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2.
Eur J Med Chem ; 258: 115617, 2023 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-37423128

RESUMEN

Tuberculosis is the number one killer of infectious diseases caused by a single microbe, namely Mycobacterium tuberculosis (Mtb). The success rate of curing this infection is decreasing due to emerging antimicrobial resistance. Therefore, novel treatments are urgently needed. As an attempt to develop new antituberculars effective against both drugs-sensitive and drug-resistant Mtb, we report the synthesis of a novel series inspired by combining fragments from the first-line agents isoniazid and pyrazinamide (series I) and isoniazid with the second-line agent 4-aminosalicylic acid (series II). We identified compound 10c from series II with selective, potent in vitro antimycobacterial activity against both drug-sensitive and drug-resistant Mtb H37Rv strains with no in vitro or in vivo cytotoxicity. In the murine model of tuberculosis, compound 10c caused a statistically significant decrease in colony-forming units (CFU) in spleen. Despite having a 4-aminosalicylic acid fragment in its structure, biochemical studies showed that compound 10c does not directly affect the folate pathway but rather methionine metabolism. In silico simulations indicated the possibility of binding to mycobacterial methionine-tRNA synthetase. Metabolic study in human liver microsomes revealed that compound 10c does not have any known toxic metabolites and has a half-life of 630 min, overcoming the main drawbacks of isoniazid (toxic metabolites) and 4-aminosalicylic acid (short half-life).


Asunto(s)
Ácido Aminosalicílico , Mycobacterium tuberculosis , Tuberculosis , Humanos , Animales , Ratones , Isoniazida/farmacología , Ácido Aminosalicílico/farmacología , Antituberculosos/química , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Metionina , Pruebas de Sensibilidad Microbiana
3.
ACS Infect Dis ; 9(1): 79-96, 2023 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-36577009

RESUMEN

Apart from the SARS-CoV-2 virus, tuberculosis remains the leading cause of death from a single infectious agent according to the World Health Organization. As part of our long-term research, we prepared a series of hybrid compounds combining pyrazinamide, a first-line antitubercular agent, and 4-aminosalicylic acid (PAS), a second-line agent. Compound 11 was found to be the most potent, with a broad spectrum of antimycobacterial activity and selectivity toward mycobacterial strains over other pathogens. It also retained its in vitro activity against multiple-drug-resistant mycobacterial strains. Several structural modifications were attempted to improve the in vitro antimycobacterial activity. The δ-lactone form of compound 11 (11') had more potent in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Compound 11 was advanced for in vivo studies, where it was proved to be nontoxic in Galleria mellonella and zebrafish models, and it reduced the number of colony-forming units in spleens in the murine model of tuberculosis. Biochemical studies showed that compound 11 targets mycobacterial dihydrofolate reductases (DHFR). An in silico docking study combined with molecular dynamics identified a viable binding mode of compound 11 in mycobacterial DHFR. The lactone 11' opens in human plasma to its parent compound 11 (t1/2 = 21.4 min). Compound 11 was metabolized by human liver fraction by slow hydrolysis of the amidic bond (t1/2 = 187 min) to yield PAS and its starting 6-chloropyrazinoic acid. The long t1/2 of compound 11 overcomes the main drawback of PAS (short t1/2 necessitating frequent administration of high doses of PAS).


Asunto(s)
Ácido Aminosalicílico , COVID-19 , Mycobacterium tuberculosis , Tuberculosis , Humanos , Animales , Ratones , Pirazinamida/farmacología , Ácido Aminosalicílico/farmacología , Pez Cebra , SARS-CoV-2 , Antituberculosos/química , Tuberculosis/tratamiento farmacológico , Lactonas
4.
Small ; 18(28): e2201853, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35691939

