Physicochemical properties, pharmacokinetic studies, DFT approach, and antioxidant activity of nitro and chloro indolinone derivatives.

The process of developing of new drugs is greatly hampered by their inadequate physicochemical, pharmacokinetic, and intrinsic characteristics. In this regard, the selected chloro indolinone, (Z)-6-chloro-3-(2-chlorobenzylidene)indolin-2-one (C1), and nitro indolinone, (Z)-6-chloro-3-(2-nitrobenzylidene)indolin-2-one (C2), were subjected to SwissADME and density function theory (DFT) analysis. For compounds C1 and C2, the BOILED-Egg pharmacokinetic model predicted intestinal absorption, blood-brain barrier (BBB) penetration, and p-glycoprotein interaction. According to the physicochemical analysis, C1 has exceptional drug-like characteristics suitable for oral absorption. Despite only being substrates for some of the major CYP 450 isoforms, compounds C1 and C2 were anticipated to have strong plasma protein binding and efficient distribution and block these isoforms. The DFT study using the B3LYP/6-311G(d,p) approach with implicit water effects was performed to assess the structural features, electronic properties, and global reactivity parameters (GRP) of C1 and C2. The DFT results provided further support for other studies, implying that C2 is more water-soluble than C1 and that both compounds can form hydrogen bonds and (weak) dispersion interactions with other molecules, such as solvents and biomolecules. Furthermore, the GRP study suggested that C1 should be more stable and less reactive than C2. A concentration-dependent 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging activity was shown by both C1 and C2. In brief, this finding has provided a strong foundation to explore further the therapeutic potential of these molecules against a variety of human disorders.

Multitarget Mechanisms of Monocarbonyl Curcuminoid Analogues against HL-60 Cancer Cells: In Vitro and Network Pharmacology-Based Approach.

This study addressed the cytotoxic potential of four compounds: monocarbonyl curcuminoid, ethyl (2E)-2-benzylidene-3-oxobutanoate 1, 1,2-dimethoxy-12-methyl-13H- [1,3] benzodioxolo[5,6-c] phenanthridine 2, 3,5-dibenzyloxybenzyl bromide 3, and (E)-4-(4-chlorobenzylidene)-1-(4-nitrophenyl)hexan-3-one 4. In vitro cytotoxic assays were carried out in HL-60 and BJ cells using the MTT assay along with analysis of apoptosis with the annexin V detection kit. Additional network pharmacology and docking analyses were carried out. In the in vitro assays, compounds 2 and 4 displayed significant antiproliferative effects in HL-60 cells, exhibiting IC50 values of 5.02 and 9.50 µM, respectively. Compound 1 showed no activity, and compound 3 displayed toxicity in BJ cells. In addition, both compounds 2 and 4 induced apoptosis in HL-60 cells. Network pharmacology and docking analyses indicated that compounds 2 and 4 had synergistic effects targeting the CASP3 and PARP1 proteins. Notably, these proteins play pivotal roles in cancer-related pathways. Thus, by modulating these proteins, monocarbonyl curcuminoid has the potential to influence various cancer-related pathways. In summary, our novel findings provide valuable insights into the potential of these compounds to serve as novel anticancer therapeutic agents, warranting further mechanistic studies and clinical exploration.

Voltammetric analysis of pholcodine on graphene-modified GNPs/PTs with green assessment.

Pholcodine, an anti-tussive medication widely used as an over-the-counter, OTC drug, has recently faced restrictions in several countries. This paper presents a sensitive electrochemical approach for pholcodine detection. The electrochemical method involved fabricating a graphene nanoplatelets electrode, incorporating polythiophene nanospheres polymer to promote electron transfer and increase the activated surface area. Characterization of the fabricated electrode was performed using transmission electron microscopy, ATR-Fourier-transform infrared spectroscopy, X-ray crystallography, X-ray photoelectron spectroscopy, and electrochemical impedance spectroscopy. The electrochemical behavior of pholcodine with the fabricated electrode was investigated using cyclic voltammetry, chronoamperometry, square wave voltammetry (SWV), and differential pulse voltammetry (DPV). The developed electrode led to a linear response for pholcodine ranging from 10 to 45 mg/L with detection limits of 1.41 and 1.51 mg/mL for SWV and DPV, respectively and quantification limits of 4.27 and 4.57 mg/L for SWV and DPV, respectively. The proposed method has accurately recovered pholcodine in spiked serum samples with a recovery percentage ranging from 1.2 to 2.9%. The optimized method is found to be accurate, precise, and robust by applying validation parameters provided by International Council for Harmonization. Two green metrics were computed to assess the method's greenness, the findings showed that the developed method is environmentally friendly with minimum sample preparation steps.

