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Tuberculosis AND cholesterol

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https://www.readbyqxmd.com/read/28335738/genome-wide-expression-profiling-establishes-novel-modulatory-roles-of-vitamin-c-in-thp-1-human-monocytic-cell-line
#1
Sakshi Dhingra Batra, Malobi Nandi, Kriti Sikri, Jaya Sivaswami Tyagi
BACKGROUND: Vitamin C (vit C) is an essential dietary nutrient, which is a potent antioxidant, a free radical scavenger and functions as a cofactor in many enzymatic reactions. Vit C is also considered to enhance the immune effector function of macrophages, which are regarded to be the first line of defence in response to any pathogen. The THP-1 cell line is widely used for studying macrophage functions and for analyzing host cell-pathogen interactions. RESULTS: We performed a genome-wide temporal gene expression and functional enrichment analysis of THP-1 cells treated with 100 μM of vit C, a physiologically relevant concentration of the vitamin...
March 23, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28250431/novel-protein-acetyltransferase-rv2170-modulates-carbon-and-energy-metabolism-in-mycobacterium-tuberculosis
#2
Wonsik Lee, Brian C VanderVen, Suzanne Walker, David G Russell
Recent data indicate that the metabolism of Mycobacterium tuberculosis (Mtb) inside its host cell is heavily dependent on cholesterol and fatty acids. Mtb exhibits a unique capacity to co-metabolize different carbon sources and the products from these substrates are compartmentalized metabolically. Isocitrate lies at one of the key nodes of carbon metabolism and can feed into either the glyoxylate shunt (via isocitrate lyase) or the TCA cycle (via isocitrate dehydrogenase (ICDH) activity) and we sought to better understand the regulation at this junction...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28237027/cholesterol-plays-a-larger-role-during-mycobacterium-tuberculosis-in%C3%A2-vitro-dormancy-and-reactivation-than-previously-suspected
#3
Maria D Soto-Ramirez, Diana A Aguilar-Ayala, Lazaro Garcia-Morales, Sofia M Rodriguez-Peredo, Claudia Badillo-Lopez, Diana E Rios-Muñiz, Mario A Meza-Segura, Gelen Y Rivera-Morales, Lizbel Leon-Solis, Jorge F Cerna-Cortes, Sandra Rivera-Gutierrez, Addy C Helguera-Repetto, Jorge A Gonzalez-Y-Merchand
It is known that cholesterol plays a key role for Mycobacterium tuberculosis (Mtb) adaptation and survival within the host, thus contributing to the establishment of dormancy. It has been extensively demonstrated that fatty acids are the main energy source of Mtb during infection and dormancy, and it has been proposed that these molecules are implicated in reactivation of bacilli from a dormant state. We used in vitro models to analyze Mtb gene expression during dormancy and reactivation when fatty acids and cholesterol are the unique carbon source in the media...
March 2017: Tuberculosis
https://www.readbyqxmd.com/read/28228760/perturbed-microrna-expression-by-mycobacterium-tuberculosis-promotes-macrophage-polarization-leading-to-pro-survival-foam-cell
#4
Pankaj Kumar Ahluwalia, Rajan Kumar Pandey, Prabodh Kumar Sehajpal, Vijay Kumar Prajapati
Tuberculosis (TB) is one of the prevalent causes of death worldwide, with 95% of these deaths occurring in developing countries, like India. The causative agent, Mycobacterium tuberculosis (MTb) has the tenacious ability to circumvent the host's immune system for its own advantage. Macrophages are one of the phagocytic cells that are central to immunity against MTb. These are highly plastic cells dependent on the milieu and can showcase M1/M2 polarization. M1 macrophages are bactericidal in action, but M2 macrophages are anti-inflammatory in their immune response...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28217856/molecular-characterization-of-a-new-gene-cluster-for-steroid-degradation-in-mycobacterium-smegmatis
#5
Lorena Fernández-Cabezón, Esther García-Fernández, Beatriz Galán, José L García
The C-19 steroids 4-androstene-3,17-dione (AD), 1,4-androstadiene-3,17-dione (ADD) or 9α-hydroxy-4-androstene-3,17-dione (9OH-AD), which have been postulated as intermediates of the cholesterol catabolic pathway in Mycobacterium smegmatis, cannot be used as sole carbon and energy sources by this bacterium. Only the ΔkstR mutant which constitutively expresses the genes repressed by the KstR regulator can metabolize AD and ADD with severe difficulties but still cannot metabolize 9OH-AD, suggesting that these compounds are not true intermediates but side products of the cholesterol pathway...
