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Fulltext Hypoxia-inducible factor 1 signalling, metabolism and its therapeutic potential in cardiovascular disease

Sousa Fialho MDL, Abd Jamil AH, Stannard GA, Heather LC

Biochim Biophys Acta Mol Basis Dis, 2019 04 01;1865(4):831-843.
PMID: 30266651 DOI: 10.1016/j.bbadis.2018.09.024

Cardiovascular disease (CVD) accounts for the largest number of deaths worldwide, necessitating the development of novel treatments and prevention strategies. Given the huge energy demands placed on the heart, it is not surprising that changes in energy metabolism play a key role in the development of cardiac dysfunction in CVD. A reduction in oxygen delivery to the heart, hypoxia, is sensed and responded to by the hypoxia-inducible factor (HIF) and its family of proteins, by regulating the oxygen-dependent signalling cascade and subsequent response. Hypoxia is one of the main drivers of metabolic change in ischaemic disease and myocardial infarction, and we therefore suggest that HIF may be an attractive therapeutic target. In this review, we assess cardiac energy metabolism in health and disease, and how these can be regulated by HIF-1α activation. We then present an overview of research in the field of hypoxia-mimetic drugs recently developed in other treatment fields, which provide insight into the potential of systemic HIF-1α activation therapy for treating the heart.

Matched MeSH terms: Up-Regulation
Fulltext Regulation of Epigenetic Modifiers, Including KDM6B, by Interferon-γ and Interleukin-4 in Human Macrophages

Yıldırım-Buharalıoğlu G, Bond M, Sala-Newby GB, Hindmarch CC, Newby AC

Front Immunol, 2017;8:92.
PMID: 28228757 DOI: 10.3389/fimmu.2017.00092

BACKGROUND: Interferon-γ (IFN-γ) or interleukin-4 (IL-4) drives widely different transcriptional programs in macrophages. However, how IFN-γ and IL-4 alter expression of histone-modifying enzymes involved in epigenetic regulation and how this affects the resulting phenotypic polarization is incompletely understood.
METHODS AND RESULTS: We investigated steady-state messenger RNA levels of 84 histone-modifying enzymes and related regulators in colony-stimulating factor-1 differentiated primary human macrophages using quantitative polymerase chain reaction. IFN-γ or IL-4 treatment for 6-48 h changed 11 mRNAs significantly. IFN-γ increased CIITA, KDM6B, and NCOA1, and IL-4 also increased KDM6B by 6 h. However, either cytokine decreased AURKB, ESCO2, SETD6, SUV39H1, and WHSC1, whereas IFN-γ alone decreased KAT2A, PRMT7, and SMYD3 mRNAs only after 18 h, which coincided with decreased cell proliferation. Rendering macrophages quiescent by growth factor starvation or adenovirus-mediated overexpression of p27(kip1) inhibited expression of AURKB, ESCO2, SUV39H1, and WHSC1, and mRNA levels were restored by overexpressing the S-phase transcription factor E2F1, implying their expression, at least partly, depended on proliferation. However, CIITA, KDM6B, NCOA1, KAT2A, PRMT7, SETD6, and SMYD3 were regulated independently of effects on proliferation. Silencing KDM6B, the only transcriptional activator upregulated by both IFN-γ and IL-4, pharmacologically or with short hairpin RNA, blunted a subset of responses to each cytokine.
CONCLUSION: These findings demonstrate that IFN-γ or IL-4 can regulate the expression of histone acetyl transferases and histone methyl transferases independently of effects on proliferation and that upregulation of the histone demethylase, KDM6B, assists phenotypic polarization by both cytokines.

Matched MeSH terms: Up-Regulation
Fulltext Integrated microRNA, gene expression and transcription factors signature in papillary thyroid cancer with lymph node metastasis

Ab Mutalib NS, Othman SN, Mohamad Yusof A, Abdullah Suhaimi SN, Muhammad R, Jamal R

