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Fulltext PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity

Poli A, Abdul-Hamid S, Zaurito AE, Campagnoli F, Bevilacqua V, Sheth B, et al.

Proc Natl Acad Sci U S A, 2021 08 03;118(31).
PMID: 34312224 DOI: 10.1073/pnas.2010053118

Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5P to PtdIns(4,5)P 2 They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Accordingly, a human single nucleotide polymorphism (SNP) near the PIP4K2C gene is linked with susceptibility to autoimmune diseases. How PIP4Ks impact on human T cell signaling is not known. Using ex vivo human primary T cells, we found that PIP4K activity is required for Treg cell signaling and immunosuppressive activity. Genetic and pharmacological inhibition of PIP4K in Tregs reduces signaling through the PI3K, mTORC1/S6, and MAPK pathways, impairs cell proliferation, and increases activation-induced cell death while sparing Tconv. PIP4K and PI3K signaling regulate the expression of the Treg master transcriptional activator FOXP3 and the epigenetic signaling protein Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). Our studies suggest that the pharmacological inhibition of PIP4K can reprogram human Treg identity while leaving Tconv cell signaling and T-helper differentiation to largely intact potentially enhancing overall immunological activity.

Matched MeSH terms: Gene Expression Regulation, Enzymologic/drug effects; Gene Expression Regulation, Enzymologic/immunology; Gene Expression Regulation, Enzymologic/physiology
Fulltext Mechanism of Human Telomerase Reverse Transcriptase (hTERT) Regulation and Clinical Impacts in Leukemia

Yik MY, Azlan A, Rajasegaran Y, Rosli A, Yusoff NM, Moses EJ

Genes (Basel), 2021 07 30;12(8).
PMID: 34440361 DOI: 10.3390/genes12081188

The proliferative capacity and continuous survival of cells are highly dependent on telomerase expression and the maintenance of telomere length. For this reason, elevated expression of telomerase has been identified in virtually all cancers, including leukemias; however, it should be noted that expression of telomerase is sometimes observed later in malignant development. This time point of activation is highly dependent on the type of leukemia and its causative factors. Many recent studies in this field have contributed to the elucidation of the mechanisms by which the various forms of leukemias increase telomerase activity. These include the dysregulation of telomerase reverse transcriptase (TERT) at various levels which include transcriptional, post-transcriptional, and post-translational stages. The pathways and biological molecules involved in these processes are also being deciphered with the advent of enabling technologies such as next-generation sequencing (NGS), ribonucleic acid sequencing (RNA-Seq), liquid chromatography-mass spectrometry (LCMS/MS), and many others. It has also been established that TERT possess diagnostic value as most adult cells do not express high levels of telomerase. Indeed, studies have shown that prognosis is not favorable in patients who have leukemias expressing high levels of telomerase. Recent research has indicated that targeting of this gene is able to control the survival of malignant cells and therefore offers a potential treatment for TERT-dependent leukemias. Here we review the mechanisms of hTERT regulation and deliberate their association in malignant states of leukemic cells. Further, we also cover the clinical implications of this gene including its use in diagnostic, prognostic, and therapeutic discoveries.

Matched MeSH terms: Gene Expression Regulation, Enzymologic
Fulltext Rutin Modulates MAPK Pathway Differently from Quercetin in Angiotensin II-Induced H9c2 Cardiomyocyte Hypertrophy

Siti HN, Jalil J, Asmadi AY, Kamisah Y

Int J Mol Sci, 2021 May 11;22(10).
PMID: 34064664 DOI: 10.3390/ijms22105063

Rutin is a flavonoid with antioxidant property. It has been shown to exert cardioprotection against cardiomyocyte hypertrophy. However, studies regarding its antihypertrophic property are still lacking, whether it demonstrates similar antihypertrophic effect to its metabolite, quercetin. Hence, this study aimed to investigate the effects of both flavonoids on oxidative stress and mitogen-activated protein kinase (MAPK) pathway in H9c2 cardiomyocytes that were exposed to angiotensin II (Ang II) to induce hypertrophy. Cardiomyocytes were exposed to Ang II (600 nM) with or without quercetin (331 μM) or rutin (50 μM) for 24 h. A group given vehicle served as the control. The concentration of the flavonoids was chosen based on the reported effective concentration to reduce cell hypertrophy or cardiac injury in H9c2 cells. Exposure to Ang II increased cell surface area, intracellular superoxide anion level, NADPH oxidase and inducible nitric oxide synthase activities, and reduced cellular superoxide dismutase activity and nitrite level, which were similarly reversed by both rutin and quercetin. Rutin had no significant effects on phosphorylated proteins of extracellular signal-related kinases (ERK1/2) and p38 but downregulated phosphorylated c-Jun N-terminal kinases (JNK1/2), which were induced by Ang II. Quercetin, on the other hand, had significantly downregulated the phosphorylated proteins of ERK1/2, p38, and JNK1/2. The quercetin inhibitory effect on JNK1/2 was stronger than the rutin. In conclusion, both flavonoids afford similar protective effects against Ang II-induced cardiomyocyte hypertrophy, but they differently modulate MAPK pathway.

