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Tuberculosis AND cholesterol

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https://www.readbyqxmd.com/read/29746303/acquired-low-cholesterol-diagnosis-and-relevance-to-safety-of-low-ldl-therapeutic-targets
#1
Handrean Soran, Jan Hoong Ho, Paul N Durrington
PURPOSE OF REVIEW: Acquired hypocholesterolaemia occurs more commonly than inherited hypocholesterolaemia but has received little attention in the literature. In this review, we discuss the causes and underlying mechanisms of acquired hypocholesterolaemia and its relevance to safety of therapeutically induced decreased LDL cholesterol levels. RECENT FINDINGS: Hypocholesterolaemia is increasingly identified as cholesterol testing becomes more widespread in the assessment of cardiovascular risk...
May 8, 2018: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/29718271/cholesterol-and-fatty-acids-grease-the-wheels-of-mycobacterium-tuberculosis-pathogenesis
#2
Kaley M Wilburn, Rachael A Fieweger, Brian C VanderVen
Tuberculosis is a distinctive disease in which the causative agent, Mycobacterium tuberculosis, can persist in humans for decades by avoiding clearance from host immunity. During infection, M. tuberculosis maintains viability by extracting and utilizing essential nutrients from the host, and this is a prerequisite for all of the pathogenic activities that are deployed by the bacterium. In particular, M. tuberculosis preferentially acquires and metabolizes host-derived lipids (fatty acids and cholesterol), and the bacterium utilizes these substrates to cause and maintain disease...
March 1, 2018: Pathogens and Disease
https://www.readbyqxmd.com/read/29593722/formation-of-foamy-macrophages-by-tuberculous-pleural-effusions-is-triggered-by-the-interleukin-10-signal-transducer-and-activator-of-transcription-3-axis-through-acat-upregulation
#3
Melanie Genoula, José Luis Marín Franco, Maeva Dupont, Denise Kviatcovsky, Ayelén Milillo, Pablo Schierloh, Eduardo Jose Moraña, Susana Poggi, Domingo Palmero, Dulce Mata-Espinosa, Erika González-Domínguez, Juan Carlos León Contreras, Paula Barrionuevo, Bárbara Rearte, Marlina Olyissa Córdoba Moreno, Adriana Fontanals, Agostina Crotta Asis, Gabriela Gago, Céline Cougoule, Olivier Neyrolles, Isabelle Maridonneau-Parini, Carmen Sánchez-Torres, Rogelio Hernández-Pando, Christel Vérollet, Geanncarlo Lugo-Villarino, María Del Carmen Sasiain, Luciana Balboa
The ability of Mycobacterium tuberculosis (Mtb) to persist in its human host relies on numerous immune evasion strategies, such as the deregulation of the lipid metabolism leading to the formation of foamy macrophages (FM). Yet, the specific host factors leading to the foamy phenotype of Mtb-infected macrophages remain unknown. Herein, we aimed to address whether host cytokines contribute to FM formation in the context of Mtb infection. Our approach is based on the use of an acellular fraction of tuberculous pleural effusions (TB-PE) as a physiological source of local factors released during Mtb infection...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29581275/ipdab-a-virulence-factor-in-mycobacterium-tuberculosis-is-a-cholesterol-ring-cleaving-hydrolase
#4
Adam M Crowe, Sean D Workman, Nobuhiko Watanabe, Liam J Worrall, Natalie C J Strynadka, Lindsay D Eltis
Mycobacterium tuberculosis ( Mtb ) grows on host-derived cholesterol during infection. IpdAB, found in all steroid-degrading bacteria and a determinant of pathogenicity, has been implicated in the hydrolysis of the last steroid ring. Phylogenetic analyses revealed that IpdAB orthologs form a clade of CoA transferases (CoTs). In a coupled assay with a thiolase, IpdAB transformed the cholesterol catabolite ( R )-2-(2-carboxyethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA (COCHEA-CoA) and CoASH to 4-methyl-5-oxo-octanedioyl-CoA (MOODA-CoA) and acetyl-CoA with high specificity ( k cat / K m = 5...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29573124/the-role-of-lipids-in-host-pathogen-interactions
#5
REVIEW
Glenn F W Walpole, Sergio Grinstein, Johannes Westman
Innate immunity relies on the effective recognition and elimination of pathogenic microorganisms. This entails sequestration of pathogens into phagosomes that promptly acquire microbicidal and degradative properties. This complex series of events, which involve cytoskeletal reorganization, membrane remodeling and the activation of multiple enzymes, is orchestrated by lipid signaling. To overcome this immune response, intracellular pathogens acquired mechanisms to subvert phosphoinositide-mediated signaling and use host lipids, notably cholesterol, as nutrients...