Duvelisib: A comprehensive profile.

Duvelisib (DUV) is chemically named as (S)-3-(1-((9H-Purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one. It is a novel drug with a small molecular weight and characterized by dual phosphoinositide-3-kinase (PI3K)- and PI3K-inhibitory activity. The Food and Drug Administration (FDA) recently approved DUV for the management of small lymphocytic lymphoma (SLL) and relapsed or refractory chronic lymphocytic leukemia (CLL) in adult patients. DUV is marketed under the brand name of Copiktra® (Verastem, Inc., Needham, MA, USA). This chapter provides a critical extensive review of the literature, the description of DUV in terms of its names, formulae, elemental composition, appearance, and use in the treatment of CLL, SLL, and follicular lymphoma. The chapter also describes the methods for preparation of DUV, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information.

Exploring HCl-HCl interactions: QZVPP calculations, improved Lennard-Jones potential, and second virial coefficient analysis for thermodynamics and industrial applications.

In this paper, we present a comprehensive analysis of HCl-HCl interactions, including QZVPP calculations, energy fitting, conformation validation, and the determination of the second virial coefficient B using improved Lennard-Jones (ILJ) potential parameters. To acquire accurate interaction energies, initial QZVPP calculations are performed on approximately 1851 randomly generated HCl-HCl conformations. Then, these energies are used to fit an improved Lennard-Jones potential energy surface, allowing for a robust description of HCl-HCl interactions. The ILJ potential parameters are then used to validate particular HCl dimer conformations, ensuring their stability and consistency with experimental observations. The correlation between calculated and experimental conformations strengthens the validity of the ILJ potential parameters. In addition, the second viral coefficient B is calculated at various temperatures using the ILJ potential. The obtained B values are compared to experimental data, demonstrating close agreement, and validating the ILJ potential's ability to accurately capture the intermolecular interactions and gas-phase behavior of the HCl-HCl system. The results of this study demonstrate the effective implementation of QZVPP calculations, energy fitting, and ILJ potential parameters in validating HCl-HCl conformations and accurately determining the second virial coefficient B. The high degree of concordance between calculated B values and experimental data demonstrates the validity of the ILJ potential and its suitability for modeling HCl-HCl interactions. This research contributes to a greater comprehension of HCl-HCl interactions and their implications for numerous chemical and atmospheric processes. The validated conformations, energy fitting method, and calculated second virial coefficients provide valuable instruments for future research and pave the way for more accurate modeling and simulations of HCl-HCl systems.

Multiomics was used to clarify the mechanism by which air pollutants affect chronic obstructive pulmonary disease: A human cohort study.

Exposure to air pollutants has been associated with various adverse health outcomes, including chronic obstructive pulmonary disease (COPD). However, the precise underlying mechanism by which air pollution impacts COPD through remains insufficiently understood. To elucidated the molecular mechanism by which air pollutant exposure contributes to alterations in the gut microbiome and metabolism in AECOPD patients, we employed metagenomics and untargeted metabolomics to analyse the gut microbial, faecal, and serum metabolites. The correlations among air pollutants, gut microbes, serum metabolites, and blood biochemical markers were assessed using generalised additive mixed models and Spearman correlation analysis. The findings revealed that for every 10 µg/m3 increase in PM2.5 concentration, the α-diversity of the gut flora decreased by 2.16% (95% CI: 1.80%-2.53%). We found seven microorganisms that were significantly associated with air pollutants, of which Enterococcus faecium, Bacteroides fragilis, Ruthenibacterium lactatiformans, and Subdoligranulum sp.4_3_54A2FAA were primarily associated with glycolysis. We identified 13 serum metabolites and 17 faecal metabolites significantly linked to air pollutants. Seven of these metabolites, which were strongly associated with air pollutants and blood biochemical indices, were found in both serum and faecal samples. Some of these metabolites, such as 2,5-furandicarboxylic acid, C-8C1P and melatonin, were closely associated with disturbances in lipid and fatty acid metabolism in AECOPD patients. These findings underscore the impact of air pollutants on overall metabolism based on influencing gut microbes and metabolites in AECOPD patients. Moreover, these altered biomarkers establish the biologic connection between air pollutant exposure and AECOPD outcomes.The identification of pertinent biomarkers provides valuable insights for the development of precision COPD prevention strategies.