PeerJ, 2016;4:e2119.
PMID: 27350898 DOI: 10.7717/peerj.2119

Background. Papillary thyroid carcinoma (PTC) is the commonest thyroid malignancy originating from the follicle cells in the thyroid. Despite a good overall prognosis, certain high-risk cases as in those with lymph node metastasis (LNM) have progressive disease and poorer prognosis. MicroRNAs are a class of non-protein-coding, 19-24 nucleotides single-stranded RNAs which regulate gene expression and these molecules have been shown to play a role in LNM. The integrated analysis of miRNAs and gene expression profiles together with transcription factors (TFs) has been shown to improve the identification of functional miRNA-target gene-TF relationships, providing a more complete view of molecular events underlying metastasis process. Objectives. We reanalyzed The Cancer Genome Atlas (TCGA) datasets on PTC to identify differentially expressed miRNAs/genes in PTC patients with LNM-positive (LNM-P) versus lymph node negative (LNN) PTC patients and to investigate the miRNA-gene-TF regulatory circuit that regulate LNM in PTC. Results. PTC patients with LNM (PTC LNM-P) have a significantly shorter disease-free survival rate compared to PTC patients without LNM (PTC LNN) (Log-rank Mantel Cox test, p = 0.0049). We identified 181 significantly differentially expressed miRNAs in PTC LNM-P versus PTC LNN; 110 were upregulated and 71 were downregulated. The five topmost deregulated miRNAs were hsa-miR-146b, hsa-miR-375, hsa-miR-31, hsa-miR-7-2 and hsa-miR-204. In addition, 395 miRNAs were differentially expressed between PTC LNM-P and normal thyroid while 400 miRNAs were differentially expressed between PTC LNN and normal thyroid. We found four significant enrichment pathways potentially involved in metastasis to the lymph nodes, namely oxidative phosphorylation (OxPhos), cell adhesion molecules (CAMs), leukocyte transendothelial migration and cytokine-cytokine receptor interaction. OxPhos was the most significantly perturbed pathway (p = 4.70E-06) involving downregulation of 90 OxPhos-related genes. Significant interaction of hsa-miR-301b with HLF, HIF and REL/NFkB transcription factors were identified exclusively in PTC LNM-P versus PTC LNN. Conclusion. We found evidence of five miRNAs differentially expressed in PTC LNM-P. Alteration in OxPhos pathway could be the central event in metastasis to the lymph node in PTC. We postulate that hsa-miR-301b might be involved in regulating LNM in PTC via interactions with HLF, HIF and REL/NFkB. To the best of our knowledge, the roles of these TFs have been studied in PTC but the precise role of this miRNA with these TFs in LNM in PTC has not been investigated.

Matched MeSH terms: Up-Regulation
A comparative transcriptome approach for identification of molecular changes in Aphanomyces invadans infected Channa striatus

Kumaresan V, Pasupuleti M, Arasu MV, Al-Dhabi NA, Arshad A, Amin SMN, et al.

Mol Biol Rep, 2018 Dec;45(6):2511-2523.
PMID: 30306509 DOI: 10.1007/s11033-018-4418-y

Snakehead murrel, Channa striatus is an economically important aquatic species in Asia and are widely cultured and captured because of its nutritious and medicinal values. Their growth is predominantly affected by epizootic ulcerative syndrome (EUS) which is primarily caused by an oomycete fungus, Aphanomyces invadans. However, the molecular mechanism of immune response in murrel against this infection is still not clear. In this study, transcriptome technique was used to understand the molecular changes involved in C. striatus during A. invadans infection. RNA from the control (CF) and infected fish (IF) groups were sequenced using Illumina Hi-seq sequencing technology. For control group, 28,952,608 clean reads were generated and de novo assembly was performed to produce 60,753 contigs. For fungus infected group, 25,470,920 clean reads were obtained and assembled to produce 58,654 contigs. Differential gene expression analysis revealed that a total of 146 genes were up-regulated and 486 genes were down regulated. Most of the differentially expressed genes were involved in innate immune mechanism such as pathogen recognition, signalling and antimicrobial mechanisms. Interestingly, few adaptive immune genes, especially immunoglobulins were also significantly up regulated during fungal infection. Also, the results were validated by qRT-PCR analysis. These results indicated the involvement of various immune genes involved in both innate and adaptive immune mechanism during fungal infection in C. striatus which provide new insights into murrel immune mechanisms against A. invadans.

Matched MeSH terms: Up-Regulation
Fulltext A new insight to biomarkers related to resistance in survived-white spot syndrome virus challenged giant tiger shrimp, Penaeus monodon

Mohd Ghani F, Bhassu S

PeerJ, 2019;7:e8107.
PMID: 31875142 DOI: 10.7717/peerj.8107

The emergence of diseases such as white spot disease has become a threat to Penaeus monodon cultivation. Although there have been a few studies utilizing RNA-Seq, the cellular processes of host-virus interaction in this species remain mostly anonymous. In the present study, P. monodon was challenged with WSSV by intramuscular injection and survived for 12 days. The effect of the host gene expression by WSSV infection in the haemocytes, hepatopancreas and muscle of P. monodon was studied using Illumina HiSeq 2000. The RNA-Seq of cDNA libraries was developed from surviving WSSV-challenged shrimp as well as from normal healthy shrimp as control. A comparison of the transcriptome data of the two groups showed 2,644 host genes to be significantly up-regulated and 2,194 genes significantly down-regulated as a result of the infection with WSSV. Among the differentially expressed genes, our study discovered HMGB, TNFSF and c-Jun in P. monodon as new potential candidate genes for further investigation for the development of potential disease resistance markers. Our study also provided significant data on the differential expression of genes in the survived WSSV infected P. monodon that will help to improve understanding of host-virus interactions in this species.

