excessive MMP activity contributes to the development of chronic wounds. Selective control of MMP activity may prove to be a valuable therapeutic approach to promote healing of chronic ulcers. Recent evidence indicates that the anticoagulant, activated protein C may be useful in the treatment of non-healing wounds by preventing excessive protease activity through inhibition of inflammation and selectively increasing MMP-2 activity to enhance angiogenesis and re-epithelialisation.

Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation.

Iron (Fe) is critical for proliferation, but its precise role in cell cycle progression remains unclear. In this study, we examined the mechanisms involved by assessing the effects of Fe chelators on the expression of molecules that play key roles in this process. In initial studies, gene arrays were used to assess gene expression after incubating cells with 2 Fe chelators, namely, desferrioxamine (DFO) and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), or the DNA-damaging agent, actinomycin D. From the genes assessed, only the N-myc downstream-regulated gene 1 (Ndrg1) was specifically up-regulated by Fe chelation. Although the function of Ndrg1 is unclear, previous studies showed it markedly slows tumor growth and acts as a potent metastasis suppressor. Incubation of cells with chelators markedly increased Ndrg1 mRNA and protein expression, but this was not found with their Fe complexes or when the Fe-binding site had been inactivated. Increased Ndrg1 expression following Fe chelation was related to the permeability and antiproliferative activity of chelators and could be reversed by Fe repletion. Moreover, Ndrg1 up-regulation after chelation occurred at the transcriptional level and was mediated by hypoxia inducible factor-1alpha (HIF-1alpha)-dependent and -independent mechanisms. Our investigation suggests Ndrg1 is a novel link between Fe metabolism and the control of proliferation.

Potent iron chelators increase the mRNA levels of the universal cyclin-dependent kinase inhibitor p21(CIP1/WAF1), but paradoxically inhibit its translation: a potential mechanism of cell cycle dysregulation.

Iron (Fe) chelators are potential antitumor agents. Cellular Fe depletion results in a G1/S arrest but the precise molecular mechanisms involved remain unclear. Recent studies have shown that this process is complex with multiple cell cycle molecules being involved. We previously showed that Fe chelators such as 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) were far more potent antitumor agents than the clinically used ligand, desferrioxamine (DFO). To further characterize the effects of chelators on cell cycle arrest, we compared their activity with the DNA-damaging agents actinomycin D (Act D) and cisplatin (CP). These latter two compounds increase the expression of p53 and its target genes such as the universal cyclin-dependent kinase inhibitor, p21(CIP1/WAF1). Incubation of normal and neoplastic cells with all agents resulted in increased nuclear p53, the effect being pronounced for Act D and CP. As expected, both Act D and CP also markedly increased nuclear p21(CIP1/WAF1) protein levels, while DFO and 311 caused a significant (P<0.0004) decrease. This latter effect was surprising, as these chelators markedly increased mRNA levels of this molecule. Immunofluorescence studies showed that Act D and CP caused nuclear localization of p21(CIP1/WAF1). In contrast, the chelators prevented translation of p21(CIP1/WAF1). This did not appear to be due to a general effect of the chelators on preventing translation, as transferrin receptor 1 was markedly up-regulated 15- to 21-fold by DFO and 311. Combination of 311 with Act D or CP prevented translation of p21(CIP1/WAF1) and its nuclear localization observed with these DNA-damaging agents. Significantly, the effect of chelation on reducing nuclear p21(CIP1/WAF1) was reversed by the Fe donor ferric ammonium citrate, indicating that p21(CIP1/WAF1) translation was dependent on intracellular Fe levels. This study demonstrates that while Fe chelators markedly up-regulate the mRNA levels of p21(CIP1/WAF1) they paradoxically inhibit translation.

The role of iron in cell cycle progression and the proliferation of neoplastic cells.

Iron (Fe) is an obligate requirement for life and it is well known that Fe depletion leads to G(1)/S arrest and apoptosis. These facts, together with studies showing that Fe chelators can inhibit the growth of aggressive tumours such as neuroblastoma, suggest that Fe-deprivation may be an important therapeutic strategy. To optimise the anti-proliferative effects of Fe chelators, the role of Fe in cell cycle control requires intense investigation. For many years, Fe chelators were known to prevent the activity of the R2 subunit of ribonucleotide reductase (RR) that catalyzes the conversion of ribonucleotides into deoxyribonucleotides (dNTPs) for DNA synthesis. In addition, Fe depletion may also inhibit the newly identified p53-inducible form of this molecule called p53R2. This protein has the same Fe-binding sites as found in R2, and its activity is thought to supply dNTPs for the critical process of DNA repair. Iron chelation also causes hypophosphorylation of the retinoblastoma protein (pRb) and decreases the expression of cyclins A, B and D, which are vital for cell cycle progression. Other regulatory molecules whose expression is affected by Fe depletion include p53 and hypoxia inducible factor-1alpha (HIF-1alpha). The levels of p53 increase following Fe chelation via the ability of HIF-1alpha to bind and stabilize p53. The activity of HIF-1alpha is controlled by an Fe-dependent enzyme known as HIF-alpha prolyl hydroxylase (PH). Chelation of Fe from this enzyme inhibits its activity, leading to stabilization of HIF-1alpha and the subsequent effects on downstream targets critical for angiogenesis and tumour growth. The levels of p53 may also increase after Fe chelation by phosphorylation of this protein at serine-15 and -37. This prevents the interaction of p53 with murine double minute-2 (mdm-2) and its degradation. Iron chelation also markedly increases the mRNA levels of the p53-inducible cyclin-dependent kinase (cdk) inhibitor, p21(WAF1/CIP1). Surprisingly, the increase in p21(WAF1/CIP1) mRNA was not reciprocated at the protein level, and this may result in cell cycle dysregulation. This review will focus on the molecular mechanisms induced following Fe chelation and the role of Fe in cell cycle progression.

Ferroportin1: a new iron export molecule?

Ferroportin1 is a newly discovered molecule that may play a role in iron export. It is expressed on the basolateral surfaces of mature enterocytes within the duodenum and in macrophages of the spleen and liver. Furthermore, this protein was found to be expressed in placental syncytiotrophoblasts and may be involved in the supply of maternal iron to the fetus. Sequence analysis of ferroportin1 predicts it has ten transmembrane domains, a reductase site and a basolateral localization signal. In addition, the ferroportin1 mRNA transcript contains an iron response element in its 5' untranslated region. This review is focused on the current state of knowledge on ferroportin1 and the medical implications of this discovery.