Evaluating solubility, stability, and inclusion complexation of oxyresveratrol with various ß-cyclodextrin derivatives using advanced computational techniques and experimental validation.

Oxyresveratrol (OXY), a natural stilbenoid in mulberry fruits, is known for its diverse pharmacological properties. However, its clinical use is hindered by low water solubility and limited bioavailability. In the present study, the inclusion complexes of OXY with ß-cyclodextrin (ßCD) and its three analogs, dimethyl-ß-cyclodextrin (DMßCD), hydroxypropyl-ß-cyclodextrin (HPßCD) and sulfobutylether-ß-cyclodextrin (SBEßCD), were investigated using in silico and in vitro studies. Molecular docking revealed two binding orientations of OXY, namely, 4',6'-dihydroxyphenyl (A-form) and 5,7-benzenediol ring (B-form). Molecular Dynamics simulations suggested the formation of inclusion complexes with ßCDs through two distinct orientations, with OXY/SBEßCD exhibiting maximum atom contacts and the lowest solvent-exposed area in the hydrophobic cavity. These results corresponded well with the highest binding affinity observed in OXY/SBEßCD when assessed using the MM/GBSA method. Beyond traditional simulation methods, Ligand-binding Parallel Cascade Selection Molecular Dynamics method was employed to investigate how the drug enters and accommodates within the hydrophobic cavity. The in silico results aligned with stability constants: SBEßCD (2060 M-1), HPßCD (1860 M-1), DMßCD (1700 M-1), and ßCD (1420 M-1). All complexes exhibited a 1:1 binding mode (AL type), with SBEßCD enhancing OXY solubility (25-fold). SEM micrographs, DSC thermograms, FT-IR and 1H NMR spectra confirm the inclusion complex formation, revealing novel surface morphologies, distinctive thermal behaviors, and new peaks. Notably, the inhibitory impact on the proliferation of breast cancer cell lines, MCF-7, exhibited by inclusion complexes particularly OXY/DMßCD, OXY/HPßCD, and OXY/SBEßCD were markedly superior compared to that of OXY alone.

Structural and thermodynamic insights into antibody light chain tetramer formation through 3D domain swapping.

Overexpression of antibody light chains in small plasma cell clones can lead to misfolding and aggregation. On the other hand, the formation of amyloid fibrils from antibody light chains is related to amyloidosis. Although aggregation of antibody light chain is an important issue, atomic-level structural examinations of antibody light chain aggregates are sparse. In this study, we present an antibody light chain that maintains an equilibrium between its monomeric and tetrameric states. According to data from X-ray crystallography, thermodynamic and kinetic measurements, as well as theoretical studies, this antibody light chain engages in 3D domain swapping within its variable region. Here, a pair of domain-swapped dimers creates a tetramer through hydrophobic interactions, facilitating the revelation of the domain-swapped structure. The negative cotton effect linked to the ß-sheet structure, observed around 215 nm in the circular dichroism (CD) spectrum of the tetrameric variable region, is more pronounced than that of the monomer. This suggests that the monomer contains less ß-sheet structures and exhibits greater flexibility than the tetramer in solution. These findings not only clarify the domain-swapped structure of the antibody light chain but also contribute to controlling antibody quality and advancing the development of future molecular recognition agents and drugs.

Structure-yeast α-glucosidase inhibitory activity relationship of 9-O-berberrubine carboxylates.