Matched MeSH terms: Up-Regulation
Fulltext Simvastatin Inhibits Endotoxin-Induced Apoptosis in Liver and Spleen Through Up-Regulation of Survivin/NF-κB/p65 Expression

Nežić L, Amidžić L, Škrbić R, Gajanin R, Nepovimova E, Vališ M, et al.

Front Pharmacol, 2019;10:54.
PMID: 30828299 DOI: 10.3389/fphar.2019.00054

Endotoxemia is associated by dysregulated apoptosis of immune and non-immune cells. We investigated whether simvastatin has anti-apoptotic effects, and induces hepatocytes and lymphocytes survival signaling in endotoxin-induced liver and spleen injuries. Wistar rats were divided into the groups pretreated with simvastatin (20 or 40 mg/kg, orally) prior to a non-lethal dose of lipopolysaccharide (LPS), the LPS group, and the control. The severity of tissue inflammatory injuries was expressed as hepatic damage scores (HDS) and spleen damage scores (SDS), respectively. The apoptotic cell was detected by TUNEL (Terminal deoxynucleotidyl transferase dUTP Nick End Labeling) and immunohistochemical staining (expression of cleaved caspase-3, and anti-apoptotic Bcl-xL, survivin and NF-κB/p65). Simvastatin dose-dependently abolished HDS and SDS induced by LPS (p < 0.01), respectively. Simvastatin 40 mg/kg significantly decreased apoptotic index and caspase-3 cleavage in hepatocytes and lymphocytes (p < 0.01 vs. LPS group, respectively), while Bcl-XL markedly increased accordingly with simvastatin doses. In the simvastatin, groups were determined markedly increased cytoplasmic expression of survivin associated with nuclear positivity of NF-κB, in both hepatocytes and lymphocytes (p < 0.01 vs. LPS group). Cell-protective effects of simvastatin against LPS seemed to be mediated by up-regulation of survivin, which leads to reduced caspase-3 activation and inhibition of hepatocytes and lymphocytes apoptosis.

Matched MeSH terms: Up-Regulation
Fulltext Zerumbone Modulates α2A-Adrenergic, TRPV1, and NMDA NR2B Receptors Plasticity in CCI-Induced Neuropathic Pain In Vivo and LPS-Induced SH-SY5Y Neuroblastoma In Vitro Models

Chia JSM, Izham NAM, Farouk AAO, Sulaiman MR, Mustafa S, Hutchinson MR, et al.

Front Pharmacol, 2020;11:92.
PMID: 32194397 DOI: 10.3389/fphar.2020.00092

Zerumbone has shown great potential in various pathophysiological models of diseases, particularly in neuropathic pain conditions. Further understanding the mechanisms of action is important to develop zerumbone as a potential anti-nociceptive agent. Numerous receptors and pathways function to inhibit and modulate transmission of pain signals. Previously, we demonstrated involvement of the serotonergic system in zerumbone's anti-neuropathic effects. The present study was conducted to determine zerumbone's modulatory potential involving noradrenergic, transient receptor potential vanilloid type 1 (TRPV1) and N-methyl-D-aspartate (NMDA) receptors in chronic constriction injury (CCI)-induced in vitro and lipopolysaccharide (LPS)-induced SH-SY5Y in vitro neuroinflammatory models. von Frey filament and Hargreaves plantar tests were used to assess allodynia and hyperalgesia in the chronic constriction injury-induced neuropathic pain mouse model. Involvement of specific adrenoceptors were investigated using antagonists- prazosin (α1-adrenoceptor antagonist), idazoxan (α2-adrenoceptor antagonist), metoprolol (β1-adrenoceptor antagonist), ICI 118,551 (β2-adrenoceptor antagonist), and SR 59230 A (β3-adrenoceptor antagonist), co-administered with zerumbone (10 mg/kg). Involvement of excitatory receptors; TRPV and NMDA were conducted using antagonists capsazepine (TRPV1 antagonist) and memantine (NMDA antagonist). Western blot was conducted to investigate the effect of zerumbone on the expression of α2A-adrenoceptor, TRPV1 and NMDA NR2B receptors in CCI-induced whole brain samples of mice as well as in LPS-induced SH-SY5Y neuroblastoma cells. Pre-treatment with α1- and α2-adrenoceptor antagonists significantly attenuated both anti-allodynic and anti-hyperalgesic effects of zerumbone. For β-adrenoceptors, only β2-adrenoceptor antagonist significantly reversed the anti-allodynic and anti-hyperalgesic effects of zerumbone. β1-adrenoceptor antagonist only reversed the anti-allodynic effect of zerumbone. The anti-allodynic and anti-hyperalgesic effects of zerumbone were both absent when TRPV1 and NMDA receptors were antagonized in both nociceptive assays. Zerumbone treatment markedly decreased the expression of α2A-adrenoceptor, while an up-regulation was observed of NMDA NR2B receptors. Expression of TRPV1 receptors however did not significantly change. The in vitro study, representing a peripheral model, demonstrated the reduction of both NMDA NR2B and TRPV1 receptors while significantly increasing α2A-adrenoceptor expression in contrast to the brain samples. Our current findings suggest that the α1-, α2-, β1- and β2-adrenoceptors, TRPV1 and NMDA NR2B are essential for the anti-allodynic and antihyperalgesic effects of zerumbone. Alternatively, we demonstrated the plasticity of these receptors through their response to zerumbone's administration.

