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Renowned as a highly invasive and lethal tumor derived from neural stem cells in the central nervous system, glioblastoma (GBM) exhibits substantial histopathological variation and genomic complexity, which drive its rapid progression and therapeutic resistance. Alterations in mitochondrial DNA (mtDNA) copy number (CN) serve a crucial role in GBM development and progression, affecting various aspects of tumor biology, including energy production, oxidative stress regulation and cellular adaptability. Fluctuations in mtDNA levels, whether elevated or diminished, can impair mitochondrial function, potentially disrupting oxidative phosphorylation and amplifying reactive oxygen species generation, thereby fueling tumor growth and influencing treatment responses. Understanding the mechanisms of mtDNA‑CN variations, and their interplay with genetic and environmental elements in the tumor microenvironment, is essential for advancing diagnostic and therapeutic strategies. Targeting mtDNA alterations could strengthen treatment efficacy, mitigate resistance and ultimately enhance the prognosis of patients with this aggressive brain tumor. The present review summarizes the existing literature on mtDNA alterations, specifically emphasizing variations in mtDNA‑CN and their association with GBM by surveying articles published between 1996 and 2024, sourced from databases such as Scopus, PubMed and Google Scholar. In addition, the review provides a brief overview of mitochondrial genome architecture, knowledge regarding the regulation of mtDNA integrity and CN, and how mitochondria significantly impact GBM tumorigenesis. This review further presents information on therapeutic approaches for restoring mtDNA‑CN that contribute to optimized mitochondrial function and improved health outcomes.

Chiari malformation type 1 (CM 1) entails a structural defect in the cerebellum, involving the herniation of cerebellar tonsils toward the foramen magnum. The symptomatic or asymptomatic nature of CM 1 is contingent upon the condition of malformation in the spinal cord. This review presents an updated perspective on the prevalence of CM 1, its pathogenesis, genetic associations, and treatment. CM 1 exhibits a higher prevalence in adult females than males. Despite the incomplete understanding of the exact cause of CM 1, recent research suggests the involvement of both genetic and environmental factors in its development. One of the reasons for the occurrence of CM 1 in individuals is the smaller posterior cranial fossa, which manifests as typical morphological features. Additionally, environmental factors can potentially interact with genetic factors, modifying the observable characteristics of the disease and affecting the symptoms, severity, and development of the condition. Notably, headaches, neck pain, dizziness, and neurological deficits may be exhibited by individuals with CM 1, highlighting the importance of early diagnosis. Magnetic resonance imaging (MRI) serves as an alternative diagnostic technique for monitoring the symptoms of CM 1. Multiple genetic factors are likely to contribute to a cascade of abnormalities in CM 1. Early studies provided evidence, including clustering within families, bone development, and co-segregation with known genetic syndromes, establishing CM 1's association with a genetic basis. Furthermore, surgery is the only available treatment option to alleviate symptoms or hinder the progression of damage to the central nervous system (CNS) in CM 1 cases., (© 2024 Siti Nornazihah Mohd Rosdi et al., published by Sciendo.)

