1,824 results on '"Sheikh F"'
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2. Gaining molecular insights towards inhibition of foodborne fungi Aspergillus fumigatus by a food colourant violacein via computational approach
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R. Sindhu, Smitha S. Bhat, Jiraporn Sangta, Chandan Dharmashekar, Bhargav Shreevatsa, Chandan Shivamallu, Devananda Devegowda, Shiva Prasad Kollur, Sheikh F. Ahmad, Sabry M. Attia, Sarana Rose Sommano, and Shashanka K. Prasad
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Aspergillus fumigatus ,Violacein ,Antifungal ,FFHP ,Nucleoside diphosphate kinase ,Food colourant ,Medicine ,Science - Abstract
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.
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- 2024
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3. Phenotypic characterization and molecular identification of Bacillus pumilus isolated from Algerian goat’s milk and evaluation of its synbiotic effect with Hammada scoparia L. extract and ZnO-NPs
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Benine Chaima, Djahra Ali Boutlelis, Laiche Ammar Touhami, Djilani Ghemam Amara, Maha Mezghani Khemakhem, Chahnez Naccache, Maria Atanassova, Wafa Zahnit, Sheikh F. Ahmad, and Mohammed Messaoudi
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Goat’s milk ,probiotics ,16S rRNA ,H. scoparia ,ZnO-NPs ,prebiotic activity ,Nutrition. Foods and food supply ,TX341-641 ,Food processing and manufacture ,TP368-456 - Abstract
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.
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- 2024
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4. System biology-based assessment of the molecular mechanism of IMPHY000797 in Parkinson’s disease: a network pharmacology and in-silico evaluation
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Gomathy Subramanian, Hannah Lalengzuali Fanai, Jagdish Chand, Sheikh F. Ahmad, Sabry M. Attia, and Talha Bin Emran
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Network pharmacology ,Parkinson’s disease ,Neuroprotection ,In-silico studies ,IMPHY000797 ,Medicine ,Science - Abstract
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.
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- 2024
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5. Exploring precision therapeutics: computational design of antisense oligonucleotides targeting AXL gene transcripts in multiple sclerosis treatment management
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Bhargav Shreevatsa, Abhigna Nagaraj, Chandan Dharmashekar, Anisha Jain, Bhavana Harendra, Siddesh V. Siddalingegowda, Haneen A. Al-Mazroua, Sheikh F. Ahmad, Shashanka K. Prasad, Chandrashekar Srinivasa, Chandan Shivamallu, and Shiva Prasad Kollur
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AXL gene ,antisense oligonucleotides ,multiple sclerosis ,neurodegeneration inflammation ,therapeutics ,Chemistry ,QD1-999 - Abstract
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.
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- 2025
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6. Diagnostic challenge of cutis Verticis Gyrata (CVG) in a patient presenting clinical features of Noonan or turner syndrome
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Muskan Kanotra, Rupinder Kaur, Chirag Pasricha, Pratima Kumari, Ravinder Singh, Varinder Singh, and Sheikh F. Ahmad
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Cutis verticis gyrata ,Noonan ,Turner syndrome ,Diagnosis ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
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.
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- 2024
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7. Salubrious effects of proanthocyanidins on behavioral phenotypes and DNA repair deficiency in the BTBR mouse model of autism
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Abdulelah F. Alhusain, Mohamed A. Mahmoud, Hussain N. Alhamami, Saad Ebrahim Alobid, Mushtaq A. Ansari, Sheikh F. Ahmad, Ahmed Nadeem, Saleh A. Bakheet, Gamaleldin I. Harisa, and Sabry M. Attia
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Autism ,Antioxidants ,DNA strand breaks ,DNA repair ,Tumor ,Therapeutics. Pharmacology ,RM1-950 - Abstract
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.
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- 2024
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8. Sesamolin, a polyphenol with potential breast cancer therapeutic benefits: Unveiling insights through structural mining of surfacesome proteins
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Sohini Chakraborty, Sai N. Pramoda, Palak Megotia, Tanvi Rathore, Sheikh F. Ahmad, and Satarupa Banerjee
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Breast cancer (BC) ,Cell surface proteins (CSPs) ,Druggable polyphenols (DPs) ,Sesamin compounds ,Binding energies ,Therapeutics ,Nutrition. Foods and food supply ,TX341-641 - Abstract
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.
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- 2024
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9. Introducing the antibacterial and photocatalytic degradation potentials of biosynthesized chitosan, chitosan–ZnO, and chitosan–ZnO/PVP nanoparticles
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Abdelatif Aouadi, Djamila Hamada Saud, Abdelkrim Rebiai, Abdelhak Achouri, Soulef Benabdesselam, Fatma Mohamed Abd El-Mordy, Pawel Pohl, Sheikh F. Ahmad, Sabry M. Attia, Hamada S. Abulkhair, Abderrahmane Ararem, and Mohammed Messaoudi
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Zinc oxide ,Chitosan ,Gram-positive bacteria ,Anti-bacterial agents ,ProTox-II ,Medicine ,Science - Abstract
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.
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- 2024
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10. A central composite design-based targeted quercetin nanoliposomal formulation: Optimization and cytotoxic studies on MCF-7 breast cancer cell lines
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E. Bhargav, Nawaz Mohammed, Udit Narayan Singh, P. Ramalingam, Ranadheer Reddy Challa, Bhaskar Vallamkonda, Sheikh F. Ahmad, Prasanth DSNBK, Praveen Kumar Pasala, and Mithun Rudrapal
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Quercetin ,Central composite design ,Nanoliposomes ,Breast cancer ,Cytotoxic ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
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.
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- 2024
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11. 3-hydroxy-3′,4′,5′-trimethoxyflavone protects rats against lead-induced neurotoxicity via chelation and modulating oxidative stress, inflammatory and monoaminergic systems
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Varinder Singh, Richa Shri, Parul Sood, Manjinder Singh, Thakur Gurjeet Singh, Ravinder Singh, Amarjot Kaur, Amit Kumar, Tanveer Singh, Sheikh F. Ahmad, and Sabry M. Attia
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Ocimum basilicum ,Lead neurotoxicity ,Neuroprotection ,Trimethoxyflavone ,Antioxidant ,Memory ,Nutrition. Foods and food supply ,TX341-641 - Abstract
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.