The Synthesis, In Vitro Bio-Evaluation, and In Silico Molecular Docking Studies of Pyrazoline-Thiazole Hybrid Analogues as Promising Anti-α-Glucosidase and Anti-Urease Agents.

In the present work, a concise library of benzothiazole-derived pyrazoline-based thiazole (1-17) was designed and synthesized by employing a multistep reaction strategy. The newly synthesized compounds were screened for their α-glucosidase and urease inhibitory activities. The scaffolds (1-17) were characterized using a combination of several spectroscopic techniques, including FT-IR, 1H-NMR, 13C-NMR, and EI-MS. The majority of the synthesized compounds demonstrated a notable potency against α-glucosidase and urease enzymes. These analogues disclosed varying degrees of α-glucosidase and urease inhibitory activities, with their IC50 values ranging from 2.50 to 17.50 µM (α-glucosidase) and 14.30 to 41.50 (urease). Compounds 6, 7, 14, and 12, with IC50 values of 2.50, 3.20, 3.40, and 3.50 µM as compared to standard acarbose (IC50 = 5.30 µM), while the same compounds showed 14.30, 19.20, 21.80, and 22.30 comparable with thiourea (IC50 = 31.40 µM), respectively, showed excellent inhibitory activity. The structure-activity relationship revealed that the size and electron-donating or electron-withdrawing effects of substituents influenced the enzymatic activities such as α-glucosidase and urease. Compound 6 was a dual potent inhibitor against α-glucosidase and urease due to the presence of -CF3 electron-withdrawing functionality on the phenyl ring. To the best of our knowledge, these synthetic compounds were found to be the most potent dual inhibitors of α-glucosidase and urease with minimum IC50 values. Moreover, in silico studies on most active compounds, i.e., 6, 7, 14, and 12, were also performed to understand the binding interaction of most active compounds with active sites of α-glucosidase and urease enzymes.

Identification of Indazole-Based Thiadiazole-Bearing Thiazolidinone Hybrid Derivatives: Theoretical and Computational Approaches to Develop Promising Anti-Alzheimer's Candidates.

A hybrid library of compounds based on indazole-based thiadiazole containing thiazolidinone moieties (1-17) was synthesized. The synthesized compounds were screened in vitro for their inhibition profile against targetedacetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. All the derivatives demonstrated a varied range of inhibitory activities having IC50 values ranging from 0.86 ± 0.33 µM to 26.73 ± 0.84 µM (AChE) and 0.89 ± 0.12 µM to 27.08 ± 0.19 µM (BuChE), respectively. The results obtained were compared with standard Donepezil drugs (IC50 = 1.26 ± 0.18 µM for AChE) and (1.35 ± 0.37 µM for BuChE), respectively. Specifically, the derivatives 1-17, 1, 9, and 14 were found to be significantly active, with IC50 values of 0.86 ± 0.30, 0.92 ± 0.10, and 1.10 ± 0.37 µM (against AChE) and 0.89 ± 0.12, 0.98 ± 0.48 and 1.19 ± 0.42 µM (against BuChE), respectively.The structure-activity relationship (SAR) studies revealed that derivatives bearing para-CF3, ortho-OH, and para-F substitutions on the phenyl ring attached to the thiadiazole skeleton, as well as meta-Cl, -NO2, and para-chloro substitutions on the phenyl ring, having a significant effect on inhibitory potential. The synthesized scaffolds have been further characterized by using 1H-NMR, 13C-NMR, and (HR-MS) to confirm the precise structures of the synthesized compounds. Additionally, the molecular docking approach was carried out for most active compounds to explore the binding interactions established by most active compounds, with the active sites of targeted enzymes and obtained results supporting the experimental data.

