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BACKGROUND: Pulmonary TB (PTB) predominantly affects individuals of working age. We sought to characterise the occupations of people newly diagnosed with PTB in Karachi, Pakistan, by type and physical intensity. DESIGN/METHODS: We did a secondary analysis of data from a study evaluating the diagnostic accuracy of artificial intelligence-based chest X-ray (CXR) analysis software, where individuals had been evaluated for active PTB using sputum cultures and had provided information on occupation. We used an accelerometer-validated US National Health and Nutrition Examination Survey-based job categorisation to assign physical activity levels to participant-reported occupations as High, Intermediate, or Low. RESULTS: Among 272 participants with microbiologically confirmed PTB (women: 130/272, 48%; median age: 29 years, IQR 22–45), 78% (211/272) had smear-positive disease, and 96% (260/272) had data on occupation. Unemployment was common (women: 70/122, 57%; men: 23/138, 17%). Most women reporting an occupation were homemakers (21/52, 40%), and 54% (28/52) had an intermediate- or a high physical activity occupation. Among men reporting an occupation, 35% (40/115) were labourers, and 79% (91/115) had an intermediate- or high-physical activity occupation. CONCLUSION: The majority of individuals with PTB were in their working age, had extensive disease, and had intermediate or high physical activity occupations, suggesting economic vulnerability due to physical impairment.

Abstract Filamentous Fungal Human Pathogens (FFHPs) such as Aspergillus fumigatus, are growing resistant to currently available antifungal drugs. One possible target, the Nucleoside diphosphate kinase (Ndk) is significant for nucleotide biosynthesis and crucial for fungal metabolism. Violacein, a natural food colorant, was examined for its antifungal effects against Aspergillus fumigatus via computational approach against the Ndk protein. Known and predicted interactions of Ndk with proteins was performed using the STRING application. Molecular docking was performed using Schrodinger Maestro software (V.14.1) under enhanced precision docking, with OPLS4 forcefield. MDS was performed for 500ns under OPLS4 forcefield and the TIP3P solvent system. The geometry optimization for DFT was performed using the Becke 3-parameter exchange functional (B3LYP) method. The Molecular Docking Studies revealed significant interactions with good binding energy between Violacein and Ndk. Subsequent MD Simulations confirmed the stability of Violacein-Ndk complex, compared to the reference ligand-complex, indicating a stable interaction between the protein and violacein. The energy band gap of violacein was found to be 0.072567 eV suggesting its softness with lower kinetic stability and higher chemical reactivity. The results suggest Violacein could potentially disrupt nucleotide metabolism by targeting Ndk, thus demonstrating antifungal activity. However, further experimental validation is required to confirm these computational findings and explore the practical use of Violacein in antifungal treatments.

This study was conducted to identify and characterize the Bacillus strain from Goat’s milk in Algeria and to evaluate the prebiotic effect of H. scoparia aqueous extract and ZnO-NPs on the isolated Bacillus strain. Potentially probiotic bacteria were isolated and identified based on phenotypic characteristics, including the morphological, physiological (growth temperature, salt tolerance), biochemical (API 10S strip kits), and confirmed by 16S rDNA gene sequencing. Bacillus pumilus specie of lactic acid bacteria were identified. The base pair length of amplified DNA for the isolate was 1500 Bp. The isolates could not grow at 10°C and 45°C and tolerate up to 6% salt. H. scoparia extract and ZnO-NPs have a beneficial effect on the Bacillus pumilus strain for acid tolerance, bile tolerance, and cell surface hydrophobicity respectively; H. scoparia extract and ZnO-NPs results are high comparing to the control group’s results. As the concentration of the tested samples increases, the percentage of probiotic characteristics of Bacillus pumilus increases, in contrast to the control sample. Therefore, they could be useful tools to define adequate combinations in colonic foods development and health benefits. The beneficial physiological and biochemical properties of isolated Bacillus pumilus space from Goat’s milk with the H. scoparia aqueous extract and ZnO-NPs revealed their potential applications in the food industry.

Abstract IMPHY000797 derivatives have been well known for their efficacy in various diseases. Moreover, IMPHY000797 derivatives have been found to modulate such genes involved in multiple neurological disorders. Hence, this study seeks to identify such genes and the probable molecular mechanism that could be involved in the pathogenesis of Parkinson’s disease. The study utilized various biological tools such as DisGeNET, STRING, Swiss target predictor, Cytoscape, AutoDock 4.2, Schrodinger suite, ClueGo, and GUSAR. All the reported genes were obtained using DisGeNET, and further, the common genes were incorporated into the STRING to get the KEGG pathway, and all the data was converted to a protein/pathway network via Cytoscape. The clustering of the genes was performed for the gene-enriched data using two-sided hypergeometrics (p-value). The binding affinity of the IMPHY000797 was verified with the highest regulated 25 proteins via utilizing the “Monte Carlo iterated search technique” and the “Emodel and Glide score” function. Three thousand five hundred eighty-three genes were identified for Parkinson’s disease and 31 genes for IMPHY000797 compound, among which 25 common genes were identified. Further, the “FOXO-signaling pathway” was identified to be a modulated pathway. Among the 25 proteins, the highest modulated genes and highest binding affinity were exhibited by SIRT3, FOXO1, and PPARGC1A with the compound IMPHY000797. Further, rat toxicity analysis provided the efficacy and safety of the compound. The study was required to identify the probable molecular mechanism, which needs more confirmation from other studies, which is still a significant hit-back.

Multiple sclerosis (MS) is a chronic autoimmune illness characterized by demyelination, neurodegeneration, and inflammation in the central nervous system. The AXL gene, which codes for a receptor tyrosine kinase, has emerged as a promising therapeutic target due to its involvement in neuroinflammation and oligodendrocyte dysfunction. In the current study, we employed in silico techniques to design Antisense Oligonucleotides (ASOs) that selectively target AXL gene transcripts to modulate AXL expression and mitigate MS pathology. Three ASOs, A1, A2, and A3, were designed to specifically target the 5′ untranslated region (5′UTR) and coding region of the AXL gene transcripts. The ASOs were optimized with a focus on stability, binding affinity, and specificity towards AXL mRNA while minimizing off-target effects. To investigate ASO-mRNA interactions and gauge their ability to alter AXL expression, Molecular Docking was performed. Our analyses showed that A1, A2, and A3 had substantial interactions with AXL mRNA, with binding affinities of −9.5 kcal/mol, −10.8 kcal/mol, and −10.6 kcal/mol, respectively. The targeting of AXL gene transcripts through ASOs shows promise in reducing MS symptoms. Precision ASO-based therapies could effectively manage MS by targeting the essential pathways involved in the disease. ASOs provide a highly targeted approach for treating MS and offer a precise therapeutic strategy for this debilitating condition. The study lays the groundwork for future in vitro and in vivo studies to confirm the therapeutic potential of these ASOs for the treatment of MS.

Wheat (Triticum aestivum) is the most important staple crop with a demand-based need to ensure food security but faces the challenges of timely harvesting at crop maturity. Harvesting operation of the wheat crop is one of the major activities during crop production and is important for food security and sustainability. The study's main purpose is to investigate the impact of vehicle speed on wheat grain losses during the harvesting operation. Varied speeds of the combine harvester were observed during the field tests and measured the grain losses by using a designed sampling method. The field observation recorded that the normal working speeds of the combine harvester were in a range of 7.54 km/hr to 11.77 km/hr during field tests with an average of 9.59 km/hr. The average grain losses were noted at 49.80 kg acre-1 with a percentage of 2.49% of total grain production in one acre. The highest grain losses were 69.11 kg acre-1 with a 3.46% percentage, identified at a vehicle speed of 11.77 km/hr, while the lowest at 7.54 km/hr that 35.35 kg acre-1 with a 1.76% percentage loss. Threshing losses significantly influenced the overall grain loss, which ranged from 1% to 1.8%, with specific grain damage from 0.36% to 1.07%, and shattering losses ranging from 0.4% to 0.65% due to variable vehicle speeds. The outcomes of the study found that field speed had a linear relationship with grain loss. Conclusively, the research findings provide guidelines to the machine operators and farmers should optimize the working speed to minimize grain loss during wheat harvesting.