Matched MeSH terms: Gene Expression Regulation, Enzymologic/drug effects*
Functional characterisation of fatty acyl desaturase, Fads2, and elongase, Elovl5, in the Boddart's goggle-eyed goby Boleophthalmus boddarti (Gobiidae) suggests an incapacity for long-chain polyunsaturated fatty acid biosynthesis

Soo HJ, Sam KK, Chong J, Lau NS, Ting SY, Kuah MK, et al.

J Fish Biol, 2020 Jul;97(1):83-99.
PMID: 32222967 DOI: 10.1111/jfb.14328

The biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFA), a process to convert C18 polyunsaturated fatty acids into eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or arachidonic acid (ARA), requires the concerted activities of two enzymes, the fatty acyl desaturase (Fads) and elongase (Elovl). This study highlights the cloning, functional characterisation and tissue expression pattern of a Fads and an Elovl from the Boddart's goggle-eyed goby (Boleophthalmus boddarti), a mudskipper species widely distributed in the Indo-Pacific region. Phylogenetic analysis revealed that the cloned fads and elovl are clustered with other teleost orthologs, respectively. The investigation of the genome of several mudskipper species, namely Boleophthalmus pectinirostris, Periophthalmus schlosseri and Periophthalmus magnuspinnatus, revealed a single Fads2 and two elongases, Elovl5 and Elovl4 for each respective species. A heterologous yeast assay indicated that the B. boddarti Fads2 possessed low desaturation activity on C18 PUFA and no desaturation on C20 and C22 PUFA substrates. In comparison, the Elovl5 showed a wide range of substrate specificity, with a capacity to elongate C18, C20 and C22 PUFA substrates. An amino acid residue that affects the capacity to elongate C22:5n-3 was identified in the B. boddarti Elovl5. Both genes are highly expressed in brain tissue. Among all tissues, DHA is highly concentrated in neuron-rich tissues, whereas EPA is highly deposited in gills. Taken together, the results showed that due to the inability to perform desaturation steps, B. boddarti is unable to biosynthesise LC-PUFA, relying on dietary intake to acquire these nutrients.

Matched MeSH terms: Gene Expression Regulation, Enzymologic
Effects of Excess and Limited Phosphate on Biomass, Lipid and Fatty Acid Contents and the Expression of Four Fatty Acid Desaturase Genes in the Tropical Selenastraceaen Messastrum gracile SE-MC4

Anne-Marie K, Yee W, Loh SH, Aziz A, Cha TS

Appl Biochem Biotechnol, 2020 Apr;190(4):1438-1456.
PMID: 31782088 DOI: 10.1007/s12010-019-03182-z

In this study, the effects of limited and excess phosphate on biomass content, oil content, fatty acid profile and the expression of three fatty acid desaturases in Messastrum gracile SE-MC4 were determined. It was found that total biomass (0.67-0.83 g L-1), oil content (30.99-38.08%) and the duration for cells to reach stationary phase (25-27 days) were not considerably affected by phosphate limitation. However, excess phosphate slightly reduced total biomass and oil content to 0.50 g L-1 and 25.36% respectively. The dominant fatty acids in M. gracile, pamitic acid (C16:0) and oleic acid (C18:1) which constitute more than 81% of the total fatty acids remained relatively high and constant across all phosphate concentrations. Reduction of phosphate concentration to 25% and below significantly increased total MUFA, whereas increasing phosphate concentration to ≥ 50% and ≥ 100% significantly increased total SFA and PUFA content respectively. The expression of omega-3 fatty acid desaturase (ω-3 FADi1, ω-3 FADi2) and omega-6 fatty acid desaturase (ω-6 FAD) was increased under phosphate limitation, especially at ≤ 12.5% phosphate, whereas levels of streoyl-ACP desaturase (SAD) transcripts were relatively unchanged across all phosphate concentrations. The first isoform of ω-3 FAD (ω-3 FADi) displayed a binary upregulation under limited (≤ 12.5%) and excess (200%) phosphate. The expression of ω-6 FAD, ω-3 FAD and SAD were inconsistent with the accumulation of oleic acid (C18:1), linoleic acid (C18:2) and alpha-linolenic acid (C18:3), suggesting that these genes may be regulated indirectly by phosphate availability via post-transcriptional or post-translational mechanisms.

