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Expression of zTOR-associated microRNAs in zebrafish embryo treated with rapamycin

Khor ES, Noor SM, Wong PF

Life Sci, 2016 Apr 1;150:67-75.
PMID: 26916825 DOI: 10.1016/j.lfs.2016.02.076

MicroRNAs (miRNAs) are vital in modulating lifespan and various biological processes including vascular function. The pivotal roles of mammalian target of rapamycin (mTOR) in regulating senescence and angiogenesis have been extensively described. However, the roles of its orthologue, zebrafish target of rapamycin (zTOR) in senescence and angiogenesis remain to be unravelled. In the present study, we aimed to investigate the role of zTOR and identify miRNAs associated with senescence and angiogenesis.
MiR-107 inhibits the sprouting of intersegmental vessels of zebrafish embryos

Khor ES, Noor SM, Wong PF

Protoplasma, 2021 Aug 09.
PMID: 34368895 DOI: 10.1007/s00709-021-01695-1

MicroRNAs (miRNAs) play important roles in various biological processes. Our previous study showed that inhibition of MTOR with rapamycin treatment suppressed human endothelial cell tube formation, concomitant with the down-regulation of miR-107. Similarly, inhibition of Ztor by rapamycin also suppressed vascular development in zebrafish embryos. To gain a better understanding of the role of miR-107 and MTOR in vascular development, the present study sought to validate its function by over-expressing miR-107 in zebrafish embryos via microinjection with mimic miR-107 duplexes. Alkaline phosphatase (ALP) staining was used to visualise blood vessels in the zebrafish embryo, and expressions of Pten, Ztor and Rap1 were investigated by immunoblotting. Over-expression of miR-107 in zebrafish embryos inhibited the sprouting of intersegmental vessels (ISVs) with concomitant down-regulation of phosphorylated Rps6 expression, which confirmed the inhibition of Ztor signalling. As expected, pten, which is the target of miR-107, was down-regulated. Interestingly, Rap1, a small GTPase protein that is involved in intersomitic vessels sprouting during angiogenesis, was also down-regulated when miR-107 was over-expressed. Overall, our findings suggest that miR-107 and Ztor-mediated suppression of vascular development in zebrafish embryo involves Rap1.
Fulltext Understanding the Role of ztor in Aging-related Diseases Using the Zebrafish Model

Khor ES, Noor SM, Wong PF

In Vivo, 2019 10 31;33(6):1713-1720.
PMID: 31662495 DOI: 10.21873/invivo.11661

The mammalian target of rapamycin (mTOR), a 289 kDa serine/threonine protein kinase of the phosphoinositide 3-kinase (PI3K)-related family is known for its role in regulating lifespan and the aging process in humans and rodents. Aging in zebrafish very much resembles aging in humans. Aged zebrafish often manifest with spinal curvature, cataracts and cognitive frailty, akin to human age-related phenotypical effects such as osteoarthritis, dwindling vision and cognitive dysfunction. However, the role of the zebrafish orthologue of mTOR, ztor, is less defined in these areas. This review paper discusses the tale of growing old in the zebrafish, the physiological roles of ztor in normal developmental processes and its involvement in the pathogenesis of aging-related diseases such as metabolic disorders and cancers.
Fulltext MiR-378 and MiR-1827 Regulate Tumor Invasion, Migration and Angiogenesis in Human Lung Adenocarcinoma by Targeting RBX1 and CRKL, Respectively