March 23, 2018: IUBMB Life
https://www.readbyqxmd.com/read/29567998/system-wide-coordinates-of-higher-order-functions-in-host-pathogen-environment-upon-mycobacterium-tuberculosis-infection
#6
P V Parvati Sai Arun, Sravan Kumar Miryala, Aarti Rana, Sreenivasulu Kurukuti, Yusuf Akhter, Sailu Yellaboina
Molecular signatures and their interactions behind the successful establishment of infection of Mycobacterium tuberculosis (Mtb) inside macrophage are largely unknown. In this work, we present an inter-system scale atlas of the gene expression signatures, their interactions and higher order gene functions of macrophage-Mtb environment at the time of infection. We have carried out large-scale meta-analysis of previously published gene expression microarray studies andhave identified a ranked list of differentially expressed genes and their higher order functions in intracellular Mtb as well as the infected macrophage...
March 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29559121/methyl-accepting-chemotaxis-like-rv3499c-mce4a-protein-in-mycobacterium-tuberculosis-h37rv-mediates-cholesterol-dependent-survival
#7
Rajesh Sinha, Pooja Singh, Neeraj K Saini, Ajit Kumar, Rakesh Pathak, Amita Chandolia, Kushal Garima, Gaurav Tyagi, Madhu Chopra, Ashok Kumar Prasad, Hanumantharao G Raj, Mridula Bose
Cholesterol, an essential cellular component in macrophages, is exploited for entry and long-term survival of Mycobacterium inside the host. Cholesterol-deficient macrophages can restrict the cholesterol-dependent entry of Mycobacterium. Rv3499c protein in Mycobacterium has high binding affinity for cholesterol. Rv3499c gene is a part of mce4 operon which is reported to act as cholesterol transport system in mycobacteria. Earlier we reported Rv3499c protein to localise on cell wall and facilitate entry of Mycobacterium inside macrophages...
March 2018: Tuberculosis
https://www.readbyqxmd.com/read/29475946/the-anaplerotic-node-is-essential-for-the-intracellular-survival-of-mycobacterium-tuberculosis
#8
Piyali Basu, Noor Sandhu, Apoorva Bhatt, Albel Singh, Ricardo Balhana, Irene Gobe, Nicola A Crowhurst, Tom A Mendum, Liang Gao, Jane L Ward, Michael H Beale, Johnjoe McFadden, Dany J V Beste
Enzymes at the phosphoenolpyruvate (PEP)-pyruvate-oxaloacetate or anaplerotic (ANA) node control the metabolic flux to glycolysis, gluconeogenesis, and anaplerosis. Here we used genetic, biochemical, and 13 C isotopomer analysis to characterize the role of the enzymes at the ANA node in intracellular survival of the world's most successful bacterial pathogen, Mycobacterium tuberculosis ( Mtb ). We show that each of the four ANA enzymes, pyruvate carboxylase (PCA), PEP carboxykinase (PCK), malic enzyme (MEZ), and pyruvate phosphate dikinase (PPDK), performs a unique and essential metabolic function during the intracellular survival of Mtb...
