A Comprehensive Investigation of Interactions between Antipsychotic Drug Quetiapine and Human Serum Albumin Using Multi-Spectroscopic, Biochemical, and Molecular Modeling Approaches

Quetiapine (QTP) is a short-acting atypical antipsychotic drug that treats schizophrenia or manic episodes of bipolar disorder. Human serum albumin (HSA) is an essential transport protein that transports hormones and various other ligands to their intended site of action. The interactions of QTP with HSA and their binding mechanism in the HSA-QTP system was studied using spectroscopic and molecular docking techniques. The UV-Vis absorption study shows hyperchromicity in the spectra of HSA on the addition of QTP, suggesting the complex formation and interactions between QTP and HSA. The results of intrinsic fluorescence indicate that QTP quenched the fluorescence of HSA and confirmed the complex formation between HSA and QTP, and this quenching mechanism was a static one. Thermodynamic analysis of the HSA-QTP system confirms the involvement of hydrophobic forces, and this complex formation is spontaneous. The competitive displacement and molecular docking experiments demonstrated that QTP is preferentially bound to HSA subdomain IB. Furthermore, the CD experiment results showed conformational changes in the HSA-QTP system. Besides this, the addition of QTP does not affect the esterase-like activity of HSA. This study will help further understand the credible mechanism of transport and delivery of QTP via HSA and design new QTP-based derivatives with greater efficacy

Utilizing Biomolecule-Rich Citrus Fruit Waste as a Medium for the Eco-Friendly Preparation of Silver Nanoparticles with Antimicrobial Properties

An ample amount of fruit waste is generated as agro-industrial waste, leading to significant nutritional, economic, and environmental challenges. Fruit peels are rich in many valuable bioactive compounds with the potential for developing nanoparticles. This study examined fresh juices of two citrus fruit peel wastes (Citrus sinensis: C. sinesis and Citrus limon: C. limon) for antioxidants and total protein. Then, we investigated their ability to produce silver nanoparticles, which were further analyzed for anti-microbial activity against thirteen pathogenic microbes. Both Citrus peel juices were rich in secondary metabolites. The formation of Ag nanoparticles was initially confirmed by UV-vis spectroscopy, with peaks at 400 nm for C. sinensis peel Ag nanoparticles and 430 nm for C. limon peel Ag nanoparticles. Further characterization was conducted using zeta sizer, zeta potential, Transmission Electron Microscopy (TEM), Scanning Electron Microscope (SEM), Energy-dispersive X-ray spectroscopy (EDX) and Fourier transform infrared (FTIR) spectroscopy. The antimicrobial activity was tested using the well diffusion method against 11 bacterial strains (five Gram-positive and six Gram-negative) and two fungal strains of Candida. TEM and SEM results revealed a spherical shape, with an average diameter of about 13 nm for C. sinensis and 21 nm for C. limon Ag. EDX confirmed the presence of silver in both nanoparticles. The FTIR spectrum of the extract indicated the presence of biomolecules, which facilitated the reduction and capping of the synthesized Ag nanoparticles. The prepared nanoparticles showed remarkable antimicrobial activity, but the nanoparticles from C. sinensis exhibited stronger antibacterial properties because of their smaller size. Citrus peel waste is a suitable medium for the eco-friendly production of silver nanoparticles

Association Mechanism and Conformational Changes in Trypsin on Its Interaction with Atrazine: A Multi- Spectroscopic and Biochemical Study with Computational Approach

Atrazine (ATR) is a herbicide globally used to eliminate undesired weeds. Herbicide usage leads to various adverse effects on human health and the environment. The primary source of herbicides in humans is the food laced with the herbicides. The ATR binding to trypsin (TYP) was investigated in this study to explore its binding potential and toxicity. In vitro interaction of ATR with TYP was studied using multi-spectroscopic methods, molecular docking, and enzyme kinetics to explore the mechanism of binding for the TYP-ATR system. The TYP-ATR complex revealed binding constants (103 M−1), suggesting a moderate binding. The free energy for the TYP-ATR complexes was negative, suggesting a spontaneous interaction. Thermodynamic parameters enthalpy (ΔH) and entropy (ΔS) obtained positive values for the TYP-ATR system suggesting hydrophobic interactions in the binding process. Micro-environmental and conformational changes in TYP molecules were induced on interaction with ATR. Reduced catalytic activity of TYP was observed after interaction with ATR owing to the changes in the secondary structure of the TYP

Unveiling sex-based differences in developing propionic acid-induced features in mice as a rodent model of ASD

Background Males are more likely to develop autism as a neurodevelopmental disorder than females are, although the mechanisms underlying male vulnerability are not fully understood. Therefore, studying the role of autism etiologies considering sex differences in the propionic acid (PPA) rodent model of autism would build greater understanding of how females are protected from autism spectrum disorder, which may be used as a treatment strategy for males with autism. Objectives This study aimed to investigate the sex differences in oxidative stress, glutamate excitotoxicity, neuroinflammation, and gut microbiota impairment as etiological mechanisms for many neurological diseases, with specific reference to autism. Method Forty albino mice were divided into four groups of 10 animals each with two control and two treated groups of both sexes received only phosphate-buffered saline or a neurotoxic dose of PPA (250 mg/kg body weight) for 3 days, respectively. Biochemical markers of energy metabolism, oxidative stress, neuroinflammation, and excitotoxicity were measured in mouse brain homogenates, whereas the presence of pathogenic bacteria was assessed in mouse stool samples. Furthermore, the repetitive behavior, cognitive ability, and physical-neural coordination of the animals were examined. Results Collectively, selected variables related to oxidative stress, glutamate excitotoxicity, neuroinflammation, and gut bacteria were impaired concomitantly with altered behavior in PPA-induced rodent model, with males being more susceptible than females. Conclusion This study explains the role of sex in the higher vulnerability of males to develop autistic biochemical and behavioral features compared with females. Female sex hormones and the higher detoxification capacity and higher glycolytic flux in females serve as neuroprotective contributors in a rodent model of autism

