Displaying publications 21 - 40 of 280 in total

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  1. Linguistic validation of stigmatisation degree, self-esteem and knowledge questionnaire among asthma patients using Rasch analysis
    Ahmad S, Ismail AI, Khan TM, Akram W, Mohd Zim MA, Ismail NE
    J Asthma, 2017 04;54(3):318-324.
    PMID: 27410725 DOI: 10.1080/02770903.2016.1208222
    BACKGROUND AND OBJECTIVE: The stigmatisation degree, self-esteem and knowledge either directly or indirectly influence the control and self-management of asthma. To date, there is no valid and reliable instrument that can assess these key issues collectively. The main aim of this study was to test the reliability and validity of the newly devised and translated "Stigmatisation Degree, Self-Esteem and Knowledge Questionnaire" among adult asthma patients using the Rasch measurement model.
    METHODOLOGY: This cross-sectional study recruited thirty adult asthma patients from two respiratory specialist clinics in Selangor, Malaysia. The newly devised self-administered questionnaire was adapted from relevant publications and translated into the Malay language using international standard translation guidelines. Content and face validation was done. The data were extracted and analysed for real item reliability and construct validation using the Rasch model.
    RESULTS AND CONCLUSION: The translated "Stigmatisation Degree, Self-Esteem and Knowledge Questionnaire" showed high real item reliability values of 0.90, 0.86 and 0.89 for stigmatisation degree, self-esteem, and knowledge of asthma, respectively. Furthermore, all values of point measure correlation (PTMEA Corr) analysis were within the acceptable specified range of the Rasch model. Infit/outfit mean square values and Z standard (ZSTD) values of each item verified the construct validity and suggested retaining all the items in the questionnaire. The reliability analyses and output tables of item measures for construct validation proved the translated Malaysian version of "Stigmatisation Degree, Self-Esteem and Knowledge Questionnaire" as a valid and highly reliable questionnaire.
    Study site: Respiratory clinics, Hospital Selayang, Hospital Sungai Buloh, Selangor, Malaysia
  2. Synthesis, characterization, monoamine oxidase inhibition, molecular docking and dynamic simulations of novel 2,1-benzothiazine-2,2-dioxide derivatives
    Ahmad S, Zaib S, Jalil S, Shafiq M, Ahmad M, Sultan S, et al.
    Bioorg Chem, 2018 10;80:498-510.
    PMID: 29996111 DOI: 10.1016/j.bioorg.2018.04.012
    In this research work, we report the synthesis and biological evaluation of two new series of 1-benzyl-4-(benzylidenehydrazono)-3,4-dihydro-1H-benzo[c] [1,2]thiazine 2,2-dioxides and 1-benzyl-4-((1-phenylethylidene)hydrazono)-3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxides. The synthetic plan involves the mesylation of methyl anthranilate with subsequent N-benzylation of the product. The methyl 2-(N-benzylmethylsulfonamido)benzoate was subjected to cyclization reaction in the presence of sodium hydride to obtain 1-benzyl-1H-benzo[c][1,2]thiazin-4(3H)-one 2,2-dioxide which was treated with hydrazine hydrate to get corresponding hydrazone precursor. Finally, the titled compounds were obtained by reaction of hydrazone with various substituted aldehydes and ketones. The synthesized derivatives were subjected to carry out their inhibition activities against monoamine oxidases along with modelling investigations to evaluate their binding interactions and dynamic stability during the docking studies. The inhibition profile of potent compounds was found as competitive for both the isozymes. The compounds were more selective inhibitors of MAO-A as compared to MAO-B. Moreover, drug likeness profile of the derivatives was evaluated to have an additional insight into the physicochemical properties. The molecular dynamic simulations predicted the behaviour of amino acids with the active site residues.
  3. Fulltext The Key Role of TNF-TNFR2 Interactions in the Modulation of Allergic Inflammation: A Review
    Ahmad S, Azid NA, Boer JC, Lim J, Chen X, Plebanski M, et al.
    Front Immunol, 2018;9:2572.
