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Tuberculosis AND cholesterol

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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
#1
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
#2
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
#3
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
https://www.readbyqxmd.com/read/28752922/molecular-and-functional-analysis-of-the-mce4-operon-in-mycobacterium-smegmatis
#4
Julia García-Fernández, Kadamba Papavinasasundaram, Beatriz Galán, Christopher M Sassetti, José L García
Mycobacterium smegmatis contains 6 homologous mce (mammalian cell entry) operons which have been proposed to encode ABC-like import systems. The mce operons encode up to 10 different proteins of unknown function that are not present in conventional ABC transporters. We have analysed the consequences of individually deleting each of the genes of the mce4 operon of M. smegmatis, which mediates the transport of cholesterol. None of the mce4 mutants were able to grow in cholesterol suggesting that all these genes are required for its uptake and that none of them can be replaced by the homologous genes of the other mce operons...
September 2017: Environmental Microbiology
https://www.readbyqxmd.com/read/28708968/rv3723-luca-coordinates-fatty-acid-and-cholesterol-uptake-in-mycobacterium-tuberculosis
#5
Evgeniya V Nazarova, Christine R Montague, Thuy La, Kaley M Wilburn, Neelima Sukumar, Wonsik Lee, Shannon Caldwell, David G Russell, Brian C VanderVen
Pathogenic bacteria have evolved highly specialized systems to extract essential nutrients from their hosts. Mycobacterium tuberculosis (Mtb) scavenges lipids (cholesterol and fatty acids) to maintain infections in mammals but mechanisms and proteins responsible for the import of fatty acids in Mtb were previously unknown. Here, we identify and determine that the previously uncharacterized protein Rv3723/LucA, functions to integrate cholesterol and fatty acid uptake in Mtb. Rv3723/LucA interacts with subunits of the Mce1 and Mce4 complexes to coordinate the activities of these nutrient transporters by maintaining their stability...
June 27, 2017: ELife
https://www.readbyqxmd.com/read/28578092/construction-of-human-masp-2-ccp1-2sp-ccp2sp-sp-plasmid-dna-nanolipoplexes-and-the-effects-on-tuberculosis-in-bcg-infected-mice
#6
Qi Gao, Xinfang Dong, Yanping Luo, Guochao Zhang, Jinyu Shan, Qian Wang, Qi He, Lifeng Zhang, Jingqiu Wang, Bingdong Zhu, Xingming Ma
The lectin pathway, one of the complement cascade systems, provides the primary line of defense against invading pathogens. The serine protease of MASP-2 plays an essential role in complement activation of the lectin pathway. The C-terminal segment of MASP-2 is comprised of the CCP1-CCP2-SP domains, and is the crucial catalytic segment. However, what is the effect of CCP1-CCP2-SP domains in controlling chronic infection is unknown. In order to evaluate the potential impact of CCP1-CCP2-SP domains on tuberculosis, we constructed the human MASP-2 CCP1/2SP, CCP2SP and SP recombinant plasmids, and delivered these plasmids by DNA-DOTAP:cholesterol cationic nanolipoplexes to BCG-infected mice...
May 31, 2017: Microbial Pathogenesis
https://www.readbyqxmd.com/read/28567068/serum-enolase-2-high-sensitivity-c-reactive-protein-and-serum-cholesterol-in-smear-positive-drug-na%C3%A3-ve-pulmonary-tuberculosis
#7
Suhail Ahmed Almani, Tariq Zaffar Shaikh, Haji Khan Khoharo, Ikramuddin Ujjan
BACKGROUND: Pulmonary tuberculosis (PTB) is a chronic granulomatous disease caused by Mycobacterium tuberculosis. The present study determined the serum human enolase-2 (ENO-2), high-sensitive C-reactive protein (hs-CRP), and serum cholesterol levels as biological marker of disease activity and treatment response in smear-positive drug-naïve PTB. MATERIALS AND METHODS: This case-control study was done in the Department of Medicine, Liaquat University of Medical and Health Sciences (LUMHS), Jamshoro/Hyderabad, Sindh, from January 2015 to April 2016...