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- 2024
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12. Impact of Ultrasound- and Microwave-Assisted Extraction on Bioactive Compounds and Biological Activities of Jania rubens and Sargassum muticum
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Kahina Hamamouche, Zoubida Elhadj, Latifa Khattabi, Wafa Zahnit, Brahim Djemoui, Omar Kharoubi, Walid Boussebaa, Mouhamed Bouderballa, Mohammed EL Moustapha Kallouche, Sabry M. Attia, Sheikh F. Ahmad, Maria Atanassova, and Mohammed Messaoudi
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Jania rubens ,Sargassum muticum ,ultrasound assisted extraction ,microwave-assisted extraction ,LC-MS analysis ,bioactive compounds ,Biology (General) ,QH301-705.5 - Abstract
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.
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- 2024
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13. Pyroptosis in Endothelial Cells and Extracellular Vesicle Release in Atherosclerosis via NF-κB-Caspase-4/5-GSDM-D Pathway
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Salman Shamas, Razia Rashid Rahil, Laveena Kaushal, Vinod Kumar Sharma, Nissar Ahmad Wani, Shabir H. Qureshi, Sheikh F. Ahmad, Sabry M. Attia, Mohammad Afzal Zargar, Abid Hamid, and Owais Mohmad Bhat
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endothelial cells ,pyroptosis ,atherosclerosis ,inflammasome ,endothelial dysfunction ,inflammation ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
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.
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- 2024
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14. Potential preventative impact of aloe-emodin nanoparticles on cerebral stroke-associated myocardial injury by targeting myeloperoxidase: In supporting with In silico and In vivo studies
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Praveen Kumar Pasala, Niranjan Kumar Raghupathi, Deepak A. Yaraguppi, Ranadheer Reddy Challa, Bhaskar Vallamkonda, Sheikh F. Ahmad, Yeswanth Chennamsetty, P.V. Kamala Kumari, and Prasanth DSNBK
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Aloe emodin ,Aloe emodin nanoparticles ,Myeloperoxidase ,Antioxidant ,Molecular dynamics ,Molecular docking ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
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.
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- 2024
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15. Sinapic acid alleviates 5-fluorouracil-induced nephrotoxicity in rats via Nrf2/HO-1 signalling
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Mushtaq Ahmad Ansari, Mudassar Shahid, Sheikh F. Ahmad, Ajaz Ahmad, Abdulrazaq Alanazi, Abdul Malik, Yousef A. Bin Jardan, Sabry M. Attia, Saleh A. Bakheet, and Mohammad Raish
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5-FU ,Sinapic acid ,Nephrotoxicity ,Oxidative stress ,Apoptosis ,Therapeutics. Pharmacology ,RM1-950 - Abstract
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.
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- 2023
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16. In Silico and In Vivo Studies of β-Sitosterol Nanoparticles as a Potential Therapy for Isoprenaline-Induced Cognitive Impairment in Myocardial Infarction, Targeting Myeloperoxidase
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Partha Saradhi Tallapalli, Yennam Dastagiri Reddy, Deepak A. Yaraguppi, Surya Prabha Matangi, Ranadheer Reddy Challa, Bhaskar Vallamkonda, Sheikh F. Ahmad, Haneen A. Al-Mazroua, Mithun Rudrapal, Prasanth Dintakurthi Sree Naga Bala Krishna, and Praveen Kumar Pasala
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β-sitosterol nanoparticle ,myeloperoxidase ,cognitive impairment ,myocardial infarction ,molecular simulation ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
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.
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- 2024
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17. Crosstalk of TNF-α, IFN-γ, NF-kB, STAT1 and redox signaling in lipopolysaccharide/d-galactosamine/dimethylsulfoxide-induced fulminant hepatic failure in mice
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Abdulrazaq Alanazi, Mahmoud N. Nagi, Dhafer Y. Alhareth, Mohammed A Al-Hamamah, Mohamed A Mahmoud, Sheikh F. Ahmad, Mushtaq A. Ansari, Ahmed Nadeem, Saleh A. Bakheet, Gamaleldin I. Harisa, and Sabry M. Attia
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Acute hepatic failure ,Animal models ,Translational study ,Caspase-3 ,Necrosis ,Therapeutics. Pharmacology ,RM1-950 - Abstract
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.
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- 2023
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18. Pharmacoscreening, molecular dynamics, and quantum mechanics of inermin from Panax ginseng: a crucial molecule inhibiting exosomal protein target associated with coronary artery disease progression
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Janakiraman V, Sudhan M, Abubakar Wani, Sheikh F. Ahmad, Ahmed Nadeem, Ashutosh Sharma, and Shiek S. S. J. Ahmed
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Exosomes ,Systems biology ,Protein network ,Density functional theory ,Molecular dynamic simulation ,Coronary artery disease ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
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.
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- 2023
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19. Exploring Bioactive Components and Assessing Antioxidant and Antibacterial Activities in Five Seaweed Extracts from the Northeastern Coast of Algeria
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Nawal Bouzenad, Nesrine Ammouchi, Nadjla Chaib, Mohammed Messaoudi, Walid Bousabaa, Chawki Bensouici, Barbara Sawicka, Maria Atanassova, Sheikh F. Ahmad, and Wafa Zahnit
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antibacterial activity ,antioxidant activity ,bioactive compounds ,elementary analysis ,nutritional and phytochemical composition ,seaweed ,Biology (General) ,QH301-705.5 - Abstract
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.
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- 2024
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20. Electric field assisted reduction of NOx emission: A numerical study
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Sheikh F. Ahmed, Ali Charchi Aghdam, Jackson Pleis, Robert Geiger, and Tanvir I. Farouk
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chemi-ionization ,electric field ,ionic wind ,NOx kinetics ,OpenFOAM ,Mechanics of engineering. Applied mechanics ,TA349-359 ,Fuel ,TP315-360 - Abstract
The paper reports simulation results on the influence of a direct-current driven radial electric field on the emission characteristics; especially NOx and CO of a premixed methane/air laminar jet flame. A multi-physics computational model is developed in the OpenFOAM framework to simulate electric-field-coupled premixed combustion process. The computational framework consists of coupled species, momentum and energy conservation together with a Poisson’s equation solver to resolve the electric field distribution. Electron and ion conservation equations are resolved to consider the ionic wind body force in the momentum conservation equation and the associated possible electric field distortion due to the space charge distribution. The simulations are conducted for a stochiometric and fuel rich condition and over a range of jet flow rates for a configuration representative of a test-scale experimental setup. The model predictions show that for an applied voltage of 50 kV, the flame structure changes significantly for both the stoichiometric and fuel rich conditions. The flame is stretched significantly by the electric field due to ionic wind. For the fuel rich condition, the ionic wind allows additional mixing of the fuel rich stream with the surrounding air and drastically altering the flame structure. The electric field was found to reduce the NOx emission significantly for both stoichiometric and rich conditions. Over the entire range of flowrate conditions, the stochiometric fuel-oxidizer mixture showed a decrease in maximum NOx by a factor of 1.6 in presence of electric field. For the fuel rich case, however as the flow rate is increased, the NOx reduction factor decreased from 12.0 to 1.6. For CO emissions, the presence of electric field reduces the concentration under fuel rich conditions and vice versa for the stoichiometric flame. The role of kinetics is analyzed and discussed.