Matched MeSH terms: Up-Regulation
Fulltext Proteomics analysis on lipid metabolism in Elaeis guineensis and Elaeis oleifera

Lau BYC, Amiruddin MD, Othman A

Data Brief, 2020 Aug;31:105714.
PMID: 32462070 DOI: 10.1016/j.dib.2020.105714

Proteome data was obtained from the fruit mesocarps of the two oil palm species, namely, the African Elaeis guineensis (commercial tenera or commonly known as D x P and MPOB-Nigerian tenera) and the South American Elaeis oleifera. Total proteins were extracted from randomly selected fruitlets and subjected to proteomics characterisation by means of liquid chromatography mass spectrometry. Number of proteins identified, the grouping of the biological replicates from five developmental weeks after anthesis, and the localisation of gene corresponded to the detected proteins on the oil palm chromosomes, were presented. A total of 4,116, 4,210 and 4,081 proteins were found in commercial tenera and MPOB Nigerian tenera for Elaeis guineensis; and Elaeis oleifera, respectively. Principal component analysis showed two distinct clusters that corresponded to Elaeis guineensis and Elaeis oleifera. Collectively, genes that corresponded to the identified proteins were found to be located in all 16 oil palm chromosomes. A total of 59 proteins from Elaeis guineensis and Elaeis oleifera were down-regulated for >5-fold change during the peak of lipid biosynthesis compared to the onset. The same comparative analysis revealed that 66 proteins were up-regulated for >5-fold change. About 60.0% of the observed proteins were involved in catalytic activity while 28.5% were associated with redox reaction. Based on same datasets, the tricarboxylic acid cycle and 5-hydroxytryptamine degradation pathways were found to be enriched the most (>36-fold change). These data can be used to support the oil palm gene model validation and lipid metabolism research, particularly in the areas of oil yield and quality. The tabulated protein lists of identified proteins and their expression changes from these varieties were provided as supplementary files. Raw MSF and mzid files for all the oil palm species were deposited in the ProteomeXchange (PXD017436).

Matched MeSH terms: Up-Regulation
Fulltext IL-4 enhances IL-10 production in Th1 cells: implications for Th1 and Th2 regulation

Mitchell RE, Hassan M, Burton BR, Britton G, Hill EV, Verhagen J, et al.

Sci Rep, 2017 Sep 12;7(1):11315.
PMID: 28900244 DOI: 10.1038/s41598-017-11803-y

IL-10 is an immunomodulatory cytokine with a critical role in limiting inflammation in immune-mediated pathologies. The mechanisms leading to IL-10 expression by CD4(+) T cells are being elucidated, with several cytokines implicated. We explored the effect of IL-4 on the natural phenomenon of IL-10 production by a chronically stimulated antigen-specific population of differentiated Th1 cells. In vitro, IL-4 blockade inhibited while addition of exogenous IL-4 to Th1 cultures enhanced IL-10 production. In the in vivo setting of peptide immunotherapy leading to a chronically stimulated Th1 phenotype, lack of IL-4Rα inhibited the induction of IL-10. Exploring the interplay of Th1 and Th2 cells through co-culture, Th2-derived IL-4 promoted IL-10 expression by Th1 cultures, reducing their pathogenicity in vivo. Co-culture led to upregulated c-Maf expression with no decrease in the proportion of T-bet(+) cells in these cultures. Addition of IL-4 also reduced the encephalitogenic capacity of Th1 cultures. These data demonstrate that IL-4 contributes to IL-10 production and that Th2 cells modulate Th1 cultures towards a self-regulatory phenotype, contributing to the cross-regulation of Th1 and Th2 cells. These findings are important in the context of Th1 driven diseases since they reveal how the Th1 phenotype and function can be modulated by IL-4.