Ho CS, Noor SM, Nagoor NH

J Cancer, 2018;9(2):331-345.
PMID: 29344280 DOI: 10.7150/jca.18188

MicroRNAs (miRNAs) have been extensively studied over the decades and have been proposed as potential molecular targets for cancer treatment. Studies have shown that miR-378 participates in numerous biological processes in various cancers; whereas miR-1827 has only been reported in pediatric glioma. The mechanism of how miRNAs modulate lung cancer metastasis remains unclear. Our previous study demonstrated that miR-378 is up-regulated while miR-1827 is down-regulated in high invasive lung cancer sub-cell lines, and their biological functions have been described. Here, we report that miR-378 and miR-1827 modulate lung cancer cell invasion and migration via epithelial-mesenchymal transition (EMT). We also demonstrated that cells treated with miR-378 inhibitors or miR-1827 mimics had reduced number of metastases and ectopic vessels in the zebrafish embryo model. We then showed that miR-378 promoted invasion and miR-1827 suppressed migration by targeting RBX1 and CRKL, respectively. Restored protein expression in miRNA-overexpressed/ miRNA-suppressed cells attenuated the inhibitory/ inducing effect of the miRNA on lung cancer cells. Collectively, our findings highlight that miR-378 and miR-1827 could serve as novel therapeutic targets in lung cancer.
Fulltext Role of Different Pfcrt and Pfmdr-1 Mutations in Conferring Resistance to Antimalaria Drugs in Plasmodium falciparum

Ibraheem ZO, Abd Majid R, Noor SM, Sedik HM, Basir R

Malar Res Treat, 2014;2014:950424.
PMID: 25506039 DOI: 10.1155/2014/950424

Emergence of drugs resistant strains of Plasmodium falciparum has augmented the scourge of malaria in endemic areas. Antimalaria drugs act on different intracellular targets. The majority of them interfere with digestive vacuoles (DVs) while others affect other organelles, namely, apicoplast and mitochondria. Prevention of drug accumulation or access into the target site is one of the mechanisms that plasmodium adopts to develop resistance. Plasmodia are endowed with series of transporters that shuffle drugs away from the target site, namely, pfmdr (Plasmodium falciparum multidrug resistance transporter) and pfcrt (Plasmodium falciparum chloroquine resistance transporter) which exist in DV membrane and are considered as putative markers of CQ resistance. They are homologues to human P-glycoproteins (P-gh or multidrug resistance system) and members of drug metabolite transporter (DMT) family, respectively. The former mediates drifting of xenobiotics towards the DV while the latter chucks them outside. Resistance to drugs whose target site of action is intravacuolar develops when the transporters expel them outside the DVs and vice versa for those whose target is extravacuolar. In this review, we are going to summarize the possible pfcrt and pfmdr mutation and their role in changing plasmodium sensitivity to different anti-Plasmodium drugs.
Fulltext VNTR markers for qualitative evaluation of engraftment in unrelated cord blood transplantations

Noor SM, Phipps ME, Fong MY, Chan LL

Med J Malaysia, 2007 Mar;62(1):23-6.
PMID: 17682565 MyJurnal

Allogeneic stem cell transplantation is a treatment option for malignant and non-malignant disorders in children. For children with no HLA-matched sibling or related stem cell donors, there is the option of unrelated cord blood donors. At the University of Malaya Medical Centre (UMMC) in Kuala Lumpur, the first unrelated cord blood transplantation (CBT) was performed in October 1997. All unrelated CBT performed in UMMC relied on cord blood units imported from overseas. DNA typing with variable number of tandem repeat (VNTR) loci was done to qualitatively evaluate engraftment in 15 unrelated CBT. In all the fifteen cases that were evaluated, molecular evidence of engraftment or non-engraftment correlated with the clinical findings.
Generation of glial cell-derived neurotrophic factor (gdnf) morphants in zebrafish larvae by cerebroventricular microinjection of vivo morpholino

Noor SM, Wong CED, Wong PF, Norazit A

Methods Cell Biol, 2024;181:17-32.
PMID: 38302238 DOI: 10.1016/bs.mcb.2022.09.004

Dopaminergic neurons in the brain are an important source of dopamine, which is a crucial neurotransmitter for wellbeing, memory, reward, and motor control. Deficiency of dopamine due to advanced age and accumulative dopaminergic neuron defects can lead to movement disorders such as Parkinson's disease. Glial cell-derived neurotrophic factor (GDNF) is one of many factors involved in dopaminergic neuron development and/or survival. However, other endogenous GDNF functions in the brain await further investigation. Zebrafish is a well-established genetic model for neurodevelopment and neurodegeneration studies. Importantly, zebrafish shares approximately 70% functional orthologs with human genes including GDNF. To gain a better understanding on the precise functional role of gdnf in dopaminergic neurons, our laboratory devised a targeted knockdown of gdnf in the zebrafish larval brain using vivo morpholino. Here, detailed protocols on the generation of gdnf morphants using vivo morpholino are outlined. This method can be applied for targeting of genes in the brain to determine specific spatiotemporal gene function in situ.
Thyroid autoimmunity and autoimmune thyroid disease in Malaysian girls with Turner syndrome: An understudied population

Lee YL, Zaini AA, Idris AN, Abdullah RA, Wong JS, Hong JS, et al.

