Novel Anti-Neuroinflammatory Properties of a Thiosemicarbazone-Pyridylhydrazone Copper(II) Complex

Neuroinflammation has a major role in several brain disorders including Alzheimer’s disease (AD), yet at present there are no effective anti-neuroinflammatory therapeutics available. Copper(II) complexes of bis(thiosemicarbazones) (CuII(gtsm) and CuII(atsm)) have broad therapeutic actions in preclinical models of neurodegeneration, with CuII(atsm) demonstrating beneficial outcomes on neuroinflammatory markers in vitro and in vivo. These findings suggest that copper(II) complexes could be harnessed as a new approach to modulate immune function in neurodegenerative diseases. In this study, we examined the anti-neuroinflammatory action of several low-molecularweight, charge-neutral and lipophilic copper(II) complexes. Our analysis revealed that one compound, a thiosemicarbazone–pyridylhydrazone copper(II) complex (CuL5 ), delivered copper into cells in vitro and increased the concentration of copper in the brain in vivo. In a primary murine microglia culture, CuL5 was shown to decrease secretion of pro-inflammatory cytokine macrophage chemoattractant protein 1 (MCP-1) and expression of tumor necrosis factor alpha (Tnf), increase expression of metallothionein (Mt1), and modulate expression of Alzheimer’s disease-associated risk genes, Trem2 and Cd33. CuL5 also improved the phagocytic function of microglia in vitro. In 5xFAD model AD mice, treatment with CuL5 led to an improved performance in a spatial working memory test, while, interestingly, increased accumulation of amyloid plaques in treated mice. These findings demonstrate that CuL5 can induce anti-neuroinflammatory effects in vitro and provide selective benefit in vivo. The outcomes provide further support for the development of copper-based compounds to modulate neuroinflammation in brain diseases.Xin Yi Choo, Lachlan E. McInnes, Alexandra Grubman, Joanna M. Wasielewska, Irina Belaya, Emma Burrows, Hazel Quek, Jorge Cañas Martín, Sanna Loppi, Annika Sorvari, Dzhessi Rait, Andrew Powell, Clare Duncan, Jeffrey R. Liddell, Heikki Tanila, Jose M. Polo, Tarja Malm, Katja M. Kanninen, Paul S. Donnelly, and Anthony R. Whit

ATP synthase: from single molecule to human bioenergetics

ATP synthase (FoF1) consists of an ATP-driven motor (F1) and a H+-driven motor (Fo), which rotate in opposite directions. FoF1 reconstituted into a lipid membrane is capable of ATP synthesis driven by H+ flux. As the basic structures of F1 (α3β3γδε) and Fo (ab2c10) are ubiquitous, stable thermophilic FoF1 (TFoF1) has been used to elucidate molecular mechanisms, while human F1Fo (HF1Fo) has been used to study biomedical significance. Among F1s, only thermophilic F1 (TF1) can be analyzed simultaneously by reconstitution, crystallography, mutagenesis and nanotechnology for torque-driven ATP synthesis using elastic coupling mechanisms. In contrast to the single operon of TFoF1, HFoF1 is encoded by both nuclear DNA with introns and mitochondrial DNA. The regulatory mechanism, tissue specificity and physiopathology of HFoF1 were elucidated by proteomics, RNA interference, cytoplasts and transgenic mice. The ATP synthesized daily by HFoF1 is in the order of tens of kilograms, and is primarily controlled by the brain in response to fluctuations in activity

OVERVIEW OF MICROBIAL RISKS IN WATER DISTRIBUTION NETWORKS AND THEIR HEALTH CONSEQUENCES: QUANTIFICATION, MODELLING, TRENDS AND FUTURE IMPLICATIONS

Microbial risks that can affect the distribution network are: intrusion, cross-connections and backflows, inadequate management of reservoirs, improper main pipe repair/maintenance work, and biofilms. Epidemiological investigations have proven that these risks have been sources of waterborne outbreaks. Increasingly since the 1990s, studies have also indicated that the contribution of these risks to the endemic level of disease is not negligible. To address the increasing health risks associated to WDNs, researchers have developed tools for risk quantification and risk management. This review aims to present the recent advancements in the field involving epidemiological investigations, use of quantitative microbial risk assessment (QMRA) for modelling, risk mitigation and decision-support. Increasing the awareness of the progress achieved, but also of the limitations and challenges faced, will aid in accelerating the implementation of QMRA tools for WDN risk management and as a decision-support tool.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

