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Mitochondrial Dysfunction in Down Syndrome: From Pathology to Therapy

Tan KL, Lee HC, Cheah PS, Ling KH

Neuroscience, 2023 Feb 10;511:1-12.
PMID: 36496187 DOI: 10.1016/j.neuroscience.2022.12.003

Mitochondrial dysfunctions have been described in Down syndrome (DS) caused by either partial or full trisomy of chromosome 21 (HSA21). Mitochondria play a crucial role in various vital functions in eukaryotic cells, especially in energy production, calcium homeostasis and programmed cell death. The function of mitochondria is primarily regulated by genes encoded in the mitochondrion and nucleus. Many genes on HSA21 are involved in oxidative phosphorylation (OXPHOS) and regulation of mitochondrial functions. This review highlights the HSA21 dosage-sensitive nuclear-encoded mitochondrial genes associated with overexpression-related phenotypes seen in DS. This includes impaired mitochondrial dynamics, structural defects and dysregulated bioenergetic profiles such as OXPHOS deficiency and reduced ATP production. Various therapeutic approaches for modulating energy deficits in DS, effects and molecular mechanism of gene therapy and drugs that exert protective effects through modulation of mitochondrial function and attenuation of oxidative stress in DS cells were discussed. It is prudent that improving DS pathophysiological conditions or quality of life may be feasible by targeting something as simple as cellular mitochondrial biogenesis and function.
Fulltext REST Targets JAK-STAT and HIF-1 Signaling Pathways in Human Down Syndrome Brain and Neural Cells

Huang T, Fakurazi S, Cheah PS, Ling KH

Int J Mol Sci, 2023 Jun 10;24(12).
PMID: 37373133 DOI: 10.3390/ijms24129980

Down syndrome (DS) is the most frequently diagnosed chromosomal disorder of chromosome 21 (HSA21) aneuploidy, characterized by intellectual disability and reduced lifespan. The transcription repressor, Repressor Element-1 Silencing Transcription factor (REST), which acts as an epigenetic regulator, is a crucial regulator of neuronal and glial gene expression. In this study, we identified and investigated the role of REST-target genes in human brain tissues, cerebral organoids, and neural cells in Down syndrome. Gene expression datasets generated from healthy controls and DS samples of human brain tissues, cerebral organoids, NPC, neurons, and astrocytes were retrieved from the Gene Ontology (GEO) and Sequence Read Archive (SRA) databases. Differential expression analysis was performed on all datasets to produce differential expression genes (DEGs) between DS and control groups. REST-targeted DEGs were subjected to functional ontologies, pathways, and network analyses. We found that REST-targeted DEGs in DS were enriched for the JAK-STAT and HIF-1 signaling pathways across multiple distinct brain regions, ages, and neural cell types. We also identified REST-targeted DEGs involved in nervous system development, cell differentiation, fatty acid metabolism and inflammation in the DS brain. Based on the findings, we propose REST as the critical regulator and a promising therapeutic target to modulate homeostatic gene expression in the DS brain.
Fulltext Potential Role of JAK-STAT Signaling Pathway in the Neurogenic-to-Gliogenic Shift in Down Syndrome Brain