J Paediatr Child Health, 2023 Jul;59(7):879-884.
PMID: 37066819 DOI: 10.1111/jpc.16405

AIMS: Knowledge on the spectrum of thyroid disorders amongst Turner syndrome (TS) patients in Southeast Asia is limited. This study aimed to evaluate the prevalence of thyroid autoimmunity, the spectrum of autoimmune thyroid disease and association with age and karyotype amongst Malaysian TS girls.
METHODS: A cross-sectional study was conducted at 11 paediatric endocrine units in Malaysia. Blood samples for antithyroglobulin antibodies, antithyroid peroxidase antibodies and thyroid function test were obtained. In patients with pre-existing thyroid disease, information on clinical and biochemical thyroid status was obtained from medical records.
RESULTS: Ninety-seven TS patients with a mean age of 13.4 ± 4.8 years were recruited. Thyroid autoimmunity was found in 43.8% of TS patients. Nineteen per cent of those with thyroid autoimmunity had autoimmune thyroid disease (Hashimoto thyroiditis in 7.3% and hyperthyroidism in 1% of total population). Patients with isochromosome X and patients with 45,X mosaicism or other X chromosomal abnormalities were more prone to have thyroid autoimmunity compared to those with 45,X karyotype (OR 5.09, 95% CI 1.54-16.88, P = 0.008 and OR 3.41, 95% CI 1.32-8.82, P = 0.01 respectively). The prevalence of thyroid autoimmunity increased with age (33.3% for age 0-9.9 years; 46.8% for age 10-19.9 years and 57.1% age for 20-29.9 years) with autoimmune thyroid disease detected in 14.3% during adulthood.
CONCLUSION: Thyroid autoimmunity was significantly associated with the non 45,X karyotype group, particularly isochromosome X. Annual screening of thyroid function should be carried out upon diagnosis of TS until adulthood with more frequent monitoring recommended in the presence of thyroid autoimmunity.
Phospholipase A2 group v in benign familial fleck retina in a set of triplets

Bin NJ, Heng HM, Poh R, Noor SM, Subrayan V

Retina, 2015 Jun;35(6):1266-72.
PMID: 25549071 DOI: 10.1097/IAE.0000000000000446

To evaluate the association of phospholipase A2, Group V (PLA2G5), with benign familial fleck retina in a consanguineous family with triplets.
Fulltext In vitro and in vivo anti-angiogenic activity of girinimbine isolated from Murraya koenigii

Iman V, Karimian H, Mohan S, Hobani YH, Noordin MI, Mustafa MR, et al.

Drug Des Devel Ther, 2015;9:1281-92.
PMID: 25767375 DOI: 10.2147/DDDT.S71557

Girinimbine is a carbazole alkaloid isolated from the stem bark and root of Murraya koenigii. Here we report that girinimbine is an inhibitor of angiogenic activity both in vitro and in vivo. MTT results showed that girinimbine inhibited proliferation of human umbilical vein endothelial cells, while results from endothelial cell invasion, migration, tube formation, and wound healing assays demonstrated significant time- and dose-dependent inhibition by girinimbine. A proteome profiler array done on girinimbine-treated human umbilical vein endothelial cells showed that girinimbine had mediated regulation of pro-angiogenic and anti-angiogenic proteins. The anti-angiogenic potential of girinimbine was also evidenced in vivo in the zebrafish embryo model wherein girinimbine inhibited neo vessel formation in zebrafish embryos following 24 hours of exposure. Together, these results showed that girinimbine could effectively suppress angiogenesis, suggestive of its therapeutic potential as a novel angiogenesis inhibitor.
Fulltext Cellular transcripts regulated during infections with Highly Pathogenic H5N1 Avian Influenza virus in 3 host systems

Balasubramaniam VR, Hassan SS, Omar AR, Mohamed M, Noor SM, Mohamed R, et al.

