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  1. Aziee, S., Haiyuni, MY, Shafini, MY, Johan, MF, Al-Jamal, HAN, Abdul Wahab, R., et al.
    MyJurnal
    The aims of the study were to investigate the anti-cancer effects of 5-
    Aza and TSA in two leukemic cell lines (CCRF-CEM and HL-60). Inhibition
    concentration of 5-Aza and TSA were measured using trypan blue exclusion
    assay. 5-Aza and TSA at IC50 were treated to both CCRF-CEM and HL-60 cell
    lines for 4-6 days. To confirm the inhibition effects of these agents, Annexin-V
    stained cells were analyzed using flow cytometry to evaluate the apoptotic
    induction. The IC50 values of CCRF-CEM were 2.01±0.1µM and 2.65±0.3µM for
    5-Aza- and TSA-treated, respectively. Whereas, the IC50 values of HL-60 were
    1.98±0.2µM and 2.35±0.2µM for 5-Aza- and TSA-treated, respectively. To
    further substantiate the findings, the time-dependent exposure of both drugs was
    studied. CCRF-CEM cells were reduced to 49.4%±5.0, 49.4%±2.5 and
    41.5%±5.6 by 5-Aza; 56.5%±7.0, 45.3%±4.2 and 40.2%±4.2 by TSA treatment
    at first, third and sixth day. HL-60 cells were reduced to 72.0%±4.5, 51.0%±1.5
    and 40.6%±2.6 by 5-Aza at first, third and sixth day. Meanwhile, HL-60 cells
    reduced to 55.6%±4.5, 45.2%±4.0 and 36.3%±2.9 by TSA at first, second and
    fourth day. Both cell lines were significantly inhibited (p
  2. Alshwaiyat NM, Ahmad A, Al-Jamal HAN
    Front Nutr, 2023;10:1155947.
    PMID: 37284649 DOI: 10.3389/fnut.2023.1155947
    INTRODUCTION: Obesity and iron deficiency are prevalent health problems that affect billions of people all over the world. Obesity is postulated to relate to iron deficiency via reduced intestinal iron absorption due to increased serum hepcidin level, which is mediated by chronic inflammation. Weight loss in individuals with overweight or obesity and iron deficiency anemia is believed to be associated with an improvement in iron status however the evidence from clinical trials is scarce. This study was conducted to evaluate the effect of diet-induced weight loss on iron status and its markers among young women with overweight/obesity and iron deficiency anemia.

    METHODS: The study design was a single-blinded, randomized controlled trial with two parallel arms (weight loss intervention vs control). Study participants were recruited using the convenience sampling method through public advertisements posted and disseminated through social media. Interested and potential participants were asked to visit the Diet Clinic for eligibility screening. A total of 62 women were recruited and randomized into weight loss intervention and control group. The intervention duration was three months. The intervention group received individual consultation sessions with the dietitian and tailored energy-restricted diets. Physical activity levels, dietary intake, anthropometric measurements and clinical markers were measured at baseline and end of the trial.

    RESULTS: There was a significant decrease (p < 0.001) in body weight of the intervention group (-7.4 ± 2.7 kg) that was associated with significant improvements in iron status and its markers (p < 0.01). The intervention group experienced a significant increase in hemoglobin (0.5 ± 0.6 g/dL), serum ferritin (5.6 ± 5.8 ng/mL), and serum iron (13.0 ± 16.2 µg/dL), and a significant decrease in high-sensitivity C-reactive protein (-5.2 ± 5.6 mg/L), and serum hepcidin level (-1.9 ± 2.2 ng/mL) at the end of the trial.

    CONCLUSION: Our findings indicate that diet-induced weight loss among participants was associated with an improvement in iron status and its related clinical markers.

    CLINICAL TRIAL REGISTRATION: [https://www.thaiclinicaltrials.org/show/TCTR20221009001], identifier [TCTR20221009001].

