A patent review of P2X7 receptor antagonists to treat inflammatory diseases (2018-present).

INTRODUCTION: The purinergic P2X7 receptor (P2X7R) is expressed on the surface of many different types of cells, including immune cells. Targeting P2X7R with antagonists has been studied for its potential therapeutic effects in a variety of inflammatory illnesses. AREA COVERED: Many chemical substances, including carboxamides, benzamides and nitrogen containing heterocyclic derivatives have demonstrated promising inhibitory potential for P2X7 receptor. The chemistry and clinical applications of P2X7R antagonists patented from 2018- present are discussed in this review. EXPERT OPINION: Purinergic receptor inhibitor discovery and application has demonstrated the potential for therapeutic intervention, as demonstrated by pharmacological research. Few chemical modalities have been authorized for use in clinical settings, despite the fact that breakthroughs in crystallography and chemical biology have increased the knowledge of purinergic signaling and its consequences in disease. The many research projects and pharmaceutical movements that sustain dynamic P2X receptor programs over decades are evidence of the therapeutic values and academic persistence in purinergic study. P2X7R is an intriguing therapeutic target and possible biomarker for inflammation. Although several companies like Merck and AstraZeneca have published patents on P2X3 antagonists, the search for P2X7R antagonists has not stopped. Numerous pharmaceutical companies have disclosed different scaffolds, and some molecules are presently being studied in clinical studies.

High-temperature corrosion-resistant alloy for waste-to-energy plants: Alloy designing, fabrication, and possible corrosion-resistance mechanism.

This study designed a novel high-temperature corrosion-resistant alloy through thermodynamic equilibrium computations. The strength was determined by the integration of precipitation-strengthening species of nickel boride and tungsten solid solution strengthening, while high-temperature corrosion-resistant property was realized through optimized compositional design. Phase stability was enabled by the presence of a face-centered cubic structure. The alloy was fabricated and its corrosion-resistance performance was experimentally compared with other commercially available nickel- and iron-based alloys under simulated municipal solid waste combustion. The designed alloy with a composition of Ni-5B-6W-28Cr-13Al showed a low corrosion rate of ∼72 % < 13CrMo4-5TS and 1.08 % > Inconel 625. Economic analysis showed that Ni-5B-6W-28Cr-13Al has a cost-effectiveness ratio of 1:1.57 with respect to Inconel 625 and 1:0.09 with respect to 13CrMo4-5TS. Corrosion-resistance mechanism was explored using scanning electron microscopy coupled with energy dispersive spectroscopy, x-ray diffractometer, and DFT computations. The corrosion resistance occurred through the formation of a uniform tungsten-chromium-oxide film which inhibits inward diffusion of corrosive chlorine species. These findings provide insights into the development of alloys for high-temperature technologies.

ML-Based Detection of DDoS Attacks Using Evolutionary Algorithms Optimization.

The escalating reliance of modern society on information and communication technology has rendered it vulnerable to an array of cyber-attacks, with distributed denial-of-service (DDoS) attacks emerging as one of the most prevalent threats. This paper delves into the intricacies of DDoS attacks, which exploit compromised machines numbering in the thousands to disrupt data services and online commercial platforms, resulting in significant downtime and financial losses. Recognizing the gravity of this issue, various detection techniques have been explored, yet the quantity and prior detection of DDoS attacks has seen a decline in recent methods. This research introduces an innovative approach by integrating evolutionary optimization algorithms and machine learning techniques. Specifically, the study proposes XGB-GA Optimization, RF-GA Optimization, and SVM-GA Optimization methods, employing Evolutionary Algorithms (EAs) Optimization with Tree-based Pipelines Optimization Tool (TPOT)-Genetic Programming. Datasets pertaining to DDoS attacks were utilized to train machine learning models based on XGB, RF, and SVM algorithms, and 10-fold cross-validation was employed. The models were further optimized using EAs, achieving remarkable accuracy scores: 99.99% with the XGB-GA method, 99.50% with RF-GA, and 99.99% with SVM-GA. Furthermore, the study employed TPOT to identify the optimal algorithm for constructing a machine learning model, with the genetic algorithm pinpointing XGB-GA as the most effective choice. This research significantly advances the field of DDoS attack detection by presenting a robust and accurate methodology, thereby enhancing the cybersecurity landscape and fortifying digital infrastructures against these pervasive threats.