Cutis Verticis Gyrata (CVG) is an uncommon condition, often classified as primary (idiopathic) or secondary to other diseases or syndromes. Its pathogenesis remains poorly understood, and its association with genetic syndromes is particularly rare. Noonan and Turner syndromes are distinct genetic disorders with characteristic phenotypes and multiple systemic involvements. This report aims to highlight the diagnostic complexities when CVG presents in the backdrop of these syndromes. A 38 years old patient was presented with chief complaints of receding hairline, dropping eyelids, cerebral deformations with deep furrows and thickened dermis. On the basis of patient's complaints, Noonan or turner syndrome was considered as possible diagnosis. This particular report presents a case of patient suffering from CVG having history of noonan and turner syndrome. With the detailed MRI, histology etc. CVG was finally confirmed. The novelty of this case lies in its rarity, diagnostic complexity, and the need for a multidisciplinary approach to unravel and manage the intersecting conditions. It contributes valuable insights to the existing medical literature, enhancing our understanding of the interplay between dermatological and genetic conditions. Patients with Noonan and turner syndrome exhibit clinical signs and symptoms that are strikingly similar to those of CVG, suggesting that this presents a significant diagnostic problem. An unfavorable outcome could arise from delayed or incorrect diagnosis. Because of this, it is recommended that healthcare fraternities should include uncommon illnesses like CVG as differential diagnosis. Considering CVG in differential diagnosis is crucial for early identification, accurate diagnosis, and comprehensive management. It ensures that associated systemic and genetic conditions are not overlooked and that patients receive holistic and personalized care.

Autism is a neurodevelopmental disorder distinguished by impaired social interaction and repetitive behaviors. Global estimates indicate that autism affects approximately 1.6% of children, with the condition progressively becoming more prevalent over time. Despite noteworthy progress in autism research, the condition remains untreatable. This serves as a driving force for scientists to explore new approaches to disease management. Autism is linked to elevated levels of oxidative stress and disturbances in the DNA repair mechanism, which may potentially play a role in its comorbidities development. The current investigation aimed to evaluate the beneficial effect of the naturally occurring flavonoid proanthocyanidins on the behavioral characteristics and repair efficacy of autistic BTBR mice. Moreover, the mechanisms responsible for these effects were clarified. The present findings indicate that repeated administration of proanthocyanidins effectively reduces altered behavior in BTBR animals without altering motor function. Proanthocyanidins decreased oxidative DNA strand breaks and accelerated the rate of DNA repair in autistic animals, as evaluated by the modified comet test. In addition, proanthocyanidins reduced the elevated oxidative stress and recovered the disrupted DNA repair mechanism in the autistic animals by decreasing the expressions of Gadd45a and Parp1 levels and enhancing the expressions of Ogg1, P53, and Xrcc1 genes. This indicates that proanthocyanidins have significant potential as a new therapeutic strategy for alleviating autistic features.

Cell-surface proteins (CSPs) have been employed extensively in cancer research as diagnostic and prognostic markers as well as targets for the creation of anticancer drugs. Few attempts have been made so far to describe the surfaceome of breast cancer (BC) patients. For enabling effective BC therapy, the identification of novel druggable biomarkers is an earnest need. In this study, publicly available databases are utilised to identify CSPs associated with BC. We also predict significantly altered receptor-ligand interactions in BC to determine significant CSPs and druggable polyphenols (DPs) with therapeutic potential to combat the disease using systems biology methods. Here, polyphenols are assessed for their druggable properties and then initially docked with CSPs. Finally, five DPs are docked and simulated against the nine significant CSPs identified in BC. The preliminary result of the analysis reports E2F8-Sesamolin to be the best-docked protein-ligand complex with a binding energy of −51.160 ± 18.054 Kcal/mol which was then simulated and compared with Olaparib, an approved drug for BC treatment that came out to be −44.441 ± 18.127 Kcal/mol. MD simulation revealed that a Sesamolin formed more H-bonds, providing a more stable and compact protein-ligand complex with E2F8 as compared to Olaparib. The result was also supported by calculating solvent-accessible surface area and analyzing the radius of gyration and MM-PBSA binding energies. Expression, oncoprint, survival and functional enrichment profiles of the significant CSPs are also analyzed to gain deeper insight into the significant CSPs and their role in BC tumorigenesis. Thus, our findings suggest a potential role of Sesamolin that can further be studied in detail for BC therapeutics, which was found to target the E2F8, a CSP receptor in a stable manner. The results can be validated in an experimental setup to explore the potential therapeutic efficacy of Sesamolin in targeting various CSPs.

Abstract The development of nanomaterials has been speedily established in recent years, yet nanoparticles synthesized by traditional methods suffer unacceptable toxicity and the sustainability of the procedure for synthesizing such nanoparticles is inadequate. Consequently, green biosynthesis, which employs biopolymers, is gaining attraction as an environmentally sound alternative to less sustainable approaches. Chitosan-encapsulated nanoparticles exhibit exceptional antibacterial properties, offering a wide range of uses. Chitosan, obtained from shrimp shells, aided in the environmentally friendly synthesis of high-purity zinc oxide nanoparticles (ZnO NPs) with desirable features such as the extraction yield (41%), the deacetylation (88%), and the crystallinity index (74.54%). The particle size of ZnO NPs was 12 nm, while that of chitosan–ZnO NPs was 21 nm, and the bandgap energies of these nanomaterials were 3.98 and 3.48, respectively. The strong antibacterial action was demonstrated by ZnO NPs, chitosan–ZnO NPs, and chitosan–ZnO/PVP, particularly against Gram-positive bacteria, making them appropriate for therapeutic use. The photocatalytic degradation abilities were also assessed for all nanoparticles. At a concentration of 6 × 10–5 M, chitosan removed 90.5% of the methylene blue (MB) dye, ZnO NPs removed 97.4%, chitosan-coated ZnO NPs removed 99.6%, while chitosan–ZnO/PVP removed 100%. In the case of toluidine blue (TB), at a concentration of 4 × 10–3 M, the respective efficiencies were 96.8%, 96.8%, 99.5%, and 100%, respectively. Evaluation of radical scavenger activity revealed increased scavenging of ABTS and DPPH radicals by chitosan–ZnO/PVP compared to individual zinc oxide or chitosan–ZnO, where the IC50 results were 0.059, 0.092, 0.079 mg/mL, respectively, in the ABTS test, and 0.095, 0.083, 0.061, and 0.064 mg/mL in the DPPH test, respectively. Moreover, in silico toxicity studies were conducted to predict the organ-specific toxicity through ProTox II software. The obtained results suggest the probable safety and the absence of organ-specific toxicity with all the tested samples.

This research was conducted to assist the head of the IT Operational & Network Education Division of the XYZ institution to reengineering the internet usage monitoring system. This monitoring system is reengineered so that query performance becomes better and the information presented is easily understood by the user. Reengineering the old system will produce a system model that is more in line with the requirements of the current system. The steps taken in this study, analysis of the monitoring system case domain, data analysis, data visualization reengineering, internet use monitoring system reengineering, software implementation and testing. In addition, testing the performance of the query system and usability testing for users from the new visualization results as the output of this study. Reengineering the internet usage monitoring system is a solution to improve query performance and make it easier for users to understand the information presented

Floods and landslides caused by extreme weather events, such as localized excessive rainfall in Japan, cause enormous devastation. Multicell clouds, on the other hand, have a common duration of over an hour and greater aerial coverage than single-cell clouds. For flood warning systems to function properly, the hazardous cloud must be detected quickly. Using pseudo and dual-Doppler vorticity approaches, the vertical vorticity estimate was extended from single-cell to multicell transitions case. According to the research, the single cells attained the peak of maximum vorticity of 0.08 and 0.01 s−1 for pseudo-vorticity and dual-Doppler vorticity, respectively. The maximum column of specific differential phase (Kdp) column above the melting layer indicated that the transition with 1 km depth as compared to differential reflectivity (Zdr) column was not observed after the cell merging. However, it was identified 5 min after the cell merged. In contrast, the Kdp column was always identified after the cell merging, and the column showed an increase in intensity 5 min after the cells merged. Vertical vorticity and multi-parameter radar analysis provided an insight into the transition from single-cell to multicell formation.