Thirty-five 9-O-berberrubine carboxylate derivatives were synthesized and evaluated for yeast α-glucosidase inhibitory activity. All compounds demonstrated better inhibitory activities than the parent compounds berberine (BBR) and berberrubine (BBRB), and a positive control, acarbose. The structure-activity correlation study indicated that most of the substituents on the benzoate moiety such as methoxy, hydroxy, methylenedioxy, benzyloxy, halogen, trifluoromethyl, nitro and alkyl can contribute to the activities except multi-methoxy, fluoro and cyano. In addition, replacing benzoate with naphthoate, cinnamate, piperate or diphenylacetate also led to an increase in inhibitory activities except with phenyl acetate. 9, 26, 27, 28 and 33 exhibited the most potent α-glucosidase inhibitory activities with the IC50 values in the range of 1.61-2.67 µM. Kinetic study revealed that 9, 26, 28 and 33 interacted with the enzyme via competitive mode. These four compounds were also proved to be not cytotoxic at their IC50 values. The competitive inhibition mechanism of these four compounds against yeast α-glucosidase was investigated using molecular docking and molecular dynamics simulations. The binding free energy calculations suggest that 26 exhibited the strongest binding affinity, and its binding stability is supported by hydrophobic interactions with D68, F157, F158 and F177. Therefore, 9, 26, 28 and 33 would be promising candidates for further studies of antidiabetic activity.

Computational Analysis of the SARS-CoV-2 RBD-ACE2-Binding Process Based on MD and the 3D-RISM Theory.

The binding process of angiotensin-converting enzyme 2 (ACE2) to the receptor-binding domain (RBD) of the severe acute respiratory syndrome-like coronavirus 2 spike protein was investigated using molecular dynamics simulation and the three-dimensional reference interaction-site model theory. The results suggested that the protein-binding process consists of a protein-protein approaching step, followed by a local structural rearrangement step. In the approaching step, the interprotein interaction energy decreased as the proteins approached each other, whereas the solvation free energy increased. As the proteins approached, the glycan of ACE2 first established a hydrogen bond with the RBD. Thereafter, the number of interprotein hydrogen bonds increased rapidly. The solvation free energy increased because of the desolvation of the protein as it approached its partner. The spatial distribution function of the solvent revealed the presence of hydrogen bonds bridged by water molecules on the RBD-ACE2 interface. Finally, principal component analysis revealed that ACE2 showed a pronounced conformational change, whereas there was no significant change in RBD.

A computational scheme of pKa values based on the three-dimensional reference interaction site model self-consistent field theory coupled with the linear fitting correction scheme.

A scheme for quantitatively computing the acid dissociation constant, pKa, of hydrated molecules is proposed. It is based on the three-dimensional reference interaction site model self-consistent field (3D-RISM-SCF) theory coupled with the linear fitting correction (LFC) scheme. In LFC/3D-RISM-SCF, pKa values of target molecules are evaluated using the Gibbs energy difference between the protonated and unprotonated states calculated by 3D-RISM-SCF and the parameters fitted by the LFC scheme to the experimental values of training set systems. The pKa values computed by LFC/3D-RISM-SCF show quantitative agreement with the experimental data.

Single event-related changes in cerebral oxygenated hemoglobin using word game in schizophrenia.

Neuroimaging studies have been conducted using word generation tasks and have shown greater hypofrontality in patients with schizophrenia compared with healthy subjects. In this study, we compared the characteristics of oxygenated hemoglobin changes involved in both phonological and categorical verbal fluency between 35 outpatients with schizophrenia and 35 healthy subjects during a Japanese "shiritori" task using single-event-related near-infrared spectroscopy. During this task, the schizophrenic patients showed significantly smaller activation in the prefrontal cortex area than the controls. In addition, a significant positive correlation was obtained between oxygenated hemoglobin changes (prefrontal cortex area, inferior parietal area) and the severity of positive psychiatric symptoms. It is possible that hypofrontality of patients may be a diagnostic assistance tool for schizophrenia, and that the relationship between activation and positive syndrome scores may be of help in predicting functional outcome in patients.

[Characteristics of single event-related cerebral hemodynamics during verbal task in emotionally charged state measured by multi-channel near-infrared spectroscopy (NIRS) in patients with schizophrenia: comparison with healthy subjects].