Lee HC, Tan KL, Cheah PS, Ling KH

Neural Plast, 2016;2016:7434191.
PMID: 26881131 DOI: 10.1155/2016/7434191

Trisomy of human chromosome 21 in Down syndrome (DS) leads to several phenotypes, such as mild-to-severe intellectual disability, hypotonia, and craniofacial dysmorphisms. These are fundamental hallmarks of the disorder that affect the quality of life of most individuals with DS. Proper brain development involves meticulous regulation of various signaling pathways, and dysregulation may result in abnormal neurodevelopment. DS brain is characterized by an increased number of astrocytes with reduced number of neurons. In mouse models for DS, the pool of neural progenitor cells commits to glia rather than neuronal cell fate in the DS brain. However, the mechanism(s) and consequences of this slight neurogenic-to-gliogenic shift in DS brain are still poorly understood. To date, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling has been proposed to be crucial in various developmental pathways, especially in promoting astrogliogenesis. Since both human and mouse models of DS brain exhibit less neurons and a higher percentage of cells with astrocytic phenotypes, understanding the role of JAK-STAT signaling in DS brain development will provide novel insight into its role in the pathogenesis of DS brain and may serve as a potential target for the development of effective therapy to improve DS cognition.
Fulltext Spatiotemporal Expression and Molecular Characterization of miR-344b and miR-344c in the Developing Mouse Brain

Leong JW, Abdullah S, Ling KH, Cheah PS

Neural Plast, 2016;2016:1951250.
PMID: 27034842 DOI: 10.1155/2016/1951250

MicroRNAs (miRNAs) are small noncoding RNA known to regulate brain development. The expression of two novel miRNAs, namely, miR-344b and miR-344c, was characterized during mouse brain developmental stages in this study. In situ hybridization analysis showed that miR-344b and miR-344c were expressed in the germinal layer during embryonic brain developmental stages. In contrast, miR-344b was not detectable in the adult brain while miR-344c was expressed exclusively in the adult olfactory bulb and cerebellar granular layer. Stem-loop RT-qPCR analysis of whole brain RNAs showed that expression of the miR-344b and miR-344c was increased as brain developed throughout the embryonic stage and maintained at adulthood. Further investigation showed that these miRNAs were expressed in adult organs, where miR-344b and miR-344c were highly expressed in pancreas and brain, respectively. Bioinformatics analysis suggested miR-344b and miR-344c targeted Olig2 and Otx2 mRNAs, respectively. However, luciferase experiments demonstrated that these miRNAs did not target Olig2 and Otx2 mRNAs. Further investigation on the locality of miR-344b and miR-344c showed that both miRNAs were localized in nuclei of immature neurons. In conclusion, miR-344b and miR-344c were expressed spatiotemporally during mouse brain developmental stages.
REST in the Road Map of Brain Development

Lam XJ, Maniam S, Cheah PS, Ling KH

Cell Mol Neurobiol, 2023 Oct;43(7):3417-3433.
PMID: 37517069 DOI: 10.1007/s10571-023-01394-w

Repressor element-1 silencing transcription factor (REST) or also known as neuron-restrictive silencing factor (NRSF), is the key initiator of epigenetic neuronal gene-expression modification. Identification of a massive number of REST-targeted genes in the brain signifies its broad involvement in maintaining the functionality of the nervous system. Additionally, REST plays a crucial role in conferring neuroprotection to the neurons against various stressors or insults during injuries. At the cellular level, nuclear localisation of REST is a key determinant for the functional transcriptional regulation of REST towards its target genes. Emerging studies reveal the implication of REST nuclear mislocalisation or dysregulation in several neurological diseases. The expression of REST varies depending on different types of neurological disorders, which has created challenges in the discovery of REST-targeted interventions. Hence, this review presents a comprehensive summary on the physiological roles of REST throughout brain development and its implications in neurodegenerative and neurodevelopmental disorders, brain tumours and cerebrovascular diseases. This review offers valuable insights to the development of potential therapeutic approaches targeting REST to improve pathologies in the brain. The important roles of REST as a key player in the nervous system development, and its implications in several neurological diseases.
Chromosomal and cellular therapeutic approaches for Down syndrome: A research update

Huang T, Fakurazi S, Cheah PS, Ling KH

Biochem Biophys Res Commun, 2024 Sep 04;735:150664.
PMID: 39260337 DOI: 10.1016/j.bbrc.2024.150664