Virol J, 2011;8:196.
PMID: 21529348 DOI: 10.1186/1743-422X-8-196

Highly pathogenic Avian Influenza (HPAI) virus is able to infect many hosts and the virus replicates in high levels in the respiratory tract inducing severe lung lesions. The pathogenesis of the disease is actually the outcome of the infection as determined by complex host-virus interactions involving the functional kinetics of large numbers of participating genes. Understanding the genes and proteins involved in host cellular responses are therefore, critical for the elucidation of the mechanisms of infection.
Fulltext Wound healing activities of rafflesia hasseltii extract in rats

Abdulla MA, Ahmed KA, Ali HM, Noor SM, Ismail S

J Clin Biochem Nutr, 2009 Nov;45(3):304-8.
PMID: 19902020 DOI: 10.3164/jcbn.09-17

The effects of topical application of Rafflesia hasseltii buds and flowers extract on the rate of wound healing and histology of healed wound were assessed. Four groups of adult male Sprague Dawley rats were experimentally wounded in the posterior neck area. A thin layer of blank placebo was applied topically to wounds of Group 1 rats. Wounds of experimental animals (Group 2 and 3) were treated with placebo containing 5% and 10% R. hasseltii buds extract, respectively. A thin layer of Intrasite gel was applied topically to wounds of Group 4 animals as reference. Macroscopically, wounds treated with placebo containing 5% and 10% R. hasseltii buds extract or Intrasite gel have been significantly accelerated the rate of wound healing compared to placebo-treated wounds. Histological analysis of healed wounds has confirmed this effect. Wounds treated with placebo containing 5%, 10% R. hasseltii buds extract or Intrasite gel showed markedly less scar width at wound enclosure and granulating tissue contained markedly more collagen and proliferating fibroblasts, but with the absence of inflammatory cells compared to wounds treated with blank placebo. In conclusion, the findings of increased rate of wound closure and contraction together with the histological findingssuggest that Rafflesia hasseltii buds extract is very effective in accelerating the wound healing process.
Fulltext Saffron: A Natural Potent Antioxidant as a Promising Anti-Obesity Drug

Mashmoul M, Azlan A, Khaza'ai H, Yusof BN, Noor SM

Antioxidants (Basel), 2013;2(4):293-308.
PMID: 26784466 DOI: 10.3390/antiox2040293

Obesity is associated with various diseases, particularly diabetes, hypertension, osteoarthritis and heart disease. Research on possibilities of herbal extracts and isolated compounds from natural products for treating obesity has an upward trend. Saffron (Crocus Sativus L. Iridaceae) is a source of plant polyphenols/carotenoids, used as important spice and food colorant in different parts of the world. It has also been used in traditional medicine for treatment of different types of illnesses since ancient times. Many of these medicinal properties of saffron can be attributed to a number of its compounds such as crocetin, crocins and other substances having strong antioxidant and radical scavenger properties against a variety of radical oxygen species and pro-inflammatory cytokines. The aim of this article is to assess the potential role of saffron and its constituents in the regulation of metabolic functions, which can beneficially alter obesity pathophysiology.
Fulltext Evaluation of red blood cell indices related disorders among eligible blood donors at the Universiti Putra Malaysia (UPM)

Riahi S, Mei IL, Idris FB, George E, Noor SM

Southeast Asian J. Trop. Med. Public Health, 2015 Sep;46(5):911-7.
PMID: 26863862