Retraction notice to "Development of a highly sensitive chemiluminescence immunoassay using a novel signal-enhanced detection system for quantitation of durvalumab, an immune-checkpoint inhibitor monoclonal antibody used for immunotherapy of lung cancer" [Heliyon 9 (2023) e15782].

[This retracts the article DOI: 10.1016/j.heliyon.2023.e15782.].

Impairments of Spatial Memory and N-methyl-d-aspartate Receptors and Their Postsynaptic Signaling Molecules in the Hippocampus of Developing Rats Induced by As, Pb, and Mn Mixture Exposure.

Exposure to metal mixtures is recognized as a real-life scenario, needing novel studies that can assess their complex effects on brain development. There is still a significant public health concern associated with chronic low levels of metal exposure. In contrast to other metals, these three metals (As, Pb, and Mn) are commonly found in various environmental and industrial contexts. In addition to additive or synergistic interactions, concurrent exposure to this metal mixture may also have neurotoxic effects that differ from those caused by exposure to single components. The NMDA receptor and several important signaling proteins are involved in learning, memory, and synaptic plasticity in the hippocampus, including CaMKII, postsynaptic density protein-95 (PSD-95), synaptic Ras GTPase activating protein (SynGAP), a negative regulator of Ras-MAPK activity, and CREB. We hypothesized that alterations in the above molecular players may contribute to metal mixture developmental neurotoxicity. Thus, the aim of this study was to investigate the effect of these metals and their mixture at low doses (As 4 mg, Pb 4 mg, and Mn 10 mg/kg bw/p.o) on NMDA receptors and their postsynaptic signaling proteins during developing periods (GD6 to PD59) of the rat brain. Rats exposed to As, Pb, and Mn individually or at the same doses in a triple-metal mixture (MM) showed impairments in learning and memory functions in comparison to the control group rats. Declined protein expressions of NR2A, PSD-95, p- CaMKII, and pCREB were observed in the metal mix-exposed rats, while the expression of SynGAP was found to be enhanced in the hippocampus as compared to the controls on PD60. Thereby, our data suggest that alterations in the NMDA receptor complex and postsynaptic signaling proteins could explain the cognitive dysfunctions caused by metal-mixture-induced developmental neurotoxicity in rats. These outcomes indicate that incessant metal mixture exposure may have detrimental consequences on brain development.

Selective Stability Indicating Liquid Chromatographic Method Based on Quality by Design Framework and In Silico Toxicity Assessment for Infigratinib and Its Degradation Products.

Infigratinib, a protein kinase inhibitor employed in the therapeutic management of cholangiocarcinoma, was subjected to various stress conditions, including hydrolytic (acidic and alkaline), oxidative, photolytic, and thermal stress, in accordance with the rules established by the International Council for Harmonization. A cumulative count of five degradation products was observed. The application of the Quality by Design principle was utilized in the development of a rapid and specific separation method for Infigratinib and its degradation products. The methodology employed in this study was derived from an experimental design approach, which was utilized to examine the critical process parameters associated with chromatographic systems. The reversed-phase high-performance liquid chromatography technique, employing a C18 column and a mobile phase composed of a gradient mixture of 25 mM ammonium acetate buffer at pH 6.0 and acetonitrile, successfully facilitated the chromatographic separation. The methodology was expanded to include the utilization of UPLC-quadrupole tandem mass spectrometry in order to conduct a comprehensive analysis of the structural properties and characterize the degradation products. Overall, five degradation products were found in different stress conditions. The method was verified at certain working points, wherein a linearity range (5.0-200.0 µg/mL) was developed and other parameters such as accuracy, repeatability, selectivity, and system suitability were evaluated. Finally, the toxicity and mutagenicity of Infigratinib and its degradation products were predicted using in silico software, namely DEREK Nexus® (version 6.2.1) and SARAH Nexus® (version 3.2.1). Various toxicity endpoints, including chromosomal damage, were predicted. Additionally, two degradation products were also predicted to be mutagenic.