Neurodegenerative diseases represent a significant challenge to modern medicine, with their complex etiology and progressive nature posing hurdles to effective treatment strategies. Among the various contributing factors, mitochondrial dysfunction has emerged as a pivotal player in the pathogenesis of several neurodegenerative disorders. This review paper provides a comprehensive overview of how mitochondrial impairment contributes to the development of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, driven by bioenergetic defects, biogenesis impairment, alterations in mitochondrial dynamics (such as fusion or fission), disruptions in calcium buffering, lipid metabolism dysregulation and mitophagy dysfunction. It also covers current therapeutic interventions targeting mitochondrial dysfunction in these diseases., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background:  Investigating the role of mitochondrial DNA (mtDNA) alterations and their impact on brain tumor progression remains a significant focus in cancer research. The research aimed to explore the specific contributions of mtDNA copy number changes and their correlations with patient survival, large mtDNA deletions, and TFAM mutations in brain tumor patients., Methods:  A total of 41 patients with confirmed brain tumors underwent DNA extraction from both tumor tissues and blood samples. The relative mtDNA copy number in comparison to the nuclear genome was quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Long-range PCR assessed largescale mtDNA deletions, and Sanger sequencing was applied to detect exon 4 TFAM mutations., Results:  Analysis revealed significantly increased mtDNA copy numbers in brain tumor tissues (80.5%) compared to matched blood samples (P < .001). Median delta Ct (∆Ct) values were 7.35 in cancerous tissues and 11.81 in blood (P <.001), with median relative mtDNA content of 0.0123 and 0.0006, respectively (P <.001). Patients with higher mtDNA copy numbers experienced longer overall survival periods (P=.045) and notably favorable outcomes, particularly in high-grade tumor cases (P=.016). Furthermore, a singlenucleotide deletion was identified in exon 4 of TFAM in a patient with glioblastoma IV, while no large-scale mtDNA deletions were found in brain tumor patients., Conclusion:  Our study strongly supports the role of increased mtDNA copy numbers as a reliable predictor for improved survival and positive outcomes in high-grade brain tumor patients.

The resistance, plasticity and heterogeneity of cancer cells, including glioblastoma (GB) cells, have prompted the investigation of various agents for possible adjuncts and alternatives to existing therapies. This includes a macrolide antibiotic, azithromycin (AZI). It possesses intriguing anticancer properties in a range of cancer models in vitro, such as antiproliferative, pro-apoptotic, anti-autophagy and anti-angiogenic effects. In fact, AZI is renowned for its ability to eradicate cancer stem cells by inhibiting mitochondrial biogenesis and respiration. AZI-containing regimens in cancer patients for different purposes have shown favourable (i.e., attributed to its antibacterial activity) and unfavourable outcomes. Whilst its direct anticancer effects have yet to be clinically proven. To that end, this review provides a summary of AZI anticancer studies and delineates its potential activities in overcoming the challenges of GB., (© 2023 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Burkitt lymphoma (BL) is a form of B-cell malignancy that progresses aggressively and is most often seen in children. While Epstein-Barr virus (EBV) is a double-stranded DNA virus that has been linked to a variety of cancers, it can transform B lymphocytes into immortalized cells, as shown in BL. Therefore, the estimated prevalence of EBV in a population may assist in the prediction of whether this population has a high risk of increased BL cases. This systematic review and meta-analysis aimed to estimate the prevalence of Epstein-Barr virus in patients with Burkitt lymphoma. Using the appropriate keywords, four electronic databases were searched. The quality of the included studies was assessed using the Joanna Briggs Institute's critical appraisal tool. The results were reported as percentages with a 95% confidence interval using a random-effects model (CI). PROSPERO was used to register the protocol (CRD42022372293), and 135 studies were included. The prevalence of Epstein-Barr virus in patients with Burkitt lymphoma was 57.5% (95% CI: 51.5 to 63.4, n = 4837). The sensitivity analyses demonstrated consistent results, and 65.2% of studies were of high quality. Egger's test revealed that there was a significant publication bias. EBV was found in a significantly high proportion of BL patients (more than 50% of BL patients). This study recommends EBV testing as an alternative for predictions and the assessment of the clinical disease status of BL.

Background: The present study aimed to understand the characterisation of human hippocampal astrocyte following hypoxia exposure. Based on the preliminary screening, 15 min was chosen as the time point and the cells were exposed to different oxygen percentages., Methods: The Trypan blue viability assay used to examine cell death. Immunofluorescence assay, glial fibrillary acidic protein (GFAP) was used to portray the morphology of astrocytes. The hypoxia-inducible factor 1 (HIF-1) staining was performed to confirm hypoxia induced cell death and there was a dramatic expression of HIF-1α displayed in exposed astrocyte cells compared to the control. In molecular level, genes were chosen, such as glyceraldehyde 3-phosphate dehydrogenase (GAPDH), GFAP, HIF-1α and B-cell lymphoma 2 (Bcl-2) and ran the reverse transcription-polymerase chain reaction (RT-PCR)., Results: Microscope revealed a filamentous and clear nucleus appearance in a control whereas the rupture nuclei with no rigid structure of the cell were found in the 3% oxygen. The control and hypoxia cells were also stained with the annexin V-fluorescein isothiocyanate (annexin V-FITC). Fluorescence microscope reveals astrocyte cells after hypoxia showed higher expression of nuclei but not in control. Merging PI and FITC showed the differences of nuclei expression between the control and hypoxia. In the molecular analysis, there were significant changes of GFAP, HIF-1α and Bcl-2 in hypoxia exposed cells when compared to the control group., Conclusion: Cells that were exposed to hypoxia (3% oxygen for 15 min) clearly showed damage. General view of human hippocampal astrocyte genomic response to hypoxia was obtained., Competing Interests: Conflict of Interest None., (© Penerbit Universiti Sains Malaysia, 2023.)