    PMID: 30473698 DOI: 10.3389/fimmu.2018.02572
    Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine, which is thought to play a major role in the pathogenesis of inflammatory diseases, including allergy. TNF is produced at the early stage of allergen sensitization, and then continues to promote the inflammation cascade in the effector phase of allergic reactions. Consequently, anti-TNF treatment has been proposed as a potential therapeutic option. However, recent studies reveal anti-intuitive effects of TNF in the activation and proliferative expansion of immunosuppressive Tregs, tolerogenic DCs and MDSCs. This immunosuppressive effect of TNF is mediated by TNFR2, which is preferentially expressed by immunosuppressive cells. These findings redefine the role of TNF in allergic reaction, and suggest that targeting TNF-TNFR2 interaction itself may represent a novel strategy in the treatment of allergy.
  4. Fulltext Numerical Investigation of 1 × 7 Steel Wire Strand under Fretting Fatigue Condition
    Ahmad S, Badshah S, Ul Haq I, Abdullah Malik S, Amjad M, Nasir Tamin M
    Materials (Basel), 2019 Oct 23;12(21).
    PMID: 31652687 DOI: 10.3390/ma12213463
    Wire ropes undergo a fretting fatigue condition when subjected to axial and bending loads. The fretting behavior of wires are classified as line contact and trellis point of contact. The experimental study on the fatigue of wire ropes indicates that most of the failure occurs due to high localized stresses at trellis point of contact. A continuum damage mechanics approach was previously proposed to estimate the fatigue life estimation of wire ropes. The approach majorly depends on the high value of localized stresses as well as the micro-slippage occurs at the contact region. Finite element approach has been used to study radial and axial distribution of stresses and displacement in order to clearly understand the evolution of stresses and existence of relative displacements between neighboring wires under various loading and frictional conditions. The relative movements of contacting wires are more when friction is not considered. In the presence of friction, the relative movement occurs at the boundaries of the contact region. The location of microslip in the presence of friction is backed by the experimental observation stating the crack is initiated at or the outer boundary of the contact spot. The existence of slip is due to different displacement of outer and central wires.
  5. Fulltext Assessment of self-stigma, self-esteem, and asthma control: A preliminary cross-sectional study among adult asthmatic patients in Selangor, Malaysia
    Ahmad S, Ismail AI, Zim MAM, Ismail NE
    Front Public Health, 2019;7:420.
    PMID: 32039131 DOI: 10.3389/fpubh.2019.00420
    Purpose: The elusive goal of asthma management guidelines is to achieve and maintain good asthma control in asthmatic patients. Against a background of long-term respiratory limitations when living with asthma, stigma and low self-esteem have also been identified as the social phenomenon among adult asthmatics. This study aimed to assess the levels of self-stigma, self-esteem, and asthma control, and to investigate the impact of self-stigma and self-esteem as psychosocial factors on asthma control in Malaysian adults living with asthma.
    Materials and Methods: In this multicenter cross-sectional study, post-ethics approval and patients' consents, 152 stable asthmatic patients (aged > 18 years old; nil cognitive disability; not diagnosed with other respiratory diseases) were recruited from four respiratory clinics in Selangor, Malaysia. The patients' socio-demographic, medical, and psychosocial (self-stigma and self-esteem) data were recorded in a pre-validated, self-designed questionnaire. All data were analyzed descriptively and inferentially (independent t-test/one-way ANOVA, and multiple linear regression) using the Statistical Package for Social Sciences (SPSS®).
    Results: The enrolled patients showed moderate levels of self-stigma (62.12 ± 6.44) and self-esteem (29.31 ± 3.29), and not well-controlled asthma (17.58 ± 3.99). The number of patients' visits to emergency rooms because of asthma [CI (-1.199, 0.317), p < 0.001] was the significant predictor to asthma control among all selected study variables from socio-demographic and medical data. Moreover, from psychosocial factors both self-stigma [CI (-0.367, 0.190), p < 0.001], and self-esteem [CI (-0.007, 0.033), p = 0.041] found to be the significant predictors of asthma control.
    Conclusion: The preliminary evidences presented in this study found that frequent emergency room visits, high self-stigma and low self-esteem in asthma patients becomes more apparent with poor asthma control. Educational interventions to reduce patients' self-stigma and improve self-esteem are needed to achieve optimal control of asthma.
    Study site: Four respiratory clinics in Selangor, Malaysia (UiTM Respiratory specialist Clinic, Hospital Selayang and Hospital Sungai Buloh)
  6. Synthesis, X-ray crystal and monoamine oxidase inhibitory activity of 4,6-dihydrobenzo[c]pyrano[2,3-e][1,2]thiazine 5,5-dioxides: In vitro studies and docking analysis
    Ahmad S, Jalil S, Zaib S, Aslam S, Ahmad M, Rasul A, et al.