In individuals with Down syndrome (DS), an additional HSA21 chromosome copy leads to the overexpression of a myriad of HSA21 genes, disrupting the transcription of the entire genome. This dysregulation in transcription and post-transcriptional modifications contributes to abnormal phenotypes across nearly all tissues and organs in DS individuals. The array of severe clinical symptoms associated with trisomy 21 poses a considerable challenge in the quest for a cure for DS. Fortunately, a wealth of research suggests that chromosome therapy, hinging on cutting-edge genome editing technologies, can potentially eliminate the extra copy of the human chromosome 21. Genome editing tools have demonstrated their efficacy in restoring trisomy to a normal diploid state in vitro DS cell models. Furthermore, we delve into the noteworthy findings in cellular therapy for DS, with recent studies showcasing the increasing feasibility of strategies involving stem cells and CAR T-cells to address corresponding clinical phenotypes.
Fulltext Molecular genetics of Dupuytren's contracture

Aissvarya S, Ling KH, Arumugam M, Thilakavathy K

EFORT Open Rev, 2024 Aug 01;9(8):723-732.
PMID: 39087497 DOI: 10.1530/EOR-23-0056

Dupuytren's contracture (DC) is a fibroproliferative disorder of the palmar fascia characterised by the digits' flexion contractures and is associated with abnormal build-up of type III collagen. The prevalence of the disease is reported to be highest among Northern European descendants. However, the disease is widespread globally with varying prevalence. DC is a multifactorial disease, having both genetic and environmental factors contributing to the causality of the disease. Over the years, various studies have been conducted to understand the molecular mechanism and genetic aspects of DC but there is a lack of reports on the variants found in the exonic regions. Most reports are backdated making it necessary to re-evaluate the variants to further understand the genetic aetiology of DC. In this review, we first highlight the genetic aspects and previous genetic studies on DC. The report is followed by a discussion on the molecular pathways suggested to be associated with DC and a summary of the genetic variants in the exonic regions found in DC and their connections with the molecular pathways. A total of nine variants were reported originating from six genes comprising three pathways. Most variants reported are involved in the Wnt signalling pathway. Moreover, all variants identified are in European/Caucasian subjects and the variants found in the exonic regions are missense variants. A comparison of these findings with variants from populations of other regions can be conducted to identify the variants with the most occurrence to act as biomarkers or therapeutic targets for DC.
The Potential of Eight Plasma Proteins as Biomarkers in Redefining Leptospirosis Diagnosis

Fish-Low CY, Than LTL, Ling KH, Sekawi Z

J Proteome Res, 2024 Sep 06;23(9):4027-4042.
PMID: 39150348 DOI: 10.1021/acs.jproteome.4c00376

Leptospirosis, a notifiable endemic disease in Malaysia, has higher mortality rates than regional dengue fever. Diverse clinical symptoms and limited diagnostic methods complicate leptospirosis diagnosis. The demand for accurate biomarker-based diagnostics is increasing. This study investigated the plasma proteome of leptospirosis patients with leptospiraemia and seroconversion compared with dengue patients and healthy subjects using isobaric tags for relative and absolute quantitation (iTRAQ)-mass spectrometry (MS). The iTRAQ analysis identified a total of 450 proteins, which were refined to a list of 290 proteins through a series of exclusion criteria. Differential expression in the plasma proteome of leptospirosis patients compared to the control groups identified 11 proteins, which are apolipoprotein A-II (APOA2), C-reactive protein (CRP), fermitin family homolog 3 (FERMT3), leucine-rich alpha-2-glycoprotein 1 (LRG1), lipopolysaccharide-binding protein (LBP), myosin-9 (MYH9), platelet basic protein (PPBP), platelet factor 4 (PF4), profilin-1 (PFN1), serum amyloid A-1 protein (SAA1), and thrombospondin-1 (THBS1). Following a study on a verification cohort, a panel of eight plasma protein biomarkers was identified for potential leptospirosis diagnosis: CRP, LRG1, LBP, MYH9, PPBP, PF4, SAA1, and THBS1. In conclusion, a panel of eight protein biomarkers offers a promising approach for leptospirosis diagnosis, addressing the limitations of the "one disease, one biomarker" concept.
Fulltext MicroRNAs and intellectual disability (ID) in Down syndrome, X-linked ID, and Fragile X syndrome