Matched MeSH terms: Gene Expression Regulation, Enzymologic
Influence of nitrogen availability on biomass, lipid production, fatty acid profile, and the expression of fatty acid desaturase genes in Messastrum gracile SE-MC4

Anne-Marie K, Yee W, Loh SH, Aziz A, Cha TS

World J Microbiol Biotechnol, 2020 Jan 07;36(1):17.
PMID: 31912247 DOI: 10.1007/s11274-019-2790-y

In this study, the effects of limited and excess nitrate on biomass, lipid production, and fatty acid profile in Messastrum gracile SE-MC4 were determined. The expression of fatty acid desaturase genes, namely stearoyl-ACP desaturase (SAD), omega-6 fatty acid desaturase (ω-6 FAD), omega-3 fatty acid desaturase isoform 1 (ω-3 FADi1), and omega-3 fatty acid desaturase isoform 2 (ω-3 FADi2) was also assessed. It was found that nitrate limitation generally increased the total oil, α-linolenic acid (C18:3n3) and total polyunsaturated fatty acid (PUFA) contents in M. gracile. The reduction of nitrate concentration from 1.76 to 0.11 mM increased the total oil content significantly from 32.5 to 41.85% (dry weight). Palmitic (C16:0) and oleic (C18:1) acids as the predominant fatty acids in this microalgae constituted between 82 and 87% of the total oil content and were relatively consistent throughout all nitrate concentrations tested. The expression of SAD, ω-6 FAD, and ω-3 FADi2 genes increased under nitrate limitation, especially at 0.11 mM nitrate. The ω-3 FADi1 demonstrated a binary up-regulation pattern of expression under both nitrate-deficient (0.11 mM) and -excess (3.55 mM) conditions. Thus, findings from this study suggested that limited or excess nitrate could be used as part of a cultivation strategy to increase oil and PUFA content following media optimisation and more efficient culture methodology. Data obtained from the expression of desaturase genes would provide valuable insights into their roles under excess and limited nitrate conditions in M. gracile, potentially paving the way for future genetic modifications.

Matched MeSH terms: Gene Expression Regulation, Enzymologic
Fulltext Palm Fruit Bioactives augment expression of Tyrosine Hydroxylase in the Nile Grass Rat basal ganglia and alter the colonic microbiome

Weinberg RP, Koledova VV, Subramaniam A, Schneider K, Artamonova A, Sambanthamurthi R, et al.

Sci Rep, 2019 Dec 09;9(1):18625.
PMID: 31819070 DOI: 10.1038/s41598-019-54461-y

Tyrosine hydroxylase (TH) catalyzes the hydroxylation of L-tyrosine to L-DOPA. This is the rate-limiting step in the biosynthesis of the catecholamines - dopamine (DA), norepinephrine (NE), and epinephrine (EP). Catecholamines (CA) play a key role as neurotransmitters and hormones. Aberrant levels of CA are associated with multiple medical conditions, including Parkinson's disease. Palm Fruit Bioactives (PFB) significantly increased the levels of tyrosine hydroxylase in the brain of the Nile Grass rat (NGR), a novel and potentially significant finding, unique to PFB among known botanical sources. Increases were most pronounced in the basal ganglia, including the caudate-putamen, striatum and substantia nigra. The NGR represents an animal model of diet-induced Type 2 Diabetes Mellitus (T2DM), exhibiting hyperglycemia, hyperinsulinemia, and insulin resistance associated with hyperphagia and accelerated postweaning weight gain induced by a high-carbohydrate diet (hiCHO). The PFB-induced increase of TH in the basal ganglia of the NGR was documented by immuno-histochemical staining (IHC). This increase in TH occurred equally in both diabetes-susceptible and diabetes-resistant NGR fed a hiCHO. PFB also stimulated growth of the colon microbiota evidenced by an increase in cecal weight and altered microbiome. The metabolites of colon microbiota, e.g. short-chain fatty acids, may influence the brain and behavior significantly.