Targeting Autophagy, Apoptosis, and Oxidative Perturbations with Dapagliflozin Mitigates Cadmium-Induced Cognitive Dysfunction in Rats.

Cognitive decline and Alzheimer-like neuropathology are common manifestations of cadmium toxicity. Thanks to its antioxidant/anti-apoptotic features, dapagliflozin has demonstrated promising neuroprotective actions. However, its effect on cadmium-induced neurotoxicity is lacking. The present work aimed to examine whether dapagliflozin could protect rats from cadmium-evoked cognitive decline. In this study, the behavioral disturbances and hippocampal biomolecular alterations were studied after receiving dapagliflozin. Herein, cadmium-induced memory/learning decline was rescued in the Morris water maze, novel object recognition task, and Y-shaped maze by dapagliflozin. Meanwhile, the hippocampal histopathological abnormalities were mitigated. The molecular mechanisms revealed that dapagliflozin lowered hippocampal expression of p-tau and Aß42 neurotoxic proteins while augmenting acetylcholine. The cognitive enhancement was triggered by hippocampal autophagy stimulation, as indicated by decreased SQSTM-1/p62 and Beclin 1 upregulation. Meanwhile, a decrease in p-mTOR/total mTOR and an increase in p-AMPK/total AMPK ratio were observed in response to dapagliflozin, reflecting AMPK/mTOR cascade stimulation. Dapagliflozin, on the other hand, dampened the pro-apoptotic processes in the hippocampus by downregulating Bax, upregulating Bcl-2, and inactivating GSK-3ß. The hippocampal oxidative insult was mitigated by dapagliflozin as seen by lipid peroxide lowering, antioxidants augmentation, and SIRT1/Nrf2/HO-1 pathway activation. In conclusion, dapagliflozin's promising neuroprotection was triggered by its pro-autophagic, anti-apoptotic, and antioxidant properties.

Comparative Study of Augmented Classical Least Squares Models for UV Assay of Co-Formulated Antiemetics Together with Related Impurities.

The classical least squares (CLS) model and three augmented CLS models are adopted and validated for the analysis of pyridoxine HCl (PYR), cyclizine HCl (CYC), and meclizine HCl (MEC) in a quinary mixture with two related impurities: the CYC main impurity, Benzhydrol (BEH), which has carcinogenic and hepatotoxic effects, and the MEC official impurity, 4-Chlorobenzophenone (BEP). The proposed augmented CLS models are orthogonal signal correction CLS (OSC-CLS), direct orthogonal signal correction CLS (DOSC-CLS), and net analyte processing CLS (NAP-CLS). These models were applied to quantify the three active constituents in their raw materials and their corresponding dosage forms using their UV spectra. To evaluate the CLS-based models sensibly, we design a comparative study involving two sets: the training set to construct models and the validation set to assess the prediction abilities of these models. A five-level, five-factor calibration design was established to produce 25 mixtures for the calibration set. In addition, 16 experiments were performed for a test set distributed equally between the in-space and out-space samples. The primary criterion for comparing the models' performance was the validation set's root mean square error of prediction (RMSEP) value. Finally, augmented CLS models showed acceptable results for assaying the three analytes. The results were compared statistically with the reported HPLC methods; however, the DOSC-CLS model proved the best for assaying the dosage forms.

Antioxidant and Anti-Aging Phytoconstituents from Faucaria tuberculosa: In Vitro and In Silico Studies.