Matched MeSH terms: Up-Regulation
Fulltext Advances in the study of nodavirus

Yong CY, Yeap SK, Omar AR, Tan WS

PeerJ, 2017;5:e3841.
PMID: 28970971 DOI: 10.7717/peerj.3841

Nodaviruses are small bipartite RNA viruses which belong to the family of Nodaviridae. They are categorized into alpha-nodavirus, which infects insects, and beta-nodavirus, which infects fishes. Another distinct group of nodavirus infects shrimps and prawns, which has been proposed to be categorized as gamma-nodavirus. Our current review focuses mainly on recent studies performed on nodaviruses. Nodavirus can be transmitted vertically and horizontally. Recent outbreaks have been reported in China, Indonesia, Singapore and India, affecting the aquaculture industry. It also decreased mullet stock in the Caspian Sea. Histopathology and transmission electron microscopy (TEM) are used to examine the presence of nodaviruses in infected fishes and prawns. For classification, virus isolation followed by nucleotide sequencing are required. In contrast to partial sequence identification, profiling the whole transcriptome using next generation sequencing (NGS) offers a more comprehensive comparison and characterization of the virus. For rapid diagnosis of nodavirus, assays targeting the viral RNA based on reverse-transcription PCR (RT-PCR) such as microfluidic chips, reverse-transcription loop-mediated isothermal amplification (RT-LAMP) and RT-LAMP coupled with lateral flow dipstick (RT-LAMP-LFD) have been developed. Besides viral RNA detections, diagnosis based on immunological assays such as enzyme-linked immunosorbent assay (ELISA), immunodot and Western blotting have also been reported. In addition, immune responses of fish and prawn are also discussed. Overall, in fish, innate immunity, cellular type I interferon immunity and humoral immunity cooperatively prevent nodavirus infections, whereas prawns and shrimps adopt different immune mechanisms against nodavirus infections, through upregulation of superoxide anion, prophenoloxidase, superoxide dismutase (SOD), crustin, peroxinectin, anti-lipopolysaccharides and heat shock proteins (HSP). Potential vaccines for fishes and prawns based on inactivated viruses, recombinant proteins or DNA, either delivered through injection, oral feeding or immersion, are also discussed in detail. Lastly, a comprehensive review on nodavirus virus-like particles (VLPs) is presented. In recent years, studies on prawn nodavirus are mainly focused on Macrobrachium rosenbergii nodavirus (MrNV). Recombinant MrNV VLPs have been produced in prokaryotic and eukaryotic expression systems. Their roles as a nucleic acid delivery vehicle, a platform for vaccine development, a molecular tool for mechanism study and in solving the structures of MrNV are intensively discussed.

Matched MeSH terms: Up-Regulation
Fulltext Orthosiphon stamineus Leaf Extract Affects TNF-α and Seizures in a Zebrafish Model

Choo BKM, Kundap UP, Kumari Y, Hue SM, Othman I, Shaikh MF

Front Pharmacol, 2018;9:139.
PMID: 29527169 DOI: 10.3389/fphar.2018.00139

Epileptic seizures result from abnormal brain activity and can affect motor, autonomic and sensory function; as well as, memory, cognition, behavior, or emotional state. Effective anti-epileptic drugs (AEDs) are available but have tolerability issues due to their side effects. The Malaysian herbOrthosiphon stamineus, is a traditional epilepsy remedy and possesses anti-inflammatory, anti-oxidant and free-radical scavenging abilities, all of which are known to protect against seizures. This experiment thus aimed to explore if an ethanolic leaf extract ofO. stamineushas the potential to be a novel symptomatic treatment for epileptic seizures in a zebrafish model; and the effects of the extract on the expression levels of several genes in the zebrafish brain which are associated with seizures. The results of this study indicate thatO. stamineushas the potential to be a novel symptomatic treatment for epileptic seizures as it is pharmacologically active against seizures in a zebrafish model. The anti-convulsive effect of this extract is also comparable to that of diazepam at higher doses and can surpass diazepam in certain cases. Treatment with the extract also counteracts the upregulation of NF-κB, NPY and TNF-α as a result of a Pentylenetetrazol (PTZ) treated seizure. The anti-convulsive action for this extract could be at least partially due to its downregulation of TNF-α. Future work could include the discovery of the active anti-convulsive compound, as well as determine if the extract does not cause cognitive impairment in zebrafish.

Matched MeSH terms: Up-Regulation
Fulltext Drosophila larvae fed palm fruit juice (PFJ) delay pupation via expression regulation of hormetic stress response genes linked to ageing and longevity

Leow SS, Luu A, Shrestha S, Hayes KC, Sambanthamurthi R

Exp Gerontol, 2018 Mar 15;106:198-221.
PMID: 29550564 DOI: 10.1016/j.exger.2018.03.013