2017: Journal of Research in Medical Sciences: the Official Journal of Isfahan University of Medical Sciences
https://www.readbyqxmd.com/read/28515464/systems-immunology-of-diabetes-tuberculosis-comorbidity-reveals-signatures-of-disease-complications
#8
Cesar A Prada-Medina, Kiyoshi F Fukutani, Nathella Pavan Kumar, Leonardo Gil-Santana, Subash Babu, Flávio Lichtenstein, Kim West, Shanmugam Sivakumar, Pradeep A Menon, Vijay Viswanathan, Bruno B Andrade, Helder I Nakaya, Hardy Kornfeld
Comorbid diabetes mellitus (DM) increases tuberculosis (TB) risk and adverse outcomes but the pathological interactions between DM and TB remain incompletely understood. We performed an integrative analysis of whole blood gene expression and plasma analytes, comparing South Indian TB patients with and without DM to diabetic and non-diabetic controls without TB. Luminex assay of plasma cytokines and growth factors delineated a distinct biosignature in comorbid TBDM in this cohort. Transcriptional profiling revealed elements in common with published TB signatures from cohorts that excluded DM...
May 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28479115/statin-use-is-associated-with-a-lower-risk-of-tb
#9
Vincent Yi-Fong Su, Wei-Juin Su, Yung-Feng Yen, Sheng-Wei Pan, Pei-Hung Chuang, Jia-Yih Feng, Kun-Ta Chou, Kuang-Yao Yang, Yu-Chin Lee, Tzeng-Ji Chen
BACKGROUND: Statins are widely used to lower cholesterol levels and cardiovascular risk. Further, studies have shown that statins may decrease the risks of infectious diseases and infection-related mortality; however, the association between statin use and active TB disease remains unclear. METHODS: Using the Taiwan National Health Insurance Research Database, we conducted a nationwide population-based study. Patients taking statins between 2000 and 2013, without antecedent TB disease, were included...
September 2017: Chest
https://www.readbyqxmd.com/read/28464471/chemical-activation-of-adenylyl-cyclase-rv1625c-inhibits-growth-of-mycobacterium-tuberculosis-on-cholesterol-and-modulates-intramacrophage-signaling
#10
Richard M Johnson, Guangchun Bai, Christopher M DeMott, Nilesh K Banavali, Christine R Montague, Caroline Moon, Alexander Shekhtman, Brian VanderVen, Kathleen A McDonough
Mycobacterium tuberculosis (Mtb) uses a complex 3', 5'-cyclic AMP (cAMP) signaling network to sense and respond to changing environments encountered during infection, so perturbation of cAMP signaling might be leveraged to disrupt Mtb pathogenesis. However, understanding of cAMP signaling pathways is hindered by the presence of at least 15 distinct adenylyl cyclases (ACs). Recently, the small molecule V-58 was shown to inhibit Mtb replication within macrophages and stimulate cAMP production in Mtb. Here we determined that V-58 rapidly and directly activates Mtb AC Rv1625c to produce high levels of cAMP regardless of the bacterial environment or growth medium...
July 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28461265/preparation-and-characterization-of-isoniazid-loaded-crude-soybean-lecithin-liposomes
#11
Christian Isalomboto Nkanga, Rui Werner Krause, Xavier Siwe Noundou, Roderick Bryan Walker
Tuberculosis (TB) is a poverty related infectious disease that is rapidly giving rise to public health concerns. Lengthy drug administration and frequent adverse side-effects associated with TB treatment make anti-tubercular drugs (ATDs) good candidates for drug delivery studies. This work aimed to formulate and prepare liposomes as a cost-effective option for ATD delivery. Liposomes were prepared by film hydration using crude soybean lecithin (CL) and not pure phospholipids as in the normal practice. Cholesterol was also used (up to 25% mass ratio), and isoniazid (INH) was encapsulated as model drug using a freeze-thaw loading technique...
April 29, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28447386/unravelling-the-pleiotropic-role-of-the-mceg-atpase-in-mycobacterium-smegmatis
#12
Julia García-Fernández, Kadamba Papavinasasundaram, Beatriz Galán, Christopher M Sassetti, José L García
The Mce systems are complex ABC transporters that are encoded by different numbers of homologous operons in Actinobacteria. While the four Mce systems of Mycobacterium tuberculosis are all energized by a single ATPase, MceG, each system appears to import different fatty acids or sterols. To explore if this behaviour can be extended to saprophytic mycobacteria, whose more complex genomes encode more Mce systems, we have identified and characterized the MceG orthologue of Mycobacterium smegmatis. This bacterium relies on MceG to energize its six Mce systems that contribute to a variety of cellular functions including sterol uptake and cell envelope maintenance...
