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  1. Fulltext mRNA transcriptome profiling of human hepatocellular carcinoma cells HepG2 treated with Catharanthus roseus-silver nanoparticles
    Azhar NA, Abu Bakar SA, Citartan M, Ahmad NH
    World J Hepatol, 2023 Mar 27;15(3):393-409.
    PMID: 37034237 DOI: 10.4254/wjh.v15.i3.393
    BACKGROUND: The demand for the development of cancer nanomedicine has increased due to its great therapeutic value that can overcome the limitations of conventional cancer therapy. However, the presence of various bioactive compounds in crude plant extracts used for the synthesis of silver nanoparticles (AgNPs) makes its precise mechanisms of action unclear.

    AIM: To assessed the mRNA transcriptome profiling of human HepG2 cells exposed to Catharanthus roseus G. Don (C. roseus)-AgNPs.

    METHODS: The proliferative activity of hepatocellular carcinoma (HepG2) and normal human liver (THLE3) cells treated with C. roseusAgNPs were measured using MTT assay. The RNA samples were extracted and sequenced using BGIseq500 platform. This is followed by data filtering, mapping, gene expression analysis, differentially expression genes analysis, Gene Ontology analysis, and pathway analysis.

    RESULTS: The mean IC50 values of C. roseusAgNPs on HepG2 was 4.38 ± 1.59 μg/mL while on THLE3 cells was 800 ± 1.55 μg/mL. Transcriptome profiling revealed an alteration of 296 genes. C. roseusAgNPs induced the expression of stress-associated genes such as MT, HSP and HMOX-1. Cellular signalling pathways were potentially activated through MAPK, TNF and TGF pathways that are responsible for apoptosis and cell cycle arrest. The alteration of ARF6, EHD2, FGFR3, RhoA, EEA1, VPS28, VPS25, and TSG101 indicated the uptake of C. roseus-AgNPs via both clathrin-dependent and clathrin-independent endocytosis.

    CONCLUSION: This study provides new insights into gene expression study of biosynthesised AgNPs on cancer cells. The cytotoxicity effect is mediated by the aberrant gene alteration, and more interestingly the unique selective antiproliferative properties indicate the C. roseusAgNPs as an ideal anticancer candidate.

  2. Suppressing growth, migration, and invasion of human hepatocellular carcinoma HepG2 cells by Catharanthus roseus‑silver nanoparticles
    Azhar NA, Ghozali SZ, Abu Bakar SA, Lim V, Ahmad NH
    Toxicol In Vitro, 2020 Sep;67:104910.
    PMID: 32526345 DOI: 10.1016/j.tiv.2020.104910
    Application of silver nanoparticles serves as a new approach in cancer treatment due to its unique features. Biosynthesis of silver nanoparticles using plant is advantageous since they are easily accessible, nontoxic and produce quicker reaction compared to other methods. To evaluate the cytotoxicity, mechanism of cell death and DNA damage of biosynthesized Catharanthus roseus-silver nanoparticles on human liver cancer (HepG2) cells. The antiproliferative activity of Catharanthus roseus‑silver nanoparticles was measured using MTT assay. The cytotoxic effects were further evaluated by measuring nitric oxide and reactive oxygen species (ROS). The mechanism of cell death was determined by annexin-FITC/propidium iodide, mitochondrial membrane potential (MMP) and cell cycle assays. The assessment of DNA damage was evaluated using Comet assay method. The uptake of the nanoparticles were evaluated by Transmission Electron Microscopy (TEM). Catharanthus roseus‑silver nanoparticles has inhibited the proliferation of HepG2 cells in a time-dependent manner with a median IC50 value of 3.871 ± 0.18 μg/mL. The concentration of nitrite and ROS were significantly higher than control. The cell death was due to apoptosis associated with MMP loss, cell cycle arrest, and extensive DNA damage. TEM analysis indicated the presence of free nanoparticles and endosomes containing the nanoparticles. The findings show that Catharanthus roseus‑silver nanoparticles have produced cytotoxic effects on HepG2 cells and thus may have a potential to be used as an anticancer treatment, particularly for hepatocellular carcinoma.
  3. Psychological Distress of Health Care Workers in the Main Admitting Hospital and Its Related Health Care Facilities in Malaysia During the COVID-19 Pandemic
    Razali S, Abdullah MN, Rahman NA, Azhar NA, Yaacob SS
    Asia Pac J Public Health, 2021 07;33(5):667-669.
    PMID: 33969738 DOI: 10.1177/10105395211014348
  4. Human mesenchymal stromal cells modulate T-cell immune response via transcriptomic regulation
    Vellasamy S, Tong CK, Azhar NA, Kodiappan R, Chan SC, Veerakumarasivam A, et al.
    Cytotherapy, 2016 10;18(10):1270-83.
    PMID: 27543068 DOI: 10.1016/j.jcyt.2016.06.017
    BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) have been identified as pan-immunosuppressant in various in vitro and in vivo inflammatory models. Although the immunosuppressive activity of MSCs has been explored in various contexts, the precise molecular signaling pathways that govern inhibitory functions remain poorly elucidated.

