The different biological behavior of cationic Fe and Mn pyridylporphyrins in Escherichia coli and mouse studies prompted us to revisit and compare their chemistry. For that purpose the series of ortho and meta isomers of Fe(III) meso-tetrakis-N-alkylpyridylporphyrins, alkyl being methyl to n-octyl, were synthesized and characterized by elemental analysis, UV/vis spectroscopy, mass spectrometry, lipophilicity, protonation equilibria of axial waters, metal-centered reduction potential, E1/2 for MIIIP/MIIP redox couple (M = Fe, Mn, P=porphyrin), kcat for the catalysis of O2•− dismutation, stability towards peroxide-driven porphyrin oxidative degradation (produced in the catalysis of ascorbate oxidation by MP), ability to affect growth of SOD-deficient E. coli and toxicity to mice. Electron-deficiency of the metal site is modulated by the porphyrin ligand, which renders Fe(III) porphyrins ≥ 5 orders of magnitude more acidic than the analogous Mn(III) porphyrins, as revealed by the pKa1 of axially coordinated waters. The 5 log units difference in the acidity between the Mn and Fe sites in porphyrin translates into the predominance of tetracationic (OH)(H2O)FeP complexes relative to pentacationic (H2O)2MnP species at pH ~7.8. This is evidenced in large differences in the thermodynamic parameters - pKa of axial waters and E1/2 of MIII/MII redox couple. The presence of hydroxo ligand labilizes trans-axial water which results in higher reactivity of Fe- relative to Mn center. The differences in the catalysis of O2•− dismutation (log kcat) between Fe and Mn porphyrins is modest, 2.5-5-fold, due to predominantly outer-sphere, with partial inner-sphere character of two reaction steps. However, the rate constant for the inner-sphere H2O2-based porphyrin oxidative degradation is 18-fold larger for (OH)(H2O)FeP than for (H2O)2MnP. The in vivo consequences of the differences between the Fe- and Mn porphyrins were best demonstrated in SOD-deficient E. coli growth. Based on fairly similar log kcat(O2.− values, very similar effect on the growth of SOD-deficient E. coli was anticipated by both metalloporphyrins. Yet, while MnTE-2-PyP5+ was fully efficacious at ≥20 μM, the Fe analog, FeTE-2-PyP5+ supported SOD-deficient E. coli growth at 200-fold lower doses in the range of 0.1 to 1 μM. Moreover the pattern of SOD-deficient E. coli growth was different with Mn- and Fe porphyrins. Such results suggested different mode of action of these metalloporphyrins. Further exploration demonstrated that: (1) 0.1 μM FeTE-2-PyP5+ provided similar growth stimulation as 0.1 μM Fe salt, while 20 μM Mn salt provides no protection to E. coli; and (2) 1 μM Fe porphyrin is fully degraded by 12 hours in E. coli cytosol and growth medium; while Mn porphyrin is not. Stimulation of the aerobic growth of SOD-deficient E. coli by the Fe porphyrin is therefore due to iron acquisition. Our data suggest that in vivo, redox-driven degradation of Fe porphyrins resulting in Fe release plays a major role in their biological action. Possibly, iron reconstitutes enzym...
The Mn porphyrins of kcat(O2˙−) as high as that of a superoxide dismutase enzyme, and of optimized lipophilicity have already been synthesized. Their exceptional in vivo potency is at least in part due to their ability to mimic site and location of mitochondrial superoxide dismutase, MnSOD. MnTnHex-2-PyP5+ is the most studied among lipophilic Mn porphyrins. It is of remarkable efficacy in animal models of oxidative stress injuries and particularly in central nervous system diseases. However, when used at high single and multiple doses it becomes toxic. The toxicity of MnTnHex-2-PyP5+ has been in part attributed to its micellar properties, i.e. the presence of polar cationic nitrogens and hydrophobic alkyl chains. The replacement of a CH2 group by oxygen atom in each of the four alkyl chains was meant to disrupt the porphyrin micellar character. When such modification occurs at the end of long alkyl chains, the oxygens become heavily solvated, which leads to a significant drop in the lipophilicity of porphyrin. However, when the oxygen atoms are buried deeper within the long heptyl chains, their excessive solvation is precluded and the lipophilicity preserved. The presence of oxygens and the high lipophilicity bestow the exceptional chemical and physical properties to Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP5+. The high SOD-like activity is fully preserved and somewhat enhanced: log kcat(O2˙−) = 7.83 vs 7.48 and 7.65 for MnTnHex-2-PyP5+ and MnTnHep-2-PyP5+, respectively. MnTnBuOE-2-PyP5+ was tested in an O2˙− - specific in vivo assay – aerobic growth of SOD-deficient yeast, Saccharomyces cerevisiae, where it was fully protective in the range of 5 – 30 µM. MnTnHep-2-PyP5+ was already toxic at 5 µM, and MnTnHex-2-PyP5+ became toxic at 30 µM. In a mouse toxicity study, MnTnBuOE-2-PyP5+ was several-fold less toxic than either MnTnHex-2-PyP5+ or MnTnHep-2-PyP5+.