This study aimed to enhance the efficacy of quercetin (QT) by formulating it into a liposomal drug delivery system utilizing the concept of central composite design. The drug:lipid ratio, cholesterol concentration, and sonication time were selected as independent variables in the study. The vesicle and percentage entrapment efficiency were selected as the dependent variables. Quercetin nanoliposomes (QT-NLs) were prepared via a combination of ethanol injection and thin film hydration. The vesicle size and entrapment efficiency of all formulations were within the ranges of 100 nm and >80 %, respectively. The zeta potential value indicated the stability of the optimized formulation. The contour plots were used to select the desired batch range. SEM studies revealed an imperfect crystalline morphology without any unwanted agglomeration. MTT assays on VERO cell lines indicated the safety of the developed formulation. MTT assays of MCF-7 cells revealed IC50 values of 5.8 μM and 7.9 μM for QT-NLs and QT, respectively. In our study, the optimized formulation exhibited late and early apoptosis and necrosis when used to treat MCF-7 cells. S and G2/M cell cycle phases of MCF-7 cell arrest were confirmed by the cell cycle report. At sub-G0/G1 phase, 2.10 ± 1.1 %; G0/G1 phase, 34.13 ± 1.9 %; S phase, 34.55 ± 0.98 %; and G2/M phase, 26.24 ± 1.7 % of cell arrest were observed. The results demonstrated the effectiveness of the proposed design for the development of corn starch-coated QT-NLs and their activity in breast cancer cell lines.

Lead (Pb) is known to cause neurological changes, but antioxidants, chelators, and anti-inflammatory agents mitigates Pb toxicity. Previously, we reported antioxidant and anti-inflammatory effects of 3-hydroxy-3′,4′,5′-trimethoxyflavone (HTMF) derived from Ocimum basilicum L. leaves. This research investigates the neuroprotective properties of HTMF against Pb induced neurotoxicity in rats. Rats were orally administered lead acetate (100 mg/kg) daily for 30 days to induce neurotoxicity, then treated with HTMF (5 and 10 mg/kg) 30 min after Pb exposure. Cognitive and motor functions and brain biochemical parameters were determined to understand HTMF’s mechanism of action. Pb exposure impaired cognition and motor skills, elevated Pb levels, TBARS, TNF-α, IL-6 and MAO A & B, and reduced GSH levels in the brain. HTMF treatment significantly improved memory, motor deficits, and metabolic abnormalities induced by Pb, attributed to its chelating, antioxidative, anti-inflammatory, and monoaminergic modulating properties, suggesting its potential as a therapeutic agent for metal-induced brain injuries.

This study represents the first investigation into the ultrasonic and microwave extraction of bioactive metabolites from Jania rubens (J. rubens) (red seaweed) and Sargassum. muticum (S. muticum) (brown seaweed), with a focus on their biological activities. The research compares ultrasound-assisted extraction (UAE) with microwave-assisted extraction (MAE) utilizing a hydromethanolic solvent to evaluate their effects on these seaweeds’ bioactive compounds and biological activities. The assessment included a series of antioxidant essays: DPPH, ABTS, phenanthroline, and total antioxidant capacity, followed by enzyme inhibition activities: alpha-amylase and urease. Results revealed significant proportions of phenolic compounds, ranging from 48.31 ± 0.32 to 74.42 ± 0.80 μg GAE/mg, depending on the extraction method. The extracts demonstrated a high antioxidant activity, with IC50 values ranging from 26.58 ± 0.39 to 87.55 ± 0.69 μg/mL. Notably, the MAE extract of S. muticum showed a value of 48.11 ± 2.75 μg/mL for alpha-amylase inhibition, which is strictly superior to the reference acarbose with an IC50 equal to 3431.01 μg/mL. UPLC-ESI-MS/MS analysis identified 14 bioactive compounds. The proportion of riboflavin with MAE was 70.58% and 59.11% for J. rubens and S. muticum fractions, respectively. These findings underscore the critical influence of extraction technique selection on bioactive compounds’ yield and efficiency, highlighting the potential of algal biomass as a sustainable alternative in various applications.

Background: Pyroptosis, an inflammatory cell death, is involved in the progression of atherosclerosis. Pyroptosis in endothelial cells (ECs) and its underlying mechanisms in atherosclerosis are poorly understood. Here, we investigated the role of a caspase-4/5-NF-κB pathway in pyroptosis in palmitic acid (PA)-stimulated ECs and EVs as players in pyroptosis. Methods: Human umbilical vein endothelial cells (HUVECs) were cultured in an endothelial cell medium, treated with Ox-LDL, PA, caspase-4/5 inhibitor, NF-κB inhibitor, and sEV release inhibitor for 24 h, respectively. The cytotoxicity of PA was determined using an MTT assay, cell migration using a scratch-wound-healing assay, cell morphology using bright field microscopy, and lipid deposition using oil red O staining. The mRNA and protein expression of GSDM-D, CASP4, CASP5, NF-κB, NLRP3, IL-1β, and IL-18 were determined with RT-PCR and Western blot. Immunofluorescence was used to determine NLRP3 and ICAM-1 expressions. Extracellular vesicles (EVs) were isolated using an exosome isolation kit and were characterized by Western blot and scanning electron microscopy. Results: PA stimulation significantly changed the morphology of the HUVECs characterized by cell swelling, plasma membrane rupture, and increased LDH release, which are features of pyroptosis. PA significantly increased lipid accumulation and reduced cell migration. PA also triggered inflammation and endothelial dysfunction, as evidenced by NLRP3 activation, upregulation of ICAM-1 (endothelial activation marker), and pyroptotic markers (NLRP3, GSDM-D, IL-1β, IL-18). Inhibition of caspase-4/5 (Ac-FLTD-CMK) and NF-κB (trifluoroacetate salt (TFA)) resulted in a significant reduction in LDH release and expression of caspase-4/5, NF-κB, and gasdermin D (GSDM-D) in PA-treated HUVECs. Furthermore, GW4869, an exosome release inhibitor, markedly reduced LDH release in PA-stimulated HUVECs. EVs derived from PA-treated HUVECs exacerbated pyroptosis, as indicated by significantly increased LDH release and augmented expression of GSDM-D, NF-κB. Conclusions: The present study revealed that inflammatory, non-canonical caspase-4/5-NF-κB signaling may be one of the crucial mechanistic pathways associated with pyroptosis in ECs, and pyroptotic EVs facilitated pyroptosis in normal ECs during atherosclerosis.

Background: Circulus arteriosus cerebri (CAC), responsible for supplying blood to the brain, presents anatomical variations that have been associated with both haemorrhagic and ischemic strokes. Therefore, it is crucial to conduct comprehensive investigations and comparisons of the diverse variant components of the CAC, published in various journals, and analyze them to identify individuals at risk of cerebrovascular pathologies, thereby ensuring enhanced and timely treatment. Methods: A scoping review according to the five-stage protocol by Arksey and O'Malley was performed between February and June 2023. Seven hundred and seventy-seven records were initially identified, and a total of 51 studies were finally included. Results: This scoping review focuses on the anatomical variations of the CAC and their clinical implications on cerebrovascular disease and includes more original articles than review s. Consistent with previous findings, most of the records included small populations or samples, while only three records reported larger populations. Surprisingly, the populations enclosed in the included records consisted of autopsied cadaveric specimens more than living subjects. Finally, the qualitative analysis highlighted three main themes concerning the relationship between the normal CAC morphology and the cerebrovascular disease onset as well as the variant CAC morphology and its main features that might be also involved in these diseases. Finally, techniques that can be used to measure CAC have also been assessed. Conclusion: Variations in the CAC, more common in the posterior part, with genetic and environmental factors influencing these variations impact cerebrovascular disorders. Understanding variants components of CAC can aid in improving brain surgeries and post-stroke care.