Matched MeSH terms: Gene Expression Regulation, Enzymologic
Fruit characteristics, soluble sugar compositions and transcriptome analysis during the development of Citrus maxima "seedless", and identification of SUS and INV genes involved in sucrose degradation

Deng S, Mai Y, Niu J

Gene, 2019 Mar 20;689:131-140.
PMID: 30576805 DOI: 10.1016/j.gene.2018.12.016

Citrus maxima "seedless" is originally from Malaysia, and now is widely cultivated in Hainan province, China. The essential features of this cultivar are thin skin, green epicarp and seedless at the ripening stage. Here, using C. maxima "seedless" as experimental material, we investigated the physical and inclusion indicators, and found the accumulation of storage compounds during 120-210 DAF leading to inconsistent increase between volume and weight. Component analysis of soluble sugar indicated that arabinose and xylose have a high content in early development of pummelo juice sacs (PJS), whereas fructose, glucose and sucrose show a significant increase during PJS maturation. To clarify a global overview of the gene expressing profiles, the PJSs from four periods (60, 120, 180 and 240 DAF) were selected for comparative transcriptome analysis. The resulting 8275 unigenes showed differential expression during PJS development. Also, the stability of 11 housekeeping genes were evaluated by geNorm method, resulting in a set of five genes (UBC, ACT, OR23, DWA2 and CYP21D) used as control for normalization of gene expression. Based on transcriptome data, 5 sucrose synthases (SUSs) and 10 invertases (INVs) were identified to be involved in sucrose degradation. Importantly, SUS4 may be responsible for arabinose and xylose biosynthesis to form the cell wall in early development, while SUS3 and VIN2 may be important in the accumulation of soluble hexose leading to cell expansion through an osmotic-independent pathway in late development. The information provides valuable metabolite and genetic resources in C. maxima "seedless", and is important for achieving high fruit yield and quality.

Matched MeSH terms: Gene Expression Regulation, Enzymologic
Effects of MAO-A and CYP450 on primaquine metabolism in healthy volunteers

Ariffin NM, Islahudin F, Kumolosasi E, Makmor-Bakry M

Parasitol Res, 2019 Mar;118(3):1011-1018.
PMID: 30706164 DOI: 10.1007/s00436-019-06210-3

Eliminating the Plasmodium vivax malaria parasite infection remains challenging. One of the main problems is its capacity to form hypnozoites that potentially lead to recurrent infections. At present, primaquine is the only drug used for the management of hypnozoites. However, the effects of primaquine may differ from one individual to another. The aim of this work is to determine new measures to reduce P. vivax recurrence, through primaquine metabolism and host genetics. A genetic study of MAO-A, CYP2D6, CYP1A2 and CYP2C19 and their roles in primaquine metabolism was undertaken of healthy volunteers (n = 53). The elimination rate constant (Ke) and the metabolite-to-parent drug concentration ratio (Cm/Cp) were obtained to assess primaquine metabolism. Allelic and genotypic analysis showed that polymorphisms MAO-A (rs6323, 891G>T), CYP2D6 (rs1065852, 100C>T) and CYP2C19 (rs4244285, 19154G>A) significantly influenced primaquine metabolism. CYP1A2 (rs762551, -163C>A) did not influence primaquine metabolism. In haplotypic analysis, significant differences in Ke (p = 0.00) and Cm/Cp (p = 0.05) were observed between individuals with polymorphisms, GG-MAO-A (891G>T), CT-CYP2D6 (100C>T) and GG-CYP2C19 (19154G>A), and individuals with polymorphisms, TT-MAO-A (891G>T), TT-CYP2D6 (100C>T) and AA-CYP2C19 (19154G>A), as well as polymorphisms, GG-MAO-A (891G>T), TT-CYP2D6 (100C>T) and GA-CYP2C19 (19154G>A). Thus, individuals with CYP2D6 polymorphisms had slower primaquine metabolism activity. The potential significance of genetic roles in primaquine metabolism and exploration of these might help to further optimise the management of P. vivax infection.

Matched MeSH terms: Gene Expression Regulation, Enzymologic/drug effects
Protein-Protein Interactions of Phosphodiesterases

Al-Nema MY, Gaurav A

Curr Top Med Chem, 2019;19(7):555-564.
PMID: 30931862 DOI: 10.2174/1568026619666190401113803

BACKGROUND: Phosphodiesterases (PDEs) are enzymes that play a key role in terminating cyclic nucleotides signalling by catalysing the hydrolysis of 3', 5'- cyclic adenosine monophosphate (cAMP) and/or 3', 5' cyclic guanosine monophosphate (cGMP), the second messengers within the cell that transport the signals produced by extracellular signalling molecules which are unable to get into the cells. However, PDEs are proteins which do not operate alone but in complexes that made up of a many proteins.
OBJECTIVE: This review highlights some of the general characteristics of PDEs and focuses mainly on the Protein-Protein Interactions (PPIs) of selected PDE enzymes. The objective is to review the role of PPIs in the specific mechanism for activation and thereby regulation of certain biological functions of PDEs.
METHODS: The article discusses some of the PPIs of selected PDEs as reported in recent scientific literature. These interactions are critical for understanding the biological role of the target PDE.
RESULTS: The PPIs have shown that each PDE has a specific mechanism for activation and thereby regulation a certain biological function.
CONCLUSION: Targeting of PDEs to specific regions of the cell is based on the interaction with other proteins where each PDE enzyme binds with specific protein(s) via PPIs.