    Eur J Pharm Sci, 2019 Apr 01;131:9-22.
    PMID: 30735822 DOI: 10.1016/j.ejps.2019.02.007
    We report the synthesis and biological evaluation of two new series of 2-amino-6-benzyl-4-phenyl-4,6-dihydrobenzo[c]pyrano[2,3-e][1,2]thiazine-3‑carbonitrile 5,5-dioxides and 2-amino-6-methyl-4-phenyl-4,6-dihydrobenzo[c]pyrano[2,3-e][1,2]thiazine-3‑carbonitrile 5,5-dioxides. The synthetic methodology involves a multistep reaction starting with methyl anthranilate which was coupled with methane sulfonyl chloride. The product of the reaction was subjected to N-benzylation and N-methylation reactions followed by ring closure with sodium hydride resulting in the formation of respective 2,1-benzothiazine 2,2-dioxides. These 2,1-benzothiazine precursors were subjected to multicomponent reaction with malononitrile and substituted benzaldehydes for the synthesis of two new series of pyranobenzothiazines (6a-r and 7a-r). The synthesized compounds were screened as selective inhibitors of monoamine oxidase A and monoamine oxidase B. The in vitro results suggested that compound 6d and 7q are the selective inhibitors of monoamine oxidase A, however, the selective and potent inhibitors of monoamine oxidase B included compounds 6h and 7r. Moreover, some dual inhibitors were noticed like 7l having more inhibitory activity towards both the isozymes. Moreover, the binding modes of the selective and potent inhibitors of monoamine oxidase A and B were investigated by molecular docking analysis. The results suggested that the synthetic derivatives may be potential towards the monoamine oxidase isozymes.
  7. Fulltext Traumatic Anterior Dislocation of Hip in a Child - Case Report
    Ahmad S, Devkota P, Mamman KG
    Malays Orthop J, 2015 Mar;9(1):30-31.
    PMID: 28435593 DOI: 10.5704/MOJ.1503.003
    Traumatic hip dislocation in children is relatively rare accounting for about 5% of all hip dislocations. Most of the hip dislocations seen in children are of the posterior type but the much rarer anterior and anterior-inferior (obturator) types have also been described. We present the case of an eight years old girl with an obturator type of hip dislocation following trivial trauma. She was treated with closed reduction and immobilisation in skin traction for three weeks. She was followed up closely for one year and did not develop any complications during that period.
  8. NETASA: neural network based prediction of solvent accessibility
    Ahmad S, Gromiha MM
    Bioinformatics, 2002 Jun;18(6):819-24.
    PMID: 12075017
    MOTIVATION: Prediction of the tertiary structure of a protein from its amino acid sequence is one of the most important problems in molecular biology. The successful prediction of solvent accessibility will be very helpful to achieve this goal. In the present work, we have implemented a server, NETASA for predicting solvent accessibility of amino acids using our newly optimized neural network algorithm. Several new features in the neural network architecture and training method have been introduced, and the network learns faster to provide accuracy values, which are comparable or better than other methods of ASA prediction.

    RESULTS: Prediction in two and three state classification systems with several thresholds are provided. Our prediction method achieved the accuracy level upto 90% for training and 88% for test data sets. Three state prediction results provide a maximum 65% accuracy for training and 63% for the test data. Applicability of neural networks for ASA prediction has been confirmed with a larger data set and wider range of state thresholds. Salient differences between a linear and exponential network for ASA prediction have been analysed.

    AVAILABILITY: Online predictions are freely available at: http://www.netasa.org. Linux ix86 binaries of the program written for this work may be obtained by email from the corresponding author.

  9. Targeting immunosuppressor cells with nanoparticles in autoimmunity: How far have we come to?
    Ahmad S, Al-Hatamleh MAI, Mohamud R
    Cell Immunol, 2021 10;368:104412.