The present study examined the potential neuroprotective effects of aloe-emodin (AE) nanoparticles on the cerebral stroke-associated target protein myeloperoxidase (MPO). We investigated the binding interactions between AE and MPO through molecular docking and molecular dynamics simulations. Molecular docking results indicated that AE exhibited a binding energy of −6.9 kcal/mol, whereas it was −7.7 kcal/mol for 2-{[3,5-bis(trifluoromethyl)benzyl]amino}-n-hydroxy-6-oxo-1,6-dihydropyrimidine-5-carboxamide (CCl). Furthermore, molecular dynamics studies demonstrated that AE possesses a stronger binding affinity (−57.137 ± 13.198 kJ/mol) than does CCl (−22.793 ± 30.727 kJ/mol), suggesting that AE has a more substantial inhibitory effect on MPO than does CCl. Despite the therapeutic potential of AE for neurodegenerative disorders, its bioavailability is limited within the body. A proposed hypothesis to enhance the bioavailability of AE is its conversion into aloe-emodin nanoparticles (AENP). The AENPs synthesized through a fabrication method were spherical with a consistent diameter of 104.4 ± 7.9 nm and a polydispersity index ranging from 0.525 to 0.586. In rats experiencing cerebral stroke, there was a notable increase in cerebral infarction size; abnormalities in electrocardiogram (ECG) and electroencephalogram (EEG) patterns; a decrease in brain and cardiac antioxidant activities; and an increase in myeloperoxidase levels compared to those in normal rats. Compared with AE treatment, AENP treatment significantly ameliorated cerebral infarction, normalized ECG and EEG patterns, enhanced brain and cardiac antioxidant activities, and reduced MPO levels in stroke rats. Histopathological evaluations revealed pronounced alterations in the rat hippocampus, with pyknotic nuclei, disarray and loosely packed cells, deterioration of cardiac muscle fibers, and extensive damage to cardiac myocytes, in contrast to those in normal rats. AENP treatment mitigated these pathological changes more effectively than AE treatment in both brain and cardiac cells. These findings support that AENP provides considerable protection against stroke-associated myocardial infarction.

Fluoropyrimidine 5-fluorouracil (5-FU) is a DNA analogue broadly used in chemotherapy, though treatment-associated nephrotoxicity limits its widespread clinical use. Sinapic acid (SA) has potent antioxidant, anti-inflammatory, and anti-apoptotic effects, we investigated its protective effects against 5-FU-induced nephrotoxicity in a rat model. We designated four treatment groups each Group I (control) received five intraperitoneal saline injections (once daily) from days 17 to 21; Group II received five intraperitoneal injections of 5-FU (50 mg/kg/day) from days 17 to 21; Group III received an oral administration of SA (40 mg/kg) for 21 days and five intraperitoneal injections of 5-FU (50 mg/kg/day) from days 17 to 21; and Group IV received an oral administration of SA (40 mg/kg) for 21 days (n-six rats in each group). blood samples were collected on day 22 from each group. Animals were sacrificed and their kidneys removed, and instantly frozen. 5-FU caused oxidative stress, inflammation, and activation of the apoptotic pathway by upregulating Bax and Caspase-3 and downregulating Bcl-2. However, SA exposure reduced serum toxicity indicators, boosted antioxidant defences, and reduced kidney apoptosis, which was confirmed by histopathological analysis. Therefore, prophylactic administration of SA could inhibit 5-FU-induced renal injuries in rats via suppression of renal inflammation and oxidative stress, primarily through regulation of NF-κB and proinflammatory cytokines, inhibition of renal apoptosis, and restoration of tubular epithelial antioxidant activities and cytoprotective defences.

Objective: This study aimed to compare the effects of β-sitosterol nanoparticles (BETNs) and β-sitosterol (BET) on cognitive impairment, oxidative stress, and inflammation in a myocardial infarction (MI) rat model using in silico and in vivo methods. Methods: β-Sitosterol (BET) and myeloperoxidase (MPO) ligand-receptor binding affinities were evaluated using Autodock Vina for docking and Gromacs for dynamics simulations. BET nanoparticles, prepared via solvent evaporation, had their size confirmed by a nanoparticle analyzer. ISO-induced cognitive impairment in rats was assessed through Morris water maze and Cook’s pole climbing tests. Oxidative stress, inflammation, and cardiac injury were evaluated by measuring GSH, SOD, MDA, MPO, CkMB, LDH, lipid profiles, and ECGs. Histopathology of the CA1 hippocampus and myocardial tissue was performed using H&E staining. Results: In silico analyses revealed strong binding affinities between BET and MPO, suggesting BET’s potential anti-inflammatory effect. BETN (119.6 ± 42.6 nm; PDI: 0.809) significantly improved MI-induced cognitive dysfunction in rats (p < 0.001 ***), increased hippocampal GSH (p < 0.01 **) and SOD (p < 0.01 **) levels, and decreased hippocampal MDA (p < 0.05 *) and MPO levels (p < 0.01 **). BETNs also elevated cardiac GSH (p < 0.01 **) and SOD (p < 0.01 **) levels and reduced cardiac MPO (p < 0.01 **), CkMB (p < 0.001 **) and LDH (p < 0.001 **) levels. It restored lipid profiles, normalized ECG patterns, and improved histology in the hippocampal CA1 region and myocardium. Conclusions: Compared with BET treatment, BETNs were more effective in improving cognitive impairment, oxidative damage, and inflammation in MI rats, suggesting its potential in treating cognitive dysfunction and associated pathological changes in MI.

This paper explores the potential of four kesterite and stannite compounds: copper iron tin sulfide (CFTS), copper nitride tin sulfide (CNTS), copper zinc tin sulfide (CZTS), and copper zinc tin selenide (CTZSe), as solid-state p-type materials to replace the liquid electrolyte in dye-sensitized solar cell (DSSC) structures. Using the SCAPS 1-D numerical simulator, we incorporate zinc oxysulfide (ZnOS) as the electron transport layer (ETL) in the proposed DSSC configuration: FTO/ZnOS/N719 dye/kesterite/Au. Our simulations reveal outstanding performance with a 200 nm thickness of CZTSe as the solid-state electrolyte, achieving a conversion efficiency of 12.91 %. This efficiency surpasses that of CZTS (12.20 %), CNTS (12.47 %), and CFTS (5.53 %) at a selected 400 nm dye thickness. In comparison to previous simulation and experimental results, our proposed configurations represent a promising alternative for advancing solid-state DSSC technology. Furthermore, we investigate the influence of kesterite thickness (ranging from 50 nm to 300 nm) with a constant defect density of 1 × 1014 cm−3 on DSSC performance. Our findings indicate almost constant conversion efficiency, with only around a 0.2 % change, demonstrating stable DSSC operation.