April 13, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29367626/il-36-lxr-axis-modulates-cholesterol-metabolism-and-immune-defense-to-mycobacterium-tuberculosis
#9
Fadhil Ahsan, Jeroen Maertzdorf, Ute Guhlich-Bornhof, Stefan H E Kaufmann, Pedro Moura-Alves
Mycobacterium tuberculosis (Mtb) is a life-threatening pathogen in humans. Bacterial infection of macrophages usually triggers strong innate immune mechanisms, including IL-1 cytokine secretion. The newer member of the IL-1 family, IL-36, was recently shown to be involved in cellular defense against Mtb. To unveil the underlying mechanism of IL-36 induced antibacterial activity, we analyzed its role in the regulation of cholesterol metabolism, together with the involvement of Liver X Receptor (LXR) in this process...
January 24, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29329815/exploring-molecular-insights-into-the-interaction-mechanism-of-cholesterol-derivatives-with-the-mce4a-a-combined-spectroscopic-and-molecular-dynamic-simulation-studies
#10
Shagufta Khan, Faez Iqbal Khan, Taj Mohammad, Parvez Khan, Gulam Mustafa Hasan, Kevin A Lobb, Asimul Islam, Faizan Ahmad, Md Imtaiyaz Hassan
Mammalian cell entry protein (Mce4A) is a member of MCE-family, and is being considered as a potential drug target of Mycobacterium tuberculosis infection because it is required for invasion and latent survival of pathogen by utilizing host's cholesterol. In the present study, we performed molecular docking followed by 100 ns MD simulation studies to understand the mechanism of interaction of Mce4A to the cholesterol derivatives and probucol. The selected ligands, cholesterol, 25-hydroxycholesterol, 5-cholesten-3β-ol-7-one and probucol bind to the predicted active site cavity of Mce4A, and complexes remain stable during entire simulation of 100 ns...
May 2018: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29247215/the-transcriptome-of-mycobacterium-tuberculosis-in-a-lipid-rich-dormancy-model-through-rnaseq-analysis
#11
Diana A Aguilar-Ayala, Laurentijn Tilleman, Filip Van Nieuwerburgh, Dieter Deforce, Juan Carlos Palomino, Peter Vandamme, Jorge A Gonzalez-Y-Merchand, Anandi Martin
Tuberculosis (TB) is currently the number one killer among infectious diseases worldwide. Lipids are abundant molecules during the infectious cycle of Mycobacterium tuberculosis (Mtb) and studies better mimicking its actual metabolic state during pathogenesis are needed. Though most studies have focused on the mycobacterial lipid metabolism under standard culture conditions, little is known about the transcriptome of Mtb in a lipid environment. Here we determined the transcriptome of Mtb H37Rv in a lipid-rich environment (cholesterol and fatty acid) under aerobic and hypoxic conditions, using RNAseq...
December 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29226217/lipid-profile-in-tuberculosis-patients-with-and-without-human-immunodeficiency-virus-infection
#12
Gebremedhin Gebremicael, Yemane Amare, Feyissa Challa, Atsbeha Gebreegziabxier, Girmay Medhin, Mistire Wolde, Desta Kassa
Background: Understanding whether the preceding low lipid profile leads to active tuberculosis (TB) or active TB leads to low lipid profile is crucial. Methods: Lipid profile concentrations were determined from 159 study participants composed of 93 active TB patients [44 HIV coinfected (HIV+TB+) and 49 HIV negative (HIV-TB+)], 41 tuberculin skin test (TST) positive cases [17 HIV coinfected (HIV+TST+) and 24 HIV negative (HIV-TST+)], and 25 healthy controls (HIV-TST-)...
