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  1. Fulltext Pathogenic mutations in ARX, CDKL5and STXBP1genes are not associated with the early-onset epileptic encephalopathy in Malaysian pediatricpatients: A pilot study
    Ameerah Jaafar, Feizel Alsiddiq, Ling, King-Hwa
    Neuroscience Research Notes, 2018;1(3):5-17.
    MyJurnal
    Gene mutation is one of the etiologies of early-onset epileptic encephalopathy (EOEE), an age-dependent seizure in infants, which leads to brain defects. Previous studies have shown that several genes namely, aristalessrelated homeobox (ARX), cyclindependent kinaselike 5 (CDKL5) and syntaxinbinding protein 1 (STXBP1) are responsible for the pathophysiology of the syndrome. Thestudy involved 20 EOEE patients and 60 control subjects, which aimed toinvestigatethe clinical association of Malaysian EOEE subjects with 13 known pathogenic mutations in the genes of interest. In addition, the entire ARX exonic region was also sequenced for known and novel mutations. PCR specificity and efficiency were optimized using conventional PCR and High Resolution Melting Analysis (HRMA). All cases and approximately 10% of control amplicon samples were purified and subjected to DNA sequencing. All known mutations reported previously were not found in control subjects and Malaysian EOEE patients with 100% confirmation by sequencing results. Sequencing of ARX exonic regionsof patient samplesdid not find any mutation in all exons. The preliminary study indicates that selected known pathogenic mutations of ARX, CDKL5and STXBP1are not associated with EOEE in Malaysian paediatric patients.
  2. Fulltext Challenges and future perspectives for 3D cerebral organoids as amodel for complex brain disorders
    Cheah, Pike-See, Mason, John O., Ling, King-Hwa
    Neuroscience Research Notes, 2019;2(1):1-6.
    MyJurnal
    The human brain is made up of billions of neurons and glial cells which are interconnected and organized into specific patternsof neural circuitry, and hence is arguably the most sophisticated organ in human, both structurally and functionally.Studying the underlying mechanisms responsible for neurologicalor neurodegenerativedisorders and the developmental basis of complex brain diseases such as autism, schizophrenia, bipolar disorder, Alzheimer’s and Parkinson’s disease has proven challenging due to practical and ethical limitations on experiments with human material and the limitationsof existing biological/animal models. Recently,cerebral organoids havebeen proposed as apromisingand revolutionary model for understanding complex brain disorders and preclinical drug screening.
  3. Fulltext Prospective stem cell lines as in vitroneurodegenerative disease models for natural product research
    Nur Izzati Mansor, Nuratiqah Azmi, Ling, King-Hwa, Rozita Rosli, Zurina Hassan, Norshariza Nordin
    Neuroscience Research Notes, 2019;2(1):16-30.
    MyJurnal
    The use of in vitromodel for screening pharmacological compounds or natural products has gained global interest. The choice of cells to be manipulated plays a vital role in coming up with the best-suitedmodel for specific diseases, including neurodegenerativediseases (ND). A good in vitro ND model should provide appropriate morphological and molecular features that mimic ND conditions where it can be used to screen potential properties of natural products in addition to unravelling the molecular mechanisms of ND. In this mini review, we intend to demonstrate two prospective stem cell lines as the potential cell source for in vitroND model and compare them to the commonly used cells. The common source of cells that have been usedas the in vitroND models is discussedbefore going into details talking about the two prospective stem cell lines.
  4. Fulltext Dopamine transporter 1 (DAT1) rs40184 single nucleotide polymorphism is not associated with the Malaysian major depressive disorder subjects
    Aldoghachi, Asraa Faris, Cheah, Pike-See, Normala Ibrahim, Lye, Munn Sann, Ling, King-Hwa
    Neuroscience Research Notes, 2019;2(4):5-13.
    MyJurnal
    Major depressive disorder (MDD) is a serious mental illness with a multifactorial aetiology that was shown to influence behaviour and affect cognition. Previous research has favoured the involvement of dopamine in the aetiology of the disorder, and since one of the critical regulators of the dopamine levels and activity in the brain is DAT1, the present study investigated the association of a single nucleotide polymorphism in the DAT1gene (rs40184) and MDD in the Malaysian population. A total of 300cases and 300 matched controls were recruited from four Klang valley hospitals and were screened for DAT1rs40184 using high resolution melting assays. The allele and genotype frequencies were analysed by using Chi-square. Hardy Weinberg equilibrium for the distribution of alleles and genotypes was tested by using Chi-square. Determination of the association between rs40184 and MDD was achieved by conditional logistic regression using SPSS. In the present study, no significant association was obtained between DAT1and MDD in the Malaysianpopulation.
