The design and development of suitable biomimetic catalytic systems capable of mimicking the functional properties of enzymes continues to be a challenge for bioinorganic chemists. In this study, we ...report on the synthesis, X-ray structures, and physicochemical characterization of the novel isostructural FeIIICoII(BPBPMP)(μ-OAc)2ClO4 (1) and GaIIICoII(BPBPMP)(μ-OAc)2ClO4 (2) complexes with the unsymmetrical dinucleating ligand H2BPBPMP (2-bis{(2-pyridyl-methyl)-aminomethyl}-6-{(2-hydroxy-benzyl)-(2-pyridyl-methyl)}-aminomethyl-4-methylphenol). The previously reported complex FeIIIZnII(BPBPMP)(μ-OAc)2ClO4 (3) was investigated here by electron paramagnetic resonance for comparison with such studies on 1 and 2. A magneto-structural correlation between the exchange parameter J (cm−1) and the average bond lengh d (Å) of the FeIII−O−MII structural unit for 1 and for related isostructural FeIIIMII complexes using the correlation J = −107 exp(−6.8d) reveals that this parameter is the major factor that determines the degree of antiferromagnetic coupling in the series (BPBPMP)FeIII(μ-OAc)2MII+ (MII = Mn, Fe, Co, Ni) of complexes. Potentiometric and spectrophotometric titrations along with electronic absorption studies show that, in aqueous solution, complexes 1 and 2 generate the (HO)MIII(μ-OH)CoII(H2O) complex as the catalytically active species in diester hydrolysis reactions. Kinetic studies on the hydrolysis of the model substrate bis(2,4-dinitrophenyl)phosphate by 1 and 2 show Michaelis−Menten behavior, with 2 being 35% more active than 1. In combination with k H/k D isotope effects, the kinetic studies suggest a mechanism in which a terminal MIII-bound hydroxide is the hydrolysis-initiating nucleophilic catalyst. In addition, the complexes show maximum catalytic activity in DNA hydrolysis near physiological pH. The modest reactivity difference between 1 and 2 is consistent with the slightly increased nucleophilic character of the GaIII−OH terminal group in comparison to FeIII−OH in the dinuclear MIIICoII species.
EPR studies of Gd(III) with the hexa(diphenylphosphinoxide)-cyclotriphosphazene ligand, PNP, can provide information about local environment of the Gd(III) ion. Furthermore, analysis of the EPR ...spectra of the Gd(III) PNP complex, carried out at X- and W-band (9.4 and 94
GHz) frequencies, provided information on the phase transition near 5.4
K as well as information on the time durability of the Gd/PNP complexes in the SiO
2 xerogel matrix.
EPR studies of Gd(III) with the hexa(diphenylphosphinoxide)-cyclotriphosphazene ligand, PNP, can provide information about local environment of the Gd(III) ion. Furthermore, analysis of the EPR ...spectra of the Gd(III) PNP complex, carried out at X- and W-band (9.4 and 94GHz) frequencies, provided information on the phase transition near 5.4K as well as information on the time durability of the Gd/PNP complexes in the SiO2 xerogel matrix.
The design and development of suitable biomimetic catalytic systems capable of mimicking the functional properties of enzymes continues to be a challenge for bioinorganic chemists. In this study, we ...report on the synthesis, X-ray structures, and physicochemical characterization of the novel isostructural Fe(III)Co(II)(BPBPMP)(mu-OAc)(2)ClO(4) (1) and Ga(III)Co(II)(BPBPMP)(mu-OAc)(2)ClO(4) (2) complexes with the unsymmetrical dinucleating ligand H(2)BPBPMP (2-bis{(2-pyridyl-methyl)-aminomethyl}-6-{(2-hydroxy-benzyl)-(2-pyridyl-methyl)}-aminomethyl-4-methylphenol). The previously reported complex Fe(III)Zn(II)(BPBPMP)(mu-OAc)(2)ClO(4) (3) was investigated here by electron paramagnetic resonance for comparison with such studies on 1 and 2. A magneto-structural correlation between the exchange parameter J (cm(-1)) and the average bond lengh d (A) of the Fe(III)-O-M(II) structural unit for 1 and for related isostructural Fe(III)M(II) complexes using the correlation J = -10(7) exp(-6.8d) reveals that this parameter is the major factor that determines the degree of antiferromagnetic coupling in the series (BPBPMP)Fe(III)(mu-OAc)(2)M(II)(+) (M(II) = Mn, Fe, Co, Ni) of complexes. Potentiometric and spectrophotometric titrations along with electronic absorption studies show that, in aqueous solution, complexes 1 and 2 generate the (HO)M(III)(mu-OH)Co(II)(H(2)O) complex as the catalytically active species in diester hydrolysis reactions. Kinetic studies on the hydrolysis of the model substrate bis(2,4-dinitrophenyl)phosphate by 1 and 2 show Michaelis-Menten behavior, with 2 being 35% more active than 1. In combination with k(H)/k(D) isotope effects, the kinetic studies suggest a mechanism in which a terminal M(III)-bound hydroxide is the hydrolysis-initiating nucleophilic catalyst. In addition, the complexes show maximum catalytic activity in DNA hydrolysis near physiological pH. The modest reactivity difference between 1 and 2 is consistent with the slightly increased nucleophilic character of the Ga(III)-OH terminal group in comparison to Fe(III)-OH in the dinuclear M(III)Co(II) species.