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- 2023
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21. Elucidating the Histone Deacetylase Gene Expression Signatures in Peripheral Blood Mononuclear Cells That Correlate Essential Cardiac Function and Aid in Classifying Coronary Artery Disease through a Logistic Regression Model
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K. Monisha, S. Mahema, M. Chokkalingam, Sheikh F. Ahmad, Talha Bin Emran, Paramasivam Prabu, and Shiek S. S. J. Ahmed
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HDAC profiling ,atherosclerosis ,epigenetic biomarkers ,coronary artery disease ,left ventricular structural indices ,Biology (General) ,QH301-705.5 - Abstract
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.
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- 2023
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22. Dapagliflozin Mitigated Elevated Disomic and Diploid Sperm in a Mouse Model of Diabetes and Recover the Disrupted Ogg1, Parp1, and P53 Gene Expression
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Norah A. Albekairi, Mohammed A. Al-Hamamah, Ali A. Alshamrani, Mohamed S. M. Attia, Ahmed Nadeem, Mushtaq A. Ansari, Sheikh F. Ahmad, Saleh A. Bakheet, and Sabry M. Attia
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hyperglycemia ,SGLT2 inhibitors ,numerical chromosomal aberrations ,birth defects ,Biology (General) ,QH301-705.5 - Abstract
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.
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- 2023
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23. Carfilzomib Mitigates Lipopolysaccharide/D-Galactosamine/Dimethylsulfoxide-Induced Acute Liver Failure in Mice
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Dhafer Y. Alhareth, Abdulrazaq Alanazi, Wael A. Alanazi, Mushtaq A. Ansari, Mahmoud N. Nagi, Sheikh F. Ahmad, Mohamed S. M. Attia, Ahmed Nadeem, Saleh A. Bakheet, and Sabry M. Attia
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animal model ,hepatotoxicity ,inflammation ,carfilzomib ,oxidative and nitrosative stress ,Biology (General) ,QH301-705.5 - Abstract
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.
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- 2023
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24. Bacillus Calmette–Guérin Vaccine Attenuates Haloperidol-Induced TD-like Behavioral and Neurochemical Alteration in Experimental Rats
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Narhari Gangaram Yedke, Shubham Upadhayay, Randhir Singh, Sumit Jamwal, Sheikh F. Ahmad, and Puneet Kumar
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tardive dyskinesia ,BCG vaccine ,haloperidol ,neurotransmitters ,antioxidants ,Microbiology ,QR1-502 - Abstract
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.
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- 2023
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25. Screening of Crucial Cytosolicproteins Interconnecting the Endoplasmic Reticulum and Mitochondria in Parkinson’s Disease and the Impact of Anti-Parkinson Drugs in the Preservation of Organelle Connectivity
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Athira Anirudhan, S. Mahema, Sheikh F. Ahmad, Talha Bin Emran, Shiek S. S. J. Ahmed, and Prabu Paramasivam
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Parkinson’s disease ,mitochondrial-ER ,mitochondria-associated membranes (MAMs) ,systems biology ,neuroinflammation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
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.
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- 2023
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26. Citronellal as a Promising Candidate for Alzheimer’s Disease Treatment: A Comprehensive Study on In Silico and In Vivo Anti-Acetylcholine Esterase Activity
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Pavani K, D S. N. B. K. Prasanth, Murthy K. R. Shadakshara, Sheikh F. Ahmad, Ramanjaneyulu Seemaladinne, Mithun Rudrapal, and Praveen Kumar Pasala
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Citronellal (CTN) ,acetylcholine esterase ,Alzheimer’s disease (AD) ,molecular dynamic ,antioxidant activity ,Microbiology ,QR1-502 - Abstract
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.
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- 2023
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27. Comparative Antibacterial and Efflux Pump Inhibitory Activity of Isolated Nerolidol, Farnesol, and α-Bisabolol Sesquiterpenes and Their Liposomal Nanoformulations
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Jorge Ederson Gonçalves Santana, Cícera Datiane de Morais Oliveira-Tintino, Gabriel Gonçalves Alencar, Gustavo Miguel Siqueira, Daniel Sampaio Alves, Talysson Felismino Moura, Saulo Relison Tintino, Irwin Rose Alencar de Menezes, João Pedro Viana Rodrigues, Vanessa Barbosa Pinheiro Gonçalves, Roberto Nicolete, Talha Bin Emran, Clara Mariana Gonçalves Lima, Sheikh F. Ahmad, Henrique Douglas Melo Coutinho, and Teresinha Gonçalves da Silva
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efflux pump ,fluorescence ,liposome ,nanoformulation ,sesquiterpenes ,Staphylococcus aureus ,Organic chemistry ,QD241-441 - Abstract
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.
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- 2023
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28. Targeted Delivery of 5-Fluorouracil and Sonidegib via Surface-Modified ZIF-8 MOFs for Effective Basal Cell Carcinoma Therapy
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Bharath Singh Padya, Gasper Fernandes, Sumukha Hegde, Sanjay Kulkarni, Abhijeet Pandey, Praful Balavant Deshpande, Sheikh F. Ahmad, Dinesh Upadhya, and Srinivas Mutalik
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5-fluorouracil ,sonidegib ,topical drug delivery ,ZIF-8 MOF ,basal cell carcinoma ,Pharmacy and materia medica ,RS1-441 - Abstract
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.
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- 2023
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29. Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study
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Sudhan M., Janakiraman V., Sheikh F. Ahmad, Sabry M. Attia, Talha Bin Emran, Rajesh B. Patil, and Shiek S. S. J. Ahmed
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paraoxonase ,variant ,oxidative stress ,molecular docking ,structural modeling ,lactones ,Medicine (General) ,R5-920 - Abstract
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.