Functional Characterization and Anti-Tumor Effect of a Novel Group II Secreted Phospholipase A₂ from Snake Venom of Saudi <i>Cerastes cerates gasperetti</i>

Secreted phospholipases A2 are snake-venom proteins with many biological activities, notably anti-tumor activity. Phospholipases from the same snake type but different geographical locations have shown similar biochemical and biological activities with minor differences in protein sequences. Thus, the discovery of a new phospholipase A2 with unique characteristics identified in a previously studied venom could suggest the origins of these differences. Here, a new Group II secreted phospholipase A2 (Cc-PLA2-II) from the snake venom of Saudi Cerastes cerastes gasperetti was isolated and characterized. The purified enzyme had a molecular weight of 13.945 kDa and showed high specific activity on emulsified phosphatidylcholine of 1560 U/mg at pH 9.5 and 50 °C with strict calcium dependence. Interestingly, stability in extreme pH and high temperatures was observed after enzyme incubation at several pH levels and temperatures. Moreover, a significant dose-dependent cytotoxic anti-tumor effect against six human cancer cell lines was observed with concentrations of Cc-PLA2 ranging from 2.5 to 8 µM. No cytotoxic effect on normal human umbilical-vein endothelial cells was noted. These results suggest that Cc-PLA2-II potentially has angiogenic activity of besides cytotoxicity as part of its anti-tumor mechanism. This study justifies the inclusion of this enzyme in many applications for anticancer drug development

Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia

Purpose: Neurodevelopmental disorders exhibit clinical and genetic heterogeneity, ergo manifest dysfunction in components of diverse cellular pathways; the precise pathomechanism for the majority remains elusive.Methods: We studied five affected individuals from three unrelated families manifesting global developmental delay, postnatal microcephaly, and hypotonia. We employed exome sequencing and prioritized variants that were subsequently characterized using immunofluorescence, immunoblotting, pulldown assays, and RNA sequencing.Results: We identified biallelic variants in ZFTRAF1, encoding a protein of yet unknown function. Four affected individuals from two unrelated families segregated two homozygous frameshift variants in ZFTRAF1, whereas, in the third family, an intronic splice site variant was detected. We investigated ZFTRAF1 at the cellular level and signified it as a nucleocytoplasmic protein in different human cell lines. ZFTRAF1 was completely absent in the fibroblasts of two affected individuals. We also identified 110 interacting proteins enriched in mRNA processing and autophagy-related pathways. Based on profiling of autophagy markers, patient-derived fibroblasts show irregularities in the protein degradation process.Conclusion: Thus, our findings suggest that biallelic variants of ZFTRAF1 cause a severe neurodevelopmental disorder

Clitoria ternatea extract-loaded chitosan nanoparticles ameliorate diabetes and oxidative stress in diabetic rats

501-515Type 2 diabetes mellitus (T2DM) is one of the expanding global health problems and is the most common metabolic disorder characterized by hyperglycemia, which significantly contributes to producing reactive oxygen species (ROS). More than 400 plant species with hypoglycemic activity have been mentioned in the literature. Clitoria ternatea (C. ternatea), often called Butterfly pea or Asian pigeonwing, is a plant species member of the Fabaceae family. The main goal of this study was to evaluate the methanolic extract of C. ternatea (CT-Mx)'s and/or chitosan-loaded nanoparticles (CHNPs) antihyperglycemic and antioxidant effects in normal and diabetic rats produced by streptozotocin (STZ). A total of 20 male albino rats had been divided into 4 groups, control non-diabetic (NC), STZ/diabetic control, STZ/diabetic + CT-Mx, and STZ/diabetic + CT-CHNPs groups. After 28 days, levels of insulin, fasting blood glucose (FBG), aspartate transaminase (AST), alanine transaminase (ALT), superoxide dismutase (SOD), glutathione (GSH), lipid peroxidation, and mRNA gene expression were assessed. Histopathological and immunohistochemical studies were performed for pancreatic tissues. In the STZ/diabetic (Gp2) rats, levels of FBG, AST, ALT, and both CDKN1A and TP53 gene expression were significantly increased. Moreover, the hyperglycemia-induced hepatic oxidative state is evidenced by a significant increment of lipid peroxidation and deterioration in SOD and GSH levels. On the contrary, both the STZ/diabetic + CT-Mx and STZ/diabetic + CT-CHNPs showed discernible improvement in diabetes-associated complications; however, STZ/diabetic + CT-CHNPs (Gp4) rats significantly suppressed the generated oxidative stress and improved antioxidant activity, liver function, and insulin secretion. Also, their pancreatic section exhibited architecture with normal regenerative pancreatic endocrine islets with normal distribution and number of beta cells and suppressing inflammatory and apoptotic gene expression compared to Gp2. Nanocarrier agents showed excellent antihyperglycemic and effects after antioxidative, making it a promising technology for diabetics