L-Arginine/NO pathway is altered in Alzheimer disease (AD). Its clinical relevance and pathway status in vascular dementia (VaD) are unknown. Using targeted metabolomics (a liquid chromatography-mass ...spectrometry) we assessed L-arginine, L-citrulline, dimethylamine (DMA), asymmetric dimethyl arginine (ADMA) and symmetric dimethylarginine (SDMA) in AD (n = 48), mixed-type dementia (MD; n = 34), VaD (n = 40) and non-demented individuals (n = 140) and determined their clinical relevance (the association with dementia pathology, cognitive impairment, and structural brain damage). L-Arginine, ADMA, L-arginine/ADMA, and L-citrulline levels were decreased in dementia and L-arginine, L-citrulline, age and sex were its independent predictors correctly classifying 91% of cases. L-Arginine and L-arginine/ADMA were differentiating between VaD and AD with moderate accuracy. L-Arginine, L-arginine/ADMA, SDMA, and DMA reflected structural brain changes. DMA and L-citrulline were elevated in patients with strategic infarcts and SDMA, L-arginine/ADMA, and DMA were independent predictors of Hachinski ischemic score. ADMA and SDMA accumulation reflected severity of cognitive impairment. In summary, L-Arginine/NO pathway is altered in neurodegenerative and vascular dementia in association with neurodegenerative and vascular markers of brain damage and severity of cognitive impairment.
The study was designed to determine the associations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginines plasma concentrations with all-cause mortality in patients with hematological ...malignancies. 33 patients with acute myeloid leukemia (AML), 31 patients with non-Hodgkin's lymphoma (nHL), 32 patients with chronic lymphocytic leukemia (CLL) and 48 patients without malignancy were enrolled into the study. Each patient was followed until death or for at least 14.5 months (range: 14.5-53). Median ADMA and SDMA were significantly elevated in AML, nHL and CLL compared to controls (ADMA: 1.36, 1.24, 1.03, 0.55 μmol/l respectively, p<0.0001; SDMA: 0.86, 0.76, 0.71, 0.52 μmol/l respectively, p<0.0001). High ADMA and SDMA were associated with increased risk for all-cause mortality in CLL group (Hazard ratio (HR) for ADMA: 3.05, 95% CI:1.58-5.88, p = 0.001; HR for SDMA: 4.71, 95% CI:1.91-11.58, p = 0.001). Our study suggests that ADMA and SDMA could be novel prognostic factors for all-cause mortality in CLL patients.