Siew WH, Tan KL, Babaei MA, Cheah PS, Ling KH

Front Cell Neurosci, 2013;7:41.
PMID: 23596395 DOI: 10.3389/fncel.2013.00041

Intellectual disability (ID) is one of the many features manifested in various genetic syndromes leading to deficits in cognitive function among affected individuals. ID is a feature affected by polygenes and multiple environmental factors. It leads to a broad spectrum of affected clinical and behavioral characteristics among patients. Until now, the causative mechanism of ID is unknown and the progression of the condition is poorly understood. Advancement in technology and research had identified various genetic abnormalities and defects as the potential cause of ID. However, the link between these abnormalities with ID is remained inconclusive and the roles of many newly discovered genetic components such as non-coding RNAs have not been thoroughly investigated. In this review, we aim to consolidate and assimilate the latest development and findings on a class of small non-coding RNAs known as microRNAs (miRNAs) involvement in ID development and progression with special focus on Down syndrome (DS) and X-linked ID (XLID) [including Fragile X syndrome (FXS)].
Improved method for the isolation of RNA from bacteria refractory to disruption, including S. aureus producing biofilm

Atshan SS, Shamsudin MN, Lung LT, Ling KH, Sekawi Z, Pei CP, et al.

Gene, 2012 Feb 25;494(2):219-24.
PMID: 22222139 DOI: 10.1016/j.gene.2011.12.010

The development of fast, reliable and inexpensive phenol protocol is described for the isolation of RNA from bacterial biofilm producers. The method was tested on Staphylococcus aureus (S. aureus) and other biofilm-producing gram-negative microorganisms and provided the highest integrity of RNA recovery in comparison to other methods reported here. In parallel experiments, bacterial lysis with Qiagen, NucleoSpin RNAII, InnuREP RNA Mini, Trizol and MasterPure RNA extraction Kits using standard protocols consistently gave low RNA yields with an absence of integrity. The boiling method presented here yielded high concentration of RNA that was free from 16S and 23S rRNA, contained 5S RNA. Higher yields due to improved biofilm bacterial cell lysis were achieved with an added hot phenol incubation step without the need for a bead mill or the enzyme. This method when used in conjunction with the Qiagen RNeasy Mini kit, RNA isolation was a success with greater integrity and contained undegraded 16S and 23S rRNA and did not require further purification. Contaminating DNA was a problem with the RNA processing samples; we used quantitative real-time PCR (RT-qPCR) to measure the recovery of RNA from bacterial biofilm cells using the method described here.
In silico identification and characterization of a putative phosphatidylinositol 4-phosphate 5-kinase (PIP5K) gene in Eimeria tenella

Ling KH, Loo SS, Rosli R, Shamsudin MN, Mohamed R, Wan KL

In Silico Biol. (Gedrukt), 2007;7(1):115-21.
PMID: 17688436

Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) play diverse roles in the cellular biology of many organisms, including signal transduction, secretion and vesicular trafficking, and regulation of cytoskeleton assembly. Discovery of the PIP5K gene in Eimeria tenella may shed light on its role in the biology of this avian protozoan, and afford further understanding of the cell-host interaction, particularly during the invasion process. In this study, we report the identification of the PIP5K coding region in the genome sequence of Eimeria tenella using in silico gene prediction approaches. Prediction of the PIP5K coding sequence was confirmed by mapping the full-length cDNA sequence, generated via the Rapid Amplification of cDNA Ends (RACE) method, to the genomic sequence. The putative PIP5K gene of Eimeria tenella is located on the complementary strand of the E1080B12.b1 contig, and comprises 12 exons. Further analysis showed that the coding region spans from exon 1 to exon 7, with all exons obeying the adopted 'gt...ag' splicing rule of intronic sequences. Consensus of the hexameric 5' donor-splice site was deduced as GTRDBB... and the consensus for the 3' acceptor-splice sites as ...BHDYAG. The gene encodes a 252-amino acid residue protein. Domain search and protein fold recognition analyses provide compelling evidences that the deduced protein is a PIP5K.
Crossing the Blood-Brain Barrier: A Review on Drug Delivery Strategies for Treatment of the Central Nervous System Diseases