2017: International Journal of Chronic Diseases
https://www.readbyqxmd.com/read/29193799/preliminary-evaluation-of-artemisinin-cholesterol-conjugates-as-potential-drugs-for-the-treatment-of-intractable-forms-of-malaria-and-tuberculosis
#13
Mokhitli Morake, Dina Coertzen, Andile Ngwane, Johannes F Wentzel, Ho Ning Wong, Frans J Smit, Lyn-Marie Birkholtz, Ray-Dean Pietersen, Bienyameen Baker, Ian Wiid, David D N'Da, Richard K Haynes
To evaluate the feasibility of developing drugs that may be active against both malaria and tuberculosis (TB) by using in part putative cholesterol transporters in the causative pathogens and through enhancement of passive diffusion in granulomatous TB, artemisinin-cholesterol conjugates were synthesized by connecting the component molecules through various linkers. The compounds were screened in vitro against Plasmodium falciparum (Pf) and Mycobacterium tuberculosis (Mtb). Antimalarial activities (IC50 ) against Pf drug-sensitive NF54, and drug-resistant K1 and W2 strains ranged from 0...
January 8, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29109182/characterization-of-an-aldolase-involved-in-cholesterol-side-chain-degradation-in-mycobacterium-tuberculosis
#14
Stephanie Gilbert, LaChae Hood, Stephen Y K Seah
The heteromeric acyl coenzyme A (acyl-CoA) dehydrogenase FadE28-FadE29 and the enoyl-CoA hydratase ChsH1-ChsH2, encoded by genes within the intracellular growth ( igr ) operon of Mycobacterium tuberculosis , catalyze the dehydrogenation of the cholesterol metabolite 3-oxo-4-pregnene-20-carboxyl-CoA (3-OPC-CoA), with a 3-carbon side chain, and subsequent hydration of the product 3-oxo-4,17-pregnadiene-20-carboxyl-CoA (3-OPDC-CoA) to form 17-hydroxy-3-oxo-4-pregnene-20-carboxyl-CoA (17-HOPC-CoA). The gene downstream of chsH2 , i...
January 15, 2018: Journal of Bacteriology
https://www.readbyqxmd.com/read/29067283/small-molecule-mediated-restoration-of-mitochondrial-function-augments-anti-mycobacterial-activity-of-human-macrophages-subjected-to-cholesterol-induced-asymptomatic-dyslipidemia
#15
Suman Asalla, Krishnaveni Mohareer, Sharmistha Banerjee
Mycobacterium tuberculosis ( M.tb) infection manifests into tuberculosis (TB) in a small fraction of the infected population that comprises the TB susceptible group. Identifying the factors potentiating susceptibility to TB persistence is one of the prime agenda of TB control programs. Recently, WHO recognized diabetes as a risk factor for TB disease progression. The closely related pathological state of metabolic imbalance, dyslipidemia, is yet another emerging risk factor involving deregulation in host immune responses...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/29050765/alveolar-macrophages-from-tuberculosis-patients-display-an-altered-inflammatory-gene-expression-profile
#16
Lelia Lavalett, Hector Rodriguez, Hector Ortega, Wolfgang Sadee, Larry S Schlesinger, Luis F Barrera
Alveolar macrophages (AMs) are major targets of Mycobacterium tuberculosis (Mtb) infection, critical during the progression of active tuberculosis (TB). The complex immunopathology of TB generates diverse microenvironments in the lung, which shape immune responses by AMs. In the current study, we perform whole genome microarray transcriptional profiling on RNA isolated from AMs from TB patients (AMsTB) compared to AMs from control subjects (AMsCT) using bronchoalveolar lavage (BAL). Our hypothesis was that systemic effects on the local lung microenvironment during TB affect the transcriptional response of AMsTB...
