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Biomedical subjects

Matthew D Hall

Publications and source records attributed to Matthew D Hall.

12 recordsLinked to original sources
PubMed2026

Ampyrone is a direct agonist of human tyrosinase and a potential therapeutic for hypopigmentation disorders.

Significant loss of pigmentation can increase visual disability, skin cancer risk, and psychosocial stress. Tyrosinase (TYR) catalyzes the first and rate-limiting step of melanin synthesis. Inhibitors of TYR are well established and are currently used in clinical settings; however, there is a dearth of direct activators of TYR. Here, using a human TYR construct, we developed high-throughput screening methods, in cell confirmatory assays employing 13C-tyrosine tracing, and computational analysis techniques, and identified ampyrone (4-aminoantipyrine) as a TYR activator. Ampyrone increased the in vitro catalytic activity of the human recombinant intramelanosomal domain of TYR (hTYR) and its hypomorphic variant, Pro406Leu (P406L), a cause of oculocutaneous albinism type 1B (OCA1B). Moreover, ampyrone induced melanin synthesis in both WT and OCA1B human melanocytes, mouse OCA2 melanocytes, as well as 3-dimensional (3D) human skin cultures. Computational studies provided additional insight into the effects of direct TYR agonists on enzyme activity. Our results identify ampyrone as a lead candidate for TYR activation, potentially supporting the development of therapies for patients with genetic and acquired diseases of hypopigmentation.

Humans↗
PubMed2006

The fate of platinum(II) and platinum(IV) anti-cancer agents in cancer cells and tumours.

SRIXE mapping has been used to gain insight into the fate of platinum(II) and platinum(IV) complexes in cells and tumours treated with anticancer active complexes to facilitate the development of improved drugs. SRIXE maps were collected of thin sections of human ovarian (A2780) cancer cells treated with bromine containing platinum complexes, cis-[PtCl(2)(3-Brpyr)(NH(3))] (3-Brpyr=3-bromopyridine) and cis,trans,cis-[PtCl(2)(OAcBr)(2)(NH(3))(2)] (OAcBr=bromoacetate), or a platinum complex with an intercalator attached cis-[PtCl(2)(2-[(3-aminopropyl)amino]-9,10-anthracenedione)(NH(3))]. After 24h the complexes appear to be localised in the cell nucleus with a lower concentration in the surrounding cytoplasm. In cells treated with cis-[PtCl(2)(3-Brpyr)(NH(3))] the concentration of bromine was substantially higher than in control cells and the bromine was co-localised with the platinum consistent with the 3-bromopyridine ligand remaining bound to the platinum. The cells treated with cis,trans,cis-[PtCl(2)(OAcBr)(2)(NH(3))(2)] also showed an increased level of bromine, but to a much lesser extent than for those treated with cis-[PtCl(2)(3-Brpyr)(NH(3))] suggestive of substantial reduction of the platinum(IV) complex. Maps were also collected from thin sections of a 4T1.2 neo 1 mammary tumour xenograft removed from a mouse 3h after treatment with cis,trans,cis-[PtCl(2)(OH)(2)(NH(3))(2)] and revealed selective uptake of platinum by one cell.

Animals↗
PubMed2006

XANES investigation of the Co oxidation state in solution and in cancer cells treated with Co(III) complexes.

XANES spectroscopy has been used to investigate whether it is possible to determine the oxidation state and coordination environment of Co complexes following treatment of cancer cells with Co(III) or Co(II) complexes. Our results show that the variation of the XANES with coordination geometry make it impossible to do this in a completely reliable way which is in contrast to the situation for platinum and chromium. It was established that the XANES spectrum obtained from cells treated with [Co(diNOsar)]Br(3) remained unchanged with respect to its XANES spectrum obtained in solution, demonstrating that the [Co(diNOsar)]Br(3) complex remained intact after 24h in cellular media (diNOsar=1,8-dinitro-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane). In contrast, the XANES spectra obtained from cells treated with Na[Co(acac)(3)] and [Co(acac)(3)] differed from the XANES spectra of the respective complexes obtained in solution, indicating a change in co-ordination environment for both complexes upon uptake in cells. The similarity of these spectra suggests that appearance of this XANES can be used as an indication of loss of the carrier ligands, a useful indicator in the study of hypoxia selective complexes. The results obtained for Na[Co(acac)(3)] and [Co(acac)(3)] are consistent with the intracellular coordination of cobalt(III) to sulfur ligands upon cellular uptake.

Cobalt↗
PubMed2004

Comparative efficacy of novel platinum(IV) compounds with established chemotherapeutic drugs in solid tumour models.