The twenty-first century is witnessing an increasing and clear interest in studying the relationship between student teachers’ motivation and their participation in professional development programs. This study was designed to find out the student teachers’ motivation toward participation in professional development programs and to identify the role of motivation in influencing the ambition, perseverance, and desire of student teachers to be effective and active in carrying out activities and tasks. The descriptive survey design was employed, 75 student teachers were chosen to participate, and data were collected using a developed instrument after ensuring its validity and reliability. The results of the study showed that the level of student teachers’ motivation toward participation in professional development programs was very high and that they are aware of the fact that professional development programs are the most effective means for developing their ambition, perseverance, and desire to participate in activities and tasks. Based on these findings, a set of conclusions and recommendations were drawn. Doi: 10.28991/ESJ-2023-SIED2-06 Full Text: PDF

Purpose: The clinical study of fulminant hepatic failure is challenging due to its high mortality and relative rarity, necessitating reliance on pre-clinical models to gain insight into its pathophysiology and develop potential therapies. Methods and Results: In our study, the combination of the commonly used solvent dimethyl sulfoxide to the current-day model of lipopolysaccharide/d-galactosamine-caused fulminant hepatic failure was found to cause significantly greater hepatic damage, as indicated by alanine aminotransferase level. The effect was dose-dependent, with the maximum increase in alanine aminotransferase observed following 200 μl/kg dimethyl sulfoxide co-administration. Co-administration of 200 μl/kg dimethyl sulfoxide also remarkably increased histopathological changes induced by lipopolysaccharide/d-galactosamine. Importantly, alanine aminotransferase levels and survival rate in the 200 μl/kg dimethyl sulfoxide co-administration groups were both greater than those in the classical lipopolysaccharide/d-galactosamine model. We found that dimethyl sulfoxide co-administration aggravated lipopolysaccharide/d-galactosamine-caused liver damage by stimulating inflammatory signaling, as indicated by tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) levels. Further, nuclear factor kappa B (NF-kB) and transcription factor activator 1 (STAT1) were upregulated, as was neutrophil recruitment, indicated by myeloperoxidase activity. Hepatocyte apoptosis was also increased, and greater nitro‐oxidative stress was noted, as determined based on nitric oxide, malondialdehyde, and glutathione levels. Conclusion: Co-treatment with low doses of dimethyl sulfoxide enhanced the lipopolysaccharide/d-galactosamine-caused hepatic failure in animals, with higher toxicity and greater survival rates. The current findings also highlight the potential danger of using dimethyl sulfoxide as a solvent in experiments involving the hepatic immune system, suggesting that the new lipopolysaccharide/d-galactosamine/dimethyl sulfoxide model described herein could be used for pharmacological screening with the goal to better understand hepatic failure and evaluate treatment approaches.

Background Exosomes, microvesicles, carry and release several vital molecules across cells, tissues, and organs. Epicardial adipose tissue exosomes are critical in the development and progression of coronary artery disease (CAD). It is hypothesized that exosomes may transport causative molecules from inflamed tissue and deliver to the target tissue and progress CAD. Thus, identifying and inhibiting the CAD-associated proteins that are being transported to other cells via exosomes will help slow the progression of CAD. Methods This study uses a systems biological approach that integrates differential gene expression in the CAD, exosomal cargo assessment, protein network construction, and functional enrichment to identify the crucial exosomal cargo protein target. Meanwhile, absorption, distribution, metabolism, and excretion (ADME) screening of Panax ginseng-derived compounds was conducted and then docked against the protein target to identify potential inhibitors and then subjected to molecular dynamics simulation (MDS) to understand the behavior of the protein-ligand complex till 100 nanoseconds. Finally, density functional theory (DFT) calculation was performed on the ligand with the highest affinity with the target. Results Through the systems biological approach, Mothers against decapentaplegic homolog 2 protein (SMAD2) was determined as a potential target that linked with PI3K-Akt signaling, Ubiquitin mediated proteolysis, and the focal adhesion pathway. Further, screening of 190 Panax ginseng compounds, 27 showed drug-likeness properties. Inermin, a phytochemical showed good docking with −5.02 kcal/mol and achieved stability confirmation with SMAD2 based on MDS when compared to the known CAD drugs. Additionally, DFT analysis of inermin showed high chemical activity that significantly contributes to effective target binding. Overall, our computational study suggests that inermin could act against SMAD2 and may aid in the management of CAD.

ABSTRACT The aim of present study was to investigate the effect of phytase supplementation on growth performance, mineral digestibility, and tibia calcium and phosphorous in broilers fed low phosphorus diets. Three hundred broiler chicks were allotted to six different treatments with five replicates each (10 chicks/replicate). T1: Control, 0.5% available phosphorus (Av.P); T2: 0.35P, 0.35% Av.P; T3: 0.20P, 0.20% Av.P; T4: 0.35P-1Phy, diet 0.35P + 1000FTU/kg phytase; T5: 0.20P-2Phy, diet 0.20P + 2000 ftu/kg phytase; T6: 0.20P-3Phy, diet 0.20P + 3000 ftu/kg phytase. Feed intake and weight gain were higher (p=0.001) in broilers fed phytase supplemented diets. Feed conversion ratio was better (p

The main goal of this study was to assess the bioactive and polysaccharide compositions, along with the antioxidant and antibacterial potentials, of five seaweeds collected from the northeastern coast of Algeria. Through Fourier transform infrared spectroscopy analysis and X-ray fluorescence spectroscopy, the study investigated the elemental composition of these seaweeds and their chemical structure. In addition, this study compared and identified the biochemical makeup of the collected seaweed by using cutting-edge methods like tandem mass spectrometry and ultra-high-performance liquid chromatography, and it searched for new sources of nutritionally valuable compounds. According to the study’s findings, Sargassum muticum contains the highest levels of extractable bioactive compounds, showing a phenolic compound content of 235.67 ± 1.13 µg GAE·mg−1 and a total sugar content of 46.43 ± 0.12% DW. Both S. muticum and Dictyota dichotoma have high concentrations of good polyphenols, such as vanillin and chrysin. Another characteristic that sets brown algae apart is their composition. It showed that Cladophora laetevirens has an extracted bioactive compound content of 12.07% and a high capacity to scavenge ABTS+ radicals with a value of 78.65 ± 0.96 µg·mL−1, indicating high antioxidant activity. In terms of antibacterial activity, S. muticum seaweed showed excellent growth inhibition. In conclusion, all five species of seaweed under investigation exhibited unique strengths, highlighting the variety of advantageous characteristics of these seaweeds, especially S. muticum.

INTRODUCTION: Obesity counselling is imperative in the management of obesity. Hence the self-efficacy of the primary care doctors (PCDs) in obesity counselling influences the outcome. This study investigated the level of self-efficacy in obesity counselling among PCDs and its associated factors. MATERIALS AND METHODS: This was a web-based cross-sectional survey involving 156 PCDs working in government health clinics. Participants were selected by simple random sampling and were invited through a letter. Participants then visited the survey website and filled up an online questionnaire. The level of self-efficacy was assessed using the Obesity, Nutrition, and Physical Activity Counselling by Residents (ONPAR) questionnaire. The data was analysed using SPSS software version 22 and presented as mean (SD) or frequency (%). Simple and multiple linear regression analysis were performed. Significant p-value was set at 0.05 with a 95% confidence interval. RESULTS: The response rate was 79.5%. The mean score for self-efficacy in obesity counselling was 66.9% (10.67) with the lowest mean score was for the "confidence in prescribing a plan for physical activity for someone with arthritic knees". The mean knowledge score was 55.4% (23.9). The level of self-efficacy was associated with knowledge on obesity management guidelines recommendations (p=0.02, 95% CI 0.02, 0.17). CONCLUSIONS: The level of self-efficacy in obesity counselling among government PCDs in East Malaysia was modest. The best predictor of higher self-efficacy in obesity counselling is knowledge of the obesity management guidelines recommendations. A structured training program is needed to improve selfefficacy among primary care doctors. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance is a critical public health issue that affects people all over the world. Since bacteria have a proclivity for rapidly acquiring and propagating the resistance gene, antimicrobial-resistant Campylobacter has a negative impact on public health. As a result, the creation of new and highly pathogenic clones is facilitated, making antimicrobial treatment more challenging. This study aimed to determine the antimicrobial resistance pattern (ARP) models, multiple drug resistance (MDR) models, and multiple antibiotic resistance (MAR) index of Campylobacter species isolated from poultry meat sold in Baghdad markets, Iraq. By employing the disc diffusion test, 30 Campylobacter strains from chicken meat, including C. jejuni (n=10) and C. coli (n=20), were exposed to tetracycline (TET), erythromycin, Gentamicin, nalidixic acid, ciprofloxacin, and norfloxacin (NOR). The ARP of the Campylobacter isolates revealed up to five antibiotypes for two species, which revealed resistance to one or more antimicrobials, and 67% of them had MDR resistance to two or more experienced antimicrobials. The NOR-TET model is the most common MDR, having a prevalence of 30% among experienced isolates. In addition, the MAR index, equal to and lower than one, was found in 87% of the isolates. Antibiotic resistance in Campylobacter raises the probability of treatment failure in humans and animals, as well as the propagation of antimicrobial resistance genes. As a result, the presence of Campylobacter in meat could pose a risk of human infection and pollution of the environment.