December 2017: Tuberculosis
https://www.readbyqxmd.com/read/28988960/pdim-and-sl1-accumulation-in-mycobacterium-tuberculosis-is-associated-with-mce4a-expression
#17
Pooja Singh, Rajesh Sinha, Gaurav Tyagi, Naresh Kumar Sharma, Neeraj K Saini, Amita Chandolia, Ashok Kumar Prasad, Mandira Varma-Basil, Mridula Bose
Lipid metabolism forms the heart and soul of Mycobacterium tuberculosis life cycle. Starting from macrophage invasion at cholesterol rich micro-domains to a sustainable survival for infection by utilizing cholesterol, Mycobacterium displays the nexus of metabolic pathways around host derived lipids. mce4 operon acts as cholesterol import system in M. tuberculosis and here we demonstrate role of mce4A gene of this operon in cholesterol catabolism. Here M. tuberculosis H37Rv overexpressing Rv3499c (mce4A) recombinant was used as a model to decipher the metabolic flux during intake and utilization of host lipids by mycobacteria...
February 5, 2018: Gene
https://www.readbyqxmd.com/read/28838610/toxicological-profile-of-iqg-607-after-single-and-repeated-oral-administration-in-minipigs-an-essential-step-towards-phase-i-clinical-trial
#18
Valnês S Rodrigues-Junior, Luciana Cintra, Pablo Machado, Adílio Dadda, Luiz Augusto Basso, Ana Carolina Cintra Nunes Mafra, Alexandre Holthausen Campos, Maria Martha Campos, Diógenes Santiago Santos
IQG-607 is an anti-tuberculosis drug candidate, with a promising safety and efficacy profile in models of tuberculosis infection both in vitro and in vivo. Here, we evaluated the safety and the possible toxic effects of IQG-607 after acute and 90-day repeated administrations in minipigs. Single oral administration of IQG-607 (220 mg/kg) to female and male minipigs did not result in any morbidity or mortality. No gross lesions were observed in the minipigs at necropsy. Repeated administration of IQG 607 (65, 30, or 15 mg/kg), given orally, for 90 days, in both male and female animals did not cause any mortality and no significant body mass alteration...
August 23, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28810840/the-association-between-tuberculosis-and-the-development-of-insulin-resistance-in-adults-with-pulmonary-tuberculosis-in-the-western-sub-district-of-the-cape-metropole-region-south-africa-a-combined-cross-sectional-cohort-study
#19
Lauren Philips, Janicke Visser, Daan Nel, Renée Blaauw
BACKGROUND: The existence of a bi-directional relationship between tuberculosis (TB) and insulin resistance (IR)/diabetes has been alluded to in literature. Although diabetes has been linked to increased tuberculosis risk, the relationship between tuberculosis as a causative factor for IR remains unclear. The study aimed to determine if an association existed between tuberculosis and IR development in adults with newly diagnosed pulmonary tuberculosis at baseline. It was additionally aimed to document changes in IR status during TB follow-up periods...
August 15, 2017: BMC Infectious Diseases
https://www.readbyqxmd.com/read/28771131/comparative-proteomic-profiles-reveal-characteristic-mycobacterium-tuberculosis-proteins-induced-by-cholesterol-during-dormancy-conditions
#20
Lazaro Garcia-Morales, Lizbel Leon-Solis, Irma E Monroy-Muñoz, Moises Talavera-Paulin, Jeanet Serafin-López, Iris Estrada-Garcia, Sandra Rivera-Gutierrez, Jorge F Cerna-Cortes, Addy C Helguera-Repetto, Jorge A Gonzalez-Y-Merchand
Cholesterol has been reported to play an important role during Mycobacterium tuberculosis infection and during its dormant state inside the host. We present the determination of proteomic profiles of M. tuberculosis H37Rv in the presence of cholesterol as the sole carbon source under exponential growth and in two in vitro dormancy phases (NRP1 and NRP2). Using 2D-PAGE, we detected that M. tuberculosis expressed a high diversity of proteins in both exponential and non-replicative phases. We also found that cholesterol was involved in the overexpression of some proteins related to sulfur metabolism (CysA2), electron transport (FixB), cell wall synthesis (Ald), iron storage (BfrB), protein synthesis (Tig and EF-Tu) and dormancy maintenance (HspX and TB 31...
August 4, 2017: Microbiology
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