Platinum(II)-based anticancer drugs are associated with high reactivity and thus a poor biological stability. The platinum(IV)-complexes display potential advantages due to their greater stability and bioreductive activation, thereby allowing a greater proportion of the drug to arrive at the target intact. All compounds tested were able to produce cytotoxicity in monolayer cell cultures, however, the potencies of platinum(IV) drugs were lower than that observed for the platinum(II) compounds or established organic chemotherapeutic agents. There was no significant alteration in the potency of platinum(II) or (IV) compounds to produce cytotoxicity in multicellular tumour spheroids (MCTS) compared to monolayer cultures. All the organic and platinum-based cytotoxic agents produced, to varying degrees, either a retardation or reduction in MCTS growth. Proliferating cells were restricted to the outer two to three cellular layers in intermediate (d=350 microm) and large (d=600 microm) MCTS. Regardless of MCTS size, drug treatment produced a larger and more widely distributed proliferating cell population, consistent with the recruitment of quiescent cells to the proliferating pool following cytotoxic damage. Histology indicated that the predominant morphological change was that of apoptosis, although there was some drug-dependent effects such as the metaphase arrest produced by vinblastine and chromatin dispersal to the periphery of nuclei produced by doxorubicin. In summary, whilst the platinum(IV) derivatives were able to produce cytotoxicity via apoptosis, the introduction of a stable axial group significantly retarded the rate at which this occurred.

Antineoplastic Agents↗
PubMed2004

The mechanism of action of platinum(IV) complexes in ovarian cancer cell lines.

The reduction potentials, lipophilicities, cellular uptake and cytotoxicity have been examined for two series of platinum(IV) complexes that yield common platinum(II) complexes on reduction: cis-[PtCl(4)(NH(3))(2)], cis,trans,cis-[PtCl(2)(OAc)(2)(NH(3))(2)], cis,trans,cis-[PtCl(2)(OH)(2)(NH(3))(2)], [PtCl(4)(en)], cis,trans-[PtCl(2)(OAc)(2)(en)] and cis,trans-[PtCl(2)(OH)(2)(en)] (en=ethane-1,2-diamine, OAc=acetate). As previously reported, the reduction occurs most readily when the axial ligand is chloride and least readily when it is hydroxide. The en series of complexes are marginally more lipophilic than their ammine analogues. The presence of axial chloride or acetate ligands results in a slighter higher lipophilicity compared with the platinum(II) analogue whereas hydroxide ligands lead to a substantially lower lipophilicity. The cellular uptake is similar for the platinum(II) species and their analogous tetrachloro complexes, but is substantially lower for the acetato and hydroxo complexes, resulting in a correlation with the reduction potential. The activities are also correlated with the reduction potentials with the tetrachloro complexes being the most active of the platinum(IV) series and the hydroxo being the least active. These results are interpreted in terms of reduction, followed by aquation reducing the amount of efflux from the cells resulting in an increase in net uptake.

Cell Line, Tumor↗
PubMed2003

The cellular distribution and oxidation state of platinum(II) and platinum(IV) antitumour complexes in cancer cells.

The cellular distribution of platinum in A2780 ovarian cancer cells treated with cisplatin and platinum(IV) complexes with a range of reduction potentials has been examined using elemental analysis (synchrotron radiation-induced X-ray emission). The cellular distribution of platinum(IV) drugs after 24 h is similar to that of cisplatin, consistent with the majority of administered platinum(IV) drugs being reduced. Micro-X-ray absorption near-edge spectra of cells treated with cisplatin and platinum(IV) complexes confirmed the reduction of platinum(IV) to platinum(II). In cells treated, the most difficult to reduce complex, cis, trans, cis-[PtCl(2)(OH)(2)(NH(3))(2)], platinum(IV) was detected in the cells along with platinum(II). The observations are in accordance with the relative ease of reduction of the platinum(IV) complexes used and support the requirement of reduction for activation of platinum(IV) complexes.

Antineoplastic Agents↗
PubMed2003

XANES determination of the platinum oxidation state distribution in cancer cells treated with platinum(IV) anticancer agents.

Here we describe the use of X-ray absorption near edge spectroscopy (XANES) to provide information about the relative proportions of platinum(II) and platinum(IV) complexes by analyzing the XANES edge height. The intracellular reduction of platinum(IV) complexes in cancer cells has been observed directly, and the proportion of reduction after 2 h was found to correlate with the reduction potentials of the complexes.

Antineoplastic Agents↗
PubMed2003

Up-regulation of IL-18BP, but not IL-18 mRNA in rat liver by LPS.