A proinflammatory role of HDACs has been implicated in the pathogenesis of atherosclerosis as an emerging novel epigenetic diagnostic biomarker. However, its association with the clinical and cardiovascular function in coronary artery disease is largely unknown. The study aimed to profile the gene expression of HDAC1–11 in human peripheral blood mononuclear cells and to evaluate their influence on hematological, biochemical, and two-dimensional echocardiographic indices in CAD. The HDAC gene expression profiles were assessed in 62 angioproven CAD patients and compared with 62 healthy controls. Among the HDACs, upregulated HDACs 1,2, 4, 6, 8, 9, and 11 were upregulated, and HDAC3 was downregulated, which was significantly (p ≤ 0.05) linked with the hematological (basophils, lymphocytes, monocytes, and neutrophils), biochemical (LDL, HDL, and TGL), and echocardiographic parameters (cardiac function: biplane LVEF, GLS, MV E/A, IVRT, and PV S/D) in CAD. Furthermore, our constructed diagnostic model with the crucial HDACs establishes the most crucial HDACs in the classification of CAD from control with an excellent accuracy of 88.6%. Conclusively, our study has provided a novel perspective on the HDAC gene expression underlying cardiac function that is useful in developing molecular methods for CAD diagnosis.

Increases in numerical chromosomal syndromes were observed in children of diabetic mothers. However, the effects of diabetes on male reproduction, specifically numerical chromosomal aberrations (aneuploidy), have not been studied. Furthermore, despite the increasing use of dapagliflozin for diabetes treatment, no data exists on its ability to affect aneuploidy levels in germ cells. Thus, our investigation aimed to evaluate the effects of diabetes on spontaneous sperm aneuploidy and whether treatment with dapagliflozin influences the frequency of aneuploidy in the sperm of an experimental diabetic animal model. Our findings show that dapagliflozin has no aneugenic effects on the meiotic stages of spermatogenesis. In contrast, diabetes raised the frequency of aneuploidy, and dapagliflozin administration decreased the elevated levels of disomic and diploid sperm. The level of oxidative stress was markedly increased in diabetic mice, but were reduced by dapagliflozin treatment. Furthermore, the expression of some of DNA repair genes was disrupted in diabetic animals, whereas dapagliflozin therapy restored these disruptions and significantly enhanced DNA repair. Thus, dapagliflozin may effectively ameliorate diabetes-induced aneugenic effects on male meiosis and treating diabetic patients with dapagliflozin may effectively mitigate the transmission of diabetes-induced chromosomal defects to offspring.

Acute liver failure (ALF) is a disease accompanied by severe liver inflammation. No effective therapy is available yet apart from liver transplantation; therefore, developing novel treatments for ALF is urgently required. Inflammatory mediators released by NF-кB activation play an essential role in ALF. Proteasome inhibitors have many medical uses, such as reducing inflammation and NF-кB inhibition, which are believed to account for most of their repurposing effects. This study was undertaken to explore the possible protective effects and the underlying mechanisms of carfilzomib, a proteasome inhibitor, in a mouse model of ALF induced by lipopolysaccharide/D-galactosamine/dimethylsulfoxide (LPS/GalN/DMSO). Carfilzomib dose-dependently protected mice from LPS/GalN/DMSO-induced liver injury, as indicated by the decrease in serum alanine aminotransferase and aspartate aminotransferase levels. LPS/GalN/DMSO increased TNF-α, NF-кB, lipid peroxidation, NO, iNOS, cyclooxygenase-II, myeloperoxidase, and caspase-3 levels. Carfilzomib administration mitigated LPS/GalN/DMSO-induced liver damage by decreasing the elevated levels of TNF-α, NF-кB, lipid peroxidation, nitric oxide, iNOS, cyclooxygenase-II, myeloperoxidase, caspase-3, and histopathological changes. A restored glutathione level was also observed in the carfilzomib-treated LPS/GalN/DMSO mice. Our results demonstrate that carfilzomib protects against LPS/GalN/DMSO-induced ALF by inhibiting NF-кB, decreasing inflammatory mediators, oxidative/nitrosative stress, neutrophil recruitment, and apoptosis, suggesting that carfilzomib may be a potential therapeutic agent for ALF.

Tardive dyskinesia (TD) is a hyperkinetic movement disorder that displays unusual involuntary movement along with orofacial dysfunction. It is predominantly associated with the long-term use of antipsychotic medications, particularly typical or first-generation antipsychotic drugs such as haloperidol. Oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis are major pathophysiological mechanisms of TD. The BCG vaccine has been reported to suppress inflammation, oxidative stress, and apoptosis and exert neuroprotection via several mechanisms. Our study aimed to confirm the neuroprotective effect of the BCG vaccine against haloperidol-induced TD-like symptoms in rats. The rats were given haloperidol (1 mg/kg, i.p.) for 21 days after 1 h single administration of the BCG vaccine (2 × 107 cfu). Various behavioral parameters for orofacial dyskinesia and locomotor activity were assessed on the 14th and 21st days after haloperidol injection. On the 22nd day, all rats were euthanized, and the striatum was isolated to estimate the biochemical, apoptotic, inflammatory, and neurotransmitter levels. The administration of the BCG vaccine reversed orofacial dyskinesia and improved motor function in regard to haloperidol-induced TD-like symptoms in rats. The BCG vaccine also enhanced the levels of antioxidant enzymes (SOD, GSH) and reduced prooxidants (MDA, nitrite) and pro-apoptotic markers (Cas-3, Cas-6, Cas-9) in rat brains. Besides this, BCG treatment also restored the neurotransmitter (DA, NE, 5-HT) levels and decreased the levels of HVA in the striatum. The study findings suggest that the BCG vaccine has antioxidant, antiapoptotic, and neuromodulatory properties that could be relevant in the management of TD.

Mitochondrial dysfunction is well-established in Parkinson’s disease (PD); however, its dysfunctions associating with cell organelle connectivity remain unknown. We aimed to establish the crucial cytosolic protein involved in organelle connectivity between mitochondria and the endopalmic reticulum (ER) through a computational approach by constructing an organelle protein network to extract functional clusters presenting the crucial PD protein connecting organelles. Then, we assessed the influence of anti-parkinsonism drugs (n = 35) on the crucial protein through molecular docking and molecular dynamic simulation and further validated its gene expression in PD participants under, istradefylline (n = 25) and amantadine (n = 25) treatment. Based on our investigation, D-aspartate oxidase (DDO )protein was found to be the critical that connects both mitochondria and the ER. Further, molecular docking showed that istradefylline has a high affinity (−9.073 kcal/mol) against DDO protein, which may disrupt mitochondrial-ER connectivity. While amantadine (−4.53 kcal/mol) shows negligible effects against DDO that contribute to conformational changes in drug binding, Successively, DDO gene expression was downregulated in istradefylline-treated PD participants, which elucidated the likelihood of an istradefylline off-target mechanism. Overall, our findings illuminate the off-target effects of anti-parkinsonism medications on DDO protein, enabling the recommendation of off-target-free PD treatments.

