Chiral separation with dipeptide-terminated polymeric surfactants: the effect of an extra heteroatom on the polar head group

Chiral recognition of two binaphthyl derivatives and three benzodiazepines were studied by use of polymeric surfactants in electrokinetic chromatography. Four specific dipeptide terminated (multichiral) micelle polymers were synthesized for this study. These include poly (sodium-N-undecanoyl-L-alanyl-leucinate)-(poly L-SUAL), poly (sodium-N-undecanoyl-L-valyl-leucinate) (poly L-SUVL), poly (sodium-N-undecanoyl-Lseryl-leucinate) (poly L-SUSL), and poly(sodium-N-undecanoyl-L-threonyl-leucinate) (poly L-SUTL). In addition to the chiral separation study, the physicochemical properties (critical micelle concentration and specific rotation) of each polymer were investigated. The molecular weights of the various dipeptide-terminated micelle polymers were determined using analytical ultracentrifugation. These dipeptide-terminated micelle polymers were designed to study the effect of the extra heteroatom at the polar head group of the micelle polymer (i.e., poly L-SUSL compared to poly L-SUAL and poly L-SUTL compared to poly L-SUVL) on the enantiomeric separation of the binaphthyl derivatives and benzodiazepines. The synergistic effect of three chiral centers (poly L-SUTL) provided improved resolution over that of two chiral centered dipeptide-terminated micelle polymer in the case of (+/-)-temazepam, (+/-)-oxazepam, (+/-)-binaphthol, and (+/-)-binaphthol phosphate. The chiral recognition mechanisms in these cases were additionally controlled by the presence of the extra heteroatom located on the polar head group of the micelle polymers.     

Combination of cyclodextrins and polymeric surfactants for chiral separations

A cyclodextrin-modified micellar electrokinetic chromatography (CD-MEKC) method was applied to the enantioseparation of three binaphthyl derivatives using neutral CDs (i.e., beta- and gamma-CD) in combination with various chiral amino acid-based polymeric surfactants (PSs). Both the D- and L-configurations of poly(sodium N-undecanoyl alaninate), poly(sodium N-undecanoyl leucinate), and poly(sodium N-undecanoyl valinate) (poly(L-SUV)) were synthesized. The retention behavior of the three binaphthyl derivatives under optimum electrophoretic conditions using a single chiral additive (PS or CD) is discussed. In addition, the effect of CD cavity size and stereochemical configuration of polymeric surfactants on selectivity (alpha) and resolution (Rs) was investigated. The enantioseparation of (+/-)1,1'-binaphthyl-2,2'-diamine gave a reversal of enantiomeric order when using beta-CD in combination with any of the three D-configuration PS. However, better enantioseparation is obtained when using the corresponding L-configuration PS with beta-CD. A reversal of migration order (RMO) for the enantiomers of (+/-)1,1'-bi-2-naphthol was observed upon the addition of 10 mM gamma-CD to poly(L-SUV). However, no RMO of (+/-)1,1'-bi-2-naphthol was seen when either beta-CD or gamma-CD was combined with D-PS. The enantiomers of (+/-)1,1'-binaphthyl-2,2'-diyl hydrogen phosphate showed little enantioselective behavior toward the PS alone. However, combined D- or L-PS and beta-CD or gamma-CD systems gave increased Rs and alpha values. The chiral recognition of binaphthyl derivatives observed resulting from the various combinations of two chiral selectors is discussed.     