February 20, 2017: Environmental Microbiology
https://www.readbyqxmd.com/read/28193630/mycolates-of-mycobacterium-tuberculosis-modulate-the-flow-of-cholesterol-for-bacillary-proliferation-in-murine-macrophages
#6
Ilke Vermeulen, Mark Baird, Juma Al-Dulayymi, Muriel Smet, Jan Verschoor, Johan Grooten
The differentiation of macrophages into lipid-filled foam cells is a hallmark of the lung granuloma that forms in patients with active tuberculosis (TB). Mycolic acids (MAs), the abundant lipid virulence factors in the cell wall of Mycobacterium tuberculosis (Mtb), can induce this foam phenotype possibly as a way to perturb host cell lipid homeostasis to support the infection. It is not exactly clear how MAs allow differentiation of foam cells during Mtb infection. Here we investigated how chemically synthetic MAs, each with a defined stereochemistry similar to natural Mtb-associated mycolates, influence cell foamy phenotype and mycobacterial proliferation in murine host macrophages...
February 13, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28043638/activity-of-drugs-against-dormant-mycobacterium-tuberculosis
#7
A Iacobino, G Piccaro, F Giannoni, A Mustazzolu, L Fattorini
OBJECTIVE/BACKGROUND: Heterogeneous mixtures of cellular and caseous granulomas coexist in the lungs of tuberculosis (TB) patients, with Mycobacterium tuberculosis (Mtb) existing from actively replicating (AR) to dormant, nonreplicating (NR) stages. Within cellular granulomas, the pH is estimated to be less than 6, whereas in the necrotic centres of hypoxic, cholesterol/triacylglycerol-rich, caseous granulomas, the pH varies between 7.2 and 7.4. To combat TB, we should kill both AR and NR stages of Mtb...
December 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28002883/cholesterol-metabolism-a-potential-therapeutic-target-in-mycobacteria
#8
REVIEW
Areej Abuhammad
Tuberculosis (TB), although a curable disease, has remained one of the most difficult infections to treat. Mycobacterium tuberculosis (M. tuberculosis.) infects 10 million people worldwide and kills 1.5 million people each year. Reactivation of latent infection is the major cause of TB. Cholesterol is a critical carbon source during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into lipid virulence factors. The M. tuberculosis genome contains a large regulon of cholesterol catabolic genes suggesting that the microorganism can utilise host sterol for infection and persistence...
December 21, 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27943261/efavirenz-or-nevirapine-in-three-drug-combination-therapy-with-two-nucleoside-or-nucleotide-reverse-transcriptase-inhibitors-for-initial-treatment-of-hiv-infection-in-antiretroviral-na%C3%A3-ve-individuals
#9
REVIEW
Lawrence Mbuagbaw, Sara Mursleen, James H Irlam, Alicen B Spaulding, George W Rutherford, Nandi Siegfried
BACKGROUND: The advent of highly active antiretroviral therapy (ART) has reduced the morbidity and mortality due to HIV infection. The World Health Organization (WHO) ART guidelines focus on three classes of antiretroviral drugs, namely nucleoside or nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors. Two of the most common medications given as first-line treatment are the NNRTIs, efavirenz (EFV) and nevirapine (NVP)...
December 10, 2016: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/27879023/potential-effect-of-ezetimibe-against-mycobacterium-tuberculosis-infection-in-type-ii-diabetes
#10
I-Fang Tsai, Chiu-Ping Kuo, Andrew B Lin, Ming-Nan Chien, Hsin-Tsung Ho, Tsai-Yin Wei, Chien-Liang Wu, Yen-Ta Lu
BACKGROUND AND OBJECTIVE: Tuberculosis (TB) risk might be increased in patients with diabetes by factors other than hyperglycaemia, such as dyslipidaemia. Host lipids are essential energy sources used by mycobacteria to persist in a latent TB state. A potential therapy targeting cholesterol catabolism of mycobacteria has been proposed, but the potential of cholesterol-lowering drugs as anti-TB therapy is unclear. The purpose of this study was to determine the effects of ezetimibe, a 2-azetidinone cholesterol absorption inhibitor, on intracellular mycobacteria survival and dormancy...