A Novel Approach To Quantify Organic Mercury (organic Hg) By Cold Vapour Atomic Fluorescence Spectroscopy (cvafs) [um Novo Método Para Quantificar Mercúrio Orgânico (hgorgânico) Empregando A Espectrometria De Fluorescência Atômica Do Vapor Frio]

In this work a simple and sensitive procedure to extract organic mercury from water and sediment samples, using methylene chloride in acidic media followed by CVAFS quantification has been developed. The method was evaluated for possible interferents, using different inorganic mercury species and humic acid, no effects being observed. The detection limit for organic mercury was 160 pg and 396 pg for water and sediment samples respectively. The accuracy of the method was evaluated using a certified reference material of methylmercury (BCR-580, estuarine sediment). Recovery tests using methylmercury as surrogate spiked with 1.0 up to 30.0 ng L-1 ranged from 90 up to 109% for water samples, whereas for sediments, recoveries ranged from 57 up to 97%.29611691174Kanno, A., Akagi, H., Takabakate, E., (1985) Eisei Kagaku-Japanese Journal of Toxicology and Environmental Health, 31, p. 260Marins, R.V., Filho, F.J.D.P., Maia, S.R.R., Lacerda, L.D., Marques, W.S., (2004) Quim. Nova, 27, p. 763Miretzky, P., Bisinoti, M.C., Jardim, W.F., Rocha, J.C., (2005) Quim. Nova, 28, p. 438Bisinoti, M.C., Jardim, W.F., (2003) J. Braz. Chem. Soc., 14, p. 244Halbach, S., (1995) Handbook of Metal-Ligant Interactions in Biological Fluids - Bioinorganic Medicine, , Berthon, G. ed., Marcel Dekker: BaselUllrich, S.M., Tanton, T.W., Abdrashitova, S.A., (2001) Crit. Rev. Environ. Sci. Technol., 31, p. 241Bisinoti, M.C., Jardim, W.F., (2004) Quim. Nova, 27, p. 593Tseng, C.M., Diego, A.D., Martin, F.M., Donard, O.F.X., (1997) J. Anal. Spectrom., 12, p. 629Westõõ, G., (1967) Acta Chem. Scand., 20, p. 1790Westõõ, G., (1968) Acta Chem. Scand., 22, p. 2277Marins, R.V., Paraquetti, H.H.M., Ayres, G.A., (2002) Quim. Nova, 25, p. 372Resende, M.D.R., Campos, R.C., Curtius, A.J., (1993) J. Anal. At. Spectrom., 8, p. 247Cossa, D., Sanjuan, J., Cloud, J., Stockwell, P.B., Torns, W.T., (1995) J. Anal. At. Spectrom., 10, p. 287Suda, I., Suda, M., Hirayama, K., (1993) Arch. Toxicol., 67, p. 365Limaverde Filho, A.M., Campos, R.C., (1999) Quim. Nova, 22, p. 477Micaroni, R.C.D.M., Bueno, M.I.M.S., Jardim, W.F., (2000) Quim. Nova, 23, p. 487Atallah, R.H., Kalman, D., (1993) J. Anal. Toxicol., 17, p. 87Jian, W., Mcleod, C.W., (1992) Talanta, 39, p. 1537Bisogni, J.J., Lawrence, A.W., (1974) Environ. Sci. Technol., 18, p. 850Lee, Y.H., Mowrer, J., (1989) Anal. Chim. Acta, 221, p. 259Akagi, H., Nishimura, H., (1991) Addvances in Mercury Toxicology, , Suzuki, T.Nobumassa, I.Clarkson, T. W., eds.Plenum Press: New YorkSzakacs, O., Lasztity, A., Horvath, Z., (1980) Anal. Chim. Acta, 121, p. 219Fadini, P.S., Jardim, W.F., (2000) Analyst, 125, p. 549Bloom, N.S., (1989) Can. J. Fish Aq. Sci., 46, p. 1120Horvat, M., Laing, L., Bloom, N.S., (1993) Anal. Chim. Acta, 281, p. 135Hintelmann, H., Falter, R., Ilgen, G., Evans, R.D., (1997) J. Anal. Chem., 358, p. 363Baeyens, W., Ebinghaus, R.E., Vasiliev, O., (1996) Global and Regional Mercury Cycles: Sources, Fluxes and Mass Balances, , Kluwer Academic Publishers: DordrechtMiller, J.C., Miller, J.N., (1993) Statistics for Analytical Chemistry, , Ellis Horwood PTR Prentice Hall: New YorkWasserman, J.C., Amouroux, D., Wasserman, M.A.V., Donard, O.F.X., (2002) Environ. Technol., 23, p. 89