Matched MeSH terms: Gene Expression Regulation, Enzymologic/physiology*
Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

Rostam MA, Shajimoon A, Kamato D, Mitra P, Piva TJ, Getachew R, et al.

J. Pharmacol. Exp. Ther., 2018 04;365(1):156-164.
PMID: 29438988 DOI: 10.1124/jpet.117.244483

Transforming growth factor-β (TGF-β) is a pleiotropic growth factor implicated in the development of atherosclerosis for its role in mediating glycosaminoglycan (GAG) chain hyperelongation on the proteoglycan biglycan, a phenomenon that increases the binding of atherogenic lipoproteins in the vessel wall. Phosphorylation of the transcription factor Smad has emerged as a critical step in the signaling pathways that control the synthesis of biglycan, both the core protein and the GAG chains. We have used flavopiridol, a well-known cyclin-dependent kinase inhibitor, to study the role of linker region phosphorylation in the TGF-β-stimulated synthesis of biglycan. We used radiosulfate incorporation and SDS-PAGE to assess proteoglycan synthesis, real-time polymerase chain reaction to assess gene expression, and chromatin immunoprecipitation to assess the binding of Smads to the promoter region of GAG Synthesizing genes. Flavopiridol blocked TGF-β-stimulated synthesis of mRNA for the GAG synthesizing enzymes, and chondroitin 4-sulfotransferase (C4ST-1), chondroitin sulfate synthase-1 (ChSy-1) and TGF-β-mediated proteoglycans synthesis as well as GAG hyperelongation. Flavopiridol blocked TGF-β-stimulated Smad2 phosphorylation at both the serine triplet and the isolated threonine residue in the linker region. The binding of Smad to the promoter region of the C4ST-1 and ChSy-1 genes was stimulated by TGF-β, and this response was blocked by flavopiridol, demonstrating that linker region phosphorylated Smad can pass to the nucleus and positively regulate transcription. These results demonstrate the validity of the kinases, which phosphorylate the Smad linker region as potential therapeutic target(s) for the development of an agent to prevent atherosclerosis.

Matched MeSH terms: Gene Expression Regulation, Enzymologic/drug effects
Fulltext Comparative genomic and transcriptomic analysis of selected fatty acid biosynthesis genes and CNL disease resistance genes in oil palm

Rosli R, Amiruddin N, Ab Halim MA, Chan PL, Chan KL, Azizi N, et al.

PLoS One, 2018;13(4):e0194792.
PMID: 29672525 DOI: 10.1371/journal.pone.0194792

Comparative genomics and transcriptomic analyses were performed on two agronomically important groups of genes from oil palm versus other major crop species and the model organism, Arabidopsis thaliana. The first analysis was of two gene families with key roles in regulation of oil quality and in particular the accumulation of oleic acid, namely stearoyl ACP desaturases (SAD) and acyl-acyl carrier protein (ACP) thioesterases (FAT). In both cases, these were found to be large gene families with complex expression profiles across a wide range of tissue types and developmental stages. The detailed classification of the oil palm SAD and FAT genes has enabled the updating of the latest version of the oil palm gene model. The second analysis focused on disease resistance (R) genes in order to elucidate possible candidates for breeding of pathogen tolerance/resistance. Ortholog analysis showed that 141 out of the 210 putative oil palm R genes had homologs in banana and rice. These genes formed 37 clusters with 634 orthologous genes. Classification of the 141 oil palm R genes showed that the genes belong to the Kinase (7), CNL (95), MLO-like (8), RLK (3) and Others (28) categories. The CNL R genes formed eight clusters. Expression data for selected R genes also identified potential candidates for breeding of disease resistance traits. Furthermore, these findings can provide information about the species evolution as well as the identification of agronomically important genes in oil palm and other major crops.