L-arginine/nitric oxide pathway metabolites are altered in colorectal cancer (CRC). We evaluated underlying changes in pathway enzymes in 55 paired tumor/tumor-adjacent samples and 20 normal mucosa ...using quantitative-PCR and assessed the impact of classic and novel oxicam analogues on enzyme expression and intracellular metabolite concentration (LC-MS/MS) in Caco-2, HCT116, and HT-29 cells. Compared to normal mucosa, ARG1, PRMT1, and PRMT5 were overexpressed in both tumor and tumor-adjacent tissue and DDAH2 solely in tumor-adjacent tissue. Tumor-adjacent tissue had higher expression of ARG1, DDAH1, and DDAH2 and lower NOS2 than patients-matched tumors. The ARG1 expression in tumors increased along with tumor grade and reflected lymph node involvement. Novel oxicam analogues with arylpiperazine moiety at the thiazine ring were more effective in downregulating DDAHs and PRMTs and upregulating ARG2 than piroxicam and meloxicam. An analogue distinguished by propylene linker between thiazine’s and piperazine’s nitrogen atoms and containing two fluorine substituents was the strongest inhibitor of DDAHs and PRMTs expression, while an analogue containing propylene linker but no fluorine substituents was the strongest inhibitor of ARG2 expression. Metabolic reprogramming in CRC includes overexpression of DDAHs and PRMTs in addition to ARG1 and NOS2 and is not restricted to tumor tissue but can be modulated by novel oxicam analogues.
Nitric oxide (NO) is a regulatory molecule involved in many biological processes. NO is produced by nitric oxide synthase by conversion of l‐arginine to l‐citrulline. l‐Arginine methylated ...derivatives, asymmetric and symmetric dimethylarginines (asymmetric dimethylarginine, ADMA, and symmetric dimethylarginine, SDMA), regulate l‐arginine availability and the activity of nitric oxide synthase. As such, they have been frequently investigated as potential biomarkers in pathologies associated with dysfunctions in NO synthesis. Here, we present a new multistep analytical methodology based on liquid chromatography combined with mass spectrometry for the accurate identification of l‐arginine, l‐citrulline, ADMA and SDMA. Compounds are measured as stable 2,3,4,5,6‐pentafluorobenzoyl chloride derivatives, which allows for simultaneous analysis of all compounds through chromatographic separation of ADMA and SDMA using a reverse‐phase column. Serum aliquots (100 μL) were spiked with isotope‐labeled internal standards and sodium carbonate buffer. The derivatization process was carried out at 25°C for 10 minu using pentafluorobenzoyl chloride as derivatization reagent. Calibration demonstrated good linearity (R2 = 0.9966–0.9986) for all derivatized compounds. Good accuracy (94.67–99.91%) and precision (1.92–11.8%) were observed for the quality control samples. The applicability of the method was evaluated in a cohort of angiological patients and healthy volunteers. The method discerned significantly lower l‐arginine and l‐citrulline in angiologic patients. This robust and fast LC‐ESI‐MS method may be a useful tool in quantitative analysis of l‐arginine, ADMA, SDMA and l‐citrulline.
•Neurodegenerative pathology in dementia was associated with significantly lower hepcidin as compared to vascular dementia.•Hepcidin revealed significantly higher in patients with moderate and severe ...loss of cognitive function.•Hepcidin concentration tended to be higher in patients with severe structural changes.•Hepcidin as a biomarker in dementia displayed 81.5% specificity and 60% sensitivity.
Hepcidin is a peptide hormone regulating iron metabolism, the dyshomeostasis of which has been implicated in dementia. Yet, data on hepcidin status in dementia are scanty, limited to Alzheimer’s disease (AD) and inconsistent due to methodological problems with its determination using immunoassays and/or lack of homogeneity of evaluated groups. Hepcidin association with vascular dementia (VaD) remains unknown. We proposed a mass spectrometry method of hepcidin quantification in sera and aimed at determining hepcidin systemic status in patients with dementia of AD, VaD, or mixed (MD) pathology, with reference to the degree of cognitive loss and structural changes in the brain as well as at evaluating the diagnostic potential of hepcidin as a biomarker. We found that hepcidin concentrations were significantly elevated in VaD and insignificantly so in AD or MD and that they positively correlated with the Clinical Dementia Rating and inversely with the Mini Mental State Examination. Hepcidin tended to be more pronouncedly elevated in patients with advanced cortical atrophy and white matter lesions. It displayed a biphasic relationship with the Hachinski Ischemic Scale and a good accuracy as dementia but not differential marker. Taken together, our results demonstrated that dementia of vascular and not neurodegenerative pathology is associated with significant elevation of systemic hepcidin. Hepcidin elevation reflects the degree of cognitive loss as well as the severity of structural changes in the brain. If confirmed in a prospective study, hepcidin quantification may hold promise as a diagnostic marker; its accuracy as a differential marker of VaD is insufficient.
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