  5. Fulltext Transcriptomic profiling of skeletal muscle from the Ts1Cje mouse model of Down syndrome suggests dysregulation of trisomic genes associated with neuromuscular junction signaling, oxidative stress and chronic inflammation
    Leong, Melody Pui Yee, Usman Bala, Lim, Chai Ling, Rozita Rosli, Cheah, Pike-See, Ling, King-Hwa
    Neuroscience Research Notes, 2018;1(1):21-41.
    MyJurnal
    Ts1Cje is a mouse model of Down syndrome (DS) with partial triplication of chromosome 16, which encompasses a high number of human chromosome 21 (HSA21) orthologous genes. The mouse model exhibits muscle weakness resembling hypotonia in DS individuals. The effect of extra gene dosages on muscle weakness or hypotonia in Ts1Cje and DS individuals remains unknown. To identify molecular dysregulation of the skeletal muscle, we compared the transcriptomic signatures of soleus and extensor digitorum longus (EDL) muscles between the adult Ts1Cje and disomic littermates. A total of 166 and 262 differentially expressed protein-coding genes (DEGs) were identified in the soleus and EDL muscles, respectively. The partial trisomy of MMU16 in Ts1Cje mice has a greater effect on gene expression in EDL. Top-down clustering analysis of all DEGs for represented functional ontologies revealed 5 functional clusters in soleus associated with signal transduction, development of reproductive system, nucleic acid biosynthesis, protein modification and metabolism as well as regulation of gene expression. On the other hand, only 3 functional clusters were observed for EDL namely neuron and cell development, protein modification and metabolic processes as well as ion transport. A total of 11 selected DEGs were validated using qPCR (disomic DEGs: Mansc1; trisomic DEGs: Itsn1, Rcan1, Synj1, Donson, Dyrk1a, Ifnar1, Ifnar2, Runx1, Sod1 and Tmem50b). The validated DEGs were implicated in neuromuscular junction signalling (Itsn1, Syn1), oxidative stress (Sod1, Runx1) and chronic inflammation processes (Runx1, Rcan1, Ifnar1, Ifnar2). Other validated DEGs have not been well-documented as involved in the skeletal muscle development or function, thus serve as interesting novel candidates for future investigations. To our knowledge, the study was the first attempt to determine the transcriptomic profiles of both soleus and EDL muscles in Ts1Cje mice. It provides new insights on the possible disrupted molecular pathways associated with hypotonia in DS individuals.
  6. Fulltext Cellular function of satellite cells does not play a role in muscle weakness of adult Ts1Cje mice
    Lim, Chai Ling, Usman Bala, Leong, Melody Pui-Yee, Johnson Stanslas, Rajesh Ramasamy, Ling, King-Hwa, et al.
    Neuroscience Research Notes, 2018;1(1):3-10.
    MyJurnal
    Down syndrome (DS) is a genetic condition resulting from triplication of human chromosome (HSA)21. Besides intellectual disability, DS is frequently associated with hypotonia. Satellite cells are the resident cells that provides robust and remarkable regenerative capacity to the skeletal muscles, and its population size has been reported to be disease-associated. However, little is known about the population size of satellite cells in DS and the association of its intrinsic cellular functionality and hypotonia seen in DS. Here, we studied the Ts1Cje mouse, a DS murine model displays the muscle weakness characteristic. Satellite cell populations were immunostained with Pax7 and myonuclei numbers in the Ts1Cje extensor digitorum longus muscle were assessed. Their cellular function was further determined via in vitro assay in high-serum conditioned medium. Subsequently, the in vitro self-renewal, proliferative, and differentiation activities of these myogenic precursor cells were assessed after 24, 48, and 72h using Pax7, MyoD, and Ki67 immunomarkers. Our results showed that the population and functionality of Ts1Cje satellite cell did not differ significantly when compared to the wildtype cells isolated from disomic littermates. In conclusion, our findings indicated that intrinsic cellular functionality of the satellite cells, do not contribute to muscle weakness in Ts1Cje mouse.