Palm fruit juice (PFJ) containing oil palm phenolics is obtained as a by-product from oil palm (Elaeis guineensis) fruit milling. It contains shikimic acid, soluble fibre and various phenolic acids including p-hydroxybenzoic acid and three caffeoylshikimic acid isomers. PFJ has also demonstrated beneficial health properties in various biological models. Increasing concentrations of PFJ and different PFJ fractions were used to assess growth dynamics and possible anti-ageing properties in fruit flies (Drosophila melanogaster) genotype w1118. Microarray gene expression analysis was performed on whole fruit fly larvae and their fat bodies, after the larvae were fed a control Standard Brandeis Diet (SBD) with or without PFJ. Transcripts from Affymetrix GeneChips were utilised to identify the possible mechanisms involved, with genes having fold changes > |1.30| and p up-regulated, while 67 were down-regulated by PFJ. Functional analysis revealed transport and metabolic processes were up-regulated, while development and morphogenesis processes, including the nutrient-sensing Tor gene, were down-regulated by PFJ, whereas microarray analysis of larval fat bodies found 161 genes were up-regulated, while 84 genes were down-regulated. Genes involved in defence response and determination of adult lifespan, including those encoding various heat shock proteins and the antioxidant enzyme Sod2, were up-regulated, while cell cycle and growth genes were down-regulated. Thus, PFJ supplementation lengthened the growth stages in fruit fly larvae that was reflected in extended ageing of adult flies, suggesting that larval expression of hormetic stress response genes was linked to subsequent ageing and longevity.

Matched MeSH terms: Up-Regulation
Fulltext In Vivo Antioxidant and Hypolipidemic Effects of Fermented Mung Bean on Hypercholesterolemic Mice

Yeap SK, Beh BK, Ho WY, Mohd Yusof H, Mohamad NE, Ali NM, et al.

Evid Based Complement Alternat Med, 2015;2015:508029.
PMID: 26074993 DOI: 10.1155/2015/508029

Legumes have previously been reported with hypolipidemic effect caused by the presence of flavonoid. This study was carried out to evaluate the antioxidant and hypolipidemic effects of fermented mung bean on hypercholesterolemic mice. Blood from all mice was collected and subjected to serum lipid and liver profiles biochemical analysis and quantitative RT-PCR for atherosclerosis related gene expressions. Besides, livers were collected for antioxidant assays and histopathology evaluation. Fermented mung bean was found to reduce the level of serum lipid and liver enzyme profiles of hypercholesterolemic mice. Furthermore, liver antioxidant and nitric oxide levels were also significantly restored by fermented mung bean in a dosage dependent manner. The gene expression study indicated that Apoe and Bcl2a1a were upregulated while Npy and Vwf expressions were downregulated after the treatment. The effects of fermented mung bean were greater than nonfermented mung bean. These results indicated that fermented mung bean possessed antioxidants that lead to its hypolipidemic effect on hypercholesterolemic mice.

Matched MeSH terms: Up-Regulation
Fulltext In Vivo Hypocholesterolemic Effect of MARDI Fermented Red Yeast Rice Water Extract in High Cholesterol Diet Fed Mice

Yeap SK, Beh BK, Kong J, Ho WY, Mohd Yusof H, Mohamad NE, et al.

Evid Based Complement Alternat Med, 2014;2014:707829.
PMID: 25031606 DOI: 10.1155/2014/707829

Fermented red yeast rice has been traditionally consumed as medication in Asian cuisine. This study aimed to determine the in vivo hypocholesterolemic and antioxidant effects of fermented red yeast rice water extract produced using Malaysian Agricultural Research and Development Institute (MARDI) Monascus purpureus strains in mice fed with high cholesterol diet. Absence of monacolin-k, lower level of γ-aminobutyric acid (GABA), higher content of total amino acids, and antioxidant activities were detected in MARDI fermented red yeast rice water extract (MFRYR). In vivo MFRYR treatment on hypercholesterolemic mice recorded similar lipid lowering effect as commercial red yeast rice extract (CRYR) as it helps to reduce the elevated serum liver enzyme and increased the antioxidant levels in liver. This effect was also associated with the upregulation of apolipoproteins-E and inhibition of Von Willebrand factor expression. In summary, MFRYR enriched in antioxidant and amino acid without monacolin-k showed similar hypocholesterolemic effect as CRYR that was rich in monacolin-k and GABA.

Matched MeSH terms: Up-Regulation
Fulltext Upregulation of Brain's Calcium Binding Proteins in Mitragynine Dependence: A Potential Cellular Mechanism to Addiction

Basheer M, Hassan Z, Gam LH

Int J Med Sci, 2023;20(1):102-113.
PMID: 36619231 DOI: 10.7150/ijms.78861

Background: Mitragyna speciosa Korth or Kratom is widely used traditionally for its medicinal values. The major alkaloid content of kratom leaves is mitragynine, which binds to opioid receptors to give opioid-like effects. This study aimed to analyse the brain proteome of animals that displayed addictive behaviors. Design and Methods: Six groups (n=6-8) of rats made up of negative control, positive control using morphine (10 mg/kg), and treatment groups at low (1mg/kg) and high doses of mitragynine (30 mg/kg) for 1 and 4 days. The rats' behaviors were evaluated and subsequently the rats' brains were harvested for proteomic analysis that was performed by using 2D gel electrophoresis and LC/MS/MS. Results: The rats developed physical dependence only on day 4 following morphine and mitragynine (1 and 30mg/kg) treatments. Among the proteins that were up-regulated in treatment groups were four calcium-binding proteins, namely calretinin, F-actin, annexin A3 and beta-centractin. Conclusions: Upregulation of calretinin acted as low Ca2+ buffering upon the blockage of Ca2+ ion channel by mitragynine in the brain, which subsequently caused a reduction of GABA released and inversely increased the dopamine secretions that contributed to dependence indicators.