    PMID: 34340162 DOI: 10.1016/j.cellimm.2021.104412
    Autoimmunity is the assault of immune response towards self-antigens, resulting to inflammation and tissue injury. It is staged into three phases and caused by malfunction of immune tolerance. In our body, immune tolerance is synchronized by several immunosuppressor cells such as regulatory T cells and B cells as well as myeloid-derived suppressor cells, which are prominently dysregulated in autoimmunity. Hence, targeting these cell populations serve as a significant potential in the therapy of autoimmunity. Nanotechnology with its advantageous properties is shown to be a remarkable tool as drug delivery system in this field. This review focused on the development of therapeutics in autoimmune diseases utilizing various nanoparticles formulation based on two targeting approaches in autoimmunity, passive and active targeting. Lastly, this review outlined the approved present nanomedicines as well as in clinical evaluations and issues regarding the lack of translation of these nanomedicines into the market, despite the abundant of positive experimental observations.
  10. Fulltext Effects of ageing on pro-arrhythmic ventricular phenotypes in incrementally paced murine Pgc-1β -/- hearts
    Ahmad S, Valli H, Edling CE, Grace AA, Jeevaratnam K, Huang CL
    Pflugers Arch., 2017 Dec;469(12):1579-1590.
    PMID: 28821956 DOI: 10.1007/s00424-017-2054-3
    A range of chronic clinical conditions accompany cardiomyocyte energetic dysfunction and constitute independent risk factors for cardiac arrhythmia. We investigated pro-arrhythmic and arrhythmic phenotypes in energetically deficient C57BL mice with genetic ablation of the mitochondrial promoter peroxisome proliferator-activated receptor-γ coactivator-1β (Pgc-1β), a known model of ventricular arrhythmia. Pro-arrhythmic and cellular action potential (AP) characteristics were compared in intact Langendorff-perfused hearts from young (12-16 week) and aged (> 52 week), wild-type (WT) and Pgc-1β -/- mice. Simultaneous electrocardiographic and intracellular microelectrode recordings were made through successive trains of 100 regular stimuli at progressively incremented heart rates. Aged Pgc-1β -/- hearts displayed an increased incidence of arrhythmia compared to other groups. Young and aged Pgc-1β -/- hearts showed higher incidences of alternans in both AP activation (maximum AP upshoot velocity (dV/dt)max and latency), recovery (action potential duration (APD90) and resting membrane potential (RMP) characteristics compared to WT hearts. This was particularly apparent at lower pacing frequencies. These findings accompanied reduced (dV/dt)max and increased AP latency values in the Pgc-1β -/- hearts. APs observed prior to termination of the protocol showed lower (dV/dt)max and longer AP latencies, but indistinguishable APD90 and RMPs in arrhythmic compared to those in non-arrhythmic hearts. APD restitution analysis showed that Pgc-1β -/- and WT hearts showed similar limiting gradients. However, Pgc-1β -/- hearts had shortened plateau AP wavelengths, particularly in aged Pgc-1β -/- hearts. Pgc-1β -/- hearts therefore show pro-arrhythmic instabilities attributable to altered AP conduction and activation rather than recovery characteristics.
  11. Cryopreservation versus fresh frozen meniscal allograft: A biomechanical comparative analysis
    Ahmad S, Singh VA, Hussein SI
    J Orthop Surg (Hong Kong), 2017 8 29;25(3):2309499017727946.
    PMID: 28844199 DOI: 10.1177/2309499017727946
    Meniscal allograft transplantation may be a better alternative for the treatment of irreparable meniscal injury compared to other forms of treatment. However, it remains to be seen whether the use fresh frozen allograft is better than cryopreserved allograft in treating this type of injury. We hypothesized that cryopreserved meniscal allograft would work better in maintaining the original biomechanical properties compared to fresh frozen ones, due to the lower amount of damage it incurs during the storage process. We examined young and healthy human menisci obtained from orthopedic oncology patients who underwent resection surgeries around the knee. The menisci obtained were preserved via cryopreservation and deep-freezing process. Traction tests were carried out on the menisci after 6 weeks of preservation. Twelve pairs ( N = 24) of menisci were divided equally into two groups, cryopreservation and deep frozen. There were six males and six female menisci donors for this study. The age range was between 15 and 35 years old (24.9 ± 8.6 years). Cryopreserved specimens had a higher ultimate tensile strength (UTS; 8.2 ± 1.3 Mpa vs. 13.3 ± 1.7 Mpa: p < 0.05) and elastic modulus (61.7 ± 27.6 Mpa vs. 87.0 ± 44.10 Mpa: p < 0.05) compared to the fresh frozen specimens. There was a significant difference in UTS ( p < 0.05) between the two groups but no significant difference in their elastic modulus ( p > 0.05). The elastic modulus of the preserved meniscus was similar to fresh normal menisci taken from other studies (60-120 Mpa; cryopreserved (87.0 ± 44.1) and fresh frozen (61.7 ± 27.5)). Cryopreserved menisci had a higher elastic modulus and point of rupture (UTS) compared to fresh frozen menisci. Cryopreservation proved to be a significantly better method of preservation, among the two methods of preservation in this study.