Research targeting natural cosmeceuticals is now increasing due to the safety and/or limited side effects of natural products that are highly valued in cosmetology. Within a research program exploring botanical sources for valuable skincare antioxidant components, the current study investigated the phytochemical content and the biological potential of Faucaria tuberculosa. Phytochemical investigation of F. tuberculosa extract resulted in purification and characterization of six phytoconstituents, including a new one. The structure of the new constituent was elucidated as (-) catechin-(2→1',4→2')-phloroglucinol (4). The structural identity of all isolated compounds were confirmed on the basis of extensive physical and spectral (1D, 2D-NMR and HRESIMS) investigations. The ethanolic extract exhibits a rich content of total phenolics (TPC) and total flavonoids (TFC), estimated as 32 ± 0.034 mg GAE/g and 43 ± 0.004 mg RE/g, respectively. In addition, the antioxidant (ABTS and FRAP), antihyaluronidase and antityrosinase activities of all purified phytoconstituents were evaluated. The results noted (-) catechin-(2→1',4→2') phloroglucinol (4) and phloroglucinol (1) for their remarkable antioxidant activity, while isorhamnetin 3-O-rutinoside (3) and 3,5-dihydroxyphenyl ß-D-glucopyranoside (2) achieved the most potent inhibitory activity against tyrosinase (IC50 22.09 ± 0.7 µM and 29.96 ± 0.44 µM, respectively) and hyaluronidase enzymes (IC50 49.30 ± 1.57 µM and 62.58 ± 0.92, respectively) that remarkably exceeds the activity of the standard drugs kojic acid (IC50 = 65.21 ± 0.47 µM) and luteolin, (IC50 = 116.16 ± 1.69 µM), respectively. A molecular docking study of the two active compounds (3 and 2) highlighted their high potential to bind to the active sites of the two enzymes involved in the study.

Dapagliflozin/Hesperidin Combination Mitigates Lipopolysaccharide-Induced Alzheimer's Disease in Rats.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorders worldwide. Its pathologic features include massive neuroinflammation with abnormal deposition of ß-amyloid peptide in the cerebral tissues leading to degeneration of the brain neurons. Adverse effects associated with the traditional drugs used for the treatment of this pathological condition have directed the research efforts towards searching for alternative effective agents with minimal adverse effects. The aim of this study was to elucidate the potential ameliorative effects of dapagliflozin and/or hesperidin on Alzheimer's disease (AD) induced by lipopolysaccharide (LPS) injection in rats. In a rodent model of AD, the effect of dapagliflozin with or without hesperidin on the biochemical parameters and the behavioral tests as well as the histopathological parameters was determined. Each of dapagliflozin and hesperidin restored the behavioral tests to the reference values, augmented the antioxidant defense mechanisms, ameliorated the neuronal inflammatory responses, combatted the changes in Toll-like receptor-4 (TLR-4)/High-mobility group box 1 (HMGB1) protein signaling and receptors of advanced glycation end products (RAGE) levels, and restored the balance between the apoptotic signals and autophagy in the hippocampal tissues. Additionally, both agents exhibited an outstanding ability to combat LPS-induced perturbations in the histopathological and electron microscopic image of the brain tissues. These favorable effects were significantly encountered in the group treated with dapagliflozin/hesperidin combination when compared versus animals treated with either dapagliflozin or hesperidin. In conclusion, inhibition of the hippocampal HMGB1/TLR4/RAGE signaling, the pro-inflammatory axis, and apoptosis alongside augmentation of the antioxidant defenses and autophagy can be regarded as beneficial effects by which dapagliflozin/hesperidin combination may combat LPS-triggered AD.

Targeting Autophagy, Apoptosis, and SIRT1/Nrf2 Axis with Topiramate Underlies Its Neuroprotective Effect against Cadmium-Evoked Cognitive Deficits in Rats.

Cadmium is an environmental toxicant that instigates cognitive deficits with excessive glutamate excitatory neuroactivity in the brain. Topiramate, a glutamate receptor antagonist, has displayed favorable neuroprotection against epilepsy, cerebral ischemia, and Huntington's disease; however, its effect on cadmium neurotoxicity remains to be investigated. In this study, topiramate was tested for its potential to combat the cognitive deficits induced by cadmium in rats with an emphasis on hippocampal oxidative insult, apoptosis, and autophagy. After topiramate intake (50 mg/kg/day; p.o.) for 8 weeks, behavioral disturbances and molecular changes in the hippocampal area were explored. Herein, Morris water maze, Y-maze, and novel object recognition test revealed that topiramate rescued cadmium-induced memory/learning deficits. Moreover, topiramate significantly lowered hippocampal histopathological damage scores. Mechanistically, topiramate significantly replenished hippocampal GLP-1 and dampened Aß42 and p-tau neurotoxic cues. Notably, it significantly diminished hippocampal glutamate content and enhanced acetylcholine and GABA neurotransmitters. The behavioral recovery was prompted by hippocampal suppression of the pro-oxidant events with notable activation of SIRT1/Nrf2/HO-1 axis. Moreover, topiramate inactivated GSK-3ß and dampened the hippocampal apoptotic changes. In tandem, stimulation of hippocampal pro-autophagy events, including Beclin 1 upregulation, was triggered by topiramate that also activated AMPK/mTOR pathway. Together, the pro-autophagic, antioxidant, and anti-apoptotic features of topiramate contributed to its neuroprotective properties in rats intoxicated with cadmium. Therefore, it may be useful to mitigate cadmium-induced cognitive deficits.