One of the primary therapeutic approaches for managing Alzheimer’s disease (AD) involves the modulation of Acetylcholine esterase (AChE) activity to elevate acetylcholine (ACh) levels inside the brain. The current study employed computational chemistry approaches to evaluate the inhibitory effects of CTN on AChE. The docking results showed that Citronellal (CTN) and standard Donepezil (DON) have a binding affinity of −6.5 and −9.2 Kcal/mol, respectively, towards AChE. Further studies using molecular dynamics (MD) simulations were carried out on these two compounds. Binding free energy calculations and ligand-protein binding patterns suggested that CTN has a binding affinity of −12.2078. In contrast, DON has a much stronger binding relationship of −47.9969, indicating that the standard DON has a much higher binding affinity than CTN for AChE. In an in vivo study, Alzheimer-type dementia was induced in mice by scopolamine (1.5 mg/kg/day i.p) for 14 days. CTN was administered (25 and 50 mg/kg. i.p) along with scopolamine (SCO) administration. DON (0.5 mg/kg orally) was used as a reference drug. CTN administration significantly improved the mice’s behavior as evaluated by the Morris water maze test, evident from decreased escape latency to 65.4%, and in the CPS test, apparent from reduced escape latency to 69.8% compared to the positive control mice. Moreover, CTN significantly increased the activities of antioxidant enzymes such as catalase and superoxide dismutase (SOD) compared to SCO. Furthermore, CTN administration significantly decreased SCO-induced elevated AChE levels in mice. These results were supported by histopathological and in silico molecular docking studies. CTN may be a potential antioxidant and neuroprotective supplement.

The efflux systems are considered important mechanisms of bacterial resistance due to their ability to extrude various antibiotics. Several naturally occurring compounds, such as sesquiterpenes, have demonstrated antibacterial activity and the ability to inhibit efflux pumps in resistant strains. Therefore, the objective of this research was to analyze the antibacterial and inhibitory activity of the efflux systems NorA, Tet(K), MsrA, and MepA by sesquiterpenes nerolidol, farnesol, and α-bisabolol, used either individually or in liposomal nanoformulation, against multi-resistant Staphylococcus aureus strains. The methodology consisted of in vitro testing of the ability of sesquiterpenes to reduce the Minimum Inhibitory Concentration (MIC) and enhance the action of antibiotics and ethidium bromide (EtBr) in broth microdilution assays. The following strains were used: S. aureus 1199B carrying the NorA efflux pump, resistant to norfloxacin; IS-58 strain carrying Tet(K), resistant to tetracyclines; RN4220 carrying MsrA, conferring resistance to erythromycin. For the EtBr fluorescence measurement test, K2068 carrying MepA was used. It was observed the individual sesquiterpenes exhibited better antibacterial activity as well as efflux pump inhibition. Farnesol showed the lowest MIC of 16.5 µg/mL against the S. aureus RN4220 strain. Isolated nerolidol stood out for reducing the MIC of EtBr to 5 µg/mL in the 1199B strain, yielding better results than the positive control CCCP, indicating strong evidence of NorA inhibition. The liposome formulations did not show promising results, except for liposome/farnesol, which reduced the MIC of EtBr against 1199B and RN4220. Further research is needed to evaluate the mechanisms of action involved in the inhibition of resistance mechanisms by the tested compounds.

The therapeutic effectiveness of the most widely used anticancer drug 5-fluorouracil (5-FU) is constrained by its high metabolism, short half-life, and rapid drug resistance after chemotherapy. Although various nanodrug delivery systems have been reported for skin cancer therapy, their retention, penetration and targeting are still a matter of concern. Hence, in the current study, a topical gel formulation that contains a metal-organic framework (zeolitic imidazole framework; ZIF-8) loaded with 5-FU and a surface modified with sonidegib (SDG; acting as a therapeutic agent as well as a targeting ligand) (5-FU@ZIF-8 MOFs) is developed against DMBA-UV-induced BCC skin cancer in rats. The MOFs were prepared using one-pot synthesis followed by post drug loading and SDG conjugation. The optimized MOFs were incorporated into hyaluronic acid-hydroxypropyl methyl cellulose gel and further subjected to characterization. Enhanced skin deposition of the 5-FU@ZIF-8-SDG MOFs was observed using ex vivo skin permeation studies. Confocal laser microscopy studies showed that 5-FU@ZIF-8-SDG MOFs permeated the skin via the transfollicular pathway. The 5-FU@ZIF-8-SDG MOFs showed stronger cell growth inhibition in A431 cells and good biocompatibility with HaCaT cells. Histopathological studies showed that the efficacy of the optimized MOF gels improved as the epithelial cells manifested modest hyperplasia, nuclear pleomorphism, and dyskeratosis. Additionally, immunohistochemistry and protein expression studies demonstrated the improved effectiveness of the 5-FU@ZIF-8-SDG MOFs, which displayed a considerable reduction in the expression of Bcl-2 protein. Overall, the developed MOF gels showed good potential for the targeted delivery of multifunctional MOFs in topical formulations for treating BCC cancer.

Background and Objectives: PON1 is a multi-functional antioxidant protein that hydrolyzes a variety of endogenous and exogenous substrates in the human system. Growing evidence suggests that the Leu55Met and Gln192Arg substitutions alter PON1 activity and are linked with a variety of oxidative-stress-related diseases. Materials and Methods: We implemented structural modeling and molecular dynamics (MD) simulation along with essential dynamics of PON1 and molecular docking with their endogenous (n = 4) and exogenous (n = 6) substrates to gain insights into conformational changes and binding affinity in order to characterize the specific functional ramifications of PON1 variants. Results: The Leu55Met variation had a higher root mean square deviation (0.249 nm) than the wild type (0.216 nm) and Gln192Arg (0.202 nm), implying increased protein flexibility. Furthermore, the essential dynamics analysis confirms the structural change in PON1 with Leu55Met vs. Gln192Arg and wild type. Additionally, PON1 with Leu55Met causes local conformational alterations at the substrate binding site, leading to changes in binding affinity with their substrates. Conclusions: Our findings highlight the structural consequences of the variants, which would increase understanding of the role of PON1 in the pathogenesis of oxidative-stress-related diseases, as well as the management of endogenous and exogenous chemicals in the treatment of diseases.

Neolamarckia cadamba (Roxb.) Bosser, a member of the Rubiaceae family, is a botanical species with recognized therapeutic properties. It is commonly used in traditional medicine to treat cardiac ailments and other disorders. However, the precise active constituents and the potential mechanisms by which they manage cardiovascular disorders remain unclear. Therefore, this study aimed to ascertain the bioactive components and investigate their underlying mechanisms of action. N. cadamba is used to treat cardiovascular disorders using the integrated metabolomic methodology. An HPLC-QTOF-MS/MS analysis determined the potential chemicals in the N. cadamba leaf ethanol extract (NCEE). A thorough investigation of the NCEE samples used in this study led to the identification of 32 phytoconstituents. Of the 32 compounds, 19 obeyed Lipinski’s rule of five (RO5). A molecular docking study directed towards HMG-CoA reductase used 19 molecules. The reference drug atorvastatin indicated a binding energy of −3.9 kcal/mol, while the other substances, Cinchonain Ib and Dukunolide B, revealed binding energies of −5.7 and −5.3 kcal/mol, respectively. Both phytocompounds showed no toxicity and exhibited favorable pharmacokinetic properties. In vivo study results concluded that treatment with NCEE significantly reduced the cardiac myocardial infarction (MI) marker CK-MB and atherogenic risk indices, such as the atherogenic index plasma (AIP), cardiac risk ratio (CRR), and atherogenic coefficient (AC) in isoproterenol-induced MI rats. In MI rats, NCEE therapy significantly improved the antioxidant system of the heart tissue, as evidenced by the increased levels of GSH and SOD, lower levels of the oxidative stress marker MDA, and significantly decreased HMG-CoA activity. Additionally, electrocardiogram (ECG) signals from rats treated with NCEE resembled those treated with traditional atorvastatin to treat myocardial infarction. This study used H&E staining to show that administering NCEE before treatment reduced cardiac myocyte degeneration in rats with myocardial infarction, increased the presence of intact nuclei, and increased myocardial fiber strength. The potential cardioprotective effect observed in myocardial infarction (MI) rats treated with NCEE can be extrapolated from computational data to be caused by Cinchonain Ib.