  12. Fulltext The role of TNFR2+ Tregs in COVID-19: An overview and a potential therapeutic strategy
    Ahmad S, Hatmal MM, Lambuk L, Al-Hatamleh MAI, Alshaer W, Mohamud R
    Life Sci, 2021 Dec 01;286:120063.
    PMID: 34673116 DOI: 10.1016/j.lfs.2021.120063
    COVID-19 is a multi-faceted disease ranging from asymptomatic to severely ill condition that primarily affects the lungs and could advance to other organs as well. It's causing factor, SARS-CoV-2 is recognized to develop robust cell-mediated immunity that responsible to either control or exaggerate the infection. As an important cell subset that control immune responses and are significantly dysregulated in COVID-19, Tregs is proposed to be considered for COVID-19 management. Among its hallmark, TNFR2 is recently recognized to play important role in the function and survival of Tregs. This review gathers available TNFR2 agonists to directly target Tregs as a potential approach to overcome immune dysregulation that affect the severity in COVID-19. Furthermore, this review performs a rigid body docking of TNF-TNFR2 interaction and such interaction with TNFR2 agonist to predict the optimal targeting approach.
  13. Fulltext Pathogenicity of Salmonella enterica subspecies enterica serovar Enteritidis phage type 1 in one-day-old specific pathogen-free chicks
    Ahmad S, Hair-Bejo M, Hussein EA, Awad EA, Saeed MI, Liew PS, et al.
    Open Vet J, 2022;12(6):839-850.
    PMID: 36650863 DOI: 10.5455/OVJ.2022.v12.i6.8
    BACKGROUND: The studies about Salmonella infection in newly hatched chicks were not extensive.

    AIM: The objective of this study was to determine the pathogenicity of Salmonella enterica subspecies enterica serovar Enteritidis (SE) phage type (PT) 1 in one-day-old specific pathogen-free (SPF) chicks.

    METHODS: Seventy, one-day-old SPF chicks, were divided into SE group (30 chicks), mortality group (10 chicks), both orally inoculated (1.0 ml) with SE PT1 (1 × 108 colony-forming unit per 1.0 ml), and one control group (30 chicks). The chicks were sacrificed at 6 and 12 hours, and days 1, 2, 3, 5, 7, 10, 14, and 21 post-inoculation (pi). Samples were collected for bacterial isolation, histological examination, and ultrastructural examination.

    RESULTS: Starting from day 2 pi, the body weight in the SE group significantly (p < 0.05) decreased. The SE isolation percentages from the liver, spleen, mid-intestinal content, cecal content, cecal tonsil, blood, and cloacal swab were 0.73, 0.77, 0.33, 0.33, 0.36, 0.40, and 0.30, respectively. The isolation percentage in the liver was significantly (p < 0.05) higher than the blood and cloacal swab. The villi heights and crypt depths in the SE group were significantly (p < 0.05) greater and smaller, respectively. Ultrastructurally, erosion and necrosis were observed in the microvilli of the cecal tonsil. The bacteria were engulfed by macrophages at the interepithelial clefts of the M-like M cells.

    CONCLUSION: It was concluded that the inoculation of SE PT 1 in one-day-old chicks caused a systemic infection with diarrhea, a decrease in the body weight and villi height in the duodenum, jejunum, and ileum, and high bacterial loading in the liver with mild gross and histological lesions of organs, erosion, and necrosis of microvilli and low mortality. The bacteria entered the body system from the intestinal tract through the interepithelial clefts of the M-like M cells of the cecal tonsil.

  14. Anti-Tumor Necrosis Factor for Supplementary Management in Severe Asthma: A Systematic Review and Meta-analysis
    Ahmad S, Mohd Noor N, Engku Nur Syafirah EAR, Irekeola AA, Shueb RH, Chan YY, et al.
    J Interferon Cytokine Res, 2023 Feb;43(2):77-85.