  3. Al-Jamal HAN, Johan MF, Mat Jusoh SA, Ismail I, Wan Taib WR
    Asian Pac J Cancer Prev, 2018 Jun 25;19(6):1585-1590.
    PMID: 29936783
    Background: Epigenetic silencing of tumor suppressor genes (TSG) is involved in development and
    progression of cancers. Re-expression of TSG is inversely proportionate with STAT3 signaling pathways.
    Demethylation of DNA by 5-Azacytidine (5-Aza) results in re-expression of silenced TSG. Forced expression of
    PRG2 by 5-Aza induced apoptosis in cancer cells. Imatinib is a tyrosine kinase inhibitor that potently inhibits BCR/
    ABL tyrosine kinase resulting in hematological remission in CML patients. However, majority of CML patients treated
    with imatinib would develop resistance under prolonged therapy. Methods: CML cells resistant to imatinib were
    treated with 5-Aza and cytotoxicity of imatinib and apoptosis were determined by MTS and annexin-V, respectively.
    Gene expression analysis was detected by real time-PCR, STATs activity examined using Western blot and methylation
    status of PRG2 was determined by pyrosequencing analysis. Result: Expression of PRG2 was significantly higher in
    K562-R+5-Aza cells compared to K562 and K562-R (p=0.001). Methylation of PRG2 gene was significantly decreased
    in K562-R+5-Aza cells compared to other cells (p=0.021). STAT3 was inactivated in K562-R+5-Aza cells which showed
    higher sensitivity to imatinib. Conclusion: PRG2 gene is a TSG and its overexpression might induce sensitivity to
    imatinib. However, further studies are required to evaluate the negative regulations of PRG2 on STAT3 signaling.
  4. Saad HKM, Taib WRW, Ismail I, Johan MF, Al-Wajeeh AS, Al-Jamal HAN
    Exp Ther Med, 2021 Dec;22(6):1402.
    PMID: 34675995 DOI: 10.3892/etm.2021.10838
    Iron homeostasis is regulated by hepcidin (HEPC) that controls the dietary iron absorption and iron recycling. HEPC deficiency contributes to iron overload in β-thalassemia patients. The present study aimed to investigate the correlation between HEPC concentration and serum iron status among hemoglobin E (HbE)/β-thalassemia patients and their parents (HbE trait and β-thalassemia trait) compared with healthy controls. This study is a comparative cross-sectional study in which iron profile and HEPC level were examined in 65 HbE/β-thalassemia patients (pretransfusion) and 65 parents at the Hospital Sultanah Nur Zahirah and in 130 students as healthy controls from Univesiti Sultan Zainal Abidin, Terengganu, Malaysia. Furthermore, six samples from each group (HbE/β-thalassemia patients, parents and healthy controls) were randomly selected for gene expression analysis of HEPC and ferroportin1 (FPN1) using reverse transcription quantitative PCR. The results demonstrated that serum HEPC level were significantly decreased in HbE/β-thalassemia patients and their parents (P<0.001) compared with healthy controls. In addition, the gene expression analysis showed a dramatically downregulated HEPC in HbE/β-thalassemia patients and their parents (P=0.001) compared with healthy controls. However, there was a marked upregulation of FPN1 in HbE/β-thalassemia patients and their parents (P=0.001) compared with healthy controls. Iron profiling results revealed a significantly increased serum ferritin in HbE/β-thalassemia patients and their parents compared with healthy controls (P<0.001). In summary, the present study demonstrated that HEPC expression level and serum level were significantly decreased in HbE/β-thalassemia patients and their parents, which was combined with a marked increased FPN1 expression level and serum ferritin level compared with healthy volunteers. These findings supported the hypothesis that downregulated HEPC could lose its function as a negative regulator of FPN1, resulting in iron overload in HbE/β-thalassemia patients. Subsequently, assessing HEPC and FPN1 gene expression may be a useful tool to determine the risk of iron toxicity in patients with HbE/β-thalassemia and their parents, and could therefore be considered as a therapeutic target in the management of iron burden in these patients.
  5. Alshwaiyat NM, Ahmad A, Wan Hassan WMR, Al-Jamal HAN
    Exp Ther Med, 2021 Nov;22(5):1268.
    PMID: 34594405 DOI: 10.3892/etm.2021.10703
    Obesity is a risk factor for several comorbidities and complications, including iron deficiency anemia. Iron deficiency anemia is a serious global public health problem, with a worldwide prevalence. The high prevalence of obesity in combination with iron deficiency incidence observed in different age and sex categories suggests an association between obesity and iron status. Obesity may disrupt iron homeostasis, resulting in iron deficiency anemia. The association between obesity and iron deficiency may be due to increased hepcidin levels mediated by chronic inflammation. Hepcidin is a small peptide hormone that functions as a negative regulator of intestinal iron absorption. Significant body weight loss in overweight and obese individuals decreases chronic inflammation and serum hepcidin levels, resulting in improved iron status due to increased iron absorption. However, further randomized controlled trials are required to confirm this effect.
  6. Al-Kafaween MA, Al-Jamal HAN, Hilmi ABM, Elsahoryi NA, Jaffar N, Zahri MK
    Iran J Microbiol, 2020 Dec;12(6):565-576.
    PMID: 33613911 DOI: 10.18502/ijm.v12i6.5031
    BACKGROUND AND OBJECTIVES: Tualang honey (TH) is a Malaysian multifloral jungle honey. In recent years, there has been a marked increase in the number of studies published in medical databases regarding its potential health benefits. The study aimed to investigate the effect of TH against Pseudomonas aeruginosa and Streptococcus pyogenes.