Matched MeSH terms: Up-Regulation
Fulltext EphrinB2 signalling modulates the neural differentiation of human dental pulp stem cells

Heng BC, Gong T, Xu J, Lim LW, Zhang C

Biomed Rep, 2018 Aug;9(2):161-168.
PMID: 29963307 DOI: 10.3892/br.2018.1108

Dental pulp stem cells (DPSCs) originate from the embryonic neural crest and have neurogenic potential. The present study investigated the roles of the forward and reverse EphrinB2 signalling pathways during DPSC neurogenesis. Treatment of DPSCs with recombinant EphrinB2-Fc protein over 7 days in a neural induction culture resulted in significant downregulation of the following neural markers: βIII-Tubulin, neural cell adhesion molecule (NCAM), nestin, neurogenin 2 (NGN2), neurofilament medium polypeptide and Musashi1. Immunocytochemistry revealed that EphrinB2-Fc-treated DPSCs exhibited more rounded morphologies with fewer neurite outgrowths as well as reduced protein expression of βIII-tubulin and NGN2. Treatment of DPSCs with a peptide inhibitor specific to the EphB4 receptor significantly upregulated expression of the neural markers microtubule-associated protein 2, Musashi1, NGN2 and neuron-specific enolase, whereas treatment with a peptide inhibitor specific to the EphB2 receptor exerted negligible effects on neurogenesis. Transgenic expression of EphrinB2 in DPSCs resulted in significant upregulation of Musashi1 and NCAM gene expression, while treatment of DPSCs with recombinant EphB4-Fc protein led to significant upregulation of only Musashi1. Thus, it may be concluded that stimulation of forward EphrinB2-EphB4 signalling markedly inhibited neurogenesis in DPSCs, whereas suppression of this forward signalling pathway with peptide inhibitor specific to EphB4 promoted neurogenesis. Meanwhile, stimulation of reverse EphB4-EphrinB2 signalling only marginally enhanced the neural differentiation of DPSCs. The present findings indicate the potential application of peptide or small molecule inhibitors of EphrinB2 forward signalling in neural tissue engineering with DPSCs.

Matched MeSH terms: Up-Regulation
Association between vascular endothelial growth factor and atrial fibrillation: a systematic review

Sharma N, Khatib MN, Roopashree R, Kaur M, Srivastava M, Barwal A, et al.

BMC Cardiovasc Disord, 2025 Jan 06;25(1):5.
PMID: 39757193 DOI: 10.1186/s12872-024-04460-3

BACKGROUND: Atrial fibrillation (AF) is the most prevalent form of sustained cardiac arrhythmia, with vascular endothelial growth factor (VEGF) increasingly recognized for its potential role in the pathogenesis of AF through mechanisms involving atrial remodeling, inflammation, and fibrosis. This systematic review aims to synthesize available evidence on the association between VEGF and AF, exploring the implications of VEGF as a biomarker and therapeutic target.
METHODS: We conducted a comprehensive search across PubMed, Embase, and Web of Science until November 10 2024, selecting studies based on pre-defined criteria that involve adults with AF and measurements of VEGF levels. The selected studies included observational and experimental designs, excluding non-English and methodologically insufficient publications. Narrative synthesis was used for summarising the results.
RESULTS: Eight studies met the inclusion criteria. The studies show a general trend of elevated VEGF levels in AF patients compared to controls, with significant heterogeneity in findings across studies. VEGF subtypes such as VEGF-A and VEGF-D demonstrated stronger associations with AF risk compared to VEGF-C. These variations point to the complex role of VEGF in AF, influencing factors like angiogenesis, endothelial function, and inflammatory responses.
CONCLUSION: VEGF is potentially a significant contributor to AF pathophysiology, with its levels reflecting disease activity. The variability observed across studies suggests a need for standardized measurement approaches and further investigation into VEGF subtypes. Future research should focus on longitudinal studies to better understand the causal relationships and the potential of VEGF as a therapeutic target and biomarker in AF management.
CLINICAL TRIAL NUMBER: Not applicable.