Mansor NI, Nordin N, Mohamed F, Ling KH, Rosli R, Hassan Z

Curr Drug Deliv, 2019;16(8):698-711.
PMID: 31456519 DOI: 10.2174/1567201816666190828153017

Many drugs have been designed to treat diseases of the central nervous system (CNS), especially neurodegenerative diseases. However, the presence of tight junctions at the blood-brain barrier has often compromised the efficiency of drug delivery to target sites in the brain. The principles of drug delivery systems across the blood-brain barrier are dependent on substrate-specific (i.e. protein transport and transcytosis) and non-specific (i.e. transcellular and paracellular) transport pathways, which are crucial factors in attempts to design efficient drug delivery strategies. This review describes how the blood-brain barrier presents the main challenge in delivering drugs to treat brain diseases and discusses the advantages and disadvantages of ongoing neurotherapeutic delivery strategies in overcoming this limitation. In addition, we discuss the application of colloidal carrier systems, particularly nanoparticles, as potential tools for therapy for the CNS diseases.
Fulltext Limited expression of non-integrating CpG-free plasmid is associated with increased nucleosome enrichment

Habib O, Mohd Sakri R, Ghazalli N, Chau DM, Ling KH, Abdullah S

PLoS One, 2020;15(12):e0244386.
PMID: 33347482 DOI: 10.1371/journal.pone.0244386

CpG-free pDNA was reported to facilitate sustained transgene expression with minimal inflammation in vivo as compared to CpG-containing pDNA. However, the expression potential and impact of CpG-free pDNA in in vitro model have never been described. Hence, in this study, we analyzed the transgene expression profiles of CpG-free pDNA in vitro to determine the influence of CpG depletion from the transgene. We found that in contrast to the published in vivo studies, CpG-free pDNA expressed a significantly lower level of luciferase than CpG-rich pDNA in several human cell lines. By comparing novel CpG-free pDNA carrying CpG-free GFP (pZGFP: 0 CpG) to CpG-rich GFP (pRGFP: 60 CpGs), we further showed that the discrepancy was not influenced by external factors such as gene transfer agent, cell species, cell type, and cytotoxicity. Moreover, pZGFP exhibited reduced expression despite having equal gene dosage as pRGFP. Analysis of mRNA distribution revealed that the mRNA export of pZGFP and pRGFP was similar; however, the steady state mRNA level of pZGFP was significantly lower. Upon further investigation, we found that the CpG-free transgene in non-integrating CpG-free pDNA backbone acquired increased nucleosome enrichment as compared with CpG-rich transgene, which may explain the observed reduced level of steady state mRNA. Our findings suggest that nucleosome enrichment could regulate non-integrating CpG-free pDNA expression and has implications on pDNA design.
Fulltext Plasma proteome profiling reveals differentially expressed lipopolysaccharide-binding protein among leptospirosis patients

Fish-Low CY, Than LTL, Ling KH, Lin Q, Sekawi Z

J Microbiol Immunol Infect, 2020 Feb;53(1):157-162.
PMID: 31029530 DOI: 10.1016/j.jmii.2018.12.015