April 26, 2017: Environmental Microbiology
https://www.readbyqxmd.com/read/28419200/switching-to-efavirenz-versus-remaining-on-ritonavir-boosted-lopinavir-in-human-immunodeficiency-virus-infected-children-exposed-to-nevirapine-long-term-outcomes-of-a-randomized-trial
#13
Pamela M Murnane, Renate Strehlau, Stephanie Shiau, Faeezah Patel, Ndileke Mbete, Gillian Hunt, Elaine J Abrams, Ashraf Coovadia, Louise Kuhn
Background: We previously demonstrated the noninferiority of switching to efavirenz (EFV) versus remaining on ritonavir-boosted lopinavir (LPV/r) for virologic control in children infected with human immunodeficiency virus (HIV) and exposed to nevirapine (NVP) for prevention of mother-to-child transmission. Here we assess outcomes up to 4 years post-randomization. Methods: From 2010-2013, 298 NVP-exposed HIV-infected children ≥3 years of age were randomized to switch to EFV or remain on LPV/r in Johannesburg, South Africa (Clinicaltrials...
August 1, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/28380256/investigation-of-the-mycobacterial-enzyme-hsad-as-a-potential-novel-target-for-anti-tubercular-agents-using-a-fragment-based-drug-design-approach
#14
Ali Ryan, Elena Polycarpou, Nathan A Lack, Dimitrios Evangelopoulos, Christian Sieg, Alice Halman, Sanjib Bhakta, Olga Eleftheriadou, Timothy D McHugh, Sebastian Keany, Edward D Lowe, Romain Ballet, Areej Abuhammad, William R Jacobs, Alessio Ciulli, Edith Sim
BACKGROUND AND PURPOSE: With the emergence of extensively drug-resistant tuberculosis, there is a need for new anti-tubercular drugs that work through novel mechanisms of action. The meta cleavage product hydrolase, HsaD, has been demonstrated to be critical for the survival of Mycobacterium tuberculosis in macrophages and is encoded in an operon involved in cholesterol catabolism, which is identical in M. tuberculosis and M. bovis BCG. EXPERIMENTAL APPROACH: We generated a mutant strain of M...
July 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28377529/catabolism-of-the-last-two-steroid-rings-in-mycobacterium-tuberculosis-and-other-bacteria
#15
Adam M Crowe, Israël Casabon, Kirstin L Brown, Jie Liu, Jennifer Lian, Jason C Rogalski, Timothy E Hurst, Victor Snieckus, Leonard J Foster, Lindsay D Eltis
Most mycolic acid-containing actinobacteria and some proteobacteria use steroids as growth substrates, but the catabolism of the last two steroid rings has yet to be elucidated. In Mycobacterium tuberculosis, this pathway includes virulence determinants and has been proposed to be encoded by the KstR2-regulated genes, which include a predicted coenzyme A (CoA) transferase gene (ipdAB) and an acyl-CoA reductase gene (ipdC). In the presence of cholesterol, ΔipdC and ΔipdAB mutants of either M. tuberculosis or Rhodococcus jostii strain RHA1 accumulated previously undescribed metabolites: 3aα-H-4α(carboxyl-CoA)-5-hydroxy-7aβ-methylhexahydro-1-indanone (5-OH HIC-CoA) and (R)-2-(2-carboxyethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA (COCHEA-CoA), respectively...
April 4, 2017: MBio
https://www.readbyqxmd.com/read/28364349/effect-of-blood-biochemical-factors-on-nontraumatic-necrosis-of-the-femoral-head-logistic-regression-analysis
#16
Ying Zhang, Ruibo Sun, Leilei Zhang, Lizhi Feng, Youwen Liu
OBJECTIVE: This case-control study aimed to identify the risk factors of nontraumatic necrosis of the femoral head (NONFH). METHODS: In all, 242 patients with NONFH treated at the hip disease research center of our hospital between March 2012 and October 2015 were included. After excluding 19 patients with tumor or tuberculosis, 223 patients were enrolled. Controls comprised 223 healthy persons selected from our hospital database. Single-factor variance analysis and t test were performed to select the index of statistical significance...
March 31, 2017: Der Orthopäde
https://www.readbyqxmd.com/read/28335738/genome-wide-expression-profiling-establishes-novel-modulatory-roles-of-vitamin-c-in-thp-1-human-monocytic-cell-line
#17
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
#18
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...
March 6, 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
#19
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
#20
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
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