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- 2023
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30. Unveiling the Cardioprotective Power: Liquid Chromatography–Mass Spectrometry (LC–MS)-Analyzed Neolamarckia cadamba (Roxb.) Bosser Leaf Ethanolic Extract against Myocardial Infarction in Rats and In Silico Support Analysis
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Raghupathi Niranjan Kumar, Dsnbk Prasanth, Praisy Gladys Midthuri, Sheikh F. Ahmad, Attuluri Venkata Badarinath, Srikanth Kumar Karumanchi, Ramanjaneyulu Seemaladinne, Rahul Nalluri, and Praveen Kumar Pasala
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Neolamarckia cadamba ,HR-LC–MS ,molecular docking ,myocardial infarction ,oxidative stress ,HMG-CoA reductase ,Botany ,QK1-989 - Abstract
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.
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- 2023
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31. Clinical Significance of Adropin and Afamin in Evaluating Renal Function and Cardiovascular Health in the Presence of CKD-MBD Biomarkers in Chronic Kidney Disease
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Rupinder Kaur, Pawan Krishan, Pratima Kumari, Tanveer Singh, Varinder Singh, Ravinder Singh, and Sheikh F. Ahmad
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CKD ,CKD-MBD ,adropin ,afamin ,cardiovascular ,biomarker ,Medicine (General) ,R5-920 - Abstract
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.
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- 2023
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32. Multi-Target Effect of Aloeresin-A against Bacterial and Host Inflammatory Targets Benefits Contact Lens-Related Keratitis: A Multi-Omics and Quantum Chemical Investigation
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Jency Roshni, Sheikh F. Ahmad, Abubakar Wani, and Shiek S. S. J. Ahmed
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keratitis ,aloeresin-A ,phytochemicals ,docking ,inflammation ,cornea ,Organic chemistry ,QD241-441 - Abstract
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.
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- 2023
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33. Unravelling the Molecular Mechanisms of a Quercetin Nanocrystal for Treating Potential Parkinson’s Disease in a Rotenone Model: Supporting Evidence of Network Pharmacology and In Silico Data Analysis
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Yeruva Sai Lakshmi, D. S. N. B. K. Prasanth, Karumuri Taraka Sunil Kumar, Sheikh F. Ahmad, Seemaladinne Ramanjaneyulu, Nalluri Rahul, and Praveen Kumar Pasala
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Parkinson’s disease ,rotenone ,quercetin nanocrystals (QNC) ,antioxidant system ,Biology (General) ,QH301-705.5 - Abstract
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.
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- 2023
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34. In Silico Approaches to Developing Novel Glycogen Synthase Kinase 3β (GSK-3β)
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Shuchi Goyal, Manjinder Singh, Divya Thirumal, Pratibha Sharma, Somdutt Mujwar, Krishna Kumar Mishra, Thakur Gurjeet Singh, Ravinder Singh, Varinder Singh, Tanveer Singh, and Sheikh F. Ahmad
- Subjects
GSK-3β ,molecular dynamics ,docking ,scaffold ,morphing ,neurofibrillary tangles ,Biology (General) ,QH301-705.5 - Abstract
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.
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- 2023
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35. Network-Derived Radioresistant Breast Cancer Target with Candidate Inhibitors from Brown Algae: A Sequential Assessment from Target Selection to Quantum Chemical Calculation
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Mahema Sivakumar, Sheikh F. Ahmad, Talha Bin Emran, Paola Isabel Angulo-Bejarano, Ashutosh Sharma, and Shiek S. S. J. Ahmed
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primary breast cancer ,radioresistant breast cancer ,protein network ,brown algae ,nahocol-A1 ,Biology (General) ,QH301-705.5 - Abstract
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.
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- 2023
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36. Computational Studies to Understand the Neuroprotective Mechanism of Action Basil Compounds
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Varinder Singh, Somdutt Mujwar, Manjinder Singh, Tanveer Singh, and Sheikh F. Ahmad
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basil compounds ,neuroprotection ,molecular docking ,molecular dynamics ,density functional theory (DFT) ,neurodegenerative diseases ,Organic chemistry ,QD241-441 - Abstract
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.
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- 2023
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37. Comparative Efficacy of Metformin and Glimepiride in Modulating Pharmacological Network to Increase BDNF Levels and Benefit Type 2 Diabetes-Related Cognitive Impairment
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Athira Anirudhan, Sheikh F. Ahmad, Talha Bin Emran, Paola Isabel Angulo-Bejarano, Ashutosh Sharma, and Shiek S. S. J. Ahmed
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type 2 diabetes ,brain-derived neurotrophic factor ,metformin ,glimepiride ,protein network ,gene and protein expression ,Biology (General) ,QH301-705.5 - Abstract
Cognitive impairment is anotable complication of type 2 diabetes (T2DM), accompanied by reduced brain-derived neurotrophic factor (BDNF) in the brain and blood. Anti-diabetic drugs reduce hyperglycemia, yet their effect on cognitive improvement is unknown. We aimed to investigate the effect of anti-diabetic drugs regulating BDNF in T2DM through computational and case-control study design. We obtained T2DMproteins viatext-mining to construct a T2DMprotein network. From the T2DMnetwork, the metformin and glimepiride interactomes and their crucial shortest-path-stimulating BDNF were identified. Using qRTPCR, the genes encoding the shortest-path proteins were assessed in four groups (untreated-T2DM, metformin-treated, glimepiride-treated, and healthy controls). Finally, ELISA was used to assess serum BDNF levels to validate drug efficacy. As a result of this investigation, aT2DMnetwork was constructed with 3683 text-mined proteins. Then, the T2DMnetwork was explored to generate a metformin and glimepiride interactome that establishes the critical shortest-path for BDNF stimulation. Metformin stimulates BDNF via APP binding to the PRKAB1 receptor. Whereas, glimepiride increases BDNF by binding to KCNJ11 via AP2M1 and ESR1 proteins. Both drug shortest-path encoding genes differed significantly between the groups. Unlike metformin, BDNF gene and protein expression rise significantly with glimepiride. Overall, glimepiride can effectively increase BDNF, which could benefit T2DM patients with cognitive deterioration.