Mitochondria are the critical organelles involved in various cellular functions. Mitochondrial biogenesis is activated by multiple cellular mechanisms which require a synchronous regulation between mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). The mitochondrial DNA copy number (mtDNA‑CN) is a proxy indicator for mitochondrial activity, and its alteration reflects mitochondrial biogenesis and function. Despite the precise mechanisms that modulate the amount and composition of mtDNA, which have not been fully elucidated, mtDNA‑CN is known to influence numerous cellular pathways that are associated with cancer and as well as multiple other diseases. In addition, the utility of current technology in measuring mtDNA‑CN contributes to its extensive assessment of diverse traits and tumorigenesis. The present review provides an overview of mtDNA‑CN variations across human cancers and an extensive summary of the existing knowledge on the regulation and machinery of mtDNA‑CN. The current information on the advanced methods used for mtDNA‑CN assessment is also presented.

Thalassemias are monogenic hematologic diseases that are classified as α- or β-thalassemia according to its quantitative abnormalities of adult α- or β-globin chains. β-thalassemia has widely spread throughout the world especially in Mediterranean countries, the Middle East, Central Asia, India, Southern China, and the Far East as well as countries along the north coast of Africa and in South America. The one and the only cure for β-thalassemia is allogenic hematopoietic stem cell transplantations (HSCT). Nevertheless, the difficulty to find matched donors has hindered the availability of this therapeutic option. Therefore, this present review explored the alternatives for β-thalassemia treatment such as RNA manipulation therapy, splice-switching, genome editing and generation of corrected induced pluripotent stem cells (iPSCs). Manipulation of β-globin RNA is mediated by antisense oligonucleotides (ASOs) or splice-switching oligonucleotides (SSOs), which redirect pre-mRNA splicing to significantly restore correct β-globin pre-mRNA splicing and gene product in cultured erythropoietic cells. Zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) are designer proteins that can alter the genome precisely by creating specific DNA double-strand breaks. The treatment of β-thalassemia patient-derived iPSCs with TALENs have been found to correct the β-globin gene mutations, implying that TALENs could be used as a therapy option for β-thalassemia. Additionally, CRISPR technologies using Cas9 have been used to fix mutations in the β-globin gene in cultured cells as well as induction of hereditary persistence of fetal hemoglobin (HPFH), and α-globin gene deletions have proposed a possible therapeutic option for β-thalassemia. Overall, the accumulated research evidence demonstrated the potential of ASOs-mediated aberrant splicing correction of β-thalassemia mutations and the advancements of genome therapy approaches using ZFNs, TALENs, and CRISPR/Cas9 that provided insights in finding the permanent cure of β-thalassemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zakaria, Bahar, Abdullah, Mohamed Yusoff, Shamsuddin, Abdul Wahab and Johan.)