Interleukin (IL)-18 is a pro-inflammatory cytokine that plays a critical role in inflammation leading to liver damage, through promotion of Fas-mediated apoptosis. Inhibition of IL-18 activity protects against LPS-induced lethality in mice and against liver damage induced by LPS after sensitisation of mice with Proprionibacterium acnes. A specific, potent, endogenous inhibitor of IL-18 (IL-18BP) has been identified in mice and humans, and IL-18BP mRNA is expressed constitutively in liver. The objectives of this study were to compare changes in IL-1beta and IL-18 mRNA expression in the liver of rats in response to peripheral injection of LPS, using real-time PCR, and also to investigate whether IL-18BP mRNA expression is affected by this treatment. LPS rapidly up-regulated IL-1beta mRNA expression, but IL-18 mRNA expression was unaffected by LPS treatment. Unlike IL-18, IL-18BP mRNA was up-regulated dramatically by approximately 12-fold above nai;ve levels, peaking 3 h after LPS injection. This ability of LPS to up-regulate expression of the endogenous IL-18 inhibitor may indicate a mechanism by which the inflammatory response to LPS is regulated.

Animals↗
PubMed2002

Structural investigations of palladium(II) and platinum(II) complexes of salicylhydroxamic acid.

Complexes of salicylhydroxamic acid (shaH) with palladium(II) and platinum(II) were investigated. The synthesis of [Pt(sha)(2)] was attempted via a number of methods, and ultimately (1)H NMR investigations revealed that salicylhydroxamate would not coordinate to chloro complexes of platinum(II). However, [Pt(sha-H)(PPh(3))(2)] was successfully synthesized and the crystal structure determined (orthorhombic, space group Pca2(1) a = 17.9325(19) A, b = 11.3102(12) A, c = 18.2829(19) A, Z = 4, R = 0.0224). The sha binds via an [O,O] binding mode, in its hydroximate form. In contrast the palladium complex [Pd(sha)(2)] was readily synthesized and crystallized as [Pd(sha)(2)](DMF)(4) in the triclinic space group P(-)1,a = 7.066(1) A, b = 9.842(2) A, c = 12.385(2) A, alpha = 99.213(3)(o), beta = 90.669(3), gamma = 109.767(3)(o), Z = 1, R = 0.037. The unexpected [N,O'] binding mode of the salicylhydroxamate ligand in [Pd(sha)(2)] prompted investigation of the stability of a number of binding modes of salicylhydroxamic acid in [M(sha)(2)] (M = Pd, Pt) by density functional theory, using the B3LYP hybrid functional at the 6-311G* level of theory. Geometry optimizations were carried out for various binding modes of the ligands and their relative energies established. It was found that the [N,O'] mode gave the more stable complex, in accord with experimental observations. Stabilization of hydroxamate binding to platinum is evidently afforded by soft ligands lying trans to them.

Crystallography, X-Ray↗
PubMed2002

Activation of astrocyte intracellular signaling pathways by interleukin-1 in rat primary striatal cultures.

The striatum has been implicated as the site of action mediating neurotoxic effects of interleukin-1 (IL-1) during ischemia. However, the molecular mechanisms underlying these events have yet to be fully addressed. In the present study, primary cultures of rat striatal cells were used as a model for the study of IL-1 signaling pathways in the striatum. Immunocytochemical analyses revealed that these cultures consisted of a mixture of neurones and astrocytes and demonstrated expression of the IL-1 type I receptor (IL-1RI) on both cell types. Treatment with IL-1 (3 units/ml) for 10 min increased phosphorylation of p38 MAP kinase in striatal cells. The endogenous IL-1RI inhibitor IL-1Ra (24 ng/ml) and the p38 MAP kinase inhibitor SB203580 (10 nM) both inhibited this response. Analysis of the effects of IL-1 on nuclear translocation of the transcription factor NF-kB revealed that NF-kB became activated in a time-dependent manner. Immunocytochemistry revealed that IL-1 stimulated p38 phosphorylation and NF-kB translocation in astrocytes only. TaqMan real-time quantitative PCR analysis revealed that IL-1 stimulated gene expression of tumor necrosis factor-alpha (TNF) in striatal cultures. The p38 MAP kinase inhibitor SB203580 failed to inhibit the effects of IL-1 on NF-kB translocation or gene transcription. These studies have demonstrated significant aspects of the IL-1 signaling cascade in cultured striatum. Of particular interest is the finding that IL-1 stimulated activation of p38 MAP kinase and NF-kB in striatal astrocytes exclusively.

Animals↗