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- 2023
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38. Aflatoxin B1 Exposure Aggravates Neurobehavioral Deficits and Immune Dysfunctions of Th1, Th9, Th17, Th22, and T Regulatory Cell-Related Transcription Factor Signaling in the BTBR T+Itpr3tf/J Mouse Model of Autism
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Mohammad Y. Alwetaid, Taghreed N. Almanaa, Saleh A. Bakheet, Mushtaq A. Ansari, Ahmed Nadeem, Sabry M. Attia, Marwa H. Hussein, and Sheikh F. Ahmad
- Subjects
autism spectrum disorder ,Aflatoxin B1 ,T cells ,CD4 cells ,BTBR mice ,C57 mice ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by impaired communication, reciprocal social interactions, restricted sociability deficits, and stereotyped behavioral patterns. Environmental factors and genetic susceptibility have been implicated in an increased risk of ASD. Aflatoxin B1 (AFB1) is a typical contaminant of food and feed that causes severe immune dysfunction in humans and animals. Nevertheless, the impact of ASD on behavioral and immunological responses has not been thoroughly examined. To investigate this phenomenon, we subjected BTBR T+Itpr3tf/J (BTBR) mice to AFB1 and evaluated their marble-burying and self-grooming behaviors and their sociability. The exposure to AFB1 resulted in a notable escalation in marble-burying and self-grooming activities while concurrently leading to a decline in social contacts. In addition, we investigated the potential molecular mechanisms that underlie the impact of AFB1 on the production of Th1 (IFN-γ, STAT1, and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A, IL-21, RORγT, and STAT3), Th22 (IL-22, AhR, and TNF-α), and T regulatory (Treg) (IL-10, TGF-β1, and FoxP3) cells in the spleen. This was achieved using RT-PCR and Western blot analyses to assess mRNA and protein expression in brain tissue. The exposure to AFB1 resulted in a significant upregulation of various immune-related factors, including IFN-γ, STAT1, T-bet, IL-9, IRF4, IL-17A, IL-21, RORγ, STAT3, IL-22, AhR, and TNF-α in BTBR mice. Conversely, the production of IL-10, TGF-β1, and FoxP3 by CD4+ T cells was observed to be downregulated. Exposure to AFB1 demonstrated a notable rise in Th1/Th9/Th22/Th17 levels and a decrease in mRNA and protein expression of Treg. The results above underscore the significance of AFB1 exposure in intensifying neurobehavioral and immunological abnormalities in BTBR mice, hence indicating the necessity for a more comprehensive investigation into the contribution of AFB1 to the development of ASD.
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- 2023
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39. LC/MS-Based Profiling of Hedyotis aspera Whole-Plant Methanolic Extract and Evaluation of Its Nephroprotective Potential against Gentamicin-Induced Nephrotoxicity in Rats Supported by In Silico Studies
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Dsnbk Prasanth, Lingareddygari Siva Sanker Reddy, Tharani Dasari, Pamula Reddy Bhavanam, Sheikh F. Ahmad, Rahul Nalluri, and Praveen Kumar Pasala
- Subjects
Hedyotis aspera whole-plant methanolic extract ,molecular docking ,Wistar rats ,nephroprotective effect ,gentamicin ,Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
Many high-altitude plants, such as Hedyotis aspera, need to be explored for their possible medicinal value. The current study explored the protective effect of Hedyotis aspera methanolic extract whole plant (HAME) against gentamicin-induced nephrotoxicity in rats. It profiled their phytocontents using HPLC-QTOF-MS/MS analytic methods. The LC-MS analysis of HAME revealed 27 compounds. Eight compounds followed Lipinski’s rule of five and were found to be potential TNF-α inhibitors with binding affinities of −6.9, −6.3, −6.3, and −6.3 Kcal/mol, such as 14,19-Dihydroaspidospermatine, coumeroic acid, lycocernuine and muzanzagenin. All potential compounds were found to be safe according to the ADMET analysis. The in vitro 2,2-diphenyl-1-picrlhydrazyl (DPPH) assay assessed the antioxidant activity. The nephroprotective activity was assessed in rats using a gentamicin-induced nephrotoxicity model. The in vivo analysis involved histological examination, tissue biochemical evaluation, including a kidney function test, catalase activity (CAT), reduced glutathione (GSH) levels, superoxide dismutase (SOD), and the inflammatory mediator TNF-α. Based on DPPH activity, HAME showed a scavenging activity IC50 of 264.8 ± 1.2 µg/mL, while results were compared with a standard vitamin C IC50 of 45 ± 0.45 µg/mL. Nephrotoxicity was successfully induced, as shown by elevated creatinine and uric acid levels, decreased kidney antioxidant levels, and increased TNF-α in gentamicin-treated rats. The HAME treatment significantly reduced serum creatinine and uric acid levels, increased GSH (p < 0.01 **), CAT (p < 0.01 **), and SOD (p < 0.001 ***), and decreased TNF-α (p < 0.001 ***) in nephrotoxic rats. The histopathological examination of the groups treated with HAME revealed a notable enhancement in the structural integrity of the kidneys as compared to the group exposed to gentamicin. Biochemical, histopathological, and phytochemical screening of HAME suggests that it has nephroprotective potential, owing to the presence of 14,19-Dihydroaspidospermatine, coumeroic acid, lycopene, and muzanzagenin.
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- 2023
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40. Auranofin Modulates Thioredoxin Reductase/Nrf2 Signaling in Peripheral Immune Cells and the CNS in a Mouse Model of Relapsing–Remitting EAE
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Layla A. Al-Kharashi, Naif O. Al-Harbi, Sheikh F. Ahmad, Sabry M. Attia, Mohammad M. Algahtani, Khalid E. Ibrahim, Saleh A. Bakheet, Mohammed M. Alanazi, Saleh A. Alqarni, Sary Alsanea, and Ahmed Nadeem
- Subjects
multiple sclerosis ,myeloid immune cells ,lymphoid immune cells ,auranofin ,thioredoxin reductase ,Nrf2 signaling ,Biology (General) ,QH301-705.5 - Abstract
Multiple sclerosis (MS) is one of the most prevalent chronic inflammatory autoimmune diseases. It causes the demyelination of neurons and the subsequent degeneration of the central nervous system (CNS). The infiltration of leukocytes of both myeloid and lymphoid origins from the systemic circulation into the CNS triggers autoimmune reactions through the release of multiple mediators. These mediators include oxidants, pro-inflammatory cytokines, and chemokines which ultimately cause the characteristic plaques observed in MS. Thioredoxin reductase (TrxR) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling plays a crucial role in the regulation of inflammation by modulating the transcription of antioxidants and the suppression of inflammatory cytokines. The gold compound auranofin (AFN) is known to activate Nrf2 through the inhibition of TrxR; however, the effects of this compound have not been explored in a mouse model of relapsing–remitting MS (RRMS). Therefore, this study explored the influence of AFN on clinical features, TrxR/Nrf2 signaling [heme oxygenase 1 (HO-1), superoxide dismutase 1 (SOD-1)] and oxidative/inflammatory mediators [IL-6, IL-17A, inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO), nitrotyrosine] in peripheral immune cells and the CNS of mice with the RR type of EAE. Our results showed an increase in TrxR activity and a decrease in Nrf2 signaling in SJL/J mice with RR-EAE. The treatment with AFN caused the amelioration of the clinical features of RR-EAE through the elevation of Nrf2 signaling and the subsequent upregulation of the levels of antioxidants as well as the downregulation of oxidative/pro-inflammatory mediators in peripheral immune cells and the CNS. These data suggest that AFN may be beneficial in the treatment of RRMS.