The phototoxicity of aged human retinal melanosomes

The purpose of this study was to determine whether an age-related increase in photoreactivity of human retinal melanosomes (MS) can cause phototoxicity to retinal pigment epithelium (RPE) cells. MS were isolated post mortem from young (20-30 years, young human melanosomes [YHMs]) and old (60-90 years, old human melanosomes [OHMs]) human eyes and from young bovine eyes (bovine melanosomes [BMs]). Confluent cultured ARPE-19 cells were fed equivalent numbers of OHMs or BMs and accumulated similar amounts of melanin as determined by electron paramagnetic resonance assay. Cells with and without MS were either maintained in the dark or exposed to blue light for up to 96 h and assessed for alterations in cell morphology, cell viability and lysosomal integrity. Incubation of cells in dark in the presence of internalized MS or irradiation of cells with blue light in the absence or presence of BMs did not significantly affect cell viability. However, exposures to blue light in the presence of OHMs resulted in abnormal cell morphology, up to approximately 75% decrease in mitochondrial activity, loss of lysosomal pH and cell death. OHMs contained significantly less melanin than YHMs, supporting the hypothesis that melanin undergoes degradation during RPE aging. Our results demonstrate that aged MS can be phototoxic to human RPE cells and support a contributing role of MS in RPE aging and in the pathogenesis of age-related macular degeneration.     

Quantitation of tryptophan and kynurenine in human plasma using 4-vinylphenylboronic acid column by capillary electrochromatography coupled with mass spectrometry

Tryptophan (TRP) is an essential amino acid catabolized mainly through the kynurenine pathway, and part of it is catabolized in the brain. The abnormal depletion of TRP and production of kynurenine (KYN) by two enzymes, tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), have been linked to various neurological diseases. The ratio of TRP/KYN in plasma is a valuable measure for IDO/TDO activity and the prognosis of disease conditions. The 4-vinylphenylboronic acid (4-VPBA) was evaluated as a novel stationary phase for OT–CEC–MS/MS. TRP, KYN, and 3-hydroxykynurenine were separated using optimum conditions of 15 mM (NH₄)₂CO₃ at pH 8 as a background electrolyte and 25 kV separation voltage on a 90 cm column. The usefulness of the 4-VPBA column for simple, fast, repeatable, and sensitive CEC–ESI–MS/MS application was demonstrated for the quantitation of TRP and KYN in the plasma of healthy human subjects and neuroinflammation subjects. The plasma sample was extracted on a zirconia-based ion-exchange cartridge for simultaneous protein precipitation and phospholipid removal. The method of standard addition, in combination with the internal standards approach, was used to prepare the calibration curve to overcome matrix matching and eliminate procedural errors. The developed quantitation method was validated according to FDA guidelines for sensitivity, accuracy, precision, and extraction recovery. The measured plasma level of TRP and KYN in healthy humans is aligned with the human metabolome database for the same two metabolites.     

Capillary Electrophoresis Mass Spectrometry: Developments and Applications for Enantioselective Analysis from 2011–2020

It is now more than 25 years since the first report of enantioselective analysis by capillary electrophoresis-mass spectrometry (CE-MS) appeared. This article reviews the power of chiral CE-MS in resolving issues on the use of chiral selector incompatibility with MS and poor detectability encountered for chiral compounds by UV detection. The review begins with the general principles, requirements, and critical aspects of chiral CE-MS instrumentation. Next, the review provides a survey of MS-compatible chiral selectors (CSs) reported during the past decade, and the key achievements encountered in the time period using these CSs. Within the context of the strategies used to combine CE and MS, special attention is paid to the approaches that feature partial filling technique, counter-migration techniques, and direct use of CS, such as molecular micelles. In particular, the development and application of moving and fixed CS for EKC-MS, MEKC-MS, and CEC-MS demonstrate how various chiral compounds analyses were solved in a simple and elegant way during the 2010–2020 review period. The most noteworthy applications in the determination of chiral compounds are critically examined. The operating analytical conditions are detailed in the Tables, and the authors provide commentary on future trends of chiral separations by CE-MS.     