    METHODS: By using a microarray-based global gene expression profiling system, this study aimed to decipher the underlying molecular pathways that may mediate the immunosuppressive activity of umbilical cord-derived MSCs (UC-MSCs) on activated T cells.

    RESULTS: In the presence of UC-MSCs, the proliferation of activated T cells was suppressed in a dose-depended manner by cell-to-cell contact mode via an active cell-cycle arrest at the G0/G1 phase of the cell cycle. The microarray analysis revealed that particularly, IFNG, CXCL9, IL2, IL2RA and CCND3 genes were down-regulated, whereas IL11, VSIG4, GFA1, TIMP3 and BBC3 genes were up-regulated by UC-MSCs. The dysregulated gene clusters associated with immune-response-related ontologies, namely, lymphocyte proliferation or activation, apoptosis and cell cycle, were further analyzed.

    CONCLUSIONS: Among the nine canonical pathways identified, three pathways (namely T-helper cell differentiation, cyclins and cell cycle regulation, and gap/tight junction signalling pathways) were highly enriched with these dysregulated genes. The pathways represent putative molecular pathways through which UC-MSCs elicit immunosuppressive activity toward activated T cells. This study provides a global snapshot of gene networks and pathways that contribute to the ability of UC-MSCs to suppress activated T cells.

  5. Pro-inflammatory cytokines and reproductive hormone responses in bucks post-challenge with Mannheimia haemolytica A2 and its outer membrane protein
    Azhar NA, Paul BT, Jesse FFA, Mohd-Lila MA, Chung ELT, Kamarulrizal MI
    Trop Anim Health Prod, 2023 Aug 17;55(5):291.
    PMID: 37589856 DOI: 10.1007/s11250-023-03706-0
    The lipopolysaccharide (LPS) endotoxin and outer membrane protein (OMP) are among the virulence factors of Gram-negative bacteria responsible for inducing pathogenicity in the infected host. OMP and LPS occur on the outer membrane of M. haemolytica A2, the primary aetiological agent of pneumonic mannheimiosis in small ruminants. While the LPS is known to mediate Gram-negative bacterial infection by activating downstream inflammatory pathways, the potential role of OMP during inflammatory responses remained unclear. Hence, this study determined the effect of the OMP of M. haemolytica A2 on the serum concentration of pro-inflammatory cytokines and the male reproductive hormones (testosterone and Luteinizing Hormone). We randomly assigned twelve bucks to three groups (n = 4 bucks each): Group 1 was challenged with 2 mL PBS buffer (pH 7.0) intranasally; Group 2 received 2 mL of 1.2 X 109 CFU/mL whole M. haemolytica A2 intranasally; and Group 3 received 2 mL of OMP extract obtained from 1.2 X 109 CFU/mL M. haemolytica A2 intramuscularly. Serum samples collected at pre-determined intervals were used for the quantitative determination of the pro-inflammatory cytokines (IL-1β, IL-6, and TNFα) and reproductive hormones (testosterone and LH) using commercial sandwich enzyme-linked immunosorbent assay (ELISA). The serum concentration of IL1β was initially increased within the first-hour post-challenge in Groups 2 and 3, followed by a significant decrease in concentration at 21d and 35d (p  0.05) lower than in Group 1 throughout the study. There was a moderate negative association between testosterone and IL1β (r = -0.473; p > 0.05) or TNFα (r = -0.527; p  0.05). The results of this study demonstrated that M. haemolytica A2 and its OMP produced marked alterations in serum levels of pro-inflammatory cytokines and male reproductive hormones. The negative correlations between serum testosterone and inflammatory cytokines would suggest the potential role of OMP in causing male infertility by mediating innate inflammatory responses to suppress testosterone production in bucks.
  6. Fulltext Effect of HIIT (high-intensity interval training) on vulnerability to dental caries
    Chauhan A, Mazlee AM, Azhar NA, Ng Bansing SA, Qing CS, Sidhu DS, et al.
    J Oral Biol Craniofac Res, 2020 09 17;10(4):670-673.
    PMID: 32995257 DOI: 10.1016/j.jobcr.2020.09.003
    Objective: High intensity workout stimulates the sympathetic nervous system and causes changes in the salivary composition. We hypothesized that activity of caries-causing bacteria in saliva may differ before and after workout. The objective of the study was to investigate if there is any difference in the oral microbial activity before and after HIIT (High Intensity Interval Training) workout.