RESUMEN

In this work, levofloxacin (LVX), a third-generation fluoroquinolone antibiotic, is encapsulated within amphiphilic polymeric nanoparticles of a chitosan-g-poly(methyl methacrylate) produced by self-assembly and physically stabilized by ionotropic crosslinking with sodium tripolyphosphate. Non-crosslinked nanoparticles display a size of 29 nm and a zeta-potential of +36 mV, while the crosslinked counterparts display 45 nm and +24 mV, respectively. The cell compatibility, uptake, and intracellular trafficking are characterized in the murine alveolar macrophage cell line MH-S and the human bronchial epithelial cell line BEAS-2B in vitro. Internalization events are detected after 10 min and the uptake is inhibited by several endocytosis inhibitors, indicating the involvement of complex endocytic pathways. In addition, the nanoparticles are detected in the lysosomal compartment. Then, the antibacterial efficacy of LVX-loaded nanoformulations (50% w/w drug content) is assessed in MH-S and BEAS-2B cells infected with Staphylococcus aureus and the bacterial burden is decreased by 49% and 46%, respectively. In contrast, free LVX leads to a decrease of 8% and 5%, respectively, in the same infected cell lines. Finally, intravenous injection to a zebrafish larval model shows that the nanoparticles accumulate in macrophages and endothelium and demonstrate the promise of these amphiphilic nanoparticles to target intracellular infections.


Asunto(s)
Quitosano , Nanopartículas , Animales , Antibacterianos/farmacología , Humanos , Macrófagos/metabolismo , Ratones , Pez Cebra
5.
Microorganisms ; 10(1)2022 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-35056629

RESUMEN

Legionnaires' disease is a severe form of lung infection caused by bacteria belonging to the genus Legionella. The disease severity depends on both host immunity and L. pneumophila virulence. The objective of this study was to describe the pathological spectrum of acute pneumonia caused by a virulent clinical isolate of L. pneumophila serogroup 1, sequence type 62. In A/JOlaHsd mice, we compared two infectious doses, namely, 104 and 106 CFU, and their impact on the mouse status, bacterial clearance, lung pathology, and blood count parameters was studied. Acute pneumonia resembling Legionnaires' disease has been described in detail.

7.
Nature ; 593(7859): 424-428, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33767445

RESUMEN

Neutralizing antibodies that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein are among the most promising approaches against COVID-191,2. A bispecific IgG1-like molecule (CoV-X2) has been developed on the basis of C121 and C135, two antibodies derived from donors who had recovered from COVID-193. Here we show that CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable spike binding to the cellular receptor of the virus, angiotensin-converting enzyme 2 (ACE2). Furthermore, CoV-X2 neutralizes wild-type SARS-CoV-2 and its variants of concern, as well as escape mutants generated by the parental monoclonal antibodies. We also found that in a mouse model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, the simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, and combines the advantages of antibody cocktails with those of single-molecule approaches.


Asunto(s)
Anticuerpos Biespecíficos/inmunología , Anticuerpos Neutralizantes/inmunología , COVID-19/inmunología , COVID-19/virología , Inmunoglobulina G/inmunología , SARS-CoV-2/inmunología , Enzima Convertidora de Angiotensina 2/antagonistas & inhibidores , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Peso Corporal , COVID-19/prevención & control , Dependovirus/genética , Modelos Animales de Enfermedad , Epítopos de Linfocito B/química , Epítopos de Linfocito B/inmunología , Femenino , Humanos , Evasión Inmune/genética , Ratones , Ratones Endogámicos C57BL , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Tratamiento Farmacológico de COVID-19
8.
bioRxiv ; 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33501434

RESUMEN

Neutralizing antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) are among the most promising approaches against coronavirus disease 2019 (COVID-19) 1,2 . We developed a bispecific, IgG1-like molecule (CoV-X2) based on two antibodies derived from COVID-19 convalescent donors, C121 and C135 3 . CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor. Furthermore, CoV-X2 neutralizes SARS-CoV-2 and its variants of concern, as well as the escape mutants generated by the parental monoclonals. In a novel animal model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, combining into a single molecule the advantages of antibody cocktails.