Neared infrared spectroscopy (NIRS) is one of the recently developed methodologies which can measure cerebral blood volumes to determine the blood hemoglobin (Hb) concentration simultaneously at multiple points with marked time resolution. Monitoring the changes in the Hb concentration yields site-specific readings on blood flow and, thus, on neural activities. The aim of this study was to examine the characteristics of a single event-related oxyhemoglobin concentration [oxy-Hb] changes in patients with schizophrenia using multi-channel NIRS during a word generation task, Japanese 'Shiritori', and single-word generation task in an emotionally charged state induced by three facial expressions of "crying", "neutral", and "smiling" babies' photographs. Thirty-four patients with schizophrenia and 34 age-matched healthy controls participated in the present study after giving consent. In healthy controls, [oxy-Hb] changes when viewing the "crying" baby's photograph were significantly larger than when viewing the "smiling" baby's photograph. On the other hand, in patients with schizophrenia, [oxy-Hb] changes when viewing the "smiling" baby's photograph were significantly larger than when viewing the "crying" baby's photograph. These results suggest that cautions/execution functions in patients with schizophrenia during the single event word "Shiritori" task measured by multi-channel NIRS were impaired. It was also suggested that, in patients with schizophrenia, the affective reaction influenced by each photograph may be different from healthy controls (mismatch). Multi-channel NIRS can be a useful tool for research and clinical purposes in psychiatry.

Reduced prefrontal cortex activation using the Trail Making Test in schizophrenia.

Schizophrenia has been associated with a deficit of the prefrontal cortex, which is involved in attention, executive processes, and working memory. The Trail Making Test (TMT) is administered in two parts, TMT-A and TMT-B. It is suggested that the difference in performance between part A and part B reflects executive processes. In this study, we compared the characteristics of hemodynamic changes during TMT tasks between 14 outpatients with schizophrenia and 14 age- and gender-matched healthy control subjects. Using multichannel near-infrared spectroscopy, we measured relative changes in oxygenated hemoglobin concentration, which reflects brain activity of the prefrontal cortex during this task. In both tasks, patients showed significantly smaller activation than controls and, in an assessment of executive functions, a subtraction of oxygenated hemoglobin (oxy-Hb) changes during TMT-A from those of TMT-B showed a decrease in cerebral lateralization and hypoactivity in patients. There was a significant negative correlation between oxy-Hb changes and the severity of psychiatric symptoms. These findings may characterize disease-related features, suggesting the usefulness of oxy-Hb change measurement during TMT tasks for assessing functional outcomes in schizophrenic patients.

State and trait markers of emotionally charged visual event-related potentials (P300) in drug-naïve schizophrenia.

AIM: In the present study, we investigated the changes in P3 component in the emotionally charged visual event-related potentials (ERP) in 30 drug-naïve schizophrenic patients for up to 1 year. METHODS: Visual oddball event-related potential was recorded from six recording sites for crying baby or smiling baby photographs. ERP were recorded before the treatment (session 1 [S1]), after 3 months (session 2 [S2]), and after 12 months (session 3 [S3]), as well as in 30 healthy subjects. RESULTS: Before taking medicine, there were no significant differences in the P300 amplitude between viewing photographs of a crying and a smiling baby. The P300 amplitude was significantly larger at S2 and S3 than at S1 for a crying baby, while there was no significant difference among sessions for a smiling baby after medication. A significant difference of the P300 amplitude was only observed between S3 and healthy subjects for a smiling baby. The P300 latency only when viewing a smiling face became significantly longer at S3 than those at S1 and S2. A significant negative correlation was obtained between the P300 amplitude changes upon viewing crying faces and negative syndrome score changes at the Pz site. CONCLUSION: The P300 amplitude induced by crying-face stimuli may be a state marker and the P300 amplitude caused by smiling-face stimuli may be a trait marker during recovery in schizophrenic patients. Atypical antipsychotic medications may be useful and may recover cognitive function reflected by the emotionally charged visual P300 components in schizophrenic patients.

Characteristics of cortical activation in schizophrenia during the card game "concentration".

