Browsing by Author "Ahmad, Sheikh F."

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Biological Assessment, GC-MS Analysis, and Molecular Docking Investigation on the Neuropharmacological, Anti-Diarrhoeal, and Cytotoxic Properties of Ficus semicordata Fruits
(Biolife Sas., 2024-06-01) Mukit, Muhammad Abdul; Fahad, Fowzul Islam; Tayab, Mohammed Abu; Azad, Jahid Hasan; Ullah, Md. Ahsan; Islam, Mohammad Nazmul; Sayeed, Mohammed Aktar; Uddin, Md. Zia; Al-Mazroua, Haneen A.; Ahmad, Sheikh F.; Barua, Rashu; Emran, Talha Bin
Background: Ficus semicordata Buch. is a well-known ethnomedicinal plant that is used to treat various ailments such as colic pain, urogenital difficulties, gastrointestinal disorders, visceral blockage, leprosy, jaundice, diabetes, and hepatitis. This study aims to investigate the phytochemical contents of the metabolites extracted (methanol) from the fruits of Ficus (F.) semicordata, and determine their neuropharmacological, anti-diarrhoeal, and cytotoxic potencies, using in vivo, in vitro, and in silico methods. Methods: The pharmacological properties of methanol extract of Ficus semicordata fruits (MEFSF) were assessed at different concentrations and its toxicity was determined using the in vitro brine shrimp lethality test. Tail suspension and forced swimming tests were used to investigate the antidepressant activity of MEFSF in mice and elevated plus maze and hole board test models were used to uncover its anxiolytic potentiality. The in vivo anti-diarrhoeal properties of MEFSF were tested on castor oil-induced diarrhoea and gastrointestinal motility models. Gas chromatography-mass spectrometry (GC-MS) analysis was conducted using a mass spectrometer. Based on the GC-MS analysis, 19 phytochemicals were investigated using molecular docking techniques against various target proteins to determine whether they mediate cytotoxic, depressive, anxiolytic, and anti-diarrhoeal effects. Results: MEFSF exhibited moderate toxicity (median lethal dose (LD50): 267.23 μg/mL). In the antidepressant assessment, MEFSF demonstrated a significant (p < 0.0001) dose-dependent decrease in immobility compared to fluoxetine. Similarly, MEFSF exhibited a dose-dependent reduction in anxiolytic-like behaviour in mice, with a 400 mg/kg dose exhibiting vigorous activity. MEFSF also significantly inhibited motility in both anti-diarrhoeal models, with a 400 mg/kg dose exhibiting highly significant (p < 0.0001) suppression. The GC-MS analysis revealed 81 bioactive components. Seven phytochemicals exhibited a strong affinity for various target proteins in the molecular investigation. Notably, beta-D-glucopyranose and 4-O-beta-D-galactopyranosyl manifested a high affinity for hER, K+ channel, SERT3, and M3MAR and exhibited cytotoxic, anxiolytic, antidepressant, and anti-diarrhoeal potential. Conclusion: The findings indicate that MEFSF can potentially contribute to the development of innovative anti-cancer, neuropharmacological, and anti-diarrhoeal treatments. However, additional research is necessary to explore this possibility.
Comparative Antibacterial and Efflux Pump Inhibitory Activity of Isolated Nerolidol, Farnesol, and α-Bisabolol Sesquiterpenes and Their Liposomal Nanoformulations
(MDPI Publications, 2023-11-17) Santana, Jorge Ederson Gonçalves; Oliveira-Tintino, Cícera Datiane de Morais; Alencar, Gabriel Gonçalves; Siqueira, Gustavo Miguel; Alves, Daniel Sampaio; Moura, Talysson Felismino; Tintino, Saulo Relison; Menezes, Irwin Rose Alencar de; Rodrigues, João Pedro Viana; Gonçalves, Vanessa Barbosa Pinheiro; Nicolete, Roberto; Emran, Talha Bin; Lima, Clara Mariana Gonçalves; Ahmad, Sheikh F.; Coutinho, Henrique Douglas Melo; Silva, Teresinha Gonçalves da
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.
Comparative Efficacy of Metformin and Glimepiride in Modulating Pharmacological Network to Increase BDNF Levels and Benefit Type 2 Diabetes-Related Cognitive Impairment
(MDPI Publications, 2023-10-31) Anirudhan, Athira; Ahmad, Sheikh F.; Emran, Talha Bin; Angulo-Bejarano, Paola Isabel; Sharma, Ashutosh; Ahmed, Shiek S. S. J.
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.
Effect of Smartphone Use on Sleep in Undergraduate Medical Students
(MDPI Publications, 2023-11-02) Goel, Ashish; Moinuddin, Arsalan; Tiwari, Rajesh; Sethi, Yashendra; Suhail, Mohammed K.; Mohan, Aditi; Kaka, Nirja; Sarthi, Parth; Dutt, Ravi; Ahmad, Sheikh F.; Attia, Sabry M.; Emran, Talha Bin; Chopra, Hitesh; Greig, Nigel H.