FEM simulations for double diffusive transport mechanism hybrid nano fluid flow in corrugated enclosure by installing uniformly heated and concentrated cylinder.

Generation of fluid flow due to simultaneous occurrence of heat and mass diffusions caused by buoyancy differences is termed as double diffusion. Pervasive applications of such diffusion arise in numerous natural and scientific systems. This article investigates double diffusion in naturally convective flow of water-based fluid saturated in corrugated enclosure and containing hybrid nano particles composed of Copper (Cu) and Alumina (Al2O3). Impact of uniformly applied magnetic field is also accounted. To produce thermosolutal convective potential circular cylinder of constant radius is also adjusted by providing uniform temperature and concentration distributions. Finite element approach is capitalized to provide solution of utilized governing equations by utilizing Multiphysics COMSOL software. Wide-range of physical parameters are incorporated to depict their influence on associated distributions (velocity, temperature and concentration). Interesting physical quantities like Nusselt number, Sherwood numbers are also calculated against involved sundry parameters. It is note worthily observed that maximum strength of stream lines [Formula: see text] is 3.3 at [Formula: see text] and drops to 1.2 when [Formula: see text] is increased to 0.04. Furthermore, in the hydrodynamic case (Ha = 0), it is observed that the velocity field exhibits an increasing trend compared to the hydromagnetic case [Formula: see text] which is proved from the attained values of stream-function i.e., [Formula: see text] (in the absence of a magnetic field) and [Formula: see text] (in the presence of a magnetic field). It is revealed from the statistics of Nusselt number that increase in volume fraction of nano particles from 0 to 0.4, heat flux coefficient upsurges up to 7% approximately. Since, present work includes novel physical aspects of thermosolutal diffusion generated due to induction of hybrid nanoparticles in water contained in corrugated enclosure, so this study will provide innovative thought to the researchers to conduct research in this direction.

A Comprehensive Review of Friction Stir Additive Manufacturing (FSAM) of Non-Ferrous Alloys.

Additive manufacturing is a key component of the fourth industrial revolution (IR4.0) that has received increased attention over the last three decades. Metal additive manufacturing is broadly classified into two types: melting-based additive manufacturing and solid-state additive manufacturing. Friction stir additive manufacturing (FSAM) is a subset of solid-state additive manufacturing that produces big area multi-layered components through plate addition fashion using the friction stir welding (FSW) concept. Because of the solid-state process in nature, the part produced has equiaxed grain structure, which leads to better mechanical properties with less residual stresses and solidification defects when compared to existing melting-based additive manufacturing processes. The current review article intends to highlight the working principle and previous research conducted by various research groups using FSAM as an emerging material synthesizing technique. The summary of affecting process parameters and defects claimed for different research materials is discussed in detail based on open access experimental data. Mechanical properties such as microhardness and tensile strength, as well as microstructural properties such as grain refinement and morphology, are summarized in comparison to the base material. Furthermore, the viability and potential application of FSAM, as well as its current academic research status with technology readiness level and future recommendations are discussed meticulously.

Influence of Operating and Electrochemical Parameters on PEMFC Performance: A Simulation Study.

Proton exchange membrane fuel cell, or polymer electrolyte fuel cell, (PEMFC) has received a significant amount of attention for green energy applications due to its low carbon emission and less other toxic pollution capacity. Herein, we develop a three-dimensional (3D) computational fluid dynamic model. The values of temperature, pressure, relative humidity, exchange coefficient, reference current density (RCD), and porosity values of the gas diffusion layer (GDL) were taken from the published literature. The results demonstrate that the performance of the cell is improved by modifying temperature and operating pressure. Current density is shown to degrade with the rising temperature as explored in this study. The findings show that at 353 K, the current density decreases by 28% compared to that at 323 K. In contrast, studies have shown that totally humidified gas passing through the gas channel results in a 10% higher current density yield, and that an evaluation of a 19% higher RCD value results in a similar current density yield.

Investigation of enhanced H2 production from municipal solid waste gasification via artificial neural network with data on tar compounds.