Based on aqueous redox chemistry and simple in vivo models of oxidative stress, Escherichia coli and Saccharomyces cerevisiae, the cationic Mn(III) N-substituted pyridylporphyrins (MnPs) have been identified as the most potent cellular redox modulators within the porphyrin class of drugs; their efficacy in animal models of diseases that have oxidative stress in common is based on their high ability to catalytically remove superoxide, peroxynitrite, carbonate anion radical, hypochlorite, nitric oxide, lipid peroxyl and alkoxyl radicals, thus suppressing the primary oxidative event. While doing so MnPs could couple with cellular reductants and redox-active proteins. Reactive species are widely accepted as regulators of cellular transcriptional activity: minute, nanomolar levels are essential for normal cell function, while submicromolar or micromolar levels impose oxidative stress, which is evidenced in increased inflammatory and immune responses. By removing reactive species, MnPs affect redox-based cellular transcriptional activity and consequently secondary oxidative stress, and in turn inflammatory processes. The equal ability to reduce and oxidize superoxide during the dismutation process and recently accumulated results suggest that pro-oxidative actions of MnPs may also contribute to their therapeutic effects. All our data identify the superoxide dismutase-like activity, estimated by log kcat(O2–), as a good measure for the therapeutic efficacy of MnPs. Their accumulation in mitochondria and their ability to cross the blood-brain barrier contribute to their remarkable efficacy. We summarize herein the therapeutic effects of MnPs in cancer, central nervous system injuries, diabetes, their radioprotective action and potential for imaging. Few of the most potent modulators of cellular redox-based pathways, MnTE2-PyP5+, MnTDE-2-ImP5+, MnTnHex-2-PyP5+ and MnTnBuOE-2-PyP5+, are under preclinical and clinical development.
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, partly because of the lack of effective treatments for DN. Curcumin has been shown to exert strong antifibrotic effects in DN, but the underlying mechanisms are not well characterized. In this study, we sought to determine the effects of curcumin on diabetic renal disease in db/db mice and characterize the underlying mechanism of action. We administered curcumin to db/db mice for 16 weeks. In comparison to mock-treated db/db mice, curcumin-treated mice showed diminished renal hypertrophy, reduced mesangial matrix expansion, and a lower level of albuminuria. Furthermore, the upregulated protein and mRNA expressions of collagen IV and fibronectin in the renal cortices of the db/db mice were inhibited by curcumin treatment. Additionally, curcumin treatment was associated with significant reductions in mature interleukin-1β, cleaved caspase-1, and NLRP3 protein levels in the renal cortices of db/db mice as well as in HK-2 cells exposed to high glucose concentration. In summary, curcumin, a potent antifibrotic agent, is a promising treatment for DN, and its renoprotective effects appear to be mediated by the inhibition of NLRP3 inflammasome activity.
Abstract. A 6-year-long high-resolution Chinese air quality reanalysis (CAQRA) dataset is presented in this study obtained from the assimilation of surface observations from the China National Environmental Monitoring Centre (CNEMC) using the ensemble Kalman filter (EnKF) and Nested Air Quality Prediction Modeling System (NAQPMS).This dataset contains surface fields of six conventional air pollutants in China (i.e. PM2.5, PM10, SO2, NO2, CO, and O3) for the period 2013–2018 at high spatial (15 km×15 km) and temporal (1 h) resolutions. This paper aims to document this dataset by providing detailed descriptions of the assimilation system and the first validation results for the above reanalysis dataset. The 5-fold cross-validation (CV) method is adopted to demonstrate the quality of the reanalysis. The CV results show that the CAQRA yields an excellent performance in reproducing the magnitude and variability of surface air pollutants in China from 2013 to 2018 (CV R2=0.52–0.81, CV root mean square error (RMSE) =0.54 mg/m3 for CO, and CV RMSE =16.4–39.3 µg/m3 for the other pollutants on an hourly scale). Through comparison to the Copernicus Atmosphere Monitoring Service reanalysis (CAMSRA) dataset produced by the European Centre for Medium-Range Weather Forecasts (ECWMF), we show that CAQRA attains a high accuracy in representing surface gaseous air pollutants in China due to the assimilation of surface observations. The fine horizontal resolution of CAQRA also makes it more suitable for air quality studies on a regional scale. The PM2.5 reanalysis dataset is further validated against the independent datasets from the US Department of State Air Quality Monitoring Program over China, which exhibits a good agreement with the independent observations (R2=0.74–0.86 and RMSE =16.8–33.6 µg/m3 in different cities). Furthermore, through the comparison to satellite-estimated PM2.5 concentrations, we show that the accuracy of the PM2.5 reanalysis is higher than that of most satellite estimates. The CAQRA is the first high-resolution air quality reanalysis dataset in China that simultaneously provides the surface concentrations of six conventional air pollutants, which is of great value for many studies, such as health impact assessment of air pollution, investigation of air quality changes in China, model evaluation and satellite calibration, optimization of monitoring sites, and provision of training data for statistical or artificial intelligence (AI)-based forecasting. All datasets are freely available at https://doi.org/10.11922/sciencedb.00053 (Tang et al., 2020a), and a prototype product containing the monthly and annual means of the CAQRA dataset has also been released at https://doi.org/10.11922/sciencedb.00092 (Tang et al., 2020b) to facilitate the evaluation of the CAQRA dataset by potential users.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.