BACKGROUND: Human leptospirosis, or commonly known as "rat urine disease" is a zoonotic disease that is caused by the bacteria called Leptospira sp. The incidence rate of leptospirosis has been under-reported due to its unspecific clinical symptoms and the limitations of current laboratory diagnostic methods. Leptospirosis can be effectively treated with antibiotics in the early stage, and it is a curable disease but the accuracy to diagnose the infection is rarely achieved.
METHODS: The present pilot study investigated plasma protein profiles of leptospirosis patients and compared them against two control groups which consisted of dengue patients and healthy individuals. The plasma protein digests were analyzed using shotgun approach by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Protein abundances were estimated from the exponentially modified protein abundance index (emPAI) values. Plasma proteins in leptospirosis patients with at least two-fold differential expression compared to dengue and healthy control groups (p
Fulltext Influence of vitamin D binding protein polymorphism, demographics and lifestyle factors on vitamin D status of healthy Malaysian pregnant women

Lee SS, Ling KH, Tusimin M, Subramaniam R, Rahim KF, Loh SP

BMC Pregnancy Childbirth, 2020 Nov 23;20(1):714.
PMID: 33228578 DOI: 10.1186/s12884-020-03397-7

BACKGROUND: Vitamin D deficiency (VDD) has been related to vitamin D binding protein (GC) gene polymorphism, demographics and lifestyle factors in different populations. However, previous studies only focused on demographic and lifestyle factors or genetic factors alone. Therefore, this cross-sectional study aimed to assess the association between GC gene polymorphism, demographics and lifestyle factors with VDD among Malaysian pregnant women.
METHOD: Information on demographic characteristics, dietary vitamin D intake from supplement and food, time spent outdoors, skin type and clothing were collected using a questionnaire. Plasma total 25-hydroxyvitamin D (25OHD) levels were measured using an Ultra-High-Performance Liquid Chromatography (UHPLC). Maternal GC single nucleotide polymorphisms (SNPs) (rs4588 and rs7041) were determined using restriction fragment length polymorphism (RFLP) technique.
RESULTS: Results showed that 50.2% of pregnant women were vitamin D deficient (25OHD
Fulltext In Silico Prediction and Validation of Gfap as an miR-3099 Target in Mouse Brain

Abidin SZ, Leong JW, Mahmoudi M, Nordin N, Abdullah S, Cheah PS, et al.

Neurosci Bull, 2017 Aug;33(4):373-382.
PMID: 28597341 DOI: 10.1007/s12264-017-0143-0

MicroRNAs are small non-coding RNAs that play crucial roles in the regulation of gene expression and protein synthesis during brain development. MiR-3099 is highly expressed throughout embryogenesis, especially in the developing central nervous system. Moreover, miR-3099 is also expressed at a higher level in differentiating neurons in vitro, suggesting that it is a potential regulator during neuronal cell development. This study aimed to predict the target genes of miR-3099 via in-silico analysis using four independent prediction algorithms (miRDB, miRanda, TargetScan, and DIANA-micro-T-CDS) with emphasis on target genes related to brain development and function. Based on the analysis, a total of 3,174 miR-3099 target genes were predicted. Those predicted by at least three algorithms (324 genes) were subjected to DAVID bioinformatics analysis to understand their overall functional themes and representation. The analysis revealed that nearly 70% of the target genes were expressed in the nervous system and a significant proportion were associated with transcriptional regulation and protein ubiquitination mechanisms. Comparison of in situ hybridization (ISH) expression patterns of miR-3099 in both published and in-house-generated ISH sections with the ISH sections of target genes from the Allen Brain Atlas identified 7 target genes (Dnmt3a, Gabpa, Gfap, Itga4, Lxn, Smad7, and Tbx18) having expression patterns complementary to miR-3099 in the developing and adult mouse brain samples. Of these, we validated Gfap as a direct downstream target of miR-3099 using the luciferase reporter gene system. In conclusion, we report the successful prediction and validation of Gfap as an miR-3099 target gene using a combination of bioinformatics resources with enrichment of annotations based on functional ontologies and a spatio-temporal expression dataset.
Fulltext Effect of zerumbone on scopolamine-induced memory impairment and anxiety-like behaviours in rats