Matched MeSH terms: Gene Expression Regulation, Enzymologic
Hepatoprotective potential of glyceryl trinitrate against chemically induced oxidative stress and hepatic injury in rats

Rahman A, Vasenwala SM, Iqbal M

Hum Exp Toxicol, 2017 Aug;36(8):785-794.
PMID: 27758841 DOI: 10.1177/0960327116665675

Glyceryl trinitrate (GTN) has been used widely as a potent vasodilator to treat heart conditions, such as angina pectoris and chronic heart failure. This study aims to elucidate the effect of exogenous nitric oxide (NO) administration, using GTN, on carbon tetrachloride (CCl4)-induced oxidative stress and liver injury in rats. The results obtained demonstrated that NO generated by the administration of GTN affords protection against CCl4-induced oxidative stress and liver injury. Administration of CCl4resulted in a significant ( p < 0.001) increase in lipid peroxidation and tissue damage markers (aspartate and alanine transaminase and lactate dehydrogenase) release in serum. Parallel to these changes, CCl4also caused downregulation of antioxidant enzymes including glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST), and several fold induction in γ-glutamyl transpeptidase (GGT) activity. Subsequent administration of GTN resulted in significant ( p < 0.001) recovery of GSH-metabolizing enzymes in a dose-dependent manner. Further, administration of NO inhibitor, NG-nitro-l-arginine methyl ester (l-NAME), exacerbated CCl4-induced oxidative tissue injury. Overall, the study suggests that GTN might suppress oxidant-induced tissue injury and hepatotoxicity in rats.

Matched MeSH terms: Gene Expression Regulation, Enzymologic/drug effects
Whence river blindness? The domestication of mammals and host-parasite co-evolution in the nematode genus Onchocerca

Lefoulon E, Giannelli A, Makepeace BL, Mutafchiev Y, Townson S, Uni S, et al.

Int J Parasitol, 2017 07;47(8):457-470.
PMID: 28344097 DOI: 10.1016/j.ijpara.2016.12.009

The genus Onchocerca includes 34 described species and represents one of the largest genera of the filarial nematodes within the family Onchocercidae. Representative members of this genus are mainly parasites of ungulates, with some exceptions such as Onchocerca lupi and Onchocerca volvulus, infecting carnivores and/or humans. For a long time, the evolutionary relationships amongst onchocercids remained poorly studied, as the systematics of this genus was impaired by the high morphological variability of species included in the taxon. Although some molecular phylogenies were developed, these studies were mainly focused on bovine Onchocerca spp. and O. volvulus, including assessments of Wolbachia endosymbionts. In the present study, we analysed 13 Onchocerca spp. from a larger host spectrum using a panel of seven different genes. Analysis of the coxI marker supports its usefulness for the identification of species within the genus. The evolutionary history of the genus has been herein revised by multi-gene phylogenies, presenting three strongly supported clades of Onchocerca spp. Analyses of co-evolutionary scenarios between Onchocerca and their vertebrate hosts underline the effect of domestication on Onchocerca speciation. Our study indicates that a host switch event occurred between Bovidae, Canidae and humans. Cophylogenetic analyses between Onchocerca and the endosymbiotic bacterium Wolbachia indicate the strongest co-evolutionary pattern ever registered within the filarial nematodes. Finally, this dataset indicates that the clade composed by O. lupi, Onchocerca gutturosa, Onchocerca lienalis, Onchocerca ochengi and O. volvulus derived from recent speciation.

Matched MeSH terms: Gene Expression Regulation, Enzymologic
Cytochrome c oxidase subunit I haplotype diversity of Angiostrongylus cantonensis (Nematoda: Angiostrongylidae)

Eamsobhana P, Song SL, Yong HS, Prasartvit A, Boonyong S, Tungtrongchitr A

Acta Trop, 2017 Jul;171:141-145.
PMID: 28347653 DOI: 10.1016/j.actatropica.2017.03.020

The rat lungworm Angiostrongylus cantonensis is a food-borne zoonotic parasite of public health importance worldwide. It is the primary etiologic agent of eosinophilic meningitis and eosinophilic meningoencephalitis in humans in many countries. It is highly endemic in Thailand especially in the northeast region. In this study, A. cantonensis adult worms recovered from the lungs of wild rats in different geographical regions/provinces in Thailand were used to determine their haplotype by means of the mitochondrial partial cytochrome c oxidase subunit I (COI) gene sequence. The results revealed three additional COI haplotypes of A. cantonensis. The geographical isolates of A. cantonensis from Thailand and other countries formed a monophyletic clade distinct from the closely related A. malaysiensis. In the present study, distinct haplotypes were identified in seven regions of Thailand - AC10 in Phitsanulok (northern region), AC11 in Nakhon Phanom (northeastern region), AC15 in Trat (eastern region), AC16 in Chantaburi (eastern region), AC4 in Samut Prakan (central region), AC14 in Kanchanaburi (western region), and AC13 in Ranong (southern region). Phylogenetic analysis revealed that these haplotypes formed distinct lineages. In general, the COI sequences did not differentiate the worldwide geographical isolates of A. cantonensis. This study has further confirmed the presence of COI haplotype diversity in various geographical isolates of A. cantonensis. The COI gene sequence will be a suitable marker for studying population structure, phylogeography and genetic diversity of the rat lungworm.

