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Tuberculosis AND cholesterol

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...
October 14, 2016: Free Radical Biology & Medicine
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...
October 5, 2016: Steroids
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
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
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
Adriana Lama, Lucía Ferreiro, María E Toubes, Antonio Golpe, Francisco Gude, José M Álvarez-Dobaño, Francisco J González-Barcala, Esther San José, Nuria Rodríguez-Núñez, Carlos Rábade, Carlota Rodríguez-García, Luis Valdés
BACKGROUND: Pseudochylothorax (PCT) (cholesterol pleurisy or chyliform effusion) is a cholesterol-rich pleural effusion (PE) that is commonly associated with chronic inflammatory disorders. Nevertheless, the characteristics of patients with PCT are poorly defined. METHODS: A systematic review was performed across two electronic databases searching for studies reporting clinical findings, PE characteristics, and the most effective treatment of PCT. Case descriptions and retrospective studies were included...
August 2016: Journal of Thoracic Disease
Manuella Bouttier, David Laperriere, Babak Memari, Joseph Mangiapane, Amanda Fiore, Eric Mitchell, Mark Verway, Marcel A Behr, Robert Sladek, Luis B Barreiro, Sylvie Mader, John H White
To understand the epigenetic regulation of transcriptional response of macrophages during early-stage M. tuberculosis (Mtb) infection, we performed ChIPseq analysis of H3K4 monomethylation (H3K4me1), a marker of poised or active enhancers. De novo H3K4me1 peaks in infected cells were associated with genes implicated in host defenses and apoptosis. Our analysis revealed that 40% of de novo regions contained human/primate-specific Alu transposable elements, enriched in the AluJ and S subtypes. These contained several transcription factor binding sites, including those for members of the MEF2 and ATF families, and LXR and RAR nuclear receptors, all of which have been implicated in macrophage differentiation, survival, and responses to stress and infection...
September 6, 2016: Nucleic Acids Research
Marc Clément, Gemma Basatemur, Leanne Masters, Lauren Baker, Patrick Bruneval, Takao Iwawaki, Manfred Kneilling, Sho Yamasaki, Jane Goodall, Ziad Mallat
BACKGROUND: Atherosclerotic lesion expansion is characterized by the development of a lipid-rich necrotic core known to be associated with the occurrence of complications. Abnormal lipid handling, inflammation, and alteration of cell survival or proliferation contribute to necrotic core formation, but the molecular mechanisms involved in this process are not properly understood. C-type lectin receptor 4e (Clec4e) recognizes the cord factor of Mycobacterium tuberculosis but also senses molecular patterns released by necrotic cells and drives inflammation...
October 4, 2016: Circulation
Hanna Nylén, Abiy Habtewold, Eyasu Makonnen, Getnet Yimer, Leif Bertilsson, Jürgen Burhenne, Ulf Diczfalusy, Eleni Aklillu
Initiation of efavirenz-based combination antiretroviral therapy (cART) is associated with Vitamin D deficiency, but the risk factors including efavirenz pharmacokinetics for cART-induced severe vitamin D deficiency (SVDD) and the impact of anti-tuberculosis (TB) cotreatment are not explored. We investigated the prevalence of SVDD in HIV and TB-HIV coinfected patients and associated risk factors for treatment-induced SVDD.Treatment-naïve Ethiopian HIV patients with (n = 102) or without (n = 89) TB co-infection were enrolled prospectively and received efavirenz-based cART...
August 2016: Medicine (Baltimore)
Adam Bohr, Jorrit J Water, Yingya Wang, Lærke Arnfast, Moritz Beck-Broichsitter
Films composed of poly(ethylene carbonate) (PEC), a biodegradable polymer, were compared with poly(lactide-co-glycolide) (PLGA) films loaded with and without the tuberculosis drug rifampicin to study the characteristics and performance of PEC as a potential carrier for controlled drug delivery to macrophages. All drug-loaded PLGA and PEC films were amorphous indicating good miscibility of the drug in the polymers, even at high drug loading (up to 50wt.%). Polymer degradation studies showed that PLGA degraded slowly via bulk erosion while PEC degraded more rapidly and near-linearly via enzyme mediated surface erosion (by cholesterol esterase)...