April 2017: Respirology: Official Journal of the Asian Pacific Society of Respirology
https://www.readbyqxmd.com/read/27867565/changes-in-cholesterol-level-correlate-with-the-course-of-pulmonary-nontuberculous-mycobacterial-disease
#11
Ji Young Hong, Go Eun Yang, Yousang Ko, Yong Bum Park, Yun Su Sim, Sung Hoon Park, Chang Youl Lee, Ki-Suck Jung, Myung Goo Lee
BACKGROUND: Nutritional assessment is important in patients with pulmonary nontuberculous mycobacterial (PNTM) disease. The therapeutic effect of a cholesterol-rich diet in tuberculosis (TB) patients has been demonstrated, but the role of cholesterol in PNTM disease is unclear. This study evaluated the sequential changes in nutritional markers, including cholesterol, total lymphocyte count and visceral fat volume, according to the PNTM disease course. METHODS: This was an age-, sex- and number of comorbid diseases-matched case-control analysis of 89 patients with PNTM disease and 356 controls, who were participants in a Korean national survey...
October 2016: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/27856345/drug-targeting-of-heme-proteins-in-mycobacterium-tuberculosis
#12
REVIEW
Kirsty J McLean, Andrew W Munro
TB, caused by the human pathogen Mycobacterium tuberculosis (Mtb), causes more deaths than any other infectious disease. Iron is crucial for Mtb to infect the host and to sustain infection, with Mtb encoding large numbers of iron-binding proteins. Many of these are hemoproteins with key roles, including defense against oxidative stress, cellular signaling and regulation, host cholesterol metabolism, and respiratory processes. Various heme enzymes in Mtb are validated drug targets and/or products of genes essential for bacterial viability or survival in the host...
November 14, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27847019/expression-profile-of-mce4-operon-of-mycobacterium-tuberculosis-following-environmental-stress
#13
Nisha Rathor, Kushal Garima, Naresh Kumar Sharma, Anshika Narang, Mandira Varma-Basil, Mridula Bose
BACKGROUND: The mce4 operon is one of the four mce operons with eight genes (yrbE4A, yrbE4B, mce4A, mce4B, mce4C, mce4D, mce4E and mce4F) of Mycobacterium tuberculosis. It expresses in the later phase of infection and imports cholesterol for long term survival of the bacilli. To cause latent infection, M. tuberculosis undergoes metabolic reprogramming of its genes to survive in the hostile environment like low availability of oxygen and nutrition depletion inside the host. OBJECTIVE: To analyze real time expression profile of mce4 operon under various stress conditions...
September 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/27804278/mycobacterium-smegmatis-is-a-suitable-cell-factory-for-the-production-of-steroidic-synthons
#14
Beatriz Galán, Iria Uhía, Esther García-Fernández, Igor Martínez, Esther Bahíllo, Juan L de la Fuente, José L Barredo, Lorena Fernández-Cabezón, José L García
A number of pharmaceutical steroid synthons are currently produced through the microbial side-chain cleavage of natural sterols as an alternative to multi-step chemical synthesis. Industrially, these synthons have been usually produced through fermentative processes using environmental isolated microorganisms or their conventional mutants. Mycobacterium smegmatis mc(2) 155 is a model organism for tuberculosis studies which uses cholesterol as the sole carbon and energy source for growth, as other mycobacterial strains...
January 2017: Microbial Biotechnology
https://www.readbyqxmd.com/read/27771519/-genetic-regulation-of-mycobacterium-tuberculosis-in-a-lipid-rich-environment
#15
REVIEW
Diana A Aguilar-Ayala, Juan Carlos Palomino, Peter Vandamme, Anandi Martin, Jorge A Gonzalez-Y-Merchand
Tuberculosis (TB) remains as one of the leading causes of morbidity and mortality among infectious diseases worldwide. Although lipids (mainly fatty acids and cholesterol) have been reported to play an important role during active and latent infection of M. tuberculosis, there are other molecular aspects of bacterial response to those substrates that are not fully understood, involving gene regulation background. This review highlights recent insights on pathogen gene expression: regulation during its active growth, during survival in presence of lipids and under variable hostile host microenvironments...