    MATERIALS AND METHODS: The effect of TH on both bacteria was investigated using MIC, MBC, growth curve, time-kill curve, scanning electron microscopy (SEM) and RT-qPCR.

    RESULTS: The MIC of TH against P. aeruginosa and S. pyogenes was 18.5% (w/v) and 13% (w/v) respectively and MBC was 25% (w/v) for both bacteria. Spectrophotometric readings of at least 90% inhibition yielded MIC90 values of TH, 18.5% (w/v) and 15% (w/v) for P. aeruginosa and S. pyogenes respectively. A time-kill curve demonstrated a bactericidal with a 4-log reduction estimated within 8 hours. Using SEM, loss of structural integrity and marked changes in cell shape were observed. RT-qPCR analysis showed that TH reduced the pattern of gene expression in both bacteria, with a trend toward reduced expression of the virulence genes of interest.

    CONCLUSION: This study suggests that TH could potentially be used as an alternative therapeutic agent for microbial infection particularly against these two organisms.

  7. Almajali B, Al-Jamal HAN, Taib WRW, Ismail I, Johan MF, Doolaanea AA, et al.
    Pharmaceuticals (Basel), 2021 Apr 16;14(4).
    PMID: 33923474 DOI: 10.3390/ph14040369
    To date, natural products are widely used as pharmaceutical agents for many human diseases and cancers. One of the most popular natural products that have been studied for anticancer properties is thymoquinone (TQ). As a bioactive compound of Nigella sativa, TQ has shown anticancer activities through the inhibition of cell proliferation, migration, and invasion. The anticancer efficacy of TQ is being investigated in several human cancers such as pancreatic cancer, breast cancer, colon cancer, hepatic cancer, cervical cancer, and leukemia. Even though TQ induces apoptosis by regulating the expression of pro- apoptotic and anti-apoptotic genes in many cancers, the TQ effect mechanism on such cancers is not yet fully understood. Therefore, the present review has highlighted the TQ effect mechanisms on several signaling pathways and expression of tumor suppressor genes (TSG). Data from relevant published experimental articles on TQ from 2015 to June 2020 were selected by using Google Scholar and PubMed search engines. The present study investigated the effectiveness of TQ alone or in combination with other anticancer therapeutic agents, such as tyrosine kinase inhibitors on cancers, as a future anticancer therapy nominee by using nanotechnology.
  8. Aziz NA, Taib WW, Kharolazaman NK, Ismail I, Al-Jamal HAN, Jamil NWWA, et al.
    Sci Rep, 2021 Aug 18;11(1):16772.
    PMID: 34408192 DOI: 10.1038/s41598-021-96018-y
    This study sought to determine the potential role of HBB haplotypes to predict beta-thalassemia in the Malaysian population. A total of 543 archived samples were selected for this study. Five tagging SNPs in the beta-globin gene (HBB; NG_000007.3) were analyzed for SNP-based and haplotype association using SHEsis online software. Single-SNP-based association analysis showed three SNPs have a statistically significant association with beta-thalassemia. When Bonferroni correction was applied, four SNPs were found statistically significant with beta-thalassemia; IVS2-74T>G (padj = 0.047), IVS2-16G>C (padj = 0.017), IVS2-666C>T (padj = 0.017) and 3'UTR + 314G>A (padj = 0.002). However, 3'UTR + 233G>C did not yield a significant association with padj value = 0.076. Further investigation using combined five SNPs for haplotype association analysis revealed three susceptible haplotypes with significant p values of which, haplotypes 1-2-2-1-1 (p = 6.49 × 10-7, OR = 10.371 [3.345-32.148]), 1-2-1-1-1 (p = 0.009, OR = 1.423 [1.095-1.850] and 1-1-1-1-1 (p = 1.39 × 10-4, OR = 10.221 [2.345-44.555]). Three haplotypes showed protective effect with significant p value of which, 2-2-1-1-1 (p = 0.006, OR = 0.668 [0.500-0.893]), 1-1-2-2-1 (p = 0.013, OR = 0.357 [0.153-0.830]) and 1-1-2-1-1 (p = 0.033, OR = 0.745 [0.567-0.977]). This study has identified the potential use of intragenic polymorphic markers in the HBB gene, which were significantly associated with beta-thalassemia. Combining these five SNPs defined a new haplotype model for beta-thalassemia and further evaluation for predicting severity in beta-thalassemia.
  9. Almajali B, Al-Jamal HAN, Wan Taib WR, Ismail I, Johan MF, Doolaanea AA, et al.
    Asian Pac J Cancer Prev, 2021 Mar 01;22(3):879-885.
    PMID: 33773553 DOI: 10.31557/APJCP.2021.22.3.879
    OBJECTIVE: The natural compound, thymoquinone (TQ) has demonstrated potential anticancer properties in inhibiting cell proliferation and promoting apoptosis in myeloid leukemia cells, breast cancer cells, and others. However, the effect mechanism of TQ on AML cells still not fully understood. In this study, the authors examined the effects of TQ on the expression of JAK/STAT-negative regulator genes SOCS-1, SOCS-3, and SHP-1, and their consequences on cell proliferation and apoptosis in HL60 leukemia cells.