  7. Fulltext Zinc transporter-3 [SLC30A3(rs11126936)]polymorphismis associated with major depressive disorderin Asian subjects
    Lye, Munn-Sann, Aishah-Farhana Shahbudin, Tey, Yin-Yee, Tor, Yin-Sim, Ling, King-Hwa, Normala Ibrahim, et al.
    Neuroscience Research Notes, 2019;2(3):20-28.
    MyJurnal
    Major depressive disorder (MDD) compromises the individual’s capacity for self-care and productivity. Single nucleotide polymorphisms (SNP) of a number of genes have been associated with MDD. The zinc transporter-3 protein, encoded by the ZnT3 (SLC30A3) gene, maintains zinc-glutamate homeostasis at the glutamatergic synapse, a disruption of which increases risk of MDD. We hypothesise that variation in SLC30A3 (rs11126936)SNP increases risk of MDD. We recruited 300 MDD cases and 300 controls, matched in theratio of 1:1 by age, gender and ethnicity. PCR-restriction fragment length polymorphism analysis was used in DNA genotyping, validated by sequencing 10%of samples. Deviation from the Hardy-Weinberg equilibrium was tested using the chi-square test. Conditional logistic regression was used to estimate adjusted odds ratios, controlling for age, gender, ethnicity, occupation and family monthly income.Genotypes G/G and G/T showed two times greater odds of developing MDD compared to variant genotype T/T (OR=1.983, 95% CI=1.031-3.815; p=0.040 and OR=2.232, 95% CI=1.100-4.533; p=0.026 respectively). Carriers of genotypes G/G and G/T of the SNP rs11126936 in SLC30A3are associated with increased risk of MDD.
  8. Fulltext Development and validation of high resolution melting assays for high-throughput screening of BDNF rs6265 and DAT1 rs40184
    Asraa Faris, Hadri Hadi Md Yusof, Shahidee Zainal Abidin, Omar Habib, Cheah, Pike-See, Stanslas, Johnson, et al.
    Malaysian Journal of Medicine and Health Sciences, 2018;14(101):64-71.
    MyJurnal
    Introduction: One of the commonly used techniques for mutation screening is High Resolution Melting (HRM) analysis. HRM is a post PCR method that relies on the detection of the fluorescent signals acquired due to the release of DNA intercalated dyes upon the melting of dsDNA to ssDNA. The method is simple, inexpensive and does not require post PCR-handling, making it suitable for high throughput screening. Methods: This study aimed to develop and validate HRM technique for the screening of two disease-associated single nucleotide polymorphisms (SNPs) namely BDNF rs6265 and DAT1 rs40184 using a total of 30 gDNA samples. The obtained results were confirmed and validated by sequencing. Results: HRM analysis showed that the predicted genotypes of BDNF rs6265 and DAT1 rs40184 among all the gDNA samples were in 100% concordance with the sequencing results, making it an accurate and sensitive method for the detection of SNPs. Conclusions: The application of HRM can accurately determine the genotype of BDNF rs6265 and DAT1 rs40184 SNPs, making it a promising tool for rapid and high-throughput screening of targeted SNPs in a large population study.
  9. Fulltext Generation and characterization of human Osteoarthritis Cartilage-derived Mesenchymal Stem Cells by modified sample processing and culture method
    Algraittee, Satar Jabbar Rahi, Lawal, Hamza, Boroojerdi, Mohadese Hashem, Sarmadi, Vahid Hosseinpour, Maqbool, Maryam, Fahrudin Che Hamzah, et al.
    Malaysian Journal of Medicine and Health Sciences, 2018;14(103):1-9.