An artificial neural network (ANN) is a biologically inspired computational technique that imitates the behavior and learning process of the human brain. In this study, ANN technique was applied to assess the gasification of municipal solid waste (MSW) with the aim of enhancing the H2 production. The experiments were conducted using a horizontal tube reactor under different parameters: temperatures, MSW loadings, residence times, and equivalence ratios. The input and output variables (released gases) were tested and trained using back-propagation algorithm, and the data distribution by K-fold contrivance. The values of the training (80% data) and validation (20% data) dataset were found satisfactory. The values of regression coefficient (R2) for the training phase were lied between 0.9392 and 0.9991, and 0.9363 and 0.993824 for the testing phase. Whereas; the values of root mean square error (RSME) for the training phase were lied between 0.4111 and 0.8422, and between 0.1476 and 0.7320 for the testing phase. Higher H2 production of 42.1 vol% was produced at the higher reaction temperature of 900 °C with LHV of 11.2 MJ/Nm3. According to the tar analysis, the dominant compounds were aromatics (17 compounds) followed by polycyclic aromatic, phenyl, aliphatic, aromatic heterocyclic, polycyclic, and aromatic ketone compounds.

A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family / 亚洲男科学杂志(英文版)

Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenozoospermia categorized by immotile spermatozoa with abnormal flagella in ejaculate. Whole-exome sequencing (WES) is used to detect pathogenic variants in patients with MMAF. In this study, a novel homozygous frameshift variant (c.6158_6159insT) in dynein axonemal heavy chain 8 (DNAH8) from two infertile brothers with MMAF in a consanguineous Pakistani family was identified by WES. Reverse transcription-polymerase chain reaction (RT-PCR) confirmed DNAH8 mRNA decay in these patients with the DNAH8 mutation. Hematoxylin-eosin staining and transmission electron microscopy revealed highly divergent morphology and ultrastructure of sperm flagella in these patients. Furthermore, an immunofluorescence assay showed the absence of DNAH8 and a reduction in its associated protein DNAH17 in the patients' spermatozoa. Collectively, our study expands the phenotypic spectrum of patients with DNAH8-related MMAF worldwide.

Recent Developments and Anticancer Therapeutics of Paclitaxel: An Update.

Plants are a source of diverse classes of secondary metabolites with anticancer properties. Paclitaxel (Taxol) is an anticancer drug isolated from various Taxus species and is used as a chemotherapeutic agent against various cancers. The biosynthesis of paclitaxel is a complex pathway, making its total chemical synthesis commercially non-viable; hence, alternative novel sources - like plant cell culture and heterologous expression systems, are being investigated to overcome this issue. Advancements in the field of genetic engineering, microbial fermentation engineering, and recombinant techniques have significantly increased the achievable yields of paclitaxel. Indeed, paclitaxel selectively targets microtubules and causes cell cycle arrest in the G2/M phase, inducing a cytotoxic effect in a concentration and time-dependent manner. Innovative drug delivery formulations, like the development of albumin-bound nanoparticles, nano-emulsions, nano-suspensions, liposomes, and polymeric micelles, have been applied to enhance the delivery of paclitaxel to tumor cells. This review focuses on the production, biosynthesis, mechanism of action, and anticancer effects of paclitaxel.

Evaluation of Insecticidal Potentials of Five Plant Extracts against the Stored Grain Pest, Callosobruchus maculatus (Coleoptera: Bruchidae).

Plant based insecticides are considered among the most economic and ecofriendly chemicals for the protection of plants and stored grains. The cowpea weevil (Callosbruchus maculatus) causes more than 90% damage to sored grains in three to six months. The current study investigates insecticidal potentials of five selected botanicals: Melia azedarach, Nicotiana rustica, Azadirachta indica, Nicotiana tabacum and Thuja orientalis. They are explored at six different concentrations (0.5, 1.0, 1.5, 2.0, 2.5 and 3.0%) against C. maculatus and compared to effects of distilled water which is used as a control. Toxicities of 3%(V/V) extracts of N. tabacum, N. rustica, A. indica and T. orientalis against C. maculatus were 100%, 86.11%, 80.56% and 72.22%, respectively. Maximum mortality was caused by N. tabacum and N. rustica (100%), followed by A. indica (82%), whereas minimum mortality was observed in T. orientalis (64%) at 2.5%. Several phytochemicals, alkaloids, saponins, diterphenes, phytosterol, flavonoids and phenols were identified in N. tabacum and N. rustica, while few were present in A. indica. Phytosterol was present in greatest abundance. Saponins were only detected in aqueous extracts of N. rustica and N. tabacum. Taken together, these results indicate the utility of N. tabacum, N. rustica and A. indica as potential botanicals to control pest beetle and cowpea weevil.