Aim: The study aims to test the hypothesis that concentrations of adropin and afamin differ between patients in various stages of chronic kidney disease when compared with healthy controls. The study also investigates the association of the biomarkers (adropin and afamin) with CKD-MBD and traditional cardiovascular risk parameters in CKD patients. Methodology: The cross-sectional study includes the subjects divided into four groups comprising the control group (healthy volunteers = 50), CKD stages 1–2 patients (n = 50), CKD stages 3–4 patients (n = 50), CKD stage 5 patients (n = 50). Serum concentrations of adropin and afamin were determined using ELISA. Clinical variables (renal, lipid, and CKD-MBD parameters) were correlated to adropin and afamin concentrations. Results: Afamin concentration was found to be higher in group IV, followed by groups III and II when compared to the control group, i.e., (83.243 ± 1.46, 64.233 ± 0.99, and 28.948 ± 0.72 vs. 14.476 ± 0.5) mg/L (p < 0.001), and adropin concentration was found to be lower in group IV as compared to groups III, II, and I (200.342 ± 8.37 vs. 284.682 ± 9.89 vs. 413.208 ± 12.32 vs. 706.542 ± 11.32) pg/mL (p < 0.001), respectively. Pearson correlation analysis showed that afamin was positively correlated with traditional cardiovascular risk biomarkers, while adropin showed a negative correlation. Conclusions: Adropin and afamin may potentially serve as futuristic predictors for the deterioration of renal function and may be involved in the pathological mechanisms of CKD and its associated complications such as CKD-MBD and high lipid levels.

Contact lens-mediated microbial keratitis caused by Pseudomonas aeruginosa and Streptococcus pneumoniae provokes corneal damage and vision loss. Recently, natural phytochemicals have become complementary medicines for corneal destruction. Herein, we aimed to identify multi-targeting Aloe vera-derived phytochemicals capable of inhibiting bacterial and host targets of keratitis through ADME (absorption, distribution, metabolism, and excretion), docking, molecular dynamics (MD) simulation, MMGBSA (molecular mechanics generalized Born surface area) and density functional theory (DFT) investigations. An extensive literature search revealed ExoU, ExoS, ExoT, ExoY, and PLY as virulent bacterial targets. Simultaneously, differential gene expression (DGE) and pathway enrichment analysis-specified host transcription factor (SPI1) influences keratitis pathogenesis. Molecular docking analysis uncovered aloeresin-A as a promising inhibitor against bacterial and host targets, demonstrating strong binding energies ranging from −7.59 to −6.20 kcal/mol. Further, MMGBSA and MD simulation analysis reflect higher binding free energies and stable interactions of aloeresin-A with the targets. In addition, DFT studies reveal the chemical reactiveness of aloeresin-A through quantum chemical calculations. Hence, our findings show aloeresin-A to be a promising candidate for effectively inhibiting keratitis. However, additional research is imperative for potential integration into lens care solutions.

The prevalence of Parkinson’s disease places a significant burden on society; therefore, there is an urgent need to develop more effective drugs. However, the development of these drugs is both expensive and risky. Quercetin (QUE) has potent pharmacological effects on neurodegenerative diseases, but its low solubility in water and poor bioavailability limit its use in pharmaceutical applications. In this study, Quercetin nanocrystals (QNC) were synthesized and compared to standard QUE. A network-pharmacology-based methodology was applied, including target prediction, network construction, a gene ontology (GO) analysis, a KEGG pathway enrichment analysis, and molecular docking. This study aimed to identify the targets of QUE relevant to the treatment of Parkinson’s disease and investigate the associated pharmacological mechanisms. Most of the predicted targets are involved in dopamine uptake during synaptic transmission. QUE regulates the key targets DRD2 and DRD4, which significantly affect dopaminergic synapses. The molecular docking results showed that QUE had a better binding affinity than the standard drug l-Dopa. From these experiments, it can be concluded that QNC effectively reduced the adverse effects caused by rotenone-induced oxidative stress in biochemical, neurochemical, and histopathological alterations. Therefore, QNC can potentially treat Parkinson’s disease, and its effectiveness should be assessed in future clinical trials.

Alzheimer’s disease (AD) is caused by plaque agglomeration and entanglement in several areas of the neural cells, which leads to apoptosis. The main etiology of AD is senile dementia, which is linked to amyloid-beta (Aβ) deregulation and tau perivascular pathogeny. Hyperphosphorylated tau has a propensity for microtubules, which elevate the instability and tau-protein congregates, leading to accumulation of neurofibrillary tangles (NFTs). Tau hyperphosphorylation is susceptible to GSK-3, which has led to an emerging hypothesis regarding the pathogenesis of AD. Accordingly, attempts have been made to conduct investigations and achieve further advancements on new analogues capable of inhibiting the GSK-3 protein, which are currently in the clinical trials. In this analysis, we have evaluated certain GSK-3 inhibitor variants utilising scaffolding and framework devised techniques with pharmacological characteristics, accompanied by computational screenings (pharmacokinetics and docking). The structure-based designed analogues interacted effectively with the active amino acids of GSK-3β target protein. The in silico pharmacokinetic studies revealed their drug-like properties. The analogues with best interactions and binding scores will be considered in the future to completely demonstrate their potential relevance as viable GSK-3 inhibitors.

Despite significant progress in early detection and treatment, a few aggressive breast cancers still exhibit resistance to therapy. This study aimed to identify a therapeutic target for radioresistant breast cancer (RRbc) through a protein network from breast cancer genes and to evaluate potent phytochemicals against the identified target. Our approach includes the integration of differential expression genes from expression datasets to create a protein network and to use survival analysis to identify the crucial RRbc protein in order to discover a therapeutic target. Next, the phytochemicals sourced from brown algae were screened through molecular docking, ADME (absorption, distribution, metabolism, and excretion), molecular dynamics (MD) simulation, MM-GBSA, and quantum mechanics against the identified target. As a result of our protein network investigation, the proto-oncogene c-KIT (KIT) protein was identified as a potent radioresistant breast cancer target. Further, phytochemical screening establishes that nahocol-A1 from brown algae has high binding characteristics (−8.56 kcal/mol) against the KIT protein. Then, quantum chemical analysis of nahocol-A1 provided insights into its electronic properties favorable for protein binding. Also, MD simulation comprehends the conformational stability of the KIT–nahocol-A1 complex. Overall, our findings suggest nahocol-A1 could serve as a promising therapeutic candidate for radioresistant breast cancer.

Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, pose a significant global health challenge, emphasizing the need for novel neuroprotective agents. Basil (Ocimum spp.) has been recognized for its therapeutic potential, and numerous studies have reported neuroprotective effects. In this manuscript, we present a computational protocol to extricate the underlying mechanism of action of basil compounds in neuroprotective effects. Molecular docking-based investigation of the chemical interactions between selected bioactive compounds from basil and key neuroprotective targets, including AChE, GSK3β, γ-secretase, and sirtuin2. Our results demonstrate that basil compound myricerone caffeoyl ester possesses a high affinity of −10.01 and −8.85 kcal/mol against GSK3β and γ-secretase, respectively, indicating their potential in modulating various neurobiological processes. Additionally, molecular dynamics simulations were performed to explore the protein–ligand complexes’ stability and to analyze the bound basil compounds’ dynamic behavior. This comprehensive computational investigation enlightens the putative mechanistic basis for the neuroprotective effects of basil compounds, providing a rationale for their therapeutic use in neurodegenerative disorders after further experimental validation.