Background: Previous studies had reported on the cytotoxic activities of generic antibiotics such as doxycycline (DOXY) and azithromycin (AZI) in multiple types of human cancers. Given that resistance to standard anti-glioblastoma multiforme (GBM) drug [temozolomide (TMZ)] is common and inevitable, alternative candidates are greatly needed., Purpose and Method: The present study was undertaken to explore the cytotoxicity and anticancer effects of DOXY and AZI on human GBM U87 cells via 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), Hoechst, Annexin V-FITC/PI, and clonogenic assays. CompuSyn software was used to determine the combination index (CI) for DOXY+AZI., Result: Individual treatment with DOXY and AZI decreased U87 cell viability in dose- and time-dependent, and quantitatively comparable to TMZ. Nevertheless, combinations of both antibiotics evidenced antagonistic behaviour in U87 cells. Increased apoptotic event was also observed with the individual treatment of DOXY and AZI. Furthermore, the proliferative and clonogenic capability of 21-day survived U87 cells was completely terminated by DOXY and AZI, but not TMZ., Conclusion: The antiproliferative and apoptosis-inducing activity exhibited by both antibiotics against U87 cells demonstrates their potential as a likely alternative to combat GBM. It would be interesting to find out more about their molecular players and cytotoxic effects in different types of GBM cells, including glioma stem cells (GSCs).

Cancer is a heterogeneous group of diseases, the progression of which demands an accumulation of genetic mutations and epigenetic alterations of the human nuclear genome or possibly in the mitochondrial genome as well. Despite modern diagnostic and therapeutic approaches to battle cancer, there are still serious concerns about the increase in death from cancer globally. Recently, a growing number of researchers have extensively focused on the burgeoning area of biomarkers development research, especially in noninvasive early cancer detection. Intergenomic cross talk has triggered researchers to expand their studies from nuclear genome-based cancer researches, shifting into the mitochondria-mediated associations with carcinogenesis. Thus, it leads to the discoveries of established and potential mitochondrial biomarkers with high specificity and sensitivity. The research field of mitochondrial DNA (mtDNA) biomarkers has the great potential to confer vast benefits for cancer therapeutics and patients in the future. This review seeks to summarize the comprehensive insights of nuclear genome cancer biomarkers and their usage in clinical practices, the intergenomic cross talk researches that linked mitochondrial dysfunction to carcinogenesis, and the current progress of mitochondrial cancer biomarker studies and development., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Siti Zulaikha Nashwa Mohd Khair et al.)

Background: To date, BRAF mutations in brain tumor patients have not been characterized in the Malaysian population. Based on the numerous reported studies, there are main mutations that exist in BRAF gene in various types of cancers. A missense mutation in codon 600 of the BRAF nuclear oncogene (BRAF V600E ) is the most prevalent hotspot point mutation that has been identified in multiple human malignancies., Aim: We here aimed to find out the frequency of BRAF V600E mutation in a series of Malaysian patients with brain tumors and if any association exists between BRAF V600E mutation and clinicopathological features of patients., Material and Methods: Fresh frozen tumor tissue samples from 50 Malaysian brain tumor patients were analyzed for BRAF V600E mutational status, and its correlation with clinicopathological features (including age, gender, and tumor localization such as intra-axial: within the brain substance or extra-axial: outside the brain substance) was examined., Results: The overall BRAF V600E mutation frequency was determined to be 22% (in 11 of 50 patients). BRAF V600E was significantly correlated with the tumor location group, which shows BRAF V600E was more frequent in the intra-axial tumor than the extra-axial tumor group. In this study, we also observed that male patients were slightly more susceptible to BRAF V600E mutation, and this mutation was predominant in patients of the age group < 40 years. However, these parameters did not translate to statistical significance., Conclusion: The data demonstrate that BRAF V600E mutation is observed significantly more often in intra-axial brain tumor patients, which can serve as baseline information for further research on genetic alteration that occurs during brain tumor progression in the Malaysian population.