Sturge-weber Syndrome with Bilateral Fronto-parieto-temporal Lobe Atrophy and Bilateral Leptomeningeal Angiomatosis: A Rare Case.

Sturge-weber Syndrome (SWS) is a phacomatosis characterised by Port-Wine stains, leptomeningeal angiomatosis, and glaucoma. Leptomeningeal angiomatosis is seen in 10% to 20% of the cases with the facial nevus, usually on the ipsilateral side. Parietal and occipital regions are the most commonly involved areas; however, it can involve any area of the brain. Bilateral involvement is detected in 15% of the patients. Bilateral Port-Wine stains have been shown to be associated with an increased risk of developing epilepsy in an early age. Here, we present a case of a 3-month child with bilateral Port-Wine stains who presented with generalised fits. On the basis of Port-Wine stains, SWS was suspected, and MRI was done which showed cerebral atrophy in bilateral fronto-parieto-temporal regions and bilateral leptomeningeal angiomatosis, which are rare findings according to the literature. Key Words: Sturge-weber syndrome, Phacomatosis, Port-wine stain, Fits.

Seroprevalence of Anti-tTg-IgA among Symptomized Celiac Disease Patients and Their Correlation with Rotavirus Infection.

Celiac disease (CD) is a chronic inflammatory disorder in the intestinal tract as a response to the use of gluten in genetically predisposed individuals. It is a worldwide problem, with a high prevalence rate in North America. This is a descriptive cross-sectional study involving 1090 samples collected from different hospitals of Rawalpindi and Islamabad, Pakistan, from January 2019 to December 2019. In this study, 1090 blood samples screened for seroprevalence of anti-tTG antibodies in CD symptomatic patients via ELISA (enzyme-linked immunosorbent assay). 1090 fecal samples from the same CD patients were collected and tested for the presence of rotavirus (RV) via ELISA and RT-PCR. Of the 1090 patients tested for seroprevalence of anti-tTG antibodies, 112/1090 (10.3%) were found to be positive. Of the 112 anti-tTG-positive patients, 78/112 (70%) were positive for RV via ELISA and 74/112 (66.1%) were RV positive via RT-PCR. A statistically significant association was reported between rotavirus infection and celiac disease (p˂0.05). Anti-tTG antibodies were higher in age group 6 (12-18 years) patients (18.4%) and at minimum in age group 3 (1-3 years) patients (4.8%). However, there was a statistically insignificant relationship between group age and CD prevalence (p > 0.05). The highest CD prevalence was noted during winter season (19.6%) and the lowest (3.0%) during fall/autumn. Our study findings demonstrate that Pakistan has a high prevalence of CD compared to other studies. Further studies in the fields of environmental risk factors and treatment with more advanced serological and histopathological studies are needed in the future.

Convective Heat and Mass Transport in Casson Fluid Flow in Curved Corrugated Cavity with Inclined Magnetic Field.

Convection in fluids produced by temperature and solute concentration differences is known as thermosolutal convection. It has valuable utilization in wide industrial and technological procedures such as electronic cooling, cleaning, and dying processes, oxidation of surface materials, storage components, heat exchangers, and thermal storage systems. In view of such prominent physical significance, focus is made to explicate double (thermal and solutal)-diffusive transport in viscoelastic fluid characterized by the Casson model enclosed in a curved enclosure with corrugations. An incliningly directed magnetic field is employed to the flow domain. A uniformly thermalized and concentrated circular cylinder is installed at the center of the enclosure to measure transport changes. Dimensionally balanced governing equations are formulated in 2D, representing governed phenomenon. Finite element-based open-sourced software known as COMSOL is utilized. The domain of the problem is distributed in the form of triangular and quadrilateral elements. Transport distributions are interpolated by linear and quadratic polynomials. The attained non-linear system is solved by a less time and computation cost consuming package known as PARDISO. Convergence tests for grid generation and validation of results are executed to assure credibility of work. The influence of involved physical parameters on concerned fields are revealed in graphical and tabular manner. Additionally, heat and mass fluxes, along with, kinetic energy variation are also evaluated.