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- 2023
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41. Recent Development of Novel Aminoethyl-Substituted Chalcones as Potential Drug Candidates for the Treatment of Alzheimer’s Disease
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Pratibha Sharma, Manjinder Singh, Varinder Singh, Thakur Gurjeet Singh, Tanveer Singh, and Sheikh F. Ahmad
- Subjects
chalcone ,Alzheimer’s disease ,AChE ,antioxidant ,dementia ,AGEs ,Organic chemistry ,QD241-441 - Abstract
No drug on the market, as a single entity, participates in different pathways involved in the pathology of Alzheimer’s disease. The current study is aimed at the exploration of multifunctional chalcone derivatives which can act on multiple targets involved in Alzheimer’s disease. A series of novel aminoethyl-substituted chalcones have been developed using in silico approaches (scaffold morphing, molecular docking, and ADME) and reported synthetic methods. The synthesized analogs were characterized and evaluated biologically using different in vitro assays against AChE, AGEs, and radical formation. Among all compounds, compound PS-10 was found to have potent AChE inhibitory activity (IC50 = 15.3 nM), even more than the standard drug (IC50 = 15.68 nM). Further, the in vivo evaluation of PS-10 against STZ-induced dementia in rats showed memory improvement (Morris Water Maze test) in rats. Also, PS-10 inhibited STZ-induced brain AChE activity and oxidative stress, further strengthening the observed in vitro effects. Further, the molecular dynamic simulation studies displayed the stability of the PS-10 and AChE complex. The novel aminoethyl-substituted chalcones might be considered potential multifunctional anti-Alzheimer’s molecules.
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- 2023
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42. Preventive Action of Beta-Carotene against the Indoxyl Sulfate-Induced Renal Dysfunction in Male Adult Zebrafish via Regulations of Mitochondrial Inflammatory and β-Carotene Oxygenase-2 Actions
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Arunachalam Muthuraman, Abu Sadat Md. Sayem, Sakthiganapathi Meenakshisundaram, Nemat Ali, Sheikh F. Ahmad, Abdullah F. AlAsmari, Shamama Nishat, Khian Giap Lim, and Yamunna Paramaswaran
- Subjects
adenosine triphosphate ,carotenoids ,glutathione peroxidase-1 ,hematoxylin staining ,intestinal flora ,reduced glutathione ,Biology (General) ,QH301-705.5 - Abstract
Indoxyl sulfate (IS) is a metabolic byproduct of indole metabolism. IS readily interacts with the mitochondrial redox metabolism, leading to altered renal function. The β-carotene oxygenase-2 (BCO2) enzyme converts carotenoids to intermediate products. However, the role of β-carotene (BC) in IS-induced renal dysfunction in zebrafish and their modulatory action on BCO2 and mitochondrial inflammations have not been explored yet. Hence, the present study is designed to investigate the role of BC in the attenuation of IS-induced renal dysfunction via regulations of mitochondrial redox balance by BCO2 actions. Renal dysfunction was induced by exposure to IS (10 mg/L/hour/day) for 4 weeks. BC (50 and 100 mg/L/hour/day) and coenzyme Q10 (CoQ10; 20 mg/L/hour/day) were added before IS exposure. BC attenuated the IS-induced increase in blood urea nitrogen (BUN) and creatinine concentrations, adenosine triphosphate (ATP), and complex I activity levels, and the reduction of renal mitochondrial biomarkers, i.e., BCO2, superoxide dismutase-2 (SOD2), glutathione peroxidase-1 (GPX1), reduced and oxidized glutathione (GSH/GSSG) ratio, and carbonylated proteins. Moreover, renal histopathological changes were analyzed by the eosin and hematoxylin staining method. As a result, the administration of BC attenuated the IS-induced renal damage via the regulation of mitochondrial function.
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- 2023
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43. Impacts of the DPP-4 Inhibitor Saxagliptin and SGLT-2 Inhibitor Dapagliflozin on the Gonads of Diabetic Mice
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Ali A. Alshamrani, Mohammed A. Al-Hamamah, Norah A. Albekairi, Mohamed S. M. Attia, Sheikh F. Ahmad, Mohammed A. Assiri, Mushtaq A. Ansari, Ahmed Nadeem, Saleh A. Bakheet, Wael A. Alanazi, and Sabry M. Attia
- Subjects
hyperglycemia ,chromosomal aberration ,metabolism ,reproduction ,oxidative stress ,Biology (General) ,QH301-705.5 - Abstract
Diabetes mellitus is a metabolic disease that can cause systemic problems, including testicular dysfunction. Several diabetes medications have demonstrated potential adverse effects on the male reproductive system; however, the effects of saxagliptin and dapagliflozin have not been sufficiently examined. This investigation studied the impacts of saxagliptin and dapagliflozin treatments on the gonads in a male mouse model of diabetes. Testicular disturbances were assessed by sperm DNA damage, diakinesis-metaphase I chromosome examination, and spermiogram analysis. Our results showed more sperm DNA damage, more spermatocyte chromosome aberrations, lower sperm motility/count, and more sperm morphological anomalies in diabetic mice than in the control mice. Dapagliflozin significantly restored all examined measures to the control values in diabetic mice, unlike saxagliptin, which exacerbated the reduction in sperm count and motility. Both drugs significantly restored the gonadal redox imbalances in diabetic mice by decreasing reactive oxygen species accumulation and increasing glutathione levels. In conclusion, our study presents preliminary evidence for the safety and efficacy of dapagliflozin in alleviating testicular abnormalities induced by diabetes, making it a promising candidate drug for patients with diabetes in their reproductive age. As saxagliptin may have negative effects on fertility, its prescription should be avoided in young male diabetic patients.