Pre-donation screening declarations and hemoglobin (Hb) testing are measures used to determine the quality of donated blood. The copper sulphate (CuSo4) method used to screen for blood abnormalities can give inaccurate results if strict quality control is not applied. Blood donors who are carriers of thalassemia and those with mild iron deficiency anemia (IDA) are usually asymptomatic and frequently missed at blood donation. The aim of this study was to evaluate the red blood cell (RBC) indices related disorders among blood donors who were deemed qualified to donate blood after screening with CuSo4 method. One hundred fifty-eight volunteer blood donors at the Universiti Putra Malaysia (UPM), who had passed the CuSo4 screening method, were recruited for this study. Their bloods specimens were examined with a complete blood count. Subjects with a low mean corpuscular hemoglobin (MCH) level were examined further by checking a serum ferritin level, Hb quantification, and molecular analysis to examine for common RBC disorders. Fourteen point six percent of subjects had a low Hb level, two (1.3%) had IDA and four (2.5%) had thalassemia or some other hemoglobinopathy. Using a MCH level < 27 pg as a cut-off point, 58 subjects (36.7%) had suspected IDA, thalassemia or some other hemoglobinopathy. Eight point nine percent of subjects with a normal Hb level had thalassemia, and 3.8% had IDA. Malaysia has a high prevalence of thalassemia and other hemoglobinopathies. Pre-donation accurate screening is crucial to protect the quality of blood transfusion products. Public education regarding RBC disorders especially among blood donors is important.
Fulltext Candida isolates from pregnant women and their antifungal susceptibility in a Malaysian tertiary-care hospital

Masri SN, Noor SM, Nor LA, Osman M, Rahman MM

Pak J Med Sci, 2015;31(3):658-61.
PMID: 26150863 DOI: 10.12669/pjms.313.7072

Pregnant women are susceptible to vaginal colonization and infection by yeast. The purpose of the study was to determine the prevalence of Candida spp in high vaginal swabs of pregnant women and their antifungal susceptibility.
gdnf affects early diencephalic dopaminergic neuron development through regulation of differentiation-associated transcription factors in zebrafish

Wong CED, Hua K, Monis S, Saxena V, Norazit A, Noor SM, et al.

J Neurochem, 2021 02;156(4):481-498.
PMID: 32583440 DOI: 10.1111/jnc.15108

Glial cell line-derived neurotrophic factor (GDNF) has been reported to enhance dopaminergic neuron survival and differentiation in vitro and in vivo, although those results are still being debated. Glial cell line-derived neurotrophic factor (gdnf) is highly conserved in zebrafish and plays a role in enteric nervous system function. However, little is known about gdnf function in the teleost brain. Here, we employed clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 to impede gdnf function in the maintenance of dopaminergic neuron development. Genotyping of gdnf crispants revealed successful deletions of the coding region with various mutant band sizes and down-regulation of gdnf transcripts at 1, 3 and 7 day(s) post fertilization. Notably, ~20% reduction in ventral diencephalic dopaminergic neuron numbers in clusters 8 and 13 was observed in the gdnf-deficient crispants. In addition, gdnf depletion caused a modest reduction in dopaminergic neurogenesis as determined by 5-ethynyl-2'-deoxyuridine pulse chase assay. These deleterious effects could be partly attributed to deregulation of dopaminergic neuron fate specification-related transcription factors (otp,lmx1b,shha,and ngn1) in both crispants and established homozygous mutants with whole mount in-situ hybridization (WISH) on gdnf mutants showing reduced otpb and lmx1b.1 expression in the ventral diencephalon. Interestingly, locomotor function of crispants was only impacted at 7 dpf, but not earlier. Lastly, as expected, gdnf deficiency heightened crispants vulnerability to 1-methyl-4-phenylpyridinium toxic insult. Our results suggest conservation of teleost gdnf brain function with mammals and revealed the interactions between gdnf and transcription factors in dopaminergic neuron differentiation.
Activation of death receptor, DR5 and mitochondria-mediated apoptosis by a 3,4,5-trimethoxybenzyloxy derivative in wild-type and p53 mutant colorectal cancer cell lines

Chan ZCK, Leong KH, Kareem HS, Norazit A, Noor SM, Ariffin A

Naunyn Schmiedebergs Arch Pharmacol, 2020 03;393(3):405-417.
PMID: 31641820 DOI: 10.1007/s00210-019-01730-2