Biorational Control of Callosobruchus maculatus (Coleoptera: Buchidae) in Stored Grains with Botanical Extracts.

Globally, around 2000 plant species are used against pest control. The utilization of botanicals is considered the most economic and biodegradable methods for the control of stored grains pests. Therefore, the current study was carried out to investigate the repellency potential of five botanicals against Callosbruchus maculatus F. in Haripur, Pakistan. The concentrations of Azadirachta indica L., Nicotiana tabacum L., Melia azedarach L., Nicotiana rustica L., and Thuja orientalis L. were, i.e., 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0% in four replicates to establish contact effects. The data were recorded after 1, 2, 3, 6, 24, 48, 72, and 96 hours. The repellency effect of these plant species against C. maculatus were increased in both the time- and dose-dependent manner, and highest effect was observed at 72 h. In addition, the repellency effect was 91% for A. indica (class: V), 86% M. azedarach, 82%, N. tabacum (class: V), 79% N. rustica (class: IV), and 75% T. orientalis (class: IV) at 3% concentration against C. maculatus. Furthermore, following 96 hours' exposure to treatment the sensitivity response of insects decreases as the time interval increases, i.e., 86% A. indica (class: V) was followed by 71% M. azedarach (class: IV), 65% N. tabacum (class: IV), 61% N. rustica (class: IV), and T. orientalis 57% (class: III) repellency at highest concentration of 3%. The current study concluded that A. indica and M. azedarach can be incorporated for the management of C. maculatus and these plant species might be helpful in the productions of new biopesticides.

Development, Molecular Docking, and In Silico ADME Evaluation of Selective ALR2 Inhibitors for the Treatment of Diabetic Complications via Suppression of the Polyol Pathway.

Diabetic complications are associated with overexpression of aldose reductase, an enzyme that catalyzes the first step of the polyol pathway. Osmotic stress in the hyperglycemic state is linked with the intracellular accumulation of sorbitol along with the depletion of NADPH and eventually leads to oxidative stress via formation of reactive oxygen species and advanced glycation end products (AGEs). These kinds of mechanisms cause the development of various diabetic complications including neuropathy, nephropathy, retinopathy, and atherosclerotic plaque formation. Various aldose reductase inhibitors have been developed to date for the treatment of diabetic complications, but all have failed in different stages of clinical trials due to toxicity and poor pharmacokinetic profiles. This toxicity is rooted in a nonselective inhibition of both ALR2 and ALR1, homologous enzymes involved in the metabolism of toxic aldehydes such as methylglyoxal and 3-oxyglucosazone. In the present study, we developed a series of thiosemicarbazone derivatives as selective inhibitors of ALR2 with both antioxidant and antiglycation potential. Among the synthesized compounds, 3c exhibited strong and selective inhibition of ALR2 (IC50 1.42 µM) along with good antioxidant and antiglycative properties. The binding mode of 3c was assessed through molecular docking and cluster analysis via MD simulations, while in silico ADME evaluation studies predicted the compounds' druglike properties. Therefore, we report 3c as a drug candidate with promising antioxidant and antiglycative properties that may be useful for the treatment of diabetic complications through selective inhibition of ALR2.

Management of university solid waste in China through gasification technology: An analysis of waste composition and energy potential.