September 25, 2016: International Journal of Pharmaceutics
Shagufta Khan, Asimul Islam, Md Imtaiyaz Hassan, Faizan Ahmad
The mce4A gene of Mycobacterium tuberculosis encodes a 400 amino acid residues protein of 43kDa, which is a mammalian cell entry protein (Mce4A) and plays important role in host cell invasion. Mce4A helps in long-term survival of M. tuberculosis by cholesterol utilization. Host cholesterol utilization mechanism by Mce4A is not clearly understood. In order to investigate the role of Mce4A in M. tuberculosis pathogenesis, we purified the recombinant protein by affinity chromatography, analyzed by SDS-PAGE and confirmed by western blot...
June 26, 2016: International Journal of Biological Macromolecules
Amita Jaswal, Monika Sharma, Suchita Raghuvanshi, Samta Sharma, Mohd Salim Reshi, Chhavi Uthra, Sangeeta Shukla
Antituberculosis drug (ATD)-induced hepatotoxicity is a major impediment for the effective treatment of tuberculosis (TB). All first-line anti-TB medications have adverse effects that interrupt the successful completion of TB treatment. This investigation focuses on the evaluation of the protective role of Nigella sativa (NS) against liver injury caused by ATDs. Female rats were treated with ATDs for 8 weeks (3 d/wk) followed by NS for 8 weeks (3 d/wk). The antioxidant activity of NS was estimated with a 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay and by analyzing total phenolic contents...
2016: Journal of Environmental Pathology, Toxicology and Oncology
Patricia B da Silva, Paula C de Souza, Giovana Maria Fioramonti Calixto, Erica de O Lopes, Regina C G Frem, Adelino V G Netto, Antonio E Mauro, Fernando R Pavan, Marlus Chorilli
Tuberculosis (TB) is an infectious disease caused mainly by the bacillus Mycobacterium tuberculosis (Mtb), presenting 9.5 million new cases and 1.5 million deaths in 2014. The aim of this study was to evaluate a nanostructured lipid system (NLS) composed of 10% phase oil (cholesterol), 10% surfactant (soy phosphatidylcholine, sodium oleate), and Eumulgin(®) HRE 40 ([castor oil polyoxyl-40-hydrogenated] in a proportion of 3:6:8), and an 80% aqueous phase (phosphate buffer pH = 7.4) as a tactic to enhance the in vitro anti-Mtb activity of the copper(II) complexes [CuCl₂(INH)₂]·H₂O (1), [Cu(NCS)₂(INH)₂]·5H₂O (2) and [Cu(NCO)₂(INH)₂]·4H₂O (3)...
2016: International Journal of Molecular Sciences
Qun Li, Fanglan Ge, Yunya Tan, Guangxiang Zhang, Wei Li
Mycobacterium smegmatis strain MC² 155 is an attractive model organism for the study of M. tuberculosis and other mycobacterial pathogens, as it can grow well using cholesterol as a carbon resource. However, its global transcriptomic response remains largely unrevealed. In this study, M. smegmatis MC² 155 cultivated in androstenedione, cholesterol and glycerol supplemented media were collected separately for a RNA-Sequencing study. The results showed that 6004, 6681 and 6348 genes were expressed in androstenedione, cholesterol and glycerol supplemented media, and 5891 genes were expressed in all three conditions, with 237 specially expressed in cholesterol added medium...
2016: International Journal of Molecular Sciences
Saikou Y Bah, Paul Dickinson, Thorsten Forster, Beate Kampmann, Peter Ghazal
Infection remains an important cause of morbidity and mortality. Natural defenses to infection are mediated by intrinsic/innate and adaptive immune responses. While our understanding is considerable it is incomplete and emerging areas of research such as those related to the immune-metabolic axis are only beginning to be appreciated. There is increasing evidence showing a connection between immune signaling and the regulation of sterol and fatty acid metabolism. In particular, metabolic intermediates of cholesterol biosynthesis and its oxidized metabolites (oxysterols) have been shown to regulate adaptive immunity and inflammation and for innate immune signaling to regulate the dynamics of cholesterol synthesis and homeostasis...