Matched MeSH terms: Gene Expression Regulation, Enzymologic
Fulltext Silver nanoparticles reduce brain inflammation and related neurotoxicity through induction of H2S-synthesizing enzymes

Gonzalez-Carter DA, Leo BF, Ruenraroengsak P, Chen S, Goode AE, Theodorou IG, et al.

Sci Rep, 2017 03 02;7:42871.
PMID: 28251989 DOI: 10.1038/srep42871

Silver nanoparticles (AgNP) are known to penetrate into the brain and cause neuronal death. However, there is a paucity in studies examining the effect of AgNP on the resident immune cells of the brain, microglia. Given microglia are implicated in neurodegenerative disorders such as Parkinson's disease (PD), it is important to examine how AgNPs affect microglial inflammation to fully assess AgNP neurotoxicity. In addition, understanding AgNP processing by microglia will allow better prediction of their long term bioreactivity. In the present study, the in vitro uptake and intracellular transformation of citrate-capped AgNPs by microglia, as well as their effects on microglial inflammation and related neurotoxicity were examined. Analytical microscopy demonstrated internalization and dissolution of AgNPs within microglia and formation of non-reactive silver sulphide (Ag2S) on the surface of AgNPs. Furthermore, AgNP-treatment up-regulated microglial expression of the hydrogen sulphide (H2S)-synthesizing enzyme cystathionine-γ-lyase (CSE). In addition, AgNPs showed significant anti-inflammatory effects, reducing lipopolysaccharide (LPS)-stimulated ROS, nitric oxide and TNFα production, which translated into reduced microglial toxicity towards dopaminergic neurons. Hence, the present results indicate that intracellular Ag2S formation, resulting from CSE-mediated H2S production in microglia, sequesters Ag+ ions released from AgNPs, significantly limiting their toxicity, concomitantly reducing microglial inflammation and related neurotoxicity.

Matched MeSH terms: Gene Expression Regulation, Enzymologic/drug effects
Pathological vicissitudes and oxidative stress enzyme responses in mice experimentally infected with reptarenavirus (isolate UPM/MY01)

Abba Y, Hassim H, Hamzah H, Ibrahim OE, Mohd Lila MA, Noordin MM

Microb Pathog, 2017 Mar;104:17-27.
PMID: 28062291 DOI: 10.1016/j.micpath.2017.01.003

Boid inclusion body disease (BIBD) is a viral disease of boid snakes believed to be caused by reptarenavirus belonging to the family Arenaviridae. Unlike most mammalian arenaviruses, the reservoir host for reptarenavirus is still unknown. In this study, the pathological responses were evaluated in a mouse model for a period of 28 days. Blood and tissue samples (lung, liver, spleen, heart, kidney and brain) were collected for evaluation of hematology, biochemistry, histopathology and oxidative enzyme levels at six time points (1, 3, 7, 14, 21 and 28 days), after viral infection (2.0 × 10(6) pfu/mL) in the infected and normal saline in the control groups. An initial increase (p

Matched MeSH terms: Gene Expression Regulation, Enzymologic
A fatty acyl desaturase (fads2) with dual Δ6 and Δ5 activities from the freshwater carnivorous striped snakehead Channa striata

Kuah MK, Jaya-Ram A, Shu-Chien AC

Comp Biochem Physiol A Mol Integr Physiol, 2016 11;201:146-155.
PMID: 27421235 DOI: 10.1016/j.cbpa.2016.07.007

There is a lack of understanding on how the environment and trophic niche affect the capability of long-chain polyunsaturated fatty acids (LC-PUFA) in freshwater carnivorous teleost. In this present study, we isolated and functionally characterised a fatty acyl desaturase (Fads) from the striped snakehead Channa striata. Sequence comparison and phylogenetic analysis suggested a Fads2 protein that is closely related to previously characterised Fads2 proteins from freshwater carnivorous and marine herbivorous fish species. We further demonstrated the capacity of Δ6 and Δ5 desaturation activities for this particular desaturase, with highest activities towards the conversion of omega-3 (n-3) polyunsaturated fatty acids (PUFA). Low Δ4 desaturation activity was also detected, although the significance of this at a physiological level remains to be studied. The expression of this striped snakehead Δ6/Δ5 fads2 gene was highest in brain, followed by liver and intestine. In liver, diet fortified with high LC-PUFA concentration impeded the expression of Δ6/Δ5 fads2 gene compared to vegetable oil (VO) based diets. The discovery of Δ6/Δ5 Fads2 desaturase here complements the previous discovery of a Δ4 Fads2 desaturase and an Elovl5 elongase, lending proof to the existence of all the required enzymatic machinery to biosynthesise LC-PUFA from C18 PUFA in a freshwater carnivorous species.