This study explored the composition and energy potential of university solid waste (USW) in China. Five combustible components, namely hard plastics (HP), paper (PP), soft plastics (SP), biomass (BM), and rubber (RB), were screened with the compositions 51%, 29%, 9%, 4%, and 3%, respectively. Each USW sample was gasified using a thermogravimetric analyzer (TGA) coupled with mass spectrometry (MS) at the heating rates of 5, 10, and 15 ℃/min and a final process temperature of 900 ℃. Thermal weight loss (TG) curves exposed the degradation in the order HP > SP > RB > BM > PP. Derivative thermogravimetric (DTG) peaks revealed that HP, PP, BM, and SP were degraded in three temperature-oriented phases in the range 172-731 ℃. The RB took an additional phase in the range 584-660 ℃. Major released gases, H2, CH4, CO, and CO2, were detected using MS via mass-to-charge (m/z) ratios. Higher H2 and total gas yield produced in the case of the HP dominated other materials at the lower heating rate of 5 ℃/min. Validation of data was assessed by equating experimental and calculated curves; therefore, the regression coefficient (R2) ranged between 0.884 and 0.997. The kinetics of the process were estimated by applying the Flynn-Wall-Ozawa (FWO) model at the conversion rates (α) of 0.2, 0.5, and 0.8, which presented reasonable results. Overall, the lower heating rates supported higher thermal conversion and a high quantity of gaseous products for all the components.

Phytochemical Analysis and In Vitro and In Vivo Pharmacological Evaluation of Parthenium hysterophorus Linn.

The main aim of this research was to explore Parthenium hysterophorus Linn phytochemically and pharmacologically. Phytochemical screening is important for the isolation of active compounds before bulk extraction. The crude extracts and their fractions were screened for enzyme (urease, α-glycosidase, and phosphodiesterase) inhibition assays, in vivo analgesic, anti-inflammatory, and sedative effects. Results indicated the presence of steroids, flavonoids, etc. The crude extracts such as methanol, hexane, aqueous, ethyl acetate, chloroform, and butanol exhibited excellent urease inhibitory activities with IC50 = 43.1 ± 1.24, 31.9 ± 2.21, 31.9 ± 2.21, 57.3 ± 1.27, 49.2 ± 2.16, and 35.3 ± 1.12, respectively, as compared to standard acetohydroxamic acid (20.3 ± 0.43). The extracts (methanol, hexane, aqueous, ethyl acetate, chloroform, and butanol) also showed promising α-glycosidase potency with IC50 = 13.1 ± 0.34, 21.2 ± 1.16, 23.1 ± 0.12, 84.2 ± 2.17, 118.6 ± 3.07, and 840 ± 1.73, respectively against acarbose (840 ± 1.73). The phosphodiesterase activity of the mentioned extracts was also excellent with IC50 = 131.1 ± 2.41, 197.2 ± 3.16, 24.2 ± 0.11, 62.4 ± 2.21, 152.4 ± 1.81, and 55.3 ± 2.15, respectively, against the standard (265.5 ± 2.25). Furthermore, butanol (14.96 ± 1.78), ethyl acetate (18.98 ± 1.71), and methanol (16.87 ± 1.00) showed dose-dependent analgesic effects with a maximum inhibition of acetic acid-induced writhes. Whereas, methanolic and butanol extracts exhibited maximum inhibition of inflammation in the carrageenan paw edema test. The aqueous (p < 0.01) and butanol (p < 0.01) extracts exhibited maximum a sedative effect followed by chloroform (p < 0.05), ethyl acetate (p < 0.05), and methanolic (p < 0.05) fractions as compared to the standard drug. The current research concluded that Parthenium hysterophorus Linn has important phytochemical constituents having inhibitory effects on urease, α-glycosidase, and phosphodiesterase enzymes. Furthermore, the plant has analgesic, anti-inflammatory, and sedative effects. The P. hysterophorus needs to further be explored for the candidate molecules responsible for the abovementioned activities.

Appraisal of novel azomethine-thioxoimidazolidinone conjugates as ecto-5'-nucleotidase inhibitors: synthesis and molecular docking studies.