Matched MeSH terms: Up-Regulation
Over-expression of the X-linked inhibitor of apoptosis protein (XIAP) delays serum deprivation-induced apoptosis in CHO-K1 cells

Liew JC, Tan WS, Alitheen NB, Chan ES, Tey BT

J Biosci Bioeng, 2010 Sep;110(3):338-44.
PMID: 20547346 DOI: 10.1016/j.jbiosc.2010.02.017

Serum deprivation inhibits cell growth and initiates apoptosis cell death in mammalian cell cultures. Since apoptosis is a genetically controlled cell death pathway, over-expression of anti-apoptotic proteins may provide a way to delay apoptosis. This study investigated the ability of the X-linked inhibitor of apoptosis protein (XIAP) to inhibit apoptosis induced by serum deprivation. Study includes evaluation of the ability of XIAP to prolong culture period and its effect on cell proliferation in serum-deprived media. The full length human XIAP was introduced into CHO-K1 cell lines and the effects of XIAP over-expression on the inhibition of apoptosis induced by serum-deprived conditions were examined. In batch cultures, cells over-expressing XIAP showed decreased levels of apoptosis and a higher number of viable cell under serum-deprived conditions compared to the control cell lines. The viability of control cells dropped to 40% after 2days of serum deprivation, the XIAP expressing cells still maintained at a viability higher than 90%. Further investigation revealed that the caspase-3 activity of the CHO-K1 cell line was inhibited as a result of XIAP expression.

Matched MeSH terms: Up-Regulation/physiology
Fulltext Xanthorrhizol induces apoptosis via the up-regulation of bax and p53 in HeLa cells

Ismail N, Pihie AH, Nallapan M

Anticancer Res, 2005 May-Jun;25(3B):2221-7.
PMID: 16158967

Xanthorrhizol is a sesquiterpenoid compound extracted from Curcuma xanthorrhiza, which is known locally as Temulawak. Traditionally, C. xanthorrhiza was found to have antibacterial, anticancer and anti-inflammatory activity. The rhizome has also been used to treat inflammation in postpartum uterine bleeding. An antiproliferative assay using methylene blue staining revealed that xanthorrhizol inhibited the proliferation of the cervical cancer cell line HeLa with an EC50 value of 6.16 microg/ml. Xanthorrhizol significantly increased apoptosis in HeLa cells, as evaluated by the Tdt-mediated dUTP nick end-labelling (TUNEL) assay and nuclear morphology by Hoechst 33258 staining. Western blot analysis, which was further confirmed by the immunostaining results, implied an up-regulation of tumor suppressor protein p53 and the pro-apoptotic protein Bax, following the treatment with xanthorrhizol. Xanthorrhizol, however, did not affect the expression of the anti-apoptotic protein, Bcl-2 and the viral oncoprotein, E6. Hence, xanthorrhizol is a promising antiproliferative and anticancer agent which induces p53 and Bax-dependent apoptosis in HeLa cervical cancer cells.

Matched MeSH terms: Up-Regulation/drug effects
Deferoxamine Preconditioning of Neural-Like Cells Derived from Human Wharton's Jelly Mesenchymal Stem Cells as a Strategy to Promote Their Tolerance and Therapeutic Potential: An In Vitro Study

Nouri F, Salehinejad P, Nematollahi-Mahani SN, Kamarul T, Zarrindast MR, Sharifi AM

Cell Mol Neurobiol, 2016 Jul;36(5):689-700.
PMID: 26242172 DOI: 10.1007/s10571-015-0249-8

Transplantation of neural-like cells is considered as a promising therapeutic strategy developed for neurodegenerative disease in particular for ischemic stroke. Since cell survival is a major concern following cell implantation, a number of studies have underlined the protective effects of preconditioning with hypoxia or hypoxia mimetic pharmacological agents such as deferoxamine (DFO), induced by activation of hypoxia inducible factor-1 (HIF-1) and its target genes. The present study has investigated the effects of DFO preconditioning on some factors involved in cell survival, angiogenesis, and neurogenesis of neural-like cells derived from human Wharton's jelly mesenchymal stem cells (HWJ-MSCs) in presence of hydrogen peroxide (H2O2). HWJ-MSCs were differentiated toward neural-like cells for 14 days and neural cell markers were identified using immunocytochemistry. HWJ-MSC-derived neural-like cells were then treated with 100 µM DFO, as a known hypoxia mimetic agent for 48 h. mRNA and protein expression of HIF-1 target genes including brain-derived neurotrophic factors (BDNF) and vascular endothelial growth factor (VEGF) significantly increased using RT-PCR and Western blotting which were reversed by HIF-1α inhibitor, while, gene expression of Akt-1, Bcl-2, and Bax did not change significantly but pAkt-1 was up-regulated as compared to poor DFO group. However, addition of H2O2 to DFO-treated cells resulted in higher resistance to H2O2-induced cell death. Western blotting analysis also showed significant up-regulation of HIF-1α, BDNF, VEGF, and pAkt-1, and decrease of Bax/Bcl-2 ratio as compared to poor DFO. These results may suggest that DFO preconditioning of HWJ-MSC-derived neural-like cells improves their tolerance and therapeutic potential and might be considered as a valuable strategy to improve cell therapy.

Matched MeSH terms: Up-Regulation/drug effects

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