Thalassemia, an inherited quantitative globin disorder, consists of two types, α- and β -thalassemia. β -thalassemia is a heterogeneous disease that can be asymptomatic, mild, or even severe. Considerable research has focused on investigating its underlying etiology. These studies found that DNA hypomethylation in the β-globin gene cluster is significantly related to fetal hemoglobin (HbF) elevation. Histone modification reactivates γ-globin gene expression in adults and increases β-globin expression. Down-regulation of γ-globin suppressor genes, i.e., BCL11A , KLF1 , HBG-XMN1 , HBS1L-MYB , and SOX6, elevates the HbF level. β -thalassemia severity is predictable through FLT1 , ARG2 , NOS2A , and MAP3K5 gene expression. NOS2A and MAP3K5 may predict the β -thalassemia patient's response to hydroxyurea, a HbF-inducing drug. The transcription factors NRF2 and BACH1 work with antioxidant enzymes, i.e., PRDX1 , PRDX2 , TRX1 , and SOD1 , to protect erythrocytes from oxidative damage, thus increasing their lifespan. A single β -thalassemia-causing mutation can result in different phenotypes, and these are predictable by IGSF4 and LARP2 methylation as well as long non-coding RNA expression levels. Finally, the coinheritance of β -thalassemia with α-thalassemia ameliorates the β -thalassemia clinical presentation. In conclusion, the management of β -thalassemia is currently limited to genetic and epigenetic approaches, and numerous factors should be further explored in the future.

Background and Objective: Meningiomas are among the most common intracranial tumors of the central nervous system. It is widely accepted that the initiation and progression of meningiomas involve the accumulation of nucleus genetic alterations, but little is known about the implication of mitochondrial genomic alterations during development of these tumors. The human mitochondrial DNA (mtDNA) contains a short hypervariable, noncoding displacement loop control region known as the D-Loop. Alterations in the mtDNA D-loop have been reported to occur in most types of human cancers. The purpose of this study was to assess the mtDNA D-loop mutations in Malaysian meningioma patients., Materials and Methods: Genomic DNA was extracted from 21 fresh-frozen tumor tissues and blood samples of the same meningioma patients. The entire mtDNA D-loop region (positions 16024-576) was polymerase chain reaction amplified using designed primers, and then amplification products were purified before the direct DNA sequencing proceeds., Results: Overall, 10 (47.6%) patients were detected to harbor a total of 27 somatic mtDNA D-loop mutations. Most of these mtDNA mutations were identified in the hypervariable segment II (40.7%), with 33.3% being located mainly in the conserved sequence block II of the D310 sequence. Furthermore, 58 different germline variations were observed at 21 nucleotide positions., Conclusion: Our results suggest that mtDNA alterations in the D-loop region may be an important and early event in developing meningioma. Further studies are needed, including validation in a larger patient cohort, to verify the clinicopathological outcomes of mtDNA mutation biomarkers in meningiomas., Competing Interests: None

Background: The 4977-bp common deletion (mtDNA) is a well-established mitochondrial genome alteration that has been described in various types of human cancers. However, to date, no studies on mtDNA in brain tumors have been reported. The present study aimed to determine mtDNA prevalence in common brain tumors, specifically, low- and high-grade gliomas (LGGs and HGGs), and meningiomas in Malaysian cases. Its correlation with clinicopathological parameters was also evaluated., Methods: A total of 50 patients with pathologically confirmed brain tumors (13 LGGs, 20 HGGs, and 17 meningiomas) were enrolled in this study. mtDNA was detected by using polymerase chain reaction (PCR) technique and later confirmed via Sanger DNA sequencing., Results: Overall, mtDNA was observed in 16 (32%) patients and it was significantly correlated with the type of tumor group and sex, being more common in the HGG group and in male patients., Conclusion: The prevalence of mtDNA in Malaysian glioma and meningioma cases has been described for the first time and it was, indeed, comparable with previously published studies. This study provides initial insights into mtDNA in brain tumor and these findings can serve as new data for the global mitochondrial DNA mutations database.