    PMID: 36795972 DOI: 10.1089/jir.2022.0211
    Tumor-necrosis factor (TNF) is recognized as a therapeutic target in inflammatory diseases, including asthma. In severe forms of asthma, biologics such as anti-TNF are rendered to be investigated as therapeutic options in severe asthma. Hence, this work is done to assess the efficacy and safety of anti-TNF as a supplementary therapy for patients with severe asthma. A systematic search of 3 databases (Cochrane Central Register of Controlled Trials, MEDLINE, ClinicalTrials.gov) was performed to identify for published and unpublished randomized controlled trials comparing anti-TNF (etanercept, adalimumab, infliximab, certolizumab pegol, golimumab) with placebo in patients diagnosed with persistent or severe asthma. Random-effects model was used to estimate risk ratios and mean differences (MDs) with confidence intervals (95% CIs). PROSPERO registration number is CRD42020172006. Four trials with 489 randomized patients were included. Comparison between etanercept and placebo involved 3 trials while comparison between golimumab and placebo involved 1 trial. Etanercept produced a small but significant impairment in forced expiratory flow in 1 second (MD 0.33, 95% CI 0.09-0.57, I2 statistic = 0%, P = 0.008) and a modest improvement of asthma control using the Asthma Control Questionnaire. However, using the Asthma Quality of Life Questionnaire, the patients exhibit an impaired quality of life with etanercept. Treatment with etanercept showed a reduced injection site reaction and gastroenteritis compared with placebo. Although treatment with anti-TNF is shown to improve asthma control, severe asthma patients did not benefit from this therapy as there is limited evidence for improvement in lung function and reduction of asthma exacerbation. Hence, it is unlikely to prescribe anti-TNF in adults with severe asthma.
  15. Status of sustainable manufacturing practices: literature review and trends of triple bottom-line-based sustainability assessment methodologies
    Ahmad S, Wong KY, Butt SI
    Environ Sci Pollut Res Int, 2023 Mar;30(15):43068-43095.
    PMID: 35904736 DOI: 10.1007/s11356-022-22172-z
    Due to significant requirement of energy, water, material, and other resources, the manufacturing industries significantly impact environmental, economic, and social dimensions of sustainability (triple bottom-line). In response, today's research is focused on finding solution towards sustainable manufacturing. In this regard, sustainability assessment is an essential strategy. In the past, a variety of tools was developed to evaluate the environmental dimension. Because of this fact, previous review studies were grounded mostly on tools for green manufacturing. Unlike previous review articles, this study was aimed to review and analyze the emerging sustainability assessment methodologies (published from 2010 to 2020) for manufacturing while considering the triple bottom-line concept of sustainability. In this way, the paper presents a decade review on this topic, starting from 2010 as the guidelines for the social dimension became available in 2009. This paper has analyzed various methods and explored recent progress patterns. First, this study critically reviewed the methods and then analyzed their different integrating tools, sustainability dimensions, nature of indicators, difficulty levels, assessment boundaries, etc. The review showed that life cycle assessment and analytic hierarchy process-based approaches were most commonly used as integrating tools. Comparatively, still, environmental dimension was more commonly considered than economic and social dimensions by most of the reviewed methods. From indicators' viewpoint, most of the studied tools were based on limited number of indicators, having no relative weights and validation from the experts. To overcome these challenges, future research directions were outlined to make these methods more inclusive and reliable. Along with putting more focus on economic and social dimensions, there is a need to employ weighted, validated, and applicable indicators in sustainability assessment methods for manufacturing.
  16. Fulltext Quantification of Berberine in Berberis vulgaris L. Root Extract and Its Curative and Prophylactic Role in Cisplatin-Induced In Vivo Toxicity and In Vitro Cytotoxicity
    Ahmad S, Hussain A, Hussain A, Abdullah I, Ali MS, Froeyen M, et al.
    Antioxidants (Basel), 2019 Jun 19;8(6).