    METHODS: MTT and trypan blue exclusion tests were conducted to determine the 50% inhibitory concentration (IC50) and cell proliferation. FITC Annexin and Guava® reagent were used to study the cell apoptosis and examine the cell cycle phases, respectively. The expression of JAK/STAT-negative regulator genes, SOCS-1, SOCS-3, and SHP-1, was investigated using reverse transcriptase- quantitative PCR (RT-qPCR).

    RESULTS: TQ demonstrated a potential inhibition of HL60 cell proliferation and a significant increase in apoptotic cells in dose and time-dependent manner. TQ significantly induced cycle arrest at G0-G1 phase (P < 0.001) and enhanced the re-expression of JAK/STAT-negative regulator genes.

    CONCLUSION: TQ potentially inhibited HL60 cell proliferation and significantly increased apoptosis with re-expression of JAK/STAT-negative regulator genes suggesting that TQ could be a new therapeutic candidate for leukemia therapy.
    .

  10. Al-Rawashde FA, Wan Taib WR, Ismail I, Johan MF, Al-Wajeeh AS, Al-Jamal HAN
    Asian Pac J Cancer Prev, 2021 Dec 01;22(12):3959-3965.
    PMID: 34967577 DOI: 10.31557/APJCP.2021.22.12.3959
    OBJECTIVE: BCR ABL oncogene encodes the BCR-ABL chimeric protein, which is a constitutively activated non-receptor tyrosine kinase. The BCR-ABL oncoprotein is a key molecular basis for the pathogenesis of chronic myeloid leukemia (CML) via activation of several downstream signaling pathways including JAK/STAT pathway. Development of leukemia involves constitutive activation of signaling molecules including, JAK2, STAT3, STAT5A and STAT5B. Thymoquinone (TQ) is a bioactive constituent of Nigella sativa that has shown anticancer properties in various cancers. The present study aimed to evaluate the effect of TQ on the expression of BCR ABL, JAK2, STAT3, STAT5A and STAT5B genes and their consequences on the cell proliferation and apoptosis in K562 CML cells.

    METHODS: BCR-ABL positive K562 CML cells were treated with TQ. Cytotoxicity was determined by Trypan blue exclusion assay. Apoptosis assay was performed by annexin V-FITC/PI staining assay and analyzed by flow cytometry. Transcription levels of BCR ABL, JAK2, STAT3, STAT5A and STAT5B genes were evaluated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Protein levels of JAK2 and STAT5 were determined by Jess Assay analysis.

    RESULTS: TQ markedly decreased the cell proliferation and induced apoptosis in K562 cells (P < 0.001) in a concentration dependent manner. TQ caused a significant decrease in the transcriptional levels of BCR ABL, JAK2, STAT3, STAT5A and STAT5B genes (P < 0.001). TQ induced a significant decrease in JAK2 and STAT5 protein levels (P < 0.001).