9.
Microorganisms ; 9(1)2020 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-33374468

RESUMEN

Early detection of biohazardous bacteria that can be misused as biological weapons is one of the most important measures to prevent the spread and outbreak of biological warfare. For this reason, many instrument platforms need to be introduced into operation in the field of biological warfare detection. Therefore the purpose of this study is to establish a new detection panel for biothreat bacteria (Bacillus anthracis, Yersinia pestis, Francisella tularensis, and Brucella spp.) and confirm it by collaborative validation by using a multiplex oligonucleotide ligation followed by polymerase chain reaction and hybridization to microspheres by MagPix detection platform (MOL-PCR). Appropriate specific sequences in bacterial DNA were selected and tested to assemble the detection panel, and MOLigo probes (short specific oligonucleotides) were designed to show no cross-reactivity when tested between bacteria and to decrease the background signal measurement on the MagPix platform. During testing, sensitivity was assessed for all target bacteria using serially diluted DNA and was determined to be at least 0.5 ng/µL. For use as a diagnostic kit and easier handling, the storage stability of ligation premixes (MOLigo probe mixes) was tested. This highly multiplex method can be used for rapid screening to prevent outbreaks arising from the use of bacterial strains for bioterrorism, because time of analysis take under 4 h.

10.
J Control Release ; 321: 312-323, 2020 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-32067995

RESUMEN

Tuberculosis represents a major global health problem for which improved approaches are needed to shorten the course of treatment and to combat the emergence of resistant strains. The development of effective and safe nanobead-based interventions can be particularly relevant for increasing the concentrations of antitubercular agents within the infected site and reducing the concentrations in the general circulation, thereby avoiding off-target toxic effects. In this work, rifampicin, a first-line antitubercular agent, was encapsulated into biocompatible and biodegradable polyester-based nanoparticles. In a well-established BALB/c mouse model of pulmonary tuberculosis, the nanoparticles provided improved pharmacokinetics and pharmacodynamics. The nanoparticles were well tolerated and much more efficient than an equivalent amount of free rifampicin.


Asunto(s)
Antibióticos Antituberculosos , Mycobacterium tuberculosis , Rifampin , Tuberculosis , Animales , Antibióticos Antituberculosos/farmacocinética , Antituberculosos , Portadores de Fármacos , Ratones , Ratones Endogámicos BALB C , Nanoestructuras , Rifampin/farmacocinética , Tuberculosis/tratamiento farmacológico
11.
J Med Chem ; 62(17): 8115-8139, 2019 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-31393122

RESUMEN

We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against Mycobacterium tuberculosis strains, including clinically isolated multidrug-resistant strains. Thorough structure-activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against M. tuberculosis H37Rv and against seven clinically isolated multidrug-resistant strains of M. tuberculosis were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 µM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-ß-d-ribofuranose 2'-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.


Asunto(s)
Oxidorreductasas de Alcohol/antagonistas & inhibidores , Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Desarrollo de Medicamentos , Mycobacterium tuberculosis/efectos de los fármacos , Oxidorreductasas de Alcohol/metabolismo , Antituberculosos/síntesis química , Antituberculosos/química , Proteínas Bacterianas/metabolismo , Dinitrobencenos/síntesis química , Dinitrobencenos/química , Dinitrobencenos/farmacología , Relación Dosis-Respuesta a Droga , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/química , Hidrocarburos Fluorados/farmacología , Modelos Moleculares , Estructura Molecular , Mycobacterium tuberculosis/enzimología , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química , Triazoles/farmacología
12.
Biomacromolecules ; 20(4): 1798-1815, 2019 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-30785284

RESUMEN

Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is an intracellular pathogen of alveolar macrophages. These cells avidly take up nanoparticles, even without the use of specific targeting ligands, making the use of nanotherapeutics ideal for the treatment of such infections. Methoxy poly(ethylene oxide)- block-poly(ε-caprolactone) nanoparticles of several different polymer blocks' molecular weights and sizes (20-110 nm) were developed and critically compared as carriers for rifampicin, a cornerstone in tuberculosis therapy. The polymeric nanoparticles' uptake, consequent organelle targeting and intracellular degradation were shown to be highly dependent on the nanoparticles' physicochemical properties (the cell uptake half-lives 2.4-21 min, the degradation half-lives 51.6 min-ca. 20 h after the internalization). We show that the nanoparticles are efficiently taken up by macrophages and are able to effectively neutralize the persisting bacilli. Finally, we demonstrate, using a zebrafish model of tuberculosis, that the nanoparticles are well tolerated, have a curative effect, and are significantly more efficient compared to a free form of rifampicin. Hence, these findings demonstrate that this system shows great promise, both in vitro and in vivo, for the treatment of tuberculosis.