The rationale of designing compounds containing a (3,4,5-trimethoxybenzyloxy) phenyl moiety is largely due to its potential antioxidant and cytotoxic activities. A previous study focused on its antioxidant mechanism, whereas in this study, we investigated the cytotoxicity of a series of 28 analogues and the mechanism of apoptosis of the most cytotoxic compound against wild-type (HCT-116) and p53 mutant (HT-29) colorectal cancer cell lines. The series of analogues comprise of different families, namely hydrazone, oxadiazole, thiosemicarbazides and triazoles. In the initial cytotoxicity screening, N-(3,4,5-trimethoxybenzylidene)-4-(3,4,5-trimethoxybenzyloxy) benzohydrazide, henceforth known as, P5H, was found to be most cytotoxic against human colorectal cancer cell lines (IC50 for HCT-116 = 11.79 μM and HT-29 = 18.52 μM). Additionally, P5H was found to have some degree of selectivity towards cancer cells compared to normal human colon cells (CCD-112 CoN). Subsequent investigation had brought insight on P5H ability to induce apoptosis in both HCT-116 and HT-29 cell lines. Cell cycle analysis showed both cell lines were arrested at the G2/M phase upon treatment. Our study concluded that P5H induced the death receptor, DR5 in HCT-116 and mitochondria-mediated apoptosis pathway in HT-29. Therefore, P5H may be a promising candidate as a chemotherapy agent against colon cancer. Graphical abstract The apoptotic pathways induced in HT-29 and HCT-116 cells upon P5H treatment.
Fulltext Regulation of embryonic hematopoiesis by a cytokine-inducible SH2 domain homolog in zebrafish

Lewis RS, Noor SM, Fraser FW, Sertori R, Liongue C, Ward AC

J Immunol, 2014 Jun 15;192(12):5739-48.
PMID: 24835394 DOI: 10.4049/jimmunol.1301376

Cytokine-inducible SH2 domain-containing protein (CISH), a member of the suppressor of cytokine signaling family of negative feedback regulators, is induced by cytokines that activate STAT5 and can inhibit STAT5 signaling in vitro. However, demonstration of a definitive in vivo role for CISH during development has remained elusive. This study employed expression analysis and morpholino-mediated knockdown in zebrafish in concert with bioinformatics and biochemical approaches to investigate CISH function. Two zebrafish CISH paralogs were identified, cish.a and cish.b, with high overall conservation (43-46% identity) with their mammalian counterparts. The cish.a gene was maternally derived, with transcripts present throughout embryogenesis, and increasing at 4-5 d after fertilization, whereas cish.b expression commenced at 8 h after fertilization. Expression of cish.a was regulated by the JAK2/STAT5 pathway via conserved tetrameric STAT5 binding sites (TTCN3GAA) in its promoter. Injection of morpholinos targeting cish.a, but not cish.b or control morpholinos, resulted in enhanced embryonic erythropoiesis, myelopoiesis, and lymphopoiesis, including a 2- 3-fold increase in erythrocytic markers. This occurred concomitantly with increased activation of STAT5. This study indicates that CISH functions as a conserved in vivo target and regulator of STAT5 in the control of embryonic hematopoiesis.
Association of ARID5B gene variants with acute lymphoblastic leukemia in Yemeni children

Al-Absi B, Noor SM, Saif-Ali R, Salem SD, Ahmed RH, Razif MF, et al.

Tumour Biol., 2017 Apr;39(4):1010428317697573.
PMID: 28381164 DOI: 10.1177/1010428317697573