    MyJurnal
    Mesenchymal stem cells (MSCs) can be isolated from different tissue sources, and show a high differentiation capacity towards osteogenic, adipogenic, chondrogenic, neurogenic and myogenic lineages upon a specific induction. Although the retrieval of MSCs from normal tissues is very straightforward, yet it could be challenging in degenerative conditions that limit the expansion of stem cells such as osteoarthritis. Thus, this study aimed to establish human MSCs culture from osteoarthritic cartilage (OA hC-MSCs) by optimising the sample processing and culture techniques. Methods: Human osteoarthritis knee cartilage samples were obtained (2-4 g) from 8 patients with a mean age of 62.75 years old during the joint replacement surgery. A conventional culture method carried along with the modified method where the period of enzyme digestion and serial plating culture procedure were incorporated. Results: The modified culture method has significantly increased the number of single cells twice after the sample processing. The time taken to form colonies and achieve confluence was also reduced when samples subjected to the modified method. The number of cell yields after passage 0 for the conventional and modified methods were 3.05±0.31 and 6.10±0.42 million cells, respectively. The adherent cells generated under these two conditions comply with criteria for MSCs in term of immunophenotyping and mesodermal differentiation. Conclusions: The current modified method enhances the production of MSCs and could be opted for samples that known to have reduced or defective stem cell pool which may impede the in vitro cell expansion.
  10. Fulltext Molecular modeling, dynamics simulations, and binding efficiency of berberine derivatives: A new group of RAF inhibitors for cancer treatment
    Jabbarzadeh Kaboli P, Ismail P, Ling KH
    PLoS One, 2018;13(3):e0193941.
    PMID: 29565994 DOI: 10.1371/journal.pone.0193941
    RAF kinases are a family of enzymes in the MAP kinase pathway that contribute to the development of different types of cancer. BRAF is the most important member of RAF kinases. BRAF mutations have been detected in 7% of all cancers and 66% of melanomas; as such, the FDA has approved a few BRAF inhibitor drugs to date. However, BRAF can activate CRAF leading to resistance to BRAF inhibitors. Berberine (BBR) is an alkaloid that is widely distributed in different plant species. Several studies have been carried out on the anti-cancer effects of BBR but direct targets of BBR are unknown. In this study, interactions of BBR derivatives against BRAF and CRAF kinases were modeled and predicted using an in silico-based approach. To analyze and identify the residues important in BRAF docking, we modeled interactions of ATP, the universal substrate of BRAF, and found that Lys483 and Asp594 are the most important residues involved in both ATP and BBR binding [(The average score = -11.5 kcal/mol (ATP); Range of scores = -7.78 to -9.55 kcal/mol (BBR)]. In addition to these polar residues, Trp530 and Phe583 are also applicable to the molecular docking of BRAF. We also observed that Asp593 was excluded from the enzyme cavity, while Phe594 was included inside the cavity, making the enzyme inactive. Finally, three alternatives for BBR were identified with dual RAF inhibition effects [The best scores against BRAF = -11.62 kcal/mol (BBR-7), -10.64 kcal/mol (BBR-9), and -11.01 kcal/mol (BBR-10); the best scores against CRAF = -9.68 kcal/mol (BBR-7), -9.60 kcal/mol (BBR-9), and -9.20 kcal/mol (BBR-10)]. Direct effects of BBR derivatives against BRAF and CRAF kinases had not yet been reported previously, and, thus, for the first time, we report three cycloprotoberberines as lead compounds against RAF kinases.
  11. Isolation, cultivation and immunostaining of single myofibers: An improved approach to study the behavior of satellite cells
    Lim CL, Ling KH, Cheah PS
    J Biol Methods, 2018;5(1):e87.
    PMID: 31453240 DOI: 10.14440/jbm.2018.219
    Satellite cells are myogenic cells responsible for muscle growth shortly after birth and muscle repair/regeneration during adulthood. Therapies based on satellite cells hold promise for treating muscular dysfunctions. Studying satellite cells is technically challenging owing to their low abundance, small size and anatomical dispersed location between the basal lamina and the sarcolemma of myofibers. In this article, we present three improved protocol strategies for studying the properties of satellite cells of the mouse during the different stages of muscle regeneration: (1) immunostaining of freshly isolated single myofibers to facilitate the study of quiescent satellite cells, (2) cultivation of single myofibers on Matrigel®-coated dish to study the myogenesis programs initiated by satellite cell activation, and (3) cultivation of single myofibers in floating conditions to analyze activated satellite cells or the doubling time of satellite cells in myofibers. In brief, when compared to previously published protocols, this article presented an improved protocol that requires shorter experimental time and less laborious approach for higher yield of intact single myofibers for downstream analyses.