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- 2023
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44. PM2.5-Induced Cardiac Structural Modifications and Declined Pro-Survival Signalling Pathways Are Responsible for the Inefficiency of GSK-3β Inhibitor in Attenuating Myocardial Ischemia-Reperfusion Injury in Rats
- Author
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Bhavana Sivakumar, Nemat Ali, Sheikh F. Ahmad, Ahmed Nadeem, Mohammad Waseem, and Gino A. Kurian
- Subjects
PM2.5 ,cardiovascular diseases ,diesel particulate matter ,GSK 3β ,SB216763 ,ischemia-reperfusion injury ,Cytology ,QH573-671 - Abstract
Circulatory GSK3β is recognized as a biomarker and therapeutic target for diseases, including myocardial diseases. However, its potential as a target for myocardial ischemia-reperfusion injury (IR) in the presence of PM2.5 exposure is unclear. Wistar rats underwent IR following either a 21-day or single exposure to PM2.5 at a concentration of 250 µg/m3. The effects of GSK3β inhibitor on cardiac physiology, tissue injury, mitochondrial function, and the PI3K/AKT/GSK3β signalling axis were examined. The inhibitor was not effective in improving hemodynamics or reducing IR-induced infarction in the myocardium exposed to PM2.5 for 21 days. However, for a single-day exposure, the inhibitor showed potential in mitigating cardiac injury. In normal hearts undergoing IR, the inhibitor activated the PI3K/AKT signalling pathway, improved mitochondrial function, and reduced oxidative stress. These positive effects were not observed in PM2.5-exposed rats. Furthermore, the inhibitor stimulated autophagy in hearts exposed to PM2.5 for 21 days and subjected to IR, resulting in increased mTOR expression and decreased AMPK expression. In normal hearts and those exposed to a single dose of PM2.5, the inhibitor effectively activated the PI3K/Akt/AMPK axis. These findings suggest that GSK3β may not be a reliable therapeutic target for IR in the presence of chronic PM2.5 exposure.
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- 2023
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45. Topical Micro-Emulsion of 5-Fluorouracil by a Twin Screw Processor-Based Novel Continuous Manufacturing Process for the Treatment of Skin Cancer: Preparation and In Vitro and In Vivo Evaluations
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Ajinkya Nitin Nikam, Angela Jacob, Ruchira Raychaudhuri, Gasper Fernandes, Abhijeet Pandey, Vinay Rao, Sheikh F. Ahmad, Ananth S. Pannala, and Srinivas Mutalik
- Subjects
5-Fluorouracil ,microemulsion ,twin-screw processor ,continuous manufacturing ,skin cancer ,squamous cell carcinoma (SCC) ,Pharmacy and materia medica ,RS1-441 - Abstract
5-Fluorouracil (5-FU), a BCS class III drug, has low oral bioavailability and is cytotoxic in nature causing severe systemic side effects when administered through the intravenous route. Topical drug delivery could potentially mitigate the systemic side-effects. Microemulsions (MEs) would be an apt solution due to enhanced partitioning of the drug to the skin. However, conventional methods for preparing MEs are inefficient since they are not continuous and are very tedious and time-consuming processes hence revealing the need for the development of continuous manufacturing technology. In our study, 5-FU MEs were prepared using a continuous manufacturing Twin Screw Process (TSP) and its efficiency in the treatment of skin cancer was evaluated. Water-in-oil MEs were prepared using isopropyl myristate as the oil phase and Aerosol OT and Tween 80 as the surfactants. The average particle size was observed to be 178 nm. Transmission electron microscopy was employed to confirm the size and shape of the MEs. FTIR study proved no physical or chemical interaction between the excipients and the drug. In vitro drug release using vertical diffusion cells and ex vivo skin permeation studies showed that the drug was released sustainably and permeated across the skin, respectively. In in vitro cytotoxicity studies, 5-FU MEs were accessed in HaCat and A431 cell lines to determine percentage cell viability and IC50. Skin irritation and histopathological examination implied that the 5-FU MEs did not cause any significant irritation to the skin. In vivo pharmacodynamics studies in rats suggested that the optimised formulation was effective in treating squamous cell carcinoma (SCC). Therefore, 5-FU MEs efficiently overcame the various drawbacks faced during oral and intravenous drug delivery. Also, TSP proved to be a technique that overcomes the various problems associated with the conventional methods of preparing MEs.
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- 2023
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46. Thioredoxin 1 and Thioredoxin Reductase 1 Redox System Is Dysregulated in Neutrophils of Subjects with Autism: In Vitro Effects of Environmental Toxicant, Methylmercury
- Author
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Samiyah Alshehri, Sheikh F. Ahmad, Norah A. Albekairi, Sana S. Alqarni, Naif O. Al-Harbi, Laila Y. Al-Ayadhi, Sabry M. Attia, Ali S. Alfardan, Saleh A. Bakheet, and Ahmed Nadeem
- Subjects
autism ,thioredoxin 1 ,methylmercury ,neutrophils ,oxidative stress ,Chemical technology ,TP1-1185 - Abstract
Autism spectrum disorder (ASD) is a complex developmental disorder in children that results in abnormal communicative and verbal behaviors. Exposure to heavy metals plays a significant role in the pathogenesis or progression of ASD. Mercury compounds pose significant risk for the development of ASD as children are more exposed to environmental toxicants. Increased concentration of mercury compounds has been detected in different body fluids/tissues in ASD children, which suggests an association between mercury exposure and ASD. Thioredoxin1 (Trx1) and thioredoxin reductase1 (TrxR1) redox system plays a crucial role in detoxification of oxidants generated in different immune cells. However, the effect of methylmercury and the Nrf2 activator sulforaphane on the Trx1/TrxR1 antioxidant system in neutrophils of ASD subjects has not been studied previously. Therefore, this study examined the effect of methylmercury on Trx1/TrxR1 expression, TrxR activity, nitrotyrosine, and ROS in neutrophils of ASD and TDC subjects. Our study shows that Trx1/TrxR1 protein expression is dysregulated in ASD subjects as compared to the TDC group. Further, methylmercury treatment significantly inhibits the activity of TrxR in both ASD and TDC groups. Inhibition of TrxR by mercury is associated with upregulation of the Trx1 protein in TDC neutrophils but not in ASD neutrophils. Furthermore, ASD neutrophils have exaggerated ROS production after exposure to methylmercury, which is much greater in magnitude than TDC neutrophils. Sulforaphane reversed methylmercury-induced effects on neutrophils through Nrf2-mediated induction of the Trx1/TrxR1 system. These observations suggest that exposure to the environmental toxicant methylmercury may elevate systemic oxidative inflammation due to a dysregulated Trx1/TrxR1 redox system in the neutrophils of ASD subjects, which may play a role in the progression of ASD.