Asunto(s)
Portadores de Fármacos , Macrófagos , Mycobacterium tuberculosis/crecimiento & desarrollo , Nanopartículas , Rifampin , Tuberculosis/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Humanos , Macrófagos/metabolismo , Macrófagos/microbiología , Ratones , Nanopartículas/química , Nanopartículas/uso terapéutico , Células RAW 264.7 , Rifampin/química , Rifampin/farmacocinética , Rifampin/farmacología , Tuberculosis/metabolismo , Tuberculosis/patología , Pez Cebra
13.
Bioorg Med Chem ; 25(20): 5468-5476, 2017 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-28835350

RESUMEN

In this work, four series of tertiary amine-containing derivatives of 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents were prepared, and their in vitro antimycobacterial effects were evaluated. We found that the studied compounds showed lipophilicity-dependent antimycobacterial activity. The N-benzylpiperazine derivatives, which had the highest lipophilicity among all of the series, showed the highest in vitro antimycobacterial activities against Mycobacterium tuberculosis CNCTC My 331/88 (H37Rv), comparable to those of the first-line drugs isoniazid and rifampicin. The presence of two tertiary amines in these N-benzylpiperazine derivatives enabled us to prepare water-soluble dihydrochloride salts, overcoming the serious drawback of previously described 3,5-dinitrophenyl tetrazole and oxadiazole lead compounds. The water-soluble 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents described in this work are good candidates for further in vitro and in vivo pharmacokinetic and pharmacodynamic studies.


Asunto(s)
Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Oxadiazoles/farmacología , Tetrazoles/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Células CACO-2 , Línea Celular , Proliferación Celular , Supervivencia Celular , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Solubilidad , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/química , Agua/química
14.
Eur J Med Chem ; 126: 369-383, 2017 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-27907875

RESUMEN

Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1H-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relationships are described. These compounds possessed excellent activity against Mycobacterium tuberculosis, including the clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with no cross resistance with first or second-line anti-TB drugs. The minimum inhibitory concentration (MIC) values of the most promising compounds reached 0.03 µM. Furthermore, these compounds had a highly selective antimycobacterial effect because they were completely inactive against 4 gram positive and 4 gram negative bacteria and eight fungal strains and had low in vitro toxicity for four mammalian cell lines, including hepatic cell lines HepG2 and HuH7. Although the structure-activity relationship study showed that the presence of two nitro groups is highly beneficial for antimycobacterial activity, the analogues with a trifluoromethyl group instead of one of the nitro groups maintained a high antimycobacterial activity, which indicates the possibility for further structural optimization of this class of antitubercular agents.


Asunto(s)
Diseño de Fármacos , Oxadiazoles/química , Compuestos de Sulfhidrilo/síntesis química , Compuestos de Sulfhidrilo/farmacología , Tetrazoles/química , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Antifúngicos/toxicidad , Antituberculosos/síntesis química , Antituberculosos/química , Antituberculosos/farmacología , Antituberculosos/toxicidad , Resistencia a Medicamentos/efectos de los fármacos , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/toxicidad
15.
Artículo en Inglés | MEDLINE | ID: mdl-23549511

RESUMEN

BACKGROUND: Francisella tularensis is a biological agent exploitable for bioterrorism and biological warfare purposes due to serious pathogenic progression and easy dissemination. Despite intensive research in the past, some adverse consequences remain unclear. One consequence of this pathogen is oxidative stress. AIMS: The aim of this study was to undertake ex vivo assays for monitoring the disease in mice and increase our knowledge of the oxidative stress induced by tularemia. METHODS: The mouse BALB/c model was chosen and the animals were infected by a dose 10(4) CFU of F. tularensis. After five days, the animals were euthanized. Blood immediately processed in plasma, spleen and liver were sampled from the cadavers. Oxidative stress markers, cytokines and histopathological were undertaken. RESULTS: There was a significant link between oxidative stress and tularemia. Particularly elevated levels of malondialdehyde and decreased levels of low molecular weight antioxidants were found in the liver and spleen of tularemia-infected animals. The histopathological findings correlated well with the oxidative stress markers. The liver and spleen were proven to be significantly at risk from the disease and an association between stress and neutrophils in the affected organs was found. The histopathology excluded risk to other organs such as the kidney and or heart. CONCLUSIONS: Oxidative stress plays a significant role in tularemia infection in mice and this was confirmed by the histology.