  12. Fulltext Harvesting the maximum length of sciatic nerve from adult mice: a step-by-step approach
    Bala U, Tan KL, Ling KH, Cheah PS
    BMC Res Notes, 2014;7:714.
    PMID: 25304607 DOI: 10.1186/1756-0500-7-714
    Over the past several decades, many studies concerning peripheral nerve damage or regeneration have been performed. Mice have been widely used for many of these studies, with the sciatic nerve being the most targeted and preferred nerve. Therefore, techniques for harvesting mouse sciatic nerves of a maximum length that is sufficient for different analyses will be highly valuable. Here we describe a simple step-by-step guide for harvesting the maximum length of mouse sciatic nerve and compare the length of the harvested nerves gathered with the proposed method with nerves obtained using a conventional mid-thigh incision approach.
  13. Targets and mechanisms of berberine, a natural drug with potential to treat cancer with special focus on breast cancer
    Jabbarzadeh Kaboli P, Rahmat A, Ismail P, Ling KH
    Eur J Pharmacol, 2014 Oct 5;740:584-95.
    PMID: 24973693 DOI: 10.1016/j.ejphar.2014.06.025
    Breast cancer is the most common cancer among women worldwide and novel therapeutic agents are needed to treat this disease. The plant-based alkaloid berberine has potential therapeutic applications for breast cancer, although a better understanding of the genes and cellular pathways regulated by this compound is needed to define the mechanism of its action in cancer treatment. In this review, the molecular targets of berberine in various cancers, particularly breast cancer, are discussed. Berberine was shown to be effective in inhibiting cell proliferation and promoting apoptosis in various cancerous cells. Some signaling pathways affected by berberine, including the MAP (mitogen-activated protein) kinase and Wnt/β-catenin pathways, are critical for reducing cellular migration and sensitivity to various growth factors. This review will discuss recent studies and consider the application of new prospective approaches based on microRNAs and other crucial regulators for use in future studies to define the action of berberine in cancer. The effects of berberine on cancer cell survival and proliferation are also outlined.
  14. Fulltext Angiotensinogen M235T gene variants and its association with essential hypertension and plasma renin activity in Malaysian subjects: a case control study
    Say YH, Ling KH, Duraisamy G, Isaac S, Rosli R
    BMC Cardiovasc Disord, 2005;5(1):7.
    PMID: 15811183
    Essential hypertension is a major public health concern worldwide where its prevalence accounts for various cerebrovascular diseases. A common molecular variant of angiotensinogen (AGT), the precursor of potent vasoactive hormone angiotensin II, has been incriminated as a marker for genetic predisposition to essential hypertension in some ethnics. This case-control study was designed not only to determine the association of the AGT M235T gene variants with essential hypertension, but also its relationship to Plasma Renin Activity (PRA) in subjects attending the Health Clinic, Kuala Lumpur, Malaysia.
  15. MicroRNA-based therapy and breast cancer: A comprehensive review of novel therapeutic strategies from diagnosis to treatment
    Kaboli PJ, Rahmat A, Ismail P, Ling KH
    Pharmacol Res, 2015 Jul;97:104-21.
    PMID: 25958353 DOI: 10.1016/j.phrs.2015.04.015
    MicroRNAs (miRNA) are 21-23 nucleotide molecules not translated into proteins that bind and target the 3' untranslated regions of mRNA. These characteristics make them a possible tool for inhibiting protein translation. Different cellular pathways involved in cancer development, such as cellular proliferation, apoptosis, and migration, are regulated by miRNAs. The objective of this review is to discuss various miRNAs involved in breast cancer in detail as well as different therapeutic strategies from the clinic to industry. A comprehensive discussion is provided on various miRNAs involved in breast cancer development, progression, and metastasis as well as the roles, targets, and related therapeutic strategies of different miRNAs associated with breast cancer. miRNAs known to be clinically useful for the diagnosis and prognosis of breast cancer are also discussed. Different strategies and challenges, including nucleic acid-based (miRNA mimics, antagomiRs, and miRNA sponges) and drug-based (drug resistance, drugs/miRNA interaction, nanodelivery, and sensing systems) approaches to suppress specific oncogenes and/or activate target tumor suppressors are discussed. In contrast to other articles written on the same topic, this review focuses on the therapeutic and clinical value of miRNAs as well as their corresponding targets in order to explore how these strategies can overcome breast cancer, which is the second most frequent type of cancer worldwide. This review focuses on promising and validated miRNAs involved in breast cancer. In particular, two miRNAs, miR-21 and miR-34, are discussed as the most promising targets for RNA-based therapy in non-invasive and invasive breast cancer, respectively. Finally, relevant and commercialized therapeutic strategies are highlighted.