Jafarian S, Ling KH, Hassan Z, Perimal-Lewis L, Sulaiman MR, Perimal EK

Alzheimers Dement (N Y), 2019;5:637-643.
PMID: 31687471 DOI: 10.1016/j.trci.2019.09.009

Introduction: We investigated the effects of zerumbone (1 and 10 mg/kg) against hyperactivity, anxiety and memory impairment in scopolamine-induced dementia in Sprague-Dawley rats.
Methods: Open field tests, elevated plus maze and Morris water maze were performed to assess general locomotor activity, anxiety-like behaviours and learning and memory processes respectively in rats pretreated with scopolamine.
Results: Scopolamine-treated rats showed high total activity, stereotype, and total distance travelled in the open field arena, reduced number of entries to open arms, decreased the percentage of time spent in open arms and higher escape latency time in the Morris water maze test. Interestingly, single administration of zerumbone (1 and 10 mg/kg) reversed the hyperactivity, anxiety-like behaviours, and learning impairment effects of scopolamine in the three experimental model studied respectively.
Discussion: Our findings demonstrated that the scopolamine-induced impairment of learning and memory was reversed by the administration of zerumbone. As a conclusion, our findings presented the positive effects of zerumbone on dementia-like behaviours in the animal model used and could possibly contribute for future research to manage hyperactivity, anxiety, and learning disabilities.
Mitragynine (Kratom) impairs spatial learning and hippocampal synaptic transmission in rats

Hassan Z, Suhaimi FW, Ramanathan S, Ling KH, Effendy MA, Müller CP, et al.

J. Psychopharmacol. (Oxford), 2019 07;33(7):908-918.
PMID: 31081443 DOI: 10.1177/0269881119844186

BACKGROUND: Mitragynine is the major alkaloid of Mitragyna speciosa (Korth.) or Kratom, a psychoactive plant widely abused in Southeast Asia. While addictive effects of the substance are emerging, adverse cognitive effects of this drug and neuropharmacological actions are insufficiently understood.
AIMS: In the present study, we investigated the effects of mitragynine on spatial learning and synaptic transmission in the CA1 region of the hippocampus.
METHODS: Male Sprague Dawley rats received daily (for 12 days) training sessions in the Morris water maze, with each session followed by treatment either with mitragynine (1, 5, or 10 mg/kg; intraperitoneally), morphine (5 mg/kg; intraperitoneally) or a vehicle. In the second experiment, we recorded field excitatory postsynaptic potentials in the hippocampal CA1 area in anesthetized rats and assessed the effects of mitragynine on baseline synaptic transmission, paired-pulse facilitation, and long-term potentiation. Gene expression of major memory- and addiction-related genes was investigated and the effects of mitragynine on Ca2+ influx was also examined in cultured primary neurons from E16-E18 rats.
RESULTS/OUTCOMES: Escape latency results indicate that animals treated with mitragynine displayed a slower rate of acquisition as compared to their control counterparts. Further, mitragynine treatment significantly reduced the amplitude of baseline (i.e. non-potentiated) field excitatory postsynaptic potentials and resulted in a minor suppression of long-term potentiation in CA1. Bdnf and αCaMKII mRNA expressions in the brain were not affected and Ca2+ influx elicited by glutamate application was inhibited in neurons pre-treated with mitragynine.
CONCLUSIONS/INTERPRETATION: These data suggest that high doses of mitragynine (5 and 10 mg/kg) cause memory deficits, possibly via inhibition of Ca2+ influx and disruption of hippocampal synaptic transmission and long-term potentiation induction.
miR-3099 promotes neurogenesis and inhibits astrogliogenesis during murine neural development

Zainal Abidin S, Fam SZ, Chong CE, Abdullah S, Cheah PS, Nordin N, et al.