Asunto(s)
Hígado/metabolismo , Estrés Oxidativo/fisiología , Bazo/metabolismo , Tularemia/fisiopatología , Animales , Antioxidantes/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Francisella tularensis , Hígado/patología , Ratones , Ratones Endogámicos BALB C , Bazo/patología , Tularemia/metabolismo , Tularemia/patología
16.
Neuro Endocrinol Lett ; 34 Suppl 2: 134-7, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24362106

RESUMEN

OBJECTIVES: Tacrine is an inhibitor of acetylcholinestrase (AChE) formerly used to treat cognitive impairment of Alzheimer disease. In previous works, we have shown that inhibitors of AChE can modulate innate immunity responses. In the present study we focused on modulation of adaptive immunity represented by production of antibodies. It is hypothesized that the cholinergic anti-inflammatory pathway is a common mechanism how inhibitors of AChE can influence immunity. Here, tularemia is used as a model disease for experimental purposes. DESIGN: A total of 64 BALB/c mice were divided into eight groups. The animals received a dose of tacrine 0.1-0.5 mg/kg with combination of saline or inoculum of Francisella tularensis. The doses of tacrine were derived from clinical trials. The animals were sacrificed after three days and total antibodies in plasma and bacterial burden in the liver were measured. RESULTS: Tacrine did not alter the antibodies level in non-infected animals. Antibodies levels of infected animals administered tacrine were reduced in a dose response manner. Tacrine also caused an increase in total bacteria numbers in the liver. CONCLUSIONS: Tacrine significantly suppressed adaptive immunity represented by the ability of the organism to produce antibodies. We infer that tacrine can modulate the cholinergic anti-inflammatory pathway by a mechanism based on inhibition of blood AChE followed by higher availability of acetylcholine. The anti-inflammatory pathway is then stimulated and the body is not able to simply resolve antigen. Application of an AChE inhibitor during infectious diseases can have detrimental consequences for the immune system.


Asunto(s)
Anticuerpos Antibacterianos/sangre , Formación de Anticuerpos/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Francisella tularensis/inmunología , Tacrina/farmacología , Tularemia/inmunología , Animales , Relación Dosis-Respuesta a Droga , Femenino , Francisella tularensis/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Tularemia/metabolismo
17.
Artículo en Inglés | MEDLINE | ID: mdl-23235722

RESUMEN

AIMS: To examine biological materials (blood, urine, cerebrospinal fluid) of patients with suspected leptospirosis using real-time PCR for detecting the gene that codes the superficial LipL32 lipoprotein, and to evaluate the contribution of the real-time PCR method for the laboratory diagnosis of the acute form of leptospirosis. MATERIAL AND METHODS: During the monitored period of April 2010 - December 2011, a total of 340 biological materials samples were examined (177x blood plasma, 88x urine, 68x, cerebrospinal fluid, 6x bronchoalveolar lavage and 1x sputum) from 216 patients with suspected leptospirosis using real-time PCR LipL32 gene detection. RESULTS: From the mentioned 216 patients suspected of leptospirosis, 8 patients were evaluated as being PCR LipL32 positive, from which 14 positive biological materials originated (9 x urine, 4x blood and 1x liquor). CONCLUSION: As demonstrated in the study, the real-time PCR method for detecting the gene for the superficial lipoprotein LipL32 is an appropriate, quick and reliable method for the diagnosis of the acute form of leptospirosis.