    PMID: 31248160 DOI: 10.3390/antiox8060185
    Cisplatin is amongst the most potent chemotherapeutic drugs with applications in more than 50% of cancer treatments, but dose-dependent side effects limit its usefulness. Berberis vulgaris L. (B. vulgaris) has a proven role in several therapeutic applications in the traditional medicinal system. High-performance liquid chromatography was used to quantify berberine, a potent alkaloid in the methanolic root extract of B. vulgaris (BvRE). Berberine chloride in BvRE was found to be 10.29% w/w. To assess the prophylactic and curative protective effects of BvRE on cisplatin-induced nephrotoxicity, hepatotoxicity, and hyperlipidemia, in vivo toxicity trials were carried out on 25 healthy male albino Wistar rats (130-180 g). Both prophylactic and curative trials included a single dose of cisplatin (4 mg/kg, i.p.) and nine doses of BvRE (500 mg/kg/day, orally). An array of marked toxicity effects appeared in response to cisplatin dosage evident by morphological condition, biochemical analysis of serum (urea, creatinine, total protein, alanine transaminase, aspartate transaminase, total cholesterol, and triglyceride), and organ tissue homogenates (malondialdehyde and catalase). Statistically-significant (p < 0.05) variations were observed in various parameters. Moreover, histological studies of liver and kidney tissues revealed that the protective effect of BvRE effectively minimized and reversed nephrotoxic, hepatotoxic, and hyperlipidemic effects caused by cisplatin in both prophylactic and curative groups with relatively promising ameliorative effects in the prophylactic regimen. The in vitro cell viability effect of cisplatin, BvRE, and their combination was determined on HeLa cells using the tetrazolium (MTT) assay. MTT clearly corroborated that HeLa cells appeared to be less sensitive to cisplatin and berberine individually, while the combination of both at the same concentrations resulted in growth inhibition of HeLa cells in a remarkable synergistic way. The present study validated the use of BvRE as a protective agent in combination therapy with cisplatin.
  17. Fulltext Gene coexpression network analysis reveals perirenal adipose tissue as an important target of prenatal malnutrition in sheep
    Ahmad S, Drag MH, Mohamad Salleh S, Cai Z, Nielsen MO
    Physiol Genomics, 2023 Sep 01;55(9):392-413.
    PMID: 37458462 DOI: 10.1152/physiolgenomics.00128.2022
    We have previously demonstrated that pre- and early postnatal malnutrition in sheep induced depot- and sex-specific changes in adipose morphological features, metabolic outcomes, and transcriptome in adulthood, with perirenal (PER) as the major target followed by subcutaneous (SUB) adipose tissue. We aimed to identify coexpressed and hub genes in SUB and PER to identify the underlying molecular mechanisms contributing to the early nutritional programming of adipose-related phenotypic outcomes. Transcriptomes of SUB and PER of male and female adult sheep with different pre- and early postnatal nutrition histories were used to construct networks of coexpressed genes likely to be functionally associated with pre- and early postnatal nutrition histories and phenotypic traits using weighted gene coexpression network analysis. The modules from PER showed enrichment of cell cycle regulation, gene expression, transmembrane transport, and metabolic processes associated with both sexes' prenatal nutrition. In SUB (only males), a module of enriched adenosine diphosphate metabolism and development correlated with prenatal nutrition. Sex-specific module enrichments were found in PER, such as chromatin modification in the male network but histone modification and mitochondria- and oxidative phosphorylation-related functions in the female network. These sex-specific modules correlated with prenatal nutrition and adipocyte size distribution patterns. Our results point to PER as a primary target of prenatal malnutrition compared to SUB, which played only a minor role. The prenatal programming of gene expression and cell cycle, potentially through epigenetic modifications, might be underlying mechanisms responsible for observed changes in PER expandability and adipocyte-size distribution patterns in adulthood in both sexes.
  18. Acetylsalicylic acid-sulfa drugs conjugates as potential urease inhibitors and anti-inflammatory agents: bio-oriented drug synthesis, molecular docking, and dynamics simulation studies
    Ahmad S, Abdul Qadir M, Ahmed M, Imran M, Yousaf N, Asari A, et al.
    J Biomol Struct Dyn, 2023 Aug 29.