October 19, 2016: Infection, Genetics and Evolution
https://www.readbyqxmd.com/read/27751911/prxq-b-from-mycobacterium-tuberculosis-is-a-monomeric-thioredoxin-dependent-and-highly-efficient-fatty-acid-hydroperoxide-reductase
#16
Aníbal M Reyes, Diego S Vazquez, Ari Zeida, Martín Hugo, M Dolores Piñeyro, María Inés De Armas, Darío Estrin, Rafael Radi, Javier Santos, Madia Trujillo
Mycobacterium tuberculosis (M. tuberculosis) is the intracellular bacterium responsible for tuberculosis disease (TD). Inside the phagosomes of activated macrophages, M. tuberculosis is exposed to cytotoxic hydroperoxides such as hydrogen peroxide, fatty acid hydroperoxides and peroxynitrite. Thus, the characterization of the bacterial antioxidant systems could facilitate novel drug developments. In this work, we characterized the product of the gene Rv1608c from M. tuberculosis, which according to sequence homology had been annotated as a putative peroxiredoxin of the peroxiredoxin Q subfamily (PrxQ B from M...
December 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27718364/uptake-and-metabolism-of-fluorescent-steroids-by-mycobacterial-cells
#17
Yaroslav Faletrov, Anna Brzostek, Renata Plocinska, Jarosław Dziadek, Elena Rudaya, Irina Edimecheva, Vladimir Shkumatov
Fluorescent steroids BODIPY-cholesterol (BPCh) and 7-nitrobenzoxadiazole-4-amino-(NBD)-labeled 22-NBD-chelesterol (22NC) as well as synthesized 20-(NBD)-pregn-5-en-3β-ol (20NP) were found to undergo bioconversions by Mycobacterium tuberculosis H37Rv and M. smegmatis mc(2) 155. The major fluorescent products were determined to be 4-en-3-one derivatives of the compounds. Degradation of NBD fluorophore was also detected in the cases of 22NC and 20NP, but neither NBD degradation nor steroidal part modification were observed for the synthesized 3-(NBD)-cholestane...
January 2017: Steroids
https://www.readbyqxmd.com/read/27677638/discovery-and-biophysical-evaluation-of-first-low-nanomolar-hits-targeting-cyp125-of-m-%C3%A2-tuberculosis
#18
Christian Brengel, Andreas Thomann, Alexander Schifrin, Jens Eberhard, Rolf W Hartmann
Tuberculosis, which is predominantly caused by Mycobacterium tuberculosis (Mtb), is still the most lethal bacterial infection with 1.5 million casualties in 2014. Moreover, the fact that the appearance of resistant mutants and long-term treatment are coupled with economic problems in developing countries hampers an efficient therapy. Interference with the essential cholesterol metabolism of Mtb could be a promising novel strategy to fight Mtb infections. CYP125, a P450 enzyme in Mtb, has been shown to play an important role in this metabolic pathway...
September 28, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27672155/inhibiting-mycobacterium-tuberculosis-within-and-without
#19
REVIEW
Stewart T Cole
Tuberculosis remains a scourge of global health with shrinking treatment options due to the spread of drug-resistant strains of Mycobacterium tuberculosis Intensive efforts have been made in the past 15 years to find leads for drug development so that better, more potent drugs inhibiting new targets could be produced and thus shorten treatment duration. Initial attempts focused on repurposing drugs that had been developed for other therapeutic areas but these agents did not meet their goals in clinical trials...
November 5, 2016: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/27632901/topical-simvastatin-as-host-directed-therapy-against-severity-of-cutaneous-leishmaniasis-in-mice
#20
Suraj P Parihar, Mary-Anne Hartley, Ramona Hurdayal, Reto Guler, Frank Brombacher
We recently demonstrated that statins mediate protection against intracellular pathogens, Mycobacterium tuberculosis and Listeria monocytogenes in mice. Here, we investigated the immunomodulatory potential of simvastatin as a topical or systemic host-directed drug therapy in controlling inflammatory responses in an experimental mouse model of cutaneous leishmaniasis caused by Leishmania major (LV39). In an ear infection model, topical application of simvastatin directly on established lesions significantly reduced severity of the disease reflected by ear lesion size and ulceration...
2016: Scientific Reports
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