    Methods: Unstimulated saliva was collected before and after HIIT workout (n = 35). The workout was performed until the participant's heart rate reached 70-80% of maximum heart rate. The microbial activity of saliva was estimated using Oratest.

    Results: The participants belonged to 4 ethnities- Indian, Malays, Chinese and Others (18-22 years). The post-workout salivary microbial activity was higher than the pre-workout levels, being statistically significant (P = 0.010). The increase in the post-workout microbial activity among females was found to be higher when compared to males. We also found significant different according to the ethnicities.

    Conclusion: We conclude that caries activity increases immediately after a vigorous workout and remains high at least for 15 min. Further studies are needed to validate the findings. Workout enthusiast should be aware of this so that they can take necessary precautions and be more regular with their dental check-ups.

  7. Responses of testosterone hormone and important inflammatory cytokines in bucks after challenge with Mannheimia haemolytica A2 and its LPS endotoxin
    Azhar NA, Paul BT, Jesse FFA, Chung ELT, Isa KM, Lila MAM, et al.
    Trop Anim Health Prod, 2021 Apr 03;53(2):242.
    PMID: 33811523 DOI: 10.1007/s11250-021-02683-6
    Previous studies have shown that Mannheimia haemolytica A2 is the principal microorganism causing pneumonic mannheimiosis, a major bacterial respiratory disease among sheep and goats. The effect of this bacteria on the respiratory system is well-established. However, its effect on the reproductive physiology remains unclear. Therefore, this study aimed to determine the alterations in the level of pro-inflammatory cytokines and testosterone hormone post-inoculation with M. haemolytica serotype A2 and its lipopolysaccharide (LPS) endotoxin which were hypothesized to affect the reproductive functions of bucks. Twelve clinically healthy adult male goats were divided equally into three groups. Goats in group 1 were treated with 2 ml of sterile phosphate-buffered saline (PBS) pH 7.0 intranasally (negative control), group 2 with 2 ml of 109 colony-forming unit (CFU) of M. haemolytica serotype A2 intranasally (positive control), and group 3 were treated with 2 ml of lipopolysaccharide extracted from 109 CFU of M. haemolytica serotype A2 intravenously. Following inoculation, blood samples were collected via jugular venipuncture into plain tubes at pre-determined intervals for serum collection to determine the concentration of interleukin (IL)-1β, IL6, tumor necrosis factor (TNF)-α, and testosterone hormone by using commercial ELISA test kits. Results from this study demonstrated that the inoculation of M. haemolytica A2 and its LPS increases the concentration of pro-inflammatory cytokines but decreases the concentration of testosterone hormone in challenged animals at most time points throughout the 56 days experimental period (p < 0.05). This study suggests that the M. haemolytica A2 and its LPS could alter the concentration of pro-inflammatory cytokines and testosterone hormone, which in turn, may negatively affect the reproductive functions of bucks.
  8. Parasitic coinfections among selected smallholder goat flocks in Malaysia
    Paul BT, Jesse FAA, Kamaludeen J, Chung ELT, Mat Isa K, Azhar NA, et al.
    Trop Biomed, 2023 Dec 01;40(4):444-452.
    PMID: 38308832 DOI: 10.47665/tb.40.4.010