    CONCLUSION: our results indicated that TQ inhibited cell growth of K562 cells via downregulation of BCR ABL/ JAK2/STAT3 and STAT5 signaling and reducing JAK2 and STAT5 protein levels.

  11. Al-Rawashde FA, Al-Sanabra OM, Alqaraleh M, Jaradat AQ, Al-Wajeeh AS, Johan MF, et al.
    Pharmaceuticals (Basel), 2023 Jun 15;16(6).
    PMID: 37375831 DOI: 10.3390/ph16060884
    The epigenetic silencing of tumor suppressor genes (TSGs) is critical in the development of chronic myeloid leukemia (CML). SHP-1 functions as a TSG and negatively regulates JAK/STAT signaling. Enhancement of SHP-1 expression by demethylation provides molecular targets for the treatment of various cancers. Thymoquinone (TQ), a constituent of Nigella sativa seeds, has shown anti-cancer activities in various cancers. However, TQs effect on methylation is not fully clear. Therefore, the aim of this study is to assess TQs ability to enhance the expression of SHP-1 through modifying DNA methylation in K562 CML cells. The activities of TQ on cell cycle progression and apoptosis were evaluated using a fluorometric-red cell cycle assay and Annexin V-FITC/PI, respectively. The methylation status of SHP-1 was studied by pyrosequencing analysis. The expression of SHP-1, TET2, WT1, DNMT1, DNMT3A, and DNMT3B was determined using RT-qPCR. The protein phosphorylation of STAT3, STAT5, and JAK2 was assessed using Jess Western analysis. TQ significantly downregulated the DNMT1 gene, DNMT3A gene, and DNMT3B gene and upregulated the WT1 gene and TET2 gene. This led to hypomethylation and restoration of SHP-1 expression, resulting in inhibition of JAK/STAT signaling, induction of apoptosis, and cell cycle arrest. The observed findings imply that TQ promotes apoptosis and cell cycle arrest in CML cells by inhibiting JAK/STAT signaling via restoration of the expression of JAK/STAT-negative regulator genes.
  12. Zakaria NA, Rosle NA, Siti Asmaa MJ, Aziee S, Haiyuni MY, Samat NA, et al.
    Int J Lab Hematol, 2021 Dec;43(6):1451-1457.
    PMID: 34125992 DOI: 10.1111/ijlh.13628
    INTRODUCTION: Calreticulin (CALR) mutations in myeloproliferative neoplasms (MPN) have been reported to be key markers in the molecular diagnosis, particularly in patients lacking JAK2 V617F mutation. In most current reports, CALR mutations were analysed by either allele-specific PCR (AS-PCR), or the more expensive quantitative real-time PCR, pyrosequencing and next-generation sequencing. Hence, we report the use of an alternative method, the conformation sensitive gel electrophoresis (CSGE) for the detection of CALR mutations in BCR-ABL1-negative MPN patients.

    METHODS: Forty BCR-ABL1-negative MPN patients' DNA: 19 polycythemia vera (PV), 7 essential thrombocytosis (ET) and 14 primary myelofibrosis (PMF), were screened for CALR mutations by CSGE. PCR primers were designed to amplify sequences spanning between exons 8 and 9 to target the mutation hotspots in CALR. Amplicons displaying abnormal CSGE profiles by electrophoresis were directly sequenced, and results were analysed by BioEdit Sequence Alignment Editor v7.2.6. CSGE results were compared with AS-PCR and confirmed by Sanger sequencing.

    RESULTS: CSGE identified 4 types of mutations; 2 PMF patients with either CALR type 1 (c.1099_1150del52) or type 2 (c.1155_1156insTTGTC), 1 ET patient with nucleotide deletion (c.1121delA) and insertion (c.1190insA) and 1 PV patient with p.K368del (c.1102_1104delAAG) and insertion (c.1135insA) inframe mutations. Three patients have an altered KDEL motif at the C-terminal of CALR protein. In comparison, AS-PCR only able to detect two PMF patients with mutations, either type 1 and type 2.

    CONCLUSION: CSGE is inexpensive, sensitive and reliable alternative method for the detection of CALR mutations in BCR-ABL1-negative MPN patients.

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