  16. Fulltext Development and Differentiation of Midbrain Dopaminergic Neuron: From Bench to Bedside
    Wang M, Ling KH, Tan JJ, Lu CB
    Cells, 2020 06 18;9(6).
    PMID: 32570916 DOI: 10.3390/cells9061489
    Parkinson's Disease (PD) is a neurodegenerative disorder affecting the motor system. It is primarily due to substantial loss of midbrain dopamine (mDA) neurons in the substantia nigra pars compacta and to decreased innervation to the striatum. Although existing drug therapy available can relieve the symptoms in early-stage PD patients, it cannot reverse the pathogenic progression of PD. Thus, regenerating functional mDA neurons in PD patients may be a cure to the disease. The proof-of-principle clinical trials showed that human fetal graft-derived mDA neurons could restore the release of dopamine neurotransmitters, could reinnervate the striatum, and could alleviate clinical symptoms in PD patients. The invention of human-induced pluripotent stem cells (hiPSCs), autologous source of neural progenitors with less ethical consideration, and risk of graft rejection can now be generated in vitro. This advancement also prompts extensive research to decipher important developmental signaling in differentiation, which is key to successful in vitro production of functional mDA neurons and the enabler of mass manufacturing of the cells required for clinical applications. In this review, we summarize the biology and signaling involved in the development of mDA neurons and the current progress and methodology in driving efficient mDA neuron differentiation from pluripotent stem cells.
  17. Fulltext Impulse control behaviours in a Malaysian Parkinson’s disease population
    Shahrul Azmin, Tan, Eng Liang, Law, Zhe Kang, Remli Rabani, Wan Yahya Nafisah, Sahathevan, Ramesh, et al.
    Neurology Asia, 2016;21(2):137-143.
    MyJurnal
    Background: Impulse control behaviours are repetitive and excessive activities that may be sub-syndromal and not fulfil the criteria for impulse control disorder. These activities have potential to negatively impact on the daily lives of sufferers. We conducted a study to investigate the prevalence of impulse control behaviours and its associated features in Parkinson’s disease in our population. Methods: We conducted a prospective cross-sectional study on consecutive patients attending neurology clinic. Inclusion criteria include idiopathic Parkinson’s disease patients with Hoehn & Yahr stage I-IV. Eighty patients were enrolled and screened for impulse control behaviours using the Questionnaire for Impulsive-Compulsive Disorder for Parkinson’s disease (QUIP). Results: Prevalence of impulse control behaviours among our cohort was 11.3%; the features significantly associated with it were higher level of education (p=0.02), advanced stage of disease (p=0.03) and higher levodopa dosage (p= 0.01). The commonest impulse control behaviour in our cohort was compulsive medication use (7.5%), followed by hobbyism (6.3%), hypersexuality (5%), compulsive buying (3.75%), punding (2.5%), walkabout (2.5%), compulsive eating (1.25%) and pathological gambling (1.3%).
    Conclusions: There is an association between impulse control behaviour and higher levodopa dosage in a study on patients with Parkinson’s disease in Malaysia. We also found a low prevalence of pathological gambling as compared to studies performed in the West.
    Study site: Neurology clinic, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia
  18. Annexin A2 extracellular translocation and virus interaction: A potential target for antivirus-drug discovery
    Aliyu IA, Ling KH, Md Hashim N, Chee HY
    Rev Med Virol, 2019 05;29(3):e2038.