Development of Novel Micellar-Enhanced High-Throughput Microwell Spectrofluorimetric Method for Quantification of Lorlatinib: Application to In Vitro Drug Release and Analysis of Urine Samples.

Lorlatinib (LOR) is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor drug. The Food and Drug Administration (FDA) has granted an approval for the use of LOR as a first therapeutic intervention for individuals diagnosed with ALK-positive metastatic and advanced non-small-cell lung cancer (NSCLC). The present study outlines, for the first time, the development and validation of an innovative microwell-based spectrofluorimetric (MW-SFL) method for the quantification of LOR. The proposed method involved the enhancement of the weak native fluorescence of LOR by its micellization into the sodium lauryl sulfate (SLS) micelles. The procedures of the method were conducted in white opaque plates with 96 microwells, and the enhanced fluorescence signals were measured by a fluorescence plate reader at 405 nm after excitation at 310 nm. The measured relative fluorescence intensity (RFI) had a linear relationship with LOR concentrations in the range of 60-1600 ng mL-1. The limit of detection (LOD) and the limit of quantification (LOQ) were found to be 19 and 56 ng mL-1, respectively. The method's accuracy and precision were assessed using a recovery study; the recovery values ranged from 99.98% to 101.40%, accompanied by relative standard deviation (RSD) values of 0.42% to 1.59%. The proposed MW-SFL method combined the advantages of the intrinsically high sensitivity of the spectrofluorimetric measurement and the excellent throughput of the microwell-based approach. The results proved the method is effective in the determination of LOR in its pharmaceutical tablets, tablet dissolution testing, as well as in spiked urine with a high degree of precision and accuracy. The MW-SFL method is notable for its simple procedures and utilization of water as a solvent, as well as minimal quantities of sample solutions. These features align with its ecofriendly approach to green chemistry principles. These advantages gave the proposed MW-SFL method a high potential value for the determination of LOR in clinical and quality control laboratories.

Neuroprotective Impact of Linagliptin against Cadmium-Induced Cognitive Impairment and Neuropathological Aberrations: Targeting SIRT1/Nrf2 Axis, Apoptosis, and Autophagy.

Cadmium is an environmental contaminant associated with marked neurotoxicity and cognitive impairment. Linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated promising neuroprotection against cerebral ischemia and diabetic dementia. However, there has been no study of its effect on cadmium-induced cognitive deficits. In the present work, linagliptin's prospective neuroprotective effects against cadmium-evoked cognitive decline were examined in vivo in rats. The molecular pathways related to oxidative stress, apoptosis, and autophagy were investigated. Histology, immunohistochemistry, ELISA, and biochemical assays were performed on brain hippocampi after receiving linagliptin (5 mg/kg/day). The current findings revealed that cadmium-induced learning and memory impairment were improved by linagliptin as seen in the Morris water maze, Y-maze, and novel object recognition test. Moreover, linagliptin lowered hippocampal neurodegeneration as seen in histopathology. At the molecular level, linagliptin curtailed hippocampal DPP-4 and augmented GLP-1 levels, triggering dampening of the hippocampal neurotoxic signals Aß42 and p-tau in rats. Meanwhile, it enhanced hippocampal acetylcholine and GABA and diminished the glutamate spike. The behavioral recovery was associated with dampening of the hippocampal pro-oxidant response alongside SIRT1/Nrf2/HO-1 axis stimulation. Meanwhile, linagliptin counteracted hippocampal apoptosis markers and inhibited the pro-apoptotic kinase GSK-3ß. In tandem, linagliptin activated hippocampal autophagy by lowering SQSTM-1/p62 accumulation, upregulating Beclin 1, and stimulating AMPK/mTOR pathway. In conclusion, linagliptin's antioxidant, antiapoptotic, and pro-autophagic properties advocated its promising neuroprotective impact. Thus, linagliptin may serve as a management approach against cadmium-induced cognitive deficits.