May 4, 2016: Journal of Steroid Biochemistry and Molecular Biology
Avril Z Soh, Cynthia Be Chee, Yee-Tang Wang, Jian-Min Yuan, Woon-Puay Koh
BACKGROUND: Experimental studies suggest that cholesterol enhances the intracellular survival of Mycobacterium tuberculosis, whereas marine ω-3 (n-3) and ω-6 (n-6) fatty acids (FAs) may modulate responses to M. tuberculosis in macrophage and animal models. However, there are no epidemiologic data from prospective studies of the relation between dietary cholesterol and FAs and the risk of developing active tuberculosis. OBJECTIVE: We aimed to investigate the relation between dietary intake of cholesterol and FAs and the risk of active tuberculosis in a prospective cohort in Singapore...
May 2016: Journal of Nutrition
Somasundram Pillay, Colleen Aldous, Fazleh Mahomed
BACKGROUND: The combination of HIV infection and diabetes mellitus (DM) represents a collision of two chronic conditions. Both HIV and DM increase the risk of developing tuberculosis (TB). Health resources in developing countries are already under strain as a result of the TB epidemic and poor diabetic control would further worsen this epidemic. Optimal diabetic control provides one avenue of curbing the TB epidemic in developing countries. OBJECTIVES: To establish if there is a difference in blood pressure, lipid and glycaemic control and complications between HIV-infected and uninfected diabetic patients; and to compare characteristics among HIV-infected diabetic patients between those with optimal and sub- optimal glycaemic control...
April 2016: South African Medical Journal, Suid-Afrikaanse Tydskrif Vir Geneeskunde
S K Gaidukevich, Yu L Mikulovich, T G Smirnova, S N Andreevskaya, G M Sorokoumova, L N Chernousova, A A Selishcheva, V I Shvets
The effects of liposomes containing phospholipid cardiolipin without antibiotic and loaded with levofloxacin on the growth of Mycobacterium tuberculosis with extensive drug resistance were studied in vitro. Liposomes consisting of cardiolipin alone in a concentration of 335 μM completely suppressed the growth of M. tuberculosis. In order to reduce the minimum inhibitory concentration of cardiolipin, complex liposome preparation consisting of phosphatidylcholin/cholesterol/cardiolipin and loaded with levofloxacin was prepared...
March 2016: Bulletin of Experimental Biology and Medicine
Nontobeko E Mvubu, Balakrishna Pillay, Junaid Gamieldien, William Bishai, Manormoney Pillay
Limited knowledge exists on pathways, networks and transcriptional factors regulated within epithelial cells by diverse Mycobacterium tuberculosis genotypes. This study aimed to elucidate these mechanisms induced in A549 epithelial cells by dominant clinical strains in KwaZulu-Natal, South Africa. RNA for sequencing was extracted from epithelial cells at 48 h post-infection with 5 strains at a multiplicity of infection of approximately 10:1. Bioinformatics analysis performed with the RNA-Seq Tuxedo pipeline identified differentially expressed genes...
March 2016: Tuberculosis
Noton K Dutta, Natalie Bruiners, Michael L Pinn, Matthew D Zimmerman, Brendan Prideaux, Véronique Dartois, Maria L Gennaro, Petros C Karakousis
BACKGROUND: The repurposing of existing agents may accelerate TB drug development. Recently, we reported that the lipid-lowering drug simvastatin, when added to the first-line antitubercular regimen, reduces the lung bacillary burden in chronically infected mice. OBJECTIVES: We investigated whether the addition of simvastatin to the first-line regimen (isoniazid/rifampicin/pyrazinamide) shortens the duration of curative TB treatment in mice. METHODS: Mycobacterium tuberculosis-infected THP-1 cells were exposed to simvastatin to determine the effect of statins on the activity of first-line anti-TB drug activity and intracellular rifampicin concentration...
June 2016: Journal of Antimicrobial Chemotherapy
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