Smartphone use, particularly at night, has been shown to provoke various circadian sleep–wake rhythm disorders such as insomnia and excessive daytime tiredness. This relationship has been mainly scrutinized among patient groups with higher rates of smartphone usage, particularly adolescents and children. However, it remains obscure how smartphone usage impacts sleep parameters in adults, especially undergraduate college students. This study sought to (1) investigate the association between smartphone use (actual screen time) and four sleep parameters: Pittsburgh sleep quality score (PSQI), self-reported screen time, bedtime, and rise time; (2) compare the seven PSQI components between good and poor sleep quality subjects. In total, 264 undergraduate medical students (aged 17 to 25 years) were recruited from the Government Doon Medical College, Dehradun, India. All participants completed a sleep questionnaire, which was electronically shared via a WhatsApp invitation link. Hierarchical and multinomial regression analyses were performed in relation to (1) and (2). The average PSQI score was 5.03 ± 0.86, with approximately one in two respondents (48.3%) having a poor sleep index. Smartphone use significantly predicted respondents’ PSQI score (β = 0.142, p = 0.040, R2 = 0.027), perceived screen time (β = 0.113, p = 0.043, R2 = 343), bedtime (β = 0.106, p = 0.042, R2 = 045), and rise time (β = 0.174, p = 0.015, R2 = 0.028). When comparing poor-quality sleep (PSQI ≥ 5) to good-quality sleep (PSQI < 5), with good-quality sleep as the reference, except sleep efficiency and sleep medications (p > 0.05), five PSQI components declined significantly: subjective sleep quality (β = −0.096, p < 0.001); sleep latency (β = −0.034, p < 0.001); sleep duration (β = −0.038, p < 0.001); sleep disturbances (β = 1.234, p < 0.001); and sleep dysfunction (β = −0.077, p < 0.001). Consequently, public health policymakers should take this evidence into account when developing guidelines around smartphone use—i.e., the when, where, and how much smartphone use—to promote improved sleep behaviour and reduce the rate of sleep–wake rhythm disorders.
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
(MDPI Publications, 2023-11-01) Monisha, K.; Mahema, S.; Chokkalingam, M.; Ahmad, Sheikh F.; Emran, Talha Bin; Prabu, Paramasivam; Ahmed, Shiek S. S. J.
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.
Molecular Docking, Quantum Mechanics and Molecular Dynamics Simulation of Anti-CAD Drugs Against High-Risk Xanthine Dehydrogenase Variants Associated with Oxidative Stress Pathways
(2024-09-15) Janakiraman, V.; Sudhan, M.; Ahmad, Sheikh F.; Attia, Sabry M.; Bin Emran, Talha; Ahmed, Shiek S. S. J.
Xanthine dehydrogenase (XDH) contributes significantly to generating reactive oxygen species in coronary artery disease (CAD). XDH has been proposed as a therapeutic target, but its genetic variants could affect protein structure and drug response. We aimed to assess protein structure modification occur due to genetic variants and to screen 215 CAD drugs for their utility in personalized CAD treatment against the XDH variants. A series of computational methods were implemented to identify pathogenic variants that cause XDH structure instability localized at the con served regions contributing to functional significance. Then, the XDH structures with the pathogenic variants were modeled using two different approaches to select the best models for docking with the CAD drugs. Finally, the stability of the docked complexes and their ability to transfer electrons were evaluated using molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculation. Among 751 variants examined; R149C and Q919R showed high pathogenicity, localized in conserved regions could alter protein structure and function. Further, docking of CAD drugs against XDH (native, R149C and Q919R) showed vericiguat with higher affinity, ranging from −7.95 kcal/mol to −10.41 kcal/mol, than the well-known XDH inhibitor (febuxostat, −5.73 kcal/mol to −8.35 kcal/mol). This indicates that vericiguat will be effective in CAD treatment, regardless of the XDH variants. Additionally, MD simulation and QM/MM confirmed vericiguat stability and electron transfer ability to form hydrogen bonds with the XDH protein. In conclusion, vericiguat will be beneficial for the personalized treatment of CAD by inhibiting XDH variants. Additional clinical studies are necessary to confirm our findings.
Network-Derived Radioresistant Breast Cancer Target with Candidate Inhibitors from Brown Algae: A Sequential Assessment from Target Selection to Quantum Chemical Calculation
(MDPI Publications, 2023-10-19) Sivakumar, Mahema; Ahmad, Sheikh F.; Emran, Talha Bin; Angulo-Bejarano, Paola Isabel; Sharma, Ashutosh; Ahmed, Shiek S. S. J.
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.
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
(MDPI Publications, 2023-11-05) Anirudhan, Athira; Mahema, S.; Ahmad, Sheikh F.; Emran, Talha Bin; Ahmed, Shiek S. S. J.; Paramasivam, Prabu
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
Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases
(MDPI Publications, 2023-10-22) M., Sudhan; V., Janakiraman; Ahmad, Sheikh F.; Attia, Sabry M.; Emran, Talha Bin; Patil, Rajesh B.; Ahmed, Shiek S. S. J.
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.