Purinergic signaling is regulated by a group of extracellular enzymes called ectonucleotidases. One of its members i.e., ecto-5'-nucleotidase (h-e5'NT) is involved in the final step of the enzymatic hydrolysis cascade that is the conversion of adenosine monophosphate (AMP) to adenosine and therefore, involves the regulation of adenosine level in extracellular space. The overexpression of h-e5'NT has been observed in various pathological conditions such as hypoxia, inflammation and cancers, and led to various complications. Hence, the identification of a potent as well as selective inhibitor of h-e5'NT is of greater importance in therapeutic treatment of various diseases. Azomethine-thioxoimidazolidinone derivatives were studied for their inhibition potential against e5'NT enzyme along with cytotoxic potential against cancer cell lines possessing overexpression of e5'NT enzyme. The derivative (E)-3-((4-((3-methoxybenzyl)oxy)benzylidene)amino)-2-thioxoimidazolidin-4-one (4g) displayed selective and significant inhibition towards h-e5'NT with an IC50 value of 0.23 ± 0.08 µM. While two other derivatives i.e., (E)-3-(((5-bromothiophen-2-yl)methylene)amino)-2-thioxoimidazolidin-4-one (4b) and 2-thioxo-3-((3,4,5-trimethoxybenzylidene)amino)imidazolidin-4-one (4e), exhibited non-selective potent inhibitory behavior against both human and rat enzymes. Moreover, these derivatives (4b, 4e and 4g) were further investigated for their effect on the expression of h-e5'NT using quantitative real time polymerase chain reaction. Additionally, molecular docking and DFT studies were also performed to determine the putative binding mode of potent inhibitors within the enzyme active site. HOMO, LUMO, ΔE, and molecular electrostatic potential maps were computed by DFT and the charge transfer regions within the molecules were identified to find out the regions for electrophilic and nucleophilic attack.

Development and exploration of novel substituted thiosemicarbazones as inhibitors of aldose reductase via in vitro analysis and computational study.

The role of aldose reductase (ALR2) in causing diabetic complications is well-studied, with overactivity of ALR2 in the hyperglycemic state leading to an accumulation of intracellular sorbitol, depletion of cytoplasmic NADPH and oxidative stress and causing a variety of different conditions including retinopathy, nephropathy, neuropathy and cardiovascular disorders. While previous efforts have sought to develop inhibitors of this enzyme in order to combat diabetic complications, non-selective inhibition of both ALR2 and the homologous enzyme aldehyde reductase (ALR1) has led to poor toxicity profiles, with no drugs targeting ALR2 currently approved for therapeutic use in the Western world. In the current study, we have synthesized a series of N-substituted thiosemicarbazones with added phenolic moieties, of which compound 3m displayed strong and selective ALR2 inhibitory activity in vitro (IC50 1.18 µM) as well as promising antioxidant activity (75.95% free radical scavenging activity). The target binding modes of 3m were studied via molecular docking studies and stable interactions with ALR2 were inferred through molecular dynamics simulations. We thus report the N-substituted thiosemicarbazones as promising drug candidates for selective inhibition of ALR2 and possible treatment of diabetic complications.

Significance of induced hybridized metallic and non-metallic nanoparticles in single-phase nano liquid flow between permeable disks by analyzing shape factor.

The current communication is designed by keeping in the mind high heat transfer capabilities of nanoliquids with the dispersion of diversified-natured nanoparticles in poorly conducting base liquids. Here, an amalgamation of metallic (Cu) and hybridization of metallic and non-metallic oxide (Cu-TiO2) nanoparticles to uplift thermophysical attributes of water is deliberated. The magnetically affected flow between rotating disks under the impact and permeability aspect is assumed. Empirical relations for effective dynamic viscosity, density, and heat capacitance to show mesmerizing features of obliged nanoparticles are also expressed. In addition, mathematical relations also depend on morphological factors like shape, size, and diameter of inducted nanoparticles. The mathematical formulation of the problem is conceded in the form of a system of ODEs after using similarity transformation on dimensional PDEs. Simulations of the complex coupled differential structure are solved by using a numerical approach by employing shooting and Runge-Kutta procedures jointly. The impact of flow concerning variables on associated distributions is revealed through tabular and graphical manner. Quantities of engineering interest associated with work like wall friction and thermal flux coefficients at walls of the disk are also calculated. It is deduced from an examination that the addition of metallic particles raises heat transfer more than non-metallic particles. A significant impression of magnetic field on shear stress is executed by hybrid nanoparticles along the surface of disks. In addition, elevation in Nusselt number and depreciation in skin friction coefficient is revealed against increasing magnitude of nanoparticle volume fraction. A positive trend in skin friction coefficient is manifested against the increasing magnitude of Reynold number. It is also observed that by increasing the size and shape of hybrid nanoparticles thermal conductivity and viscosity of the base fluid increases.