Stimulation of Autophagy by Dapagliflozin Mitigates Cadmium-Induced Testicular Dysfunction in Rats: The Role of AMPK/mTOR and SIRT1/Nrf2/HO-1 Pathways.

Cadmium (Cd) is a widespread environmental pollutant that triggers testicular dysfunction. Dapagliflozin is a selective sodium-glucose co-transporter-2 inhibitor with notable antioxidant and anti-apoptotic features. It has shown marked cardio-, reno-, hepato-, and neuroprotective effects. Yet, its effect on Cd-evoked testicular impairment has not been examined. Hence, the goal of the current study was to investigate the potential positive effect of dapagliflozin against Cd-induced testicular dysfunction in rats, with an emphasis on autophagy, apoptosis, and oxidative insult. Dapagliflozin (1 mg/kg/day) was given by oral gavage, and testicular dysfunction, impaired spermatogenesis, and biomolecular events were studied via immunohistochemistry, histopathology, and ELISA. The current findings demonstrated that dapagliflozin improved relative testicular weight, serum testosterone, and sperm count/motility and reduced sperm abnormalities, signifying mitigation of testicular impairment and spermatogenesis disruption. Moreover, dapagliflozin attenuated Cd-induced histological abnormalities and preserved testicular structure. The testicular function recovery was prompted by stimulating the cytoprotective SIRT1/Nrf2/HO-1 axis, lowering the testicular oxidative changes, and augmenting cellular antioxidants. As regards apoptosis, dapagliflozin counteracted the apoptotic machinery by downregulating the pro-apoptotic signals together with Bcl-2 upregulation. Meanwhile, dapagliflozin reactivated the impaired autophagy, as seen by a lowered accumulation of SQSTM-1/p62 and Beclin 1 upregulation. In the same context, the testicular AMPK/mTOR pathway was stimulated as evidenced by the increased p-AMPK (Ser487)/total AMPK ratio alongside the lowered p-mTOR (Ser2448)/total mTOR ratio. Together, the favorable mitigation of Cd-induced testicular impairment/disrupted spermatogenesis was driven by the antioxidant, anti-apoptotic, and pro-autophagic actions of dapagliflozin. Thus, it could serve as a tool for the management of Cd-evoked testicular dysfunction.

Quetiapine Albumin Nanoparticles as an Efficacious Platform for Brain Deposition and Potentially Improved Antipsychotic Activity.

Quetiapine (QP) is a second-generation short-acting antipsychotic drug extensively metabolized in the liver, producing pharmacologically inactive metabolites and leading to diminished bioavailability. Therefore, this study aimed to develop an intravenous QP albumin nanoparticles (NPs) system for improving QP antipsychotic activity and brain targeting. QP-loaded albumin NPs were prepared by the desolvation method. The fabricated NPs were characterized in terms of particle size, zeta potential, entrapment efficiency (EE%), and in vitro drug release. In vivo pharmacokinetics and biodistribution in rats were studied. In addition, the antipsychotic activity of the optimized platform was also investigated. Human serum albumin (HSA) concentration, pH, and stirring time were modulated to optimize QP albumin NPs with a particle size of 103.54 ± 2.36 nm and a QP EE% of 96.32 ± 3.98%. In addition, the intravenous administration of QP albumin NPs facilitated QP brain targeting with a 4.9-fold increase in targeting efficiency compared to the oral QP solution. The QP albumin NPs improved the QP antipsychotic activity, indicated by suppressing rats' hypermobility and reducing the QP's extrapyramidal side effects. The obtained results proposed that intravenous QP- NPs could improve QP brain targeting and its antipsychotic efficiency.