Biocompatibility Study of Curcumin-Loaded Pluronic F127 Nanoformulation (NanoCUR) against the Embryonic Development of Zebrafish (Danio rerio)

Curcumin (CUR) has been studied for its biomedical applications due to its active biological properties. However, CUR has limitations such as poor solubility, low bioavailability, and rapid degradation. Thus, CUR was nanoformulated with the application of polymeric micelle. Previous studies of CUR-loaded Pluronic F127 nanoformulation (NanoCUR) were generally prioritized toward cancer cells and its therapeutic values. There are reports that emphasize the toxicity of CUR, but reports on the toxicity of NanoCUR on embryonic developmental stages is still scarce. The present study aims to investigate the toxicity effects of NanoCUR on the embryonic development of zebrafish (Danio rerio). NanoCUR was synthesized via thin film hydration method and then characterized using DLS, UV-Vis, FTIR, FESEM, and XRD. The toxicity assessment of NanoCUR was conducted using zebrafish embryos, in comparison to native CUR, as well as Pluronic F127 (PF) as the controls, and ROS assay was further carried out. It was revealed that NanoCUR showed an improved toxicity profile compared to native CUR. NanoCUR displayed a delayed toxicity response and showed a concentration- and time-dependent toxicity response. NanoCUR was also observed to generate a significantly low reactive oxygen species (ROS) compared to native CUR in ROS assay. Overall, the results obtained highlight the potential of NanoCUR to be developed in clinical settings due to its improved toxicity profile compared to CUR.     

Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches

Microtubule affinity regulating kinase 4 (MARK4) regulates the mechanism of microtubules by its ability to phosphorylate the microtubule-associated proteins (MAP’s). MARK4 is known for its major role in tau phosphorylation via phosphorylating Ser²⁶² residue in the KXGS motif, which results in the detachment of tau from microtubule. In lieu of this vital role in tau pathology, a hallmark of Alzheimer’s disease (AD), MARK4 is a druggable target to treat AD and other neurodegenerative disorders (NDs). There is growing evidence that NDs and diabetes are connected with many pieces of literature demonstrating a high risk of developing AD in diabetic patients. Metformin (Mtf) has been a drug in use against type 2 diabetes mellitus (T2DM) for a long time; however, recent studies have established its therapeutic effect in neurodegenerative diseases (NDs), namely AD, Parkinson’s disease (PD) and amnestic mild cognitive impairment. In this study, we have explored the MARK4 inhibitory potential of Mtf, employing in silico and in vitro approaches. Molecular docking demonstrated that Mtf binds to MARK4 with a significant affinity of −6.9 kcal/mol forming interactions with binding pocket’s critical residues. Additionally, molecular dynamics (MD) simulation provided an atomistic insight into the binding of Mtf with MARK4. ATPase assay of MARK4 in the presence of Mtf shows that it inhibits MARK4 with an IC₅₀ = 7.05 µM. The results of the fluorescence binding assay demonstrated significant binding of MARK4 with a binding constant of 0.6 × 10⁶ M⁻¹. The present study provides an additional axis towards the utilization of Mtf as MARK4 inhibitor targeting diabetes with NDs.     

Evaluation of Gaussian hypergeometric series using Huff’s models of elliptic curves

The Ramanujan Journal - A Huff curve over a field K is an elliptic curve defined by the equation $$ax(y^2-1)=by(x^2-1)$$ where $$a,b\in K$$ are such that $$a^2\ne b^2$$ . In a similar fashion, a...     

An indirect shooting method based on the POD/DEIM technique for distributed optimal control of the wave equation

This paper presents a fast numerical method, based on the indirect shooting method and Proper Orthogonal Decomposition (POD) technique, for solving distributed optimal control of the wave equation. To solve this problem, we consider the first‐order optimality conditions and then by using finite element spatial discretization and shooting strategy, the solution of the optimality conditions is reduced to the solution of a series of initial value problems (IVPs). Generally, these IVPs are high‐order and thus their solution is time‐consuming. To overcome this drawback, we present a POD indirect shooting method, which uses the POD technique to approximate IVPs with smaller ones and faster run times. Moreover, in the presence of the nonlinear term, to reduce the order of the nonlinear calculations, a discrete empirical interpolation method (DEIM) is applied and a POD/DEIM indirect shooting method is developed. We investigate the performance and accuracy of the proposed methods by means of 4 numerical experiments. We show that the presented POD and POD/DEIM indirect shooting methods dramatically reduce the CPU time compared to the full indirect shooting method, whereas there is no significant difference between the accuracy of the reduced and full indirect shooting methods.