Purpose: To determine the mutational analyses of familial exudative vitreoretinopathy (FEVR)-causing genes in Malay patients with retinopathy of prematurity (ROP) to obtain preliminary data for gene alterations in the Malay community., Methods: A comparative cross-sectional study involving 86 Malay premature babies (ROP = 41 and non-ROP = 45) was performed from September 2012 to December 2014. Mutation analyses in (FEVR)-causing genes ( NDP , FZD4 , LRP5 , and TSPAN12 ) were performed using DNA from premature babies using polymerase chain reaction (PCR) and direct sequencing. Sequencing results were confirmed with PCR-Restriction Fragment Length Polymorphism (RFLP)., Results: We found variants of FZD4, LRP5 , and TSPAN12 in this study. One patient from each group showed a non-synonymous alteration in FZD4 , c.502C>T (p.P168S). A synonymous variant of LRP5 [c.3357G>A (p.V1119V)] was found in 30 ROP and 28 non-ROP patients. Two variants of TSPAN12 , c.765G>T (p.P255P) and c.*39C>T (3'UTR), were also recorded (29 and 21 in ROP, 33 and 26 in non-ROP, respectively). Gestational age and birth weight were found to be significantly associated with ROP ( P value < 0.001 and 0.001, respectively)., Conclusion: Analysis of data obtained from the ROP Malay population will enhance our understanding of these FEVR-causing gene variants. The c.3357G>A (p.V1119V) variant of LRP5 , and c.765G>T (p.P255P) and c.*39C>T variants of TSPAN12 could be common polymorphisms in the Malay ethnic group; however, this requires further elucidation. Future studies using larger groups and higher numbers of advanced cases are necessary to evaluate the relationship between FEVR-causing gene variants and the risk of ROP susceptibility in Malaysian infants., Competing Interests: There are no conflicts of interest.

Background: Mitochondria are major cellular sources of reactive oxygen species (ROS) generation which can induce mitochondrial DNA damage and lead to carcinogenesis. The mitochondrial 10398A>G alteration in NADH-dehydrogenase subunit 3 (ND3) can severely impair complex I, a key component of ROS production in the mitochondrial electron transport chain. Alteration in ND3 10398A>G has been reported to be linked with diverse neurodegenerative disorders and cancers. The aim of this study was to find out the association of mitochondrial ND3 10398A>G alteration in brain tumor of Malaysian patients., Methods: Brain tumor tissues and corresponding blood specimens were obtained from 45 patients. The ND3 10398A>G alteration at target codon 114 was detected using the PCR-RFLP analysis and later was confirmed by DNA sequencing., Results: Twenty-six (57.8%) patients showed ND3 10398A>G mutation in their tumor specimens, in which 26.9% of these mutations were heterozygous mutations. ND3 10398A>G mutation was not significantly correlated with age, gender, and histological tumor grade, however was found more frequently in intra-axial than in extra-axial tumors (62.5% vs. 46.2%, p<0.01)., Conclusion: For the first time, we have been able to describe the occurrence of ND3 10398A>G mutations in a Malaysian brain tumor population. It can be concluded that mitochondrial ND3 10398A>G alteration is frequently present in brain tumors among Malaysian population and it shows an impact on the intra-axial tumors., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2018 The Korean Brain Tumor Society, The Korean Society for Neuro-Oncology, and The Korean Society for Pediatric Neuro-Oncology.)

Background: Bamboo shoot has been used as a treatment for epilepsy in traditional Chinese medicine for generations to treat neuronal disorders such as convulsive, dizziness and headaches. 4-hydroxybenzoic acid (4-hba) is a non-flavonoid phenol found abundantly in Dendrocalamus asper shoots (bamboo), fruits (strawberries and apples) and flowers. Kv1.4 is a rapidly inactivating Shaker -related member of the voltage-gated potassium channels with two inactivation mechanisms; the fast N-type and slow C-type. It plays vital roles in repolarisation, hyperpolarisation and signaling the restoration of resting membrane potential through the regulation of the movement of K + across the cellular membrane., Methods: Chemical compounds from Dendrocalamus asper bamboo shoots were purified and identified as major palmitic acids mixed with other minor fatty acids, palmitic acid, 4-hydroxybenzaldehyde, lauric acid, 4-hydroxybenzoic acid and cholest-4-ene-3-one. The response of synthetic 4-hydroxybenzoic acid was tested on Kv1.4 potassium channel which was injected into viable oocytes that was extracted from Xenopus laevis . The current were detected by the two-microelectrode voltage clamp, holding potential starting from -80 mV with 20 mV step-up until +80 mV. Readings of treatments with 0.1% DMSO, 4-hba concentrations and K channel blockers were taken at +60 mV. The ratio of tail/peak amplitude is the index of the activity of the Kv1.4 channels with n ≥ 6 (number of oocytes tested). The decreases of the ratios of five different concentrations (1 μM, 10 μM, 100 μM, 1 mM and 2.5 mM) were compared with 0.1% DMSO as the control., Results: All concentration showed statistically significant results with P < 0.05 except for 100 μM. The normalised current of the 4-hba concentrations were compared with potassium channel blockers (TEA and 4-AP) and all groups showed statistically significant results. This study also showed that time taken for each concentration to affect Kv1.4 does not play any significant roles., Conclusion: 4-hydroxybenzoic acid was found to be able to enhance the inactivation of Kv1.4 by lowering the membrane potential so that the abnormal neuronal firing can be inhibited. With IC50 slightly higher than 10 μM, increasing concentrations (100 μM, 1 mM and 2.5 mM) had shown to exhibit toxicity effects. The best concentration from this study is 10 μM with Hill slope of 0.1799., Competing Interests: Conflict of Interest There were no conflicts of interest stated by the authors.