    This paper describes the occurrence of multiple parasitic infection with special reference to emerging haemotropic Mycoplasma ovis. A cross-sectional survey of four selected goat flocks was conducted to collect samples and management information. Blood samples were processed using microhaematocrit centrifugation to determine the packed cell volume (PCV). Detection and morphological identification of blood protozoa and haemotropic Mycoplasma ovis from Giemsa-stained smears were done microscopically. M. ovis infection was classified mild (1-29% infected cells), moderate (30-59% infected cells), or severe (above 60% infected cells). Faecal floatation and McMaster faecal egg count were used to detect and classify strongyle infections as negative (no eggs/oocysts), light (< 500 epg), Moderate (500 - 1000 epg), or severe (>1000 epg) and coccidia infection as light (<1800 opg), moderate (1800 - 6000 opg), or severe (>6000 opg). There were 149 goats with blood protozoa (57.98%; 95% CI: 51.87 - 63.85) and 204 goats with GI parasites (79.38%; 95% CI: 74.02 - 83.87) involved in single (15.8%; 95% CI: 11.7 - 21.0) or multiple (84.2%; 95% CI: 79.0 - 88.3) infections. The risk of Strongyles increases by 2.49 (95% CI: 1.24 - 4.99) in females versus males and 6.79 (95% CI: 3.25 - 14.18, p =0.000) in adults versus young. The risk of Eimeria species increases by 7.32 (95% CI: 3.45 - 15.50, p =0.000) in adults versus young, while M. ovis coinfection risk increases by 4.51 (95% CI: 1.40 - 14.50, p =0.000) in female versus males. Thin animals had a significantly higher (p<0.05) mean burden of Strongyle (1370.37 ± 345.49) and Eimeria (1594.12 ± 695.26) than the moderate and fat goats. The PCV was negatively associated with mean faecal egg count (FEC) (p<0.05) such that a lower PCV was recorded in animals with a higher Strongyle epg output. A severe burden of M. ovis was accompanied by an increased nematode FEC and decreased haematocrit (p<0.05). Coinfections of Strongyles, or Eimeria species involving M. ovis were associated with a higher parasitaemia compared with single infections (p<0.05). This study highlights the importance of M. ovis and Strongyle or Eimeria species coinfections among goat flocks and provides valuable data for developing and implementing an integrated herd health management program for parasite control among low-input smallholder flocks.
  9. Seroprevalence and contributing factors of transboundary animal diseases in sheep and goats: a study in Peninsular Malaysia
    Jimale YA, Jesse FFA, Paul BT, Chung ELT, Zakaria A, Azhar NA, et al.
    Trop Anim Health Prod, 2024 Jul 13;56(6):212.
    PMID: 39002035 DOI: 10.1007/s11250-024-04061-4
    Diseases caused by small ruminant lentiviruses, Mycobacterium avium ssp. paratuberculosis (MAP), Schmallenberg virus, and peste des petits ruminants virus (PPR) is globally recognised as serious threats to the ruminant industry due to their potential to spread rapidly across boundaries. Despite their global distribution and negative impacts on ruminant production, there is a gap in knowledge of the current trends in their epidemiology among sheep and goat populations in Peninsular Malaysia. This study was therefore designed to fill the gap of knowledge concerning the seroprevalence and contributing factors of CAEV, paratuberculosis, SBV, and PPRV among small ruminants from selected flocks in Selangor, Negeri Sembilan, and Pahang states in Peninsular Malaysia. A cross-sectional study design was used to collect animal data and blood samples for serological assays simultaneously. The ID Screen (ID.VET, France) indirect ELISA screening tests were used to detect serum antibodies directed against CAEV/MVV (VISNAS Ver 0922), paratuberculosis (PARAS Ver 0516), SBV (SBVC Ver 1114) and PPRV (PPRC Ver 0821). There was 45.4% (95% CI = 40.74-50.74), 6.8% (95% CI = 4.66-9.69), 27.8% (95% CI = 