Matched MeSH terms: Gene Expression Regulation, Enzymologic
Inhibition of Human Group IIA-Secreted Phospholipase A2 and THP-1 Monocyte Recruitment by Maslinic Acid

Yap WH, Ahmed N, Lim YM

Lipids, 2016 10;51(10):1153-1159.
PMID: 27540737 DOI: 10.1007/s11745-016-4186-1

Maslinic acid is a natural pentacyclic triterpenoid which has anti-inflammatory properties. A recent study showed that secretory phospholipase A2 (sPLA2) may be a potential binding target of maslinic acid. The human group IIA (hGIIA)-sPLA2 is found in human sera and their levels are correlated with severity of inflammation. This study aims to determine whether maslinic acid interacts with hGIIA-sPLA2 and inhibits inflammatory response induced by this enzyme. It is shown that maslinic acid enhanced intrinsic fluorescence of hGIIA-sPLA2 and inhibited its enzyme activity in a concentration-dependent manner. Molecular docking revealed that maslinic acid binds to calcium binding and interfacial phospholipid binding site, suggesting that it inhibit access of catalytic calcium ion for enzymatic reaction and block binding of the enzyme to membrane phospholipid. The hGIIA-sPLA2 enzyme is also responsible in mediating monocyte recruitment and differentiation. Results showed that maslinic acid inhibit hGIIA-sPLA2-induced THP-1 cell differentiation and migration, and the effect observed is specific to hGIIA-sPLA2 as cells treated with maslinic acid alone did not significantly affect the number of adherent and migrated cells. Considering that hGIIA-sPLA2 enzyme is known to hydrolyze glyceroacylphospholipids present in lipoproteins and cell membranes, maslinic acid may bind and inhibit hGIIA-sPLA2 enzymatic activity, thereby reduces the release of fatty acids and lysophospholipids which stimulates monocyte migration and differentiation. This study is the first to report on the molecular interaction between maslinic acid and inflammatory target hGIIA-sPLA2 as well as its effect towards hGIIA-sPLA2-induced THP-1 monocyte adhesive and migratory capabilities, an important immune-inflammation process in atherosclerosis.

Matched MeSH terms: Gene Expression Regulation, Enzymologic
The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle

Rostam MA, Kamato D, Piva TJ, Zheng W, Little PJ, Osman N

Cell Signal, 2016 08;28(8):956-66.
PMID: 27153775 DOI: 10.1016/j.cellsig.2016.05.002

Hyperelongation of glycosaminoglycan chains on proteoglycans facilitates increased lipoprotein binding in the blood vessel wall and the development of atherosclerosis. Increased mRNA expression of glycosaminoglycan chain synthesizing enzymes in vivo is associated with the development of atherosclerosis. In human vascular smooth muscle, transforming growth factor-β (TGF-β) regulates glycosaminoglycan chain hyperelongation via ERK and p38 as well as Smad2 linker region (Smad2L) phosphorylation. In this study, we identified the involvement of TGF-β receptor, intracellular serine/threonine kinases and specific residues on transcription factor Smad2L that regulate glycosaminoglycan synthesizing enzymes. Of six glycosaminoglycan synthesizing enzymes, xylosyltransferase-1, chondroitin sulfate synthase-1, and chondroitin sulfotransferase-1 were regulated by TGF-β. In addition ERK, p38, PI3K and CDK were found to differentially regulate mRNA expression of each enzyme. Four individual residues in the TGF-β receptor mediator Smad2L can be phosphorylated by these kinases and in turn regulate the synthesis and activity of glycosaminoglycan synthesizing enzymes. Smad2L Thr220 was phosphorylated by CDKs and Smad2L Ser250 by ERK. p38 selectively signalled via Smad2L Ser245. Phosphorylation of Smad2L serine residues induced glycosaminoglycan synthesizing enzymes associated with glycosaminoglycan chain elongation. Phosphorylation of Smad2L Thr220 was associated with XT-1 enzyme regulation, a critical enzyme in chain initiation. These findings provide a deeper understanding of the complex signalling pathways that contribute to glycosaminoglycan chain modification that could be targeted using pharmacological agents to inhibit the development of atherosclerosis.

Matched MeSH terms: Gene Expression Regulation, Enzymologic/drug effects

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