Oxidative stress has been reported to be associated with the progression of renal pathology as well as with the onset of complications associated with this condition. Bardoxolone methyl, a nuclear ...factor-erythroid 2-related factor 2 (Nrf2) activator with anti-oxidative and inflammatory modulation effects, has been reported to improve renal function in clinical trials. As of this writing, there have been no systems for the quantitative evaluation of oxidative stress that could be applied as a clinical test. We recently reported on post-translational modifications of albumin using electrospray-ionization time-of-flight mass spectrometry (ESI-TOF MS) and the results indicated that oxidized albumin (cysteinylated albumin: a molecule that was oxidatively cysteinylated at Cys34) was found to increase with the progression of renal pathology. A clinical study demonstrated that monitoring the levels of oxidized albumin could be useful for the early diagnosis of diabetic kidney disease and for predicting renal prognosis. Higher levels of serum oxidized albumin were also associated with cardiovascular complications or sarcopenia in patients who were undergoing hemodialysis. The overall findings indicate that oxidized albumin could also be an index of therapeutic efficacy against kidney disease. Oxidized albumin is not only a marker for kidney disease but also a nephrotoxic substance. This suggests that measuring the levels of oxidized albumin could be a biomarker for diagnosing the progression of and complications associated with renal disease in addition to evaluating the efficacy of therapeutic drugs.
Chronic kidney disease (CKD), a chronic catabolic condition, is characterized by muscle wasting and decreased muscle endurance. Many insights into the molecular mechanisms of muscle wasting in CKD ...have been obtained. A persistent imbalance between protein degradation and synthesis in muscle causes muscle wasting. During muscle wasting, high levels of reactive oxygen species (ROS) and inflammatory cytokines are detected in muscle. These increased ROS and inflammatory cytokine levels induce the expression of myostatin. The myostatin binding to its receptor activin A receptor type IIB stimulates the expression of atrogenes such as atrogin-1 and muscle ring factor 1, members of the muscle-specific ubiquitin ligase family. Impaired mitochondrial function also contributes to reducing muscle endurance. The increased protein-bound uremic toxin, parathyroid hormone, glucocorticoid, and angiotensin II levels that are observed in CKD all have a negative effect on muscle mass and endurance. Among the protein-bound uremic toxins, indoxyl sulfate, an indole-containing compound has the potential to induce muscle atrophy by stimulating ROS-mediated myostatin and atrogenes expression. Indoxyl sulfate also impairs mitochondrial function. Some potential therapeutic approaches based on the muscle wasting mechanisms in CKD are currently in the testing stages.
A quantum chemical treatment of solvation effects using the standard quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations is challenging due to QM and MM solvent exchange ...near the QM solute. To this end, various adaptive QM/MM methods have been proposed; free solvent exchanges are allowed via flexible switching of their identities between QM and MM systems depending on their distances from the QM solute. However, temporal and spatial discontinuities remain in the standard implementations of adaptive QM/MM approaches and continue to hamper stable and accurate dynamics simulations. We previously demonstrated that the size-consistent multipartitioning (SCMP) method achieves temporal continuity while, to some extent, avoiding spatial discontinuities. In the present study, we demonstrate that residual spatial discontinuities may lead to severe artifacts under certain conditions. Through quantitative analyses, we show that all multiscale including QM/MM methods might experience these problems, which so far have not been investigated in depth. To alleviate these artifacts, we propose a correction scheme in the framework of the SCMP approach and demonstrate its effectiveness using bulk water simulations.
For condensed systems, the incorporation of quantum chemical solvent effects into molecular dynamics simulations has been a major concern. To this end, quantum mechanical/molecular mechanical (QM/MM) ...techniques are popular and powerful options to treat gigantic systems. However, they cannot be directly applied because of temporal and spatial discontinuity problems. To overcome these problems, in a previous study, we proposed a corrective QM/MM method, size-consistent multipartitioning (SCMP) QM/MM and successfully demonstrated that, using SCMP, it is possible to perform stable molecular dynamics simulations by effectively taking into account solvent quantum chemical effects. The SCMP method is characterized by two original features: size-consistency of a QM region among all QM/MM partitioning and partitioning update. However, in our previous study, the performance was not fully elicited compared to the theoretical upper bound and the optimal partitioning update protocol and parameters were not fully verified. To elicit the potential performance, in the present study, we simplified the theoretical framework and modified the partitioning protocol.