23.35-32.77), and 2.6% (95% CI = 1.11-0.51) true seroprevalence for CAEV, paratuberculosis, SBV, and PPR, respectively. Geographical location and species were the risk factors for CAEV and paratuberculosis, while the management system and age of small ruminants were the risk factors for SBV. The present study is the first to document a large-scale seroprevalence of MAP and PPR infection among sheep and goat flocks in Peninsular Malaysia. The presence of PPRV and MAP antibodies among small ruminant flocks is signalling current or previous exposure to the pathogens or cross reactions with similar antigens. This finding further suggests the potential for future outbreaks of these devastating diseases among sheep and goats in Malaysia. The high seroprevalence of CAEV and SBV among small ruminants indicates high levels of exposure to the viruses in the environment, which is a potential threat to production.
  10. Fulltext A systematic review of efficacy and safety of newer drugs approved from 2016 to 2023 for the treatment of complicated urinary tract infections
    Sivanandy P, Manirajan P, Wen Qi O, Teng Khai O, Chun Wei O, Wei Ying N, et al.
    Ann Med, 2024 Dec;56(1):2403724.
    PMID: 39530664 DOI: 10.1080/07853890.2024.2403724
    Background: Complicated urinary tract infections are a significant cause of morbidity, hospitalization, and elevated hospital costs associated with kidney transplantations. The treatment of complicated urinary tract infections is very challenging, due to varying severities of infection and lower cure rates. The available drug options for treating these infections are limited, each with different mechanisms of action, efficacy, and safety profiles, making drug selection more difficult for healthcare professionals. Objectives: A systematic review was conducted to evaluate the safety and efficacy of drugs approved by the United States Food and Drug Administration for the treatment of complicated urinary tract infections between 2016 and 2023. The primary endpoint for all drugs used in treating complicated urinary tract infections was the cure rate. Results: Among the drugs used for treating complicated urinary tract infections, meropenem had the highest cure rate at 91.4%, followed by plazomicin at 88% and cefiderocol at 73% when used as monotherapy. In combination therapy, meropenem-vaborbactam had the highest cure rate at 98.4%, followed by piperacillin-tazobactam at 94%, and ceftazidime-avibactam at 87.5%. The safety profiles of the drugs indicated that almost all drugs caused gastrointestinal symptoms, with imipenem-relebactam and colistin-imipenem combinations having the most serious adverse events. Cefiderocol had a low magnitude of adverse events, with most side effects being mild gastrointestinal symptoms. Conclusion: The study concludes that appropriate drug selection and treatment adherence are crucial for preventing complicated urinary tract infections and improving health outcomes.
  11. Fulltext Combination of Goniothalamin and Sol-Gel-Derived Bioactive Glass 45S5 Enhances Growth Inhibitory Activity via Apoptosis Induction and Cell Cycle Arrest in Breast Cancer Cells MCF-7
    Bakar SAA, Ali AM, Noor SNFM, Hamid SBS, Azhar NA, Mohamad NM, et al.
    Biomed Res Int, 2022;2022:5653136.
    PMID: 35872839 DOI: 10.1155/2022/5653136
    BACKGROUND: Combination of natural products with chemically synthesised biomaterials as cancer therapy has attracted great interest lately. Hence, this study is aimed at investigating the combined effects of goniothalamin and bioactive glass 45S5 (GTN-BG) and evaluating their anticancer properties on human breast cancer cells MCF-7.