    PMID: 37643014 DOI: 10.1080/07391102.2023.2252083
    To explore the new mode of action and reduce side effects, making conjugates of existing drugs is becoming an attractive tool in the realm of medicinal chemistry. In this work, we exploited this approach and synthesized new conjugates to assess their activities against the enzymes involved in different pathological conditions. Specifically, we design and synthesized conjugates involving acetylsalicylic acid and sulfa drugs, validating the newly crafted conjugates using techniques like IR, 1HNMR, 13CNMR, and elemental analysis. These conjugates underwent assessment for their ability to inhibit cyclooxygenase-2 (COX-2), urease enzymes, and their anti-inflammatory potential. A competitive mode of urease inhibition was observed for acetylsalicylic acid conjugated with sulfanilamide, sulfacetamide, and sulfadiazine with IC50 of 2.49 ± 0.35 µM, 6.21 ± 0.28 µM, and 6.57 ± 0.44 µM, respectively. Remarkably, the acetylsalicylic acid-sulfamethoxazole conjugate exhibited exceptional anti-inflammatory activity, effectively curtailing induced edema by 83.7%, a result akin to the reference anti-inflammatory drug indomethacin's performance (86.8%). Additionally, it demonstrated comparable COX-2 inhibition (75.8%) to the reference selective COX-2 inhibitor celecoxib that exhibited 77.1% inhibition at 10 µM concentration. To deepen our understanding, we employed molecular docking techniques to predict the binding interactions of competitive inhibitors with COX-2 and urease receptors. Additionally, MD simulations were carried out, confirming the stability of inhibitor-target complexes throughout the simulation period, devoid of significant conformational changes. Collectively, our research underscores the potential of coupling approved medicinal compounds to usher in novel categories of pharmacological agents, holding promise for addressing a wide spectrum of pathological disorders involving COX-2 and urease enzymes.Communicated by Ramaswamy H. Sarma.
  19. Fulltext Fragment-based in silico design of SARS-CoV-2 main protease inhibitors
    Ahmad S, Usman Mirza M, Yean Kee L, Nazir M, Abdul Rahman N, Trant JF, et al.
    Chem Biol Drug Des, 2021 Oct;98(4):604-619.
    PMID: 34148292 DOI: 10.1111/cbdd.13914
    3CLpro is essential for SARS-CoV-2 replication and infection; its inhibition using small molecules is a potential therapeutic strategy. In this study, a comprehensive crystallography-guided fragment-based drug discovery approach was employed to design new inhibitors for SARS-CoV-2 3CLpro. All small molecules co-crystallized with SARS-CoV-2 3CLpro with structures deposited in the Protein Data Bank were used as inputs. Fragments sitting in the binding pocket (87) were grouped into eight geographical types. They were interactively coupled using various synthetically reasonable linkers to generate larger molecules with divalent binding modes taking advantage of two different fragments' interactions. In total, 1,251 compounds were proposed, and 7,158 stereoisomers were screened using Glide (standard precision and extra precision), AutoDock Vina, and Prime MMGBSA. The top 22 hits having conformations approaching the linear combination of their constituent fragments were selected for MD simulation on Desmond. MD simulation suggested 15 of these did adopt conformations very close to their constituent pieces with far higher binding affinity than either constituent domain alone. These structures could provide a starting point for the further design of SARS-CoV-2 3CLpro inhibitors with improved binding, and structures are provided.
  20. Fulltext Reduced cardiomyocyte Na+ current in the age-dependent murine Pgc-1β-/- model of ventricular arrhythmia
    Ahmad S, Valli H, Smyth R, Jiang AY, Jeevaratnam K, Matthews HR, et al.
    J Cell Physiol, 2019 Apr;234(4):3921-3932.
    PMID: 30146680 DOI: 10.1002/jcp.27183
    Peroxisome proliferator-activated receptor-γ coactivator-1 deficient (Pgc-1β-/- ) murine hearts model the increased, age-dependent, ventricular arrhythmic risks attributed to clinical conditions associated with mitochondrial energetic dysfunction. These were accompanied by compromised action potential (AP) upstroke rates and impaired conduction velocities potentially producing arrhythmic substrate. We tested a hypothesis implicating compromised Na+ current in these electrophysiological phenotypes by applying loose patch-clamp techniques in intact young and aged, wild-type (WT) and Pgc-1β-/- , ventricular cardiomyocyte preparations for the first time. This allowed conservation of their in vivo extracellular and intracellular conditions. Depolarising steps elicited typical voltage-dependent activating and inactivating inward Na+ currents with peak amplitudes increasing or decreasing with their respective activating or preceding inactivating voltage steps. Two-way analysis of variance associated Pgc-1β-/- genotype with independent reductions in maximum peak ventricular Na+ currents from -36.63 ± 2.14 (n = 20) and -35.43 ± 1.96 (n = 18; young and aged WT, respectively), to -29.06 ± 1.65 (n = 23) and -27.93 ± 1.63 (n = 20; young and aged Pgc-1β-/- , respectively) pA/μm2 (p 
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