Gene, 2019 May 20;697:201-212.
PMID: 30769142 DOI: 10.1016/j.gene.2019.02.014

MicroRNA-3099 is highly expressed during neuronal differentiation and development of the central nervous system. Here we characterised the role of miR-3099 during neural differentiation and embryonic brain development using a stable and regulatable mouse embryonic stem cell culture system for miR-3099 expression and in utero electroporation of miR-3099 expression construct into E15.5 embryonic mouse brains. In the in vitro system, miR-3099 overexpression upregulated gene related to neuronal markers such as Tuj1, NeuN, Gat1, vGluT1 and vGluT2. In contrast, gene related to astrocyte markers (Gfap, S100β and Slc1a3) were suppressed upon overexpression of miR-3099. Furthermore, miR-3099 overexpression between E15.5 and E18.5 mouse embryonic brains led to disorganised neuronal migration potentially due to significantly decreased Gfap+ cells. Collectively, our results indicated that miR-3099 plays a role in modulating and regulating expression of key markers involved in neuronal differentiation. In silico analysis was also performed to identify miR-3099 homologues in the human genome, and candidates were validated by stem-loop RT-qPCR. Analysis of the miR-3099 seed sequence AGGCUA against human transcriptomes revealed that a potential miRNA, mds21 (Chr21:39186698-39186677) (GenBank accession ID: MK521584), was 100% identical to the miR-3099 seed sequence. Mds21 expression was observed and validated in various human cell lines (293FT, human Wharton's jelly and dental pulp mesenchymal stem cells, and MCF-7, MDA-MB-231, C-Sert, SW780, RT112, 5637, EJ28 and SH-SY5Y cells), with the highest levels detected in human mesenchymal stem cell lines. The analysis validated mds21 as a novel miRNA and a novel homologue of miR-3099 in the human genome.
Directional capacity of human mesenchymal stem cells to support hematopoietic stem cell proliferation in vitro

Hashem Boroojerdi M, Hosseinpour Sarmadi V, Maqbool M, Ling KH, Safarzadeh Kozani P, Safarzadeh Kozani P, et al.

Gene, 2022 Feb 05;820:146218.
PMID: 35134469 DOI: 10.1016/j.gene.2022.146218

OBJECTIVES: Hematopoietic stem cells (HSCs) reside in a specialised microenvironment in the bone marrow, which is majorly composed of mesenchymal stem cells (MSCs) and its' derivatives. This study aimed to investigate the regulatory role of MSCs to decipher the cellular and humoral communications on HSCs' proliferation, self-renewal, and differentiation at the transcriptomic level.
MATERIALS AND METHODS: Microarray assay was employed to analyse the gene expression profile of HSCs that imparted by MSCs during co-culture.
RESULTS: The proliferation of human umbilical cord blood-derived HSCs (hUC-HSCs) markedly propagated when MSCs were used as the feeder layer, without disturbing the undifferentiated state of HSCs, and reduced the cell death of HSCs. Upon co-culture with MSCs, the global microarray analysis of HSCs disclosed 712 differentially expressed genes (DEGs) (561 up-regulated and 151 down-regulated). The dysregulations of various transcripts were enriched for cellular functions such as cell cycle (including CCND1), apoptosis (including TNF), and genes related to signalling pathways governing self-renewal, as well as WNT5A from the Wnt signalling pathway, MAPK, Hedgehog, FGF2 from FGF, Jak-STAT, and PITX2 from the TGF-β signalling pathway. To concur this, real-time quantitative PCR (RT-qPCR) was utilised for corroborating the microarray results from five of the most dysregulated genes.
CONCLUSION: This study elucidates the underlying mechanisms of the mitogenic influences of MSCs on the propagation of HSCs. The exploitation of such mechanisms provides a potential means for achieving larger quantities of HSCs in vitro, thus obviating the need for manipulating their differentiation potential for clinical application.

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