    PMID: 30746844 DOI: 10.1002/rmv.2038
    Annexin A2 is a membrane scaffolding and binding protein, which mediated various cellular events. Its functions are generally affected by cellular localization. In the cytoplasm, they interacted with different phospholipid membranes in Ca2+ -dependent manner and play vital roles including actin binding, remodeling and dynamics, cytoskeletal rearrangement, and lipid-raft microdomain formation. However, upon cell exposure to certain stimuli, annexin A2 translocates to the external leaflets of the plasma membrane where annexin A2 was recently reported to serve as a virus receptor, play an important role in the formation of virus replication complex, or implicated in virus assembly and budding. Here, we review some of annexin A2 roles in virus infections and the potentiality of targeting annexin A2 in the design of novel and promising antivirus agent that may have a broader consequence in virus therapy.
  19. Antitumor effects of berberine against EGFR, ERK1/2, P38 and AKT in MDA-MB231 and MCF-7 breast cancer cells using molecular modelling and in vitro study
    Jabbarzadeh Kaboli P, Leong MP, Ismail P, Ling KH
    Pharmacol Rep, 2019 Feb;71(1):13-23.
    PMID: 30343043 DOI: 10.1016/j.pharep.2018.07.005
    BACKGROUND: Berberine is an alkaloid plant-based DNA intercalator that affects gene regulation, particularly expression of oncogenic and tumor suppressor proteins. The effects of berberine on different signaling proteins remains to be elucidated. The present study aimed to identify the effects of berberine against key oncogenic proteins in breast cancer cells.

    METHODS: Molecular docking and molecular dynamics simulations were used for EGFR, p38, ERK1/2, and AKT. The effects of berberine and lapatinib on MAPK and PI3K pathways in MDA-MB231 and MCF-7 cells were evaluated using immunoflorescence assays, and the amounts of phosphorylated kinases were compared to total kinases after treating with different concentrations of berberine.

    RESULTS: Simulations showed berberine accurately interacted with EGFR, AKT, P38, and ERK1/2 active sites in silico (scores = -7.57 to -7.92 Kcal/mol) and decreased the levels of active forms of corresponding enzymes in both cell lines; however, berberine binding to p38 showed less stability. Cytotoxicity analysis indicated that MDA-MB231 cells were resistant to berberine compared to MCF-7 cells [72 h IC50 = 50 versus 15 μM, respectively). Also, lapatinib strongly activated AKT but suppressed EGFR in MDA-MB231 cells. The activity of EGFR, AKT, P38, and ERK1/2 were affected by berberine; however, berberine dramatically reduced EGFR and AKT phosphorylation.

    CONCLUSION: By way of its multikinase inhibitory effects, berberine might be a useful replacement for lapatinib, an EGFR inhibitor which can cause acquired drug resistance in patients.

  20. Molecular Modelling of Berberine Derivatives as Inhibitors of Human Smoothened Receptor and Hedgehog Signalling Pathway Using a Newly Developed Algorithm on Anti-Cancer Drugs
    Kaboli PJ, Bazrafkan M, Ismail P, Ling KH
    Recent Pat Anticancer Drug Discov, 2017 Nov 20;12(4):384-400.
    PMID: 28969581 DOI: 10.2174/1574892812666170929131247
    BACKGROUND: Protoberberine isoquinoline alkaloids are found in many plant species. They consist of a diverse class of secondary metabolites with many pharmacologically active members, such as different derivatives of berberine already patented. In the development of approximately 20-25% of all cancers, altered hedgehog (Hh) signalling is involved where the smoothened (Smo) transmembrane receptor triggers Hh signalling pathway towards Gli1 gene expression.

    OBJECTIVE: The current study aimed to model and verify the anti-Smo activity of berberine and its derivatives using a novel automated script.

    METHOD: Based on the patented inventions filed on ADMET modelling until 2016, which also predicts ADMET parameters and binding efficiency indices for all molecules, a script was developed to run automated molecular docking for a large number of small molecules.

    RESULTS: Berberine was found to interact with Lys395 of Smo receptor via hydrogen bonding and cation-π interactions. In addition, π-π interactions between berberine aromatic rings and two aromatic residues in the Smo transmembrane domain, Tyr394 and Phe484, were noted. Binding efficiency indices using an in silico approach to plot the Smo-specific binding potency of each ligand was performed. The mRNA level of Gli1 was studied as the outcome of Hh signalling pathway to show the effect of berberine on hedgehog signalling.

    CONCLUSION: This study predicted the role of berberine as an inhibitor of Smo receptor, suggesting its effectiveness in hedgehog signalling during cancer treatment.

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