Studies have shown an association between ARID5B gene polymorphisms and childhood acute lymphoblastic leukemia. However, the association between ARID5B variants and acute lymphoblastic leukemia among the Arab population still needs to be studied. The aim of this study was to investigate the association between ARID5B variants with acute lymphoblastic leukemia in Yemeni children. A total of 14 ARID5B gene single nucleotide polymorphisms (SNPs) were genotyped in 289 Yemeni children, of whom 136 had acute lymphoblastic leukemia and 153 were controls, using the nanofluidic Dynamic Array (Fluidigm 192.24 Dynamic Array). Using logistic regression adjusted for age and gender, the risks of acute lymphoblastic leukemia were presented as odds ratios and 95% confidence intervals. We found that nine SNPs were associated with acute lymphoblastic leukemia under additive genetic models: rs7073837, rs10740055, rs7089424, rs10821936, rs4506592, rs10994982, rs7896246, rs10821938, and rs7923074. Furthermore, the recessive models revealed that six SNPs were risk factors for acute lymphoblastic leukemia: rs10740055, rs7089424, rs10994982, rs7896246, rs10821938, and rs7923074. The gender-specific impact of these SNPs under the recessive genetic model revealed that SNPs rs10740055, rs10994982, and rs6479779 in females, and rs10821938 and rs7923074 in males were significantly associated with acute lymphoblastic leukemia risk. Under the dominant model, SNPs rs7073837, rs10821936, rs7896246, and rs6479778 in males only showed striking association with acute lymphoblastic leukemia. The additive model revealed that SNPs with significant association with acute lymphoblastic leukemia were rs10821936 (both males and females); rs7073837, rs10740055, rs10994982, and rs4948487 (females only); and rs7089424, rs7896246, rs10821938, and rs7923074 (males only). In addition, the ARID5B haplotype block (CGAACACAA) showed a higher risk for acute lymphoblastic leukemia. The haplotype (CCCGACTGC) was associated with protection against acute lymphoblastic leukemia. In conclusion, our study has shown that ARID5B variants are associated with acute lymphoblastic leukemia in Yemeni children with several gender biases of ARID5B single nucleotide polymorphisms reported.
Fulltext Anticancer and anti-inflammatory activities of girinimbine isolated from Murraya koenigii

Iman V, Mohan S, Abdelwahab SI, Karimian H, Nordin N, Fadaeinasab M, et al.

Drug Des Devel Ther, 2017;11:103-121.
PMID: 28096658 DOI: 10.2147/DDDT.S115135

Therapy that directly targets apoptosis and/or inflammation could be highly effective for the treatment of cancer. Murraya koenigii is an edible herb that has been traditionally used for cancer treatment as well as inflammation. Here, we describe that girinimbine, a carbazole alkaloid isolated from M. koenigii, induced apoptosis and inhibited inflammation in vitro as well as in vivo. Induction of apoptosis in human colon cancer cells (HT-29) by girinimbine revealed decreased cell viability in HT-29, whereas there was no cytotoxic effect on normal colon cells. Changes in mitochondrial membrane potential, nuclear condensation, cell permeability, and cytochrome c translocation in girinimbine-treated HT-29 cells demonstrated involvement of mitochondria in apoptosis. Early-phase apoptosis was shown in both acridine orange/propidium iodide and annexin V results. Girinimbine treatment also resulted in an induction of G0/G1 phase arrest which was further corroborated with the upregulation of two cyclin-dependent kinase proteins, p21 and p27. Girinimbine treatment activated apoptosis through the intrinsic pathway by activation of caspases 3 and 9 as well as cleaved caspases 3 and 9 which ended by triggering the execution pathway. Moreover, apoptosis was confirmed by downregulation of Bcl-2 and upregulation of Bax in girinimbine-treated cells. In addition, the key tumor suppressor protein, p53, was seen to be considerably upregulated upon girinimbine treatment. Induction of apoptosis by girinimbine was also evidenced in vivo in zebrafish embryos, with results demonstrating significant distribution of apoptotic cells in embryos after a 24-hour treatment period. Meanwhile, anti-inflammatory action was evidenced by the significant dose-dependent girinimbine inhibition of nitric oxide production in lipopolysaccharide/interferon-gamma-induced cells along with significant inhibition of nuclear factor-kappa B translocation from the cytoplasm to nucleus in stimulated RAW 264.7 cells. Girinimbine was also shown to have considerable antioxidant activity whereby 20 μg/mL of girinimbine was equivalent to 82.17±1.88 μM of Trolox. In mice with carrageenan-induced peritonitis, oral pretreatment with girinimbine helped limit total leukocyte migration (mainly of neutrophils), and reduced pro-inflammatory cytokine levels (interleukin-1beta and tumor necrosis factor-alpha) in the peritoneal fluid. These findings strongly suggest that girinimbine could act as a chemopreventive and/or chemotherapeutic agent by inducing apoptosis while suppressing inflammation. There is a potential for girinimbine to be further investigated for its applicability in treating early stages of cancer.

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