- Published
- 2023
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47. Naringin from Coffee Inhibits Foodborne Aspergillus fumigatus via the NDK Pathway: Evidence from an In Silico Study
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Shashanka K. Prasad, Smitha S. Bhat, Olga Koskowska, Jiraporn Sangta, Sheikh F. Ahmad, Ahmed Nadeem, and Sarana Rose Sommano
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coffee ,Aspergillus fumigatus ,nucleoside diphosphate kinase ,in silico ,antifungal ,Organic chemistry ,QD241-441 - Abstract
In the tropics, coffee has been one of the most extensively cultivated economic crops, especially Arabica coffee (Coffea arabica L.). The coffee pulp, which includes phytochemicals with a proven antifungal action, is one of the most insufficiently utilized and neglected byproducts of coffee refining. In the current experiment, we carried out in silico screening of the isolated Arabica coffee phytochemicals for antifungal activity against Aspergillus fumigatus: a foodborne fungus of great public health importance. As determined by the molecular docking interactions of the library compounds indicated, the best interactions were found to occur between the nucleoside-diphosphate kinase protein 6XP7 and the test molecules Naringin (−6.771 kcal/mol), followed by Epigallocatechin gallate (−5.687 kcal/mol). Therefore, Naringin was opted for further validation with molecular dynamic simulations. The ligand–protein complex RMSD indicated a fairly stable Naringin-NDK ligand–protein complex throughout the simulation period (2–16 Å). In ADME and gastrointestinal absorbability testing, Naringin was observed to be orally bioavailable, with very low intestinal absorption and a bioavailability score of 0.17. This was further supported by the boiled egg analysis data, which clearly indicated that the GI absorption of the Naringin molecule was obscure. We found that naringin could be harmful only when swallowed at a median lethal dose between 2000 and 5000 mg/kg. In accordance with these findings, the toxicity prediction reports suggested that Naringin, found especially in citrus fruits and tomatoes, is safe for human consumption after further investigation. Overall, Naringin may be an ideal candidate for developing anti-A. fumigatus treatments and food packaging materials. Thus, this study addresses the simultaneous problems of discarded coffee waste management and antifungal resistance to available medications.
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- 2023
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48. Aflatoxin B1 Exacerbates Genomic Instability and Apoptosis in the BTBR Autism Mouse Model via Dysregulating DNA Repair Pathway
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Ali A. Alshamrani, Mohammad Y. Alwetaid, Mohammed A. Al-Hamamah, Mohamed S. M. Attia, Sheikh F. Ahmad, Majed A. Algonaiah, Ahmed Nadeem, Mushtaq A. Ansari, Saleh A. Bakheet, and Sabry M. Attia
- Subjects
autism ,food pollutants ,DNA damage ,DNA repair ,carcinogenesis ,Chemical technology ,TP1-1185 - Abstract
The pathophysiology of autism is influenced by a combination of environmental and genetic factors. Furthermore, individuals with autism appear to be at a higher risk of developing cancer. However, this is not fully understood. Aflatoxin B1 (AFB1) is a potent food pollutant carcinogen. The effects of AFB1 on genomic instability in autism have not yet been investigated. Hence, we have aimed to investigate whether repeated exposure to AFB1 causes alterations in genomic stability, a hallmark of cancer and apoptosis in the BTBR autism mouse model. The data revealed increased micronuclei generation, oxidative DNA strand breaks, and apoptosis in BTBR animals exposed to AFB1 when compared to unexposed animals. Lipid peroxidation in BTBR mice increased with a reduction in glutathione following AFB1 exposure, demonstrating an exacerbated redox imbalance. Furthermore, the expressions of some of DNA damage/repair- and apoptosis-related genes were also significantly dysregulated. Increases in the redox disturbance and dysregulation in the DNA damage/repair pathway are thus important determinants of susceptibility to AFB1-exacerbated genomic instability and apoptosis in BTBR mice. This investigation shows that AFB1-related genomic instability can accelerate the risk of cancer development. Moreover, approaches that ameliorate the redox balance and DNA damage/repair dysregulation may mitigate AFB1-caused genomic instability.
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- 2023
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49. Alleviation of cisplatin-induced neuropathic pain, neuronal apoptosis, and systemic inflammation in mice by rapamycin
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Moureq Alotaibi, Faten Al-Aqil, Faleh Alqahtani, Miteb Alanazi, Ahmed Nadeem, Sheikh F. Ahmad, Rebeca Lapresa, Metab Alharbi, Abdulrahman Alshammari, Muteb Alotaibi, Tareq Saleh, and Raed Alrowis
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CIPN ,p21 ,cisplatin ,rapamycin ,IL-17A ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Platinum-based chemotherapeutic treatment of cancer patients is associated with debilitating adverse effects. Several adverse effects have been well investigated, and can be managed satisfactorily, but chemotherapy-induced peripheral neuropathy (CIPN) remains poorly treated. Our primary aim in this study was to investigate the neuroprotective effect of the immunomodulatory drug rapamycin in the mitigation of cisplatin-induced neurotoxicity. Pain assays were performed in vivo to determine whether rapamycin would prevent or significantly decrease cisplatin-induced neurotoxicity in adult male Balb/c mice. Neuropathic pain induced by both chronic and acute exposure to cisplatin was measured by hot plate assay, cold plate assay, tail-flick test, and plantar test. Rapamycin co-treatment resulted in significant reduction in cisplatin-induced nociceptive-like symptoms. To understand the underlying mechanisms behind rapamycin-mediated neuroprotection, we investigated its effect on certain inflammatory mediators implicated in the propagation of chemotherapy-induced neurotoxicity. Interestingly, cisplatin was found to significantly increase peripheral IL-17A expression and CD8- T cells, which were remarkably reversed by the pre-treatment of mice with rapamycin. In addition, rapamycin reduced the cisplatin-induced neuronal apoptosis marked by decreased neuronal caspase-3 activity. The rapamycin neuroprotective effect was also associated with reversal of the changes in protein expression of p21Cip1, p53, and PUMA. Collectively, rapamycin alleviated some features of cisplatin-induced neurotoxicity in mice and can be further investigated for the treatment of cisplatin-induced peripheral neuropathy.
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- 2022
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50. Insight into the Loading and Release Properties of an Exfoliated Kaolinite/Cellulose Fiber (EXK/CF) Composite as a Carrier for Oxaliplatin Drug: Cytotoxicity and Release Kinetics
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Lijun Tian, Mostafa R. Abukhadra, Aya S. Mohamed, Ahmed Nadeem, Sheikh F. Ahmad, and Khalid E. Ibrahim
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Chemistry ,QD1-999 - Published
- 2020
- Full Text
- View/download PDF
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