    METHODS: The BG 45S5 was prepared using the sol-gel process followed by characterisation using PSA, BET, SEM/EDS, XRD, and FTIR. The effects of GTN-BG on the proliferation of MCF-7 were assessed by MTT, PrestoBlue, and scratch wound assays. The cell cycle analysis, Annexin-FITC assay, and activation of caspase-3/7, caspase-8, and caspase-9 assays were determined to further explore its mechanism of action.

    RESULTS: The synthesised BG 45S5 was classified as a fine powder, having a rough surface, and contains mesopores of 12.6 nm. EDS analysis revealed that silica and calcium elements are the primary components of BG powders. Both crystalline and amorphous structures were detected with 73% and 27% similarity to Na2Ca2(Si2O7) and hydroxyapatite, respectively. The combination of GTN-BG was more potent than GTN in inhibiting the proliferation of MCF-7 cells. G0/G1 and G2/M phases of the cell cycle were arrested by GTN and GTN-BG. The percentage of viable cells in GTN-BG treatment was significantly lower than that in GTN. In terms of activation of initiator caspases for both extrinsic and intrinsic apoptosis pathways, caspase-8 and caspase-9 were found more effective in response to GTN-BG than GTN.

    CONCLUSION: The anticancer effect of GTN in MCF-7 cells was improved when combined with BG. The findings provide significant insight into the mechanism of GTN-BG against MCF-7 cells, which can potentially be used as a novel anticancer therapeutic approach.

  12. Fulltext Lack of clinical manifestations in asymptomatic dengue infection is attributed to broad down-regulation and selective up-regulation of host defence response genes
    Yeo AS, Azhar NA, Yeow W, Talbot CC, Khan MA, Shankar EM, et al.
    PLoS One, 2014;9(4):e92240.
    PMID: 24727912 DOI: 10.1371/journal.pone.0092240
    Dengue represents one of the most serious life-threatening vector-borne infectious diseases that afflicts approximately 50 million people across the globe annually. Whilst symptomatic infections are frequently reported, asymptomatic dengue remains largely unnoticed. Therefore, we sought to investigate the immune correlates conferring protection to individuals that remain clinically asymptomatic.
  13. Fulltext In Vitro Cell Proliferation and Migration Properties of Oral Mucosal Fibroblasts: A Comparative Study on the Effects of Cord Blood- and Peripheral Blood-Platelet Lysate
    Azmi AF, Yahya MAAM, Azhar NA, Ibrahim N, Ghafar NA, Ghani NAA, et al.
    Int J Mol Sci, 2023 Mar 17;24(6).
    PMID: 36982842 DOI: 10.3390/ijms24065775
    Cord blood-platelet lysate (CB-PL), containing growth factors such as a platelet-derived growth factor, has a similar efficacy to peripheral blood-platelet lysate (PB-PL) in initiating cell growth and differentiation, which makes it a unique alternative to be implemented into oral ulceration healing. This research study aimed to compare the effectiveness of CB-PL and PB-PL in promoting oral wound closure in vitro. Alamar blue assay was used to determine the optimal concentration of CB-PL and PB-PL in enhancing the proliferation of human oral mucosal fibroblasts (HOMF). The percentage of wound closure was measured using the wound-healing assay for CB-PL and PB-PL at the optimal concentration of 1.25% and 0.3125%, respectively. The gene expressions of cell phenotypic makers (Col. I, Col. III, elastin and fibronectin) were determined via qRT-PCR. The concentrations of PDGF-BB were quantified using ELISA. We found that CB-PL was as effective as PB-PL in promoting wound-healing and both PL were more effective compared to the control (CTRL) group in accelerating the cell migration in the wound-healing assay. The gene expressions of Col. III and fibronectin were significantly higher in PB-PL compared to CB-PL. The PDGF-BB concentration of PB-PL was the highest and it decreased after the wound closed on day 3. Therefore, we concluded that PL from both sources can be a beneficial treatment for wound-healing, but PB-PL showed the most promising wound-healing properties in this study.
  14. Fulltext Post-discharge spirometry evaluation in patients recovering from moderate-to-critical COVID-19: a cross-sectional study
    Chai CS, Bin Ibrahim MA, Binti Azhar NA, Binti Roslan Z, Binti Harun R, Krishnabahawan SL, et al.
    Sci Rep, 2024 Jul 16;14(1):16413.
    PMID: 39013943 DOI: 10.1038/s41598-024-67536-2
    Understanding the prevalence of abnormal lung function and its associated factors among patients recovering from COVID-19 is crucial for enhancing post-COVID care strategies. This study primarily aimed to determine the prevalence and types of spirometry abnormalities among post-COVID-19 patients in Malaysia, with a secondary objective of identifying its associated factors. Conducted at the COVID-19 Research Clinic, Faculty of Medicine, University Technology MARA, from March 2021 to December 2022, this study included patients at least three months post-discharge from hospitals following moderate-to-critical COVID-19. Of 408 patients studied, abnormal spirometry was found in 46.8%, with 28.4% exhibiting a restrictive pattern, 17.4% showing preserved ratio impaired spirometry (PRISm), and 1.0% displaying an obstructive pattern. Factors independently associated with abnormal spirometry included consolidation on chest X-ray (OR 8.1, 95% CI 1.75-37.42, p = 0.008), underlying cardiovascular disease (OR 3.5, 95% CI 1.19-10.47, p = 0.023), ground-glass opacity on chest X-ray (OR 2.6, 95% CI 1.52-4.30, p 
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