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Expression profile of genes modulated by Aloe emodin in human U87 glioblastoma cells

Haris K, Ismail S, Idris Z, Abdullah JM, Yusoff AA

Asian Pac J Cancer Prev, 2014;15(11):4499-505.
PMID: 24969876

Glioblastoma, the most aggressive and malignant form of glioma, appears to be resistant to various chemotherapeutic agents. Hence, approaches have been intensively investigated to targeti specific molecular pathways involved in glioblastoma development and progression. Aloe emodin is believed to modulate the expression of several genes in cancer cells. We aimed to understand the molecular mechanisms underlying the therapeutic effect of Aloe emodin on gene expression profiles in the human U87 glioblastoma cell line utilizing microarray technology. The gene expression analysis revealed that a total of 8,226 gene alterations out of 28,869 genes were detected after treatment with 58.6 μg/ml for 24 hours. Out of this total, 34 genes demonstrated statistically significant change (p<0.05) ranging from 1.07 to 1.87 fold. The results revealed that 22 genes were up-regulated and 12 genes were down-regulated in response to Aloe emodin treatment. These genes were then grouped into several clusters based on their biological functions, revealing induction of expression of genes involved in apoptosis (programmed cell death) and tissue remodelling in U87 cells (p<0.01). Several genes with significant changes of the expression level e.g. SHARPIN, BCAP31, FIS1, RAC1 and TGM2 from the apoptotic cluster were confirmed by quantitative real-time PCR (qRT-PCR). These results could serve as guidance for further studies in order to discover molecular targets for the cancer therapy based on Aloe emodin treatment.
Enhanced induction of cell cycle arrest and apoptosis via the mitochondrial membrane potential disruption in human U87 malignant glioma cells by aloe emodin

Ismail S, Haris K, Abdul Ghani AR, Abdullah JM, Johan MF, Mohamed Yusoff AA

J Asian Nat Prod Res, 2013 Sep;15(9):1003-12.
PMID: 23869465 DOI: 10.1080/10286020.2013.818982

Aloe emodin, one of the active compounds found in Aloe vera leaves, plays an important role in the regulation of cell growth and death. It has been reported to promote the anti-cancer effects in various cancer cells by inducing apoptosis. However, the mechanism of inducing apoptosis by this agent is poorly understood in glioma cells. This research is to investigate the apoptosis and cell cycle arrest inducing by aloe emodin on U87 human malignant glioma cells. Aloe emodin showed a time- and dose-dependent inhibition of U87 cells proliferation and decreased the percentage of viable U87 cells via the induction of apoptosis. Characteristic morphological changes, such as the formation of apoptotic bodies, were observed with confocal microscope by Annexin V-FITC/PI staining, supporting our viability study and flow cytometry analysis results. Our data also demonstrated that aloe emodin arrested the cell cycle in the S phase and promoted the loss of mitochondrial membrane potential in U87 cells that indicated the early event of the mitochondria-induced apoptotic pathway.
Fulltext Increased Nociceptive Responses in Streptozotocin-Induced Diabetic Rats and the Related Expression of Spinal NR2B Subunit of N-Methyl-D-Aspartate Receptors

Ismail CAN, Suppian R, Abd Aziz CB, Haris K, Long I

Diabetes Metab J, 2019 Apr;43(2):222-235.
PMID: 30604591 DOI: 10.4093/dmj.2018.0020

BACKGROUND: This study investigated the role of NR2B in a modulated pain process in the painful diabetic neuropathy (PDN) rat using various pain stimuli.
METHODS: Thirty-two Sprague-Dawley male rats were randomly allocated into four groups (n=8): control, diabetes mellitus (DM) rats and diabetic rats treated with ifenprodil at a lower dose (0.5 μg/day) (I 0.5) or higher dose (1.0 μg/day) (I 1.0). DM was induced by a single injection of streptozotocin at 60 mg/kg on day 0 of experimentation. Diabetic status was assessed on day 3 of the experimentation. The responses on both tactile and thermal stimuli were assessed on day 0 (baseline), day 14 (pre-intervention), and day 22 (post-intervention). Ifenprodil was given intrathecally for 7 days from day 15 until day 21. On day 23, 5% formalin was injected into the rats' hind paw and the nociceptive responses were recorded for 1 hour. The rats were sacrificed 72 hours post-formalin injection and an analysis of the spinal NR2B expression was performed.
RESULTS: DM rats showed a significant reduction in pain threshold in response to the tactile and thermal stimuli and higher nociceptive response during the formalin test accompanied by the higher expression of phosphorylated spinal NR2B in both sides of the spinal cord. Ifenprodil treatment for both doses showed anti-allodynic and anti-nociceptive effects with lower expression of phosphorylated and total spinal NR2B.
CONCLUSION: We suggest that the pain process in the streptozotocin-induced diabetic rat that has been modulated is associated with the higher phosphorylation of the spinal NR2B expression in the development of PDN, which is similar to other models of neuropathic rats.
Detection of somatic mutations in the mitochondrial DNA control region D-loop in brain tumors: The first report in Malaysian patients

Mohamed Yusoff AA, Mohd Nasir KN, Haris K, Mohd Khair SZN, Abdul Ghani ARI, Idris Z, et al.

Oncol Lett, 2017 Nov;14(5):5179-5188.
PMID: 29098023 DOI: 10.3892/ol.2017.6851

Although the role of nuclear-encoded gene alterations has been well documented in brain tumor development, the involvement of the mitochondrial genome in brain tumorigenesis has not yet been fully elucidated and remains controversial. The present study aimed to identify mutations in the mitochondrial DNA (mtDNA) control region D-loop in patients with brain tumors in Malaysia. A mutation analysis was performed in which DNA was extracted from paired tumor tissue and blood samples obtained from 49 patients with brain tumors. The D-loop region DNA was amplified using the PCR technique, and genetic data from DNA sequencing analyses were compared with the published revised Cambridge sequence to identify somatic mutations. Among the 49 brain tumor tissue samples evaluated, 25 cases (51%) had somatic mutations of the mtDNA D-loop, with a total of 48 mutations. Novel mutations that had not previously been identified in the D-loop region (176 A-deletion, 476 C>A, 566 C>A and 16405 A-deletion) were also classified. No significant associations between the D-loop mutation status and the clinicopathological parameters were observed. To the best of our knowledge, the current study presents the first evidence of alterations in the mtDNA D-loop regions in the brain tumors of Malaysian patients. These results may provide an overview and data regarding the incidence of mitochondrial genome alterations in Malaysian patients with brain tumors. In addition to nuclear genome aberrations, these specific mitochondrial genome alterations may also be considered as potential cancer biomarkers for the diagnosis and staging of brain cancers.