Various functional imaging studies have demonstrated reduced lateralization of cortical activation during neurocognitive tasks in schizophrenia. -A well-known card game, "concentration", reflects working memory (WM). We compared characteristics of hemodynamic changes in the prefrontal to temporo-parietal areas of the brain during this card game between 24 outpatients with schizophrenia and 24 age- and gender-matched healthy control subjects. Using multi-channel near-infrared spectroscopy, we measured relative changes in oxygenated hemoglobin concentration (oxy-Hb changes), which reflects brain activity during this task. Patients showed reduced lateralization in the midfrontal area, which is involved in executive functions, and in the inferior parietal area, involved in WM subcomponents. We also found a significant negative correlation between left midfrontal region oxy-Hb changes and severity of negative symptoms of schizophrenia. Our results characterized disease-related features, suggesting the usefulness of oxy-Hb change measurement during this card game for assessing functional outcome in schizophrenic patients.

Effects of emotionally affect adult and baby' photographs in healthy controls and schizophrenic patients evaluating by exploratory eye movements.

The relationship between mother and baby is of fundamental importance in the development of cognitive function and emotion. In this study we investigated the effects of affective photographs of a mother and baby (crying or smiling faces) and other stimuli (neutral mother or baby faces) on visual cognitive function in schizophrenic patents. We recorded exploratory eye movements in 22 healthy controls and 22 age-matched schizophrenic patients. Total number of right and left field gaze points (right TNGP, left TNGP) in the visual fields were determined using an eye-mark recorder as subjects viewed affectively charged or neutral photographs (crying, smiling or neutral faces). Left TNGP for all mother photographs (crying, smiling or neutral) were significantly larger in controls than patients, and right TNGP for neutral mother photographs were significantly larger in controls than in patients. Right TNGP for photographs of smiling babies were significantly larger in controls than patients, and left TNGP for photographs of both smiling and crying babies were significantly larger in controls than patients. Within the patient group, right TNGP were significantly larger than left TNGP for all mother photographs (crying, smiling or neutral). Left TNGP for photographs of mothers and babies correlated negatively with negative symptom scores. These results suggest that exploratory eye movements when viewing emotionally laded twin stimuli such as photographs of a mother and baby are a useful marker of visual cognitive function in both healthy controls and schizophrenic patients.

Brain activities on fMRI using the shiritori task in normal subjects.

Shiritori is a popular Japanese word chain game that resembles verbal fluency tasks used in Western countries. Recently, shiritori has been used to determine the dominant hemisphere for language and as a rehabilitation tool. However, there are few reports of neuroimaging during shiritori. We used functional magnetic resonance imaging (fMRI) to conduct a detailed study of brain activities during shiritori and observed activation not only of the left inferior frontal gyrus (including the pars opecularis, the pars triangularis and the pars orbitalis), which is a language-related area, but also of the left superior and middle frontal gyri, the right pars orbitalis (inferior frontal gyrus), and the right cerebellar hemisphere. Shiritori is a useful tool for psychological study and rehabilitation.

A case of hilar bile duct cancer with intestinal Behçet's disease.

We encountered a hilar bile duct cancer patient with intestinal Behçet's disease who manifested various symptoms during a short period in the acute stage after liver resection. Under a diagnosis of hilar bile duct cancer, a 52-year-old Japanese male was referred and admitted to our hospital. Hepatectomy and resection of the extrahepatic bile duct were performed. During the postoperative course, a large number of painful aphthous ulcers developed in the oral mucosa, along with a genital ulcer. A deep excavation-type ulcer was confirmed by colonoscopy in the ileum on the orifice side. We administered colchicine and mesalazine. Thereafter, the patient was treated at the outpatient clinic. Recurrent localized hilar bile duct cancer developed, and the patient died about 8 months after surgery. We present the clinical details of this rare case of hilar bile duct cancer with intestinal Behçet's disease.