Asunto(s)
Proteínas de la Membrana Bacteriana Externa/genética , Leptospira/genética , Leptospira/patogenicidad , Leptospirosis/diagnóstico , Leptospirosis/microbiología , Lipoproteínas/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad
18.
Iran Biomed J ; 16(3): 156-61, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23023217

RESUMEN

BACKGROUND: Galantamine is a drug used for the treatment of Alzheimer's disease and some other cognitive disorders. It is an inhibitor of acetylcholinesterase; however, interaction with nicotinic acetylcholine receptors has also been reported. Owing to the significant role of cholinergic anti-inflammatory pathways in neuro-immunomodulation, we decided to examine the effect of galantamine on tularemia-infected BALB/c mice. METHODS: Animals were infected with Francisella tularensis LVS and treated with galantamine (0.1 mg/kg of body weight). Total mortality over the course of tularemia infection was assessed and interleukin 6 (IL-6) and interferon gamma (IFN-gamma) in plasma samples were measured by enzyme-linked immunosorbent assays. Apart from the cytokine assays, biochemical markers such as inorganic phosphate, uric acid, lactate dehydrogenase, gamma glutamyltransferase, creatinine phosphokinase and amylase were assayed. RESULTS: The modulation of immunity by galantamine depended on two opposing processes: up-regulation of IFN-gamma and down-regulation of IL-6. Tularemia infection resulted in significant nephropathy, as hyperphosphataemia and hyperuricaemia occurred in infected animals. In addition, galantamine resulted in the mitigation of nephropathy, and markers of kidney dysfunction were modulated. Alterations in mortality were also found in this study. CONCLUSIONS: Galantamine can significantly influence the immune response via the cholinergic anti-inflammatory pathway. Despite the decrease in IL-6 levels, galantamine treatment enhanced protection against the intracellular pathogen F. tularensis, resulting in the remission of some pathology and reduced mortality.


Asunto(s)
Galantamina/uso terapéutico , Tularemia/tratamiento farmacológico , Tularemia/microbiología , Animales , Femenino , Francisella tularensis/efectos de los fármacos , Galantamina/farmacología , Interferón gamma/sangre , Interleucina-6/sangre , Ratones , Ratones Endogámicos BALB C , Análisis de Supervivencia , Tularemia/sangre
19.
J Microbiol ; 50(3): 401-8, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22752903

RESUMEN

Francisella tularensis is the causative agent of tularemia. It is an intracellular pathogen with the ability to survive within phagosomes and induce pyroptotic cell death. In this study, we attempted to prove whether oxidative imbalance plays a significant role in tularemia pathogenesis. In our experimental model, we subcutaneously infected female BALB/c mice (dose 10(5) CFU of F. tularensis LVS). Liver, spleen, and blood were collected from mice at regular intervals from days 1-15 after infection. The bacterial burden was assessed by a cultivation test. The burden was unchanging from the 2(nd) to 6(th) day after infection. The bacterial burden corresponded to the plasmatic level of IFN-γ, IL-6, and liver malondialdehyde. After the phase of acute bacteraemia and the innate immunity reaction, the levels of reduced glutathione and total low molecular weight antioxidants decreased significantly and the activity of caspase-3 increased in the liver. The level of reduced glutathione decreased to 25% of the original level, and the total level of low molecular weight antioxidants was less than 50% of the initial amount. The demonstrated effects of tularemia-induced pathology had a more extensive impact on the liver than on the spleen.


Asunto(s)
Antioxidantes/análisis , Francisella tularensis/patogenicidad , Estrés Oxidativo , Tularemia/patología , Animales , Carga Bacteriana , Sangre/microbiología , Modelos Animales de Enfermedad , Femenino , Interferón gamma/sangre , Interleucina-6/sangre , Hígado/microbiología , Malondialdehído/análisis , Ratones , Ratones Endogámicos BALB C , Bazo/microbiología , Tularemia/microbiología
20.
Interdiscip Toxicol ; 5(1): 21-4, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22783145

RESUMEN

The present experiment was aimed at assessing the application of neostigmine, an acetylcholinesterase (AChE) pseudo-irreversible inhibitor with poor penetration through the hematoencephalitic barrier, and the neurotransmitter acetylcholine (ACh). The experiment was done to evaluate their ability to modulate an infectious disease: tularemia. Mice infected with Franciselle tularensis and exposed to either ACh or neostigmine had a higher mortality and spleen bacterial burden when compared to infected mice exposed to saline solution only. The activated cholinergic anti-inflammatory pathway suppressed pathways necessary for tularemia resolution. Administration of AChE inhibitors to the individuals suffering from tularemia is contra-indicatory. Drugs based on AChE inhibition should be restricted when tularemia or disease with a similar pathogenesis is suspected.

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