In MtrF, an outer-membrane multiheme cytochrome, the 10 heme groups are arranged in heme binding domains II and IV along the pseudo-C₂ axis, forming the electron transfer (ET) pathways. Previous ...reports based on molecular dynamics simulations showed that the redox potential (E
m) values for the heme pairs located in symmetrical positions in domains II and IV were similar, forming bidirectional ET pathways Breuer M, Zarzycki P, Blumberger J, Rosso KM (2012) J Am Chem Soc 134(24):9868–9871. Here, we present the E
m values of the 10 hemes in MtrF, solving the linear Poisson–Boltzmann equation and considering the protonation states of all titratable residues and heme propionic groups. In contrast to previous studies, the E
m values indicated that the ET is more likely to be downhill from domain IV to II because of localization of acidic residues in domain IV. Reduction of hemes in MtrF lowered the E
m values, resulting in switching to alternative downhill ET pathways that extended to the flavin binding sites. These findings present an explanation of how MtrF serves as an electron donor to extracellular substrates.
Transport of ions in polymer electrolytes is of significant practical interest, however, differences in the transport of anions and cations have not been comprehensively addressed. We present ...measurements of the electrochemical transport properties of lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) in poly(ethylene oxide) (PEO) over a wide range of PEO molecular weights and salt concentrations. Individual self-diffusion coefficients of the Li+ and TFSI– ions, D + and D –, were measured using pulsed-field gradient nuclear magnetic resonance both in the dilute limit and at high salt concentrations. Conductivities calculated from the measured D + and D – values based on the Nernst–Einstein equation were in agreement with experimental measurements reported in the literature, indicating that the salt is fully dissociated in these PEO/LiTFSI mixtures. This enables determination of the molecular weight dependence of the cation transference number in both dilute and concentrated solutions. We introduce a new parameter, s, the number of lithium ions per polymer chain, that allows us to account for both the effect of salt concentration and molecular weight on cation and anion diffusion. Expressing cation and anion diffusion coefficients as functions of s results in a collapse of D + and D – onto a single master curve.
In bilaterian central nervous systems, coordination of neurotransmission by glial cells enables highly sophisticated neural functions. The diversity of transcription factors (TFs) involved in ...gliogenesis suggests multiple evolutionary origins of various glial cell types of bilaterians. Many of these TFs including the glial cells missing (Gcm) are also present in genomes of Cnidaria, the closest outgroup to Bilateria, but their function remains to be elucidated. In this study, we analyzed the function of Gcm, a multifunctional TF involved in development of glial and non-glial cell types, in the sea anemone, Nematostella vectensis. siRNA-mediated knockdown of Nematostella Gcm altered expression of cell adhesion proteins, glutamate and GABA transporters, ion channels, metabolic enzymes, and zinc finger and Ets-related TFs. NvGcm and mRNAs of downstream genes are expressed in broad neural cell clusters. However, immunostaining of a NvGcm target protein, the glutamate transporter, NvEAAT1, visualized a novel class of cells with flat cell bodies and no clear processes. Together with the finding of unique morphological features of NvEAAT1-functioning cells, these data suggest that extracellular glutamate metabolism, one of major glial functions, is deployed downstream of Gcm in specific neural cell types in Cnidaria.
The cyanobacterial photosystem II (PSII) crystal structure includes more than 1300 water molecules in each monomer unit; however, their precise roles in water oxidation are unclear. To understand the ...origins of water molecules in the PSII crystal structure, the accessibility of bulk water molecules to channel inner spaces in PSII was investigated using the water-removed PSII structure and molecular dynamics (MD) simulations. The inner space of the channel that proceeds toward the D1-Glu65/D2-Glu312 pair (E65/E312 channel) was entirely filled with water molecules from the bulk region. In the same channel, a diamond-shaped cluster of water molecules formed near redox-active TyrZ in MD simulations. Reorientation of the D2-Leu352 side chain resulted in formation of a hexagonal water network at the Cl–2 binding site. Water molecules could not enter the main region of the O4–water chain, which proceeds from the O4 site of the Mn4CaO5 cluster. However, in the O4–water chain, the two water binding sites that are most distant from the protein bulk surface were occupied by water molecules that approached along the E65/E312 channel, one of which formed an H-bond with the O4 site. These findings provide key insights into the significance of the channel ends, which may utilize water molecules during the PSII photocycle.
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