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.

Background: Brain tumors, constituting one of the most deadly forms of cancer worldwide, result from the accumulation of multiple genetic and epigenetic alterations in genes and signaling pathways. Isocitrate dehydrogenase enzyme isoform 1 (IDH1) mutations are frequently identified in primary brain tumors and acute myeloid leukemia. Studies on IDH1 gene mutations have been extensively performed in various populations worldwide but not in Malaysia. This work was conducted to study the prevalence of IDH1 c.395G>A (R132H) hotspot mutations in a group of Malaysian patients with brain tumors in order to gain local data for the IDH1 mutation profile in our population. Methods: Mutation analysis of c.395G>A (R132H) of IDH1 was performed in 40 brain tumor specimens by the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) and then verified by direct sequencing. Associations between the IDH1 c.395G>A (R132H) mutation and clinicopathologic characteristics were also analyzed. Results: The IDH1 c.395G>A (R132H) mutation was detected in 14/40 patients (35%). A significant association was found with histological tumor types, but not with age, gender and race. Conclusions: IDH1 is frequently mutated and associated with histological subtypes in Malay brain tumors., (Creative Commons Attribution License)

Brain tumor is molecularly a heterogeneous group of diseases, and genetic factors seem to play a crucial role in its genesis. Even though multiple alterations in the nuclear-encoded genes such as tumor suppressor and oncogenes are believed to play a key role in brain tumorigenesis, the involvement of the mitochondrial genome to this event remains controversial to date. Mitochondrial DNA (mtDNA) has been suspected to be associated with the carcinogenesis because of its high sensitivity to mutations and inefficient repair mechanisms in comparison to nuclear DNA. Thus, defects in mtDNA could also lead to the development of brain tumor. By virtue of their clonal nature and high copy number, mtDNA mutations may provide a new effective molecular biomarker for the cancer detection. It has been suggested that establishing mtDNA defective pattern might be useful in cancer diagnostics and detection, the prognosis of cancer outcome, and/or the response to certain treatments. This mini-review gives a brief overview on the several aspects of mtDNA, with a particular focus on its role in tumorigenesis and progression of brain tumor. Understanding the role of mitochondria and brain tumor development could potentially translate into therapeutic strategies for patients with these tumors.

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.

Generalized epilepsy with febrile seizures plus (GEFS+) comprises a group of clinically and genetically heterogeneous epilepsy syndrome. Here, we provide the first report of clinical presentation and mutational analysis of SCN1A gene in 36 Malaysian GEFS+ patients. Mutational analysis of SCN1A gene revealed twenty seven sequence variants (missense mutation and silent polymorphism also intronic polymorphism), as well as 2 novel de-novo mutations were found in our patients at coding regions, c.5197A>G (N1733D) and c.4748A>G (H1583R). Our findings provide potential genetic insights into the pathogenesis of GEFS+ in Malaysian populations concerning the SCN1A gene mutations., (Copyright © 2012 Elsevier B.V. All rights reserved.)