RESUMO
Salmonella enterica serovar Typhimurium causes gastroenteritis and systemic infections in humans. For this bacterium the expression of a type III secretion system (T3SS) and effector proteins encoded in the Salmonella pathogenicity island-1 (SPI-1), is keystone for the virulence of this bacterium. Expression of these is controlled by a regulatory cascade starting with the transcriptional regulators HilD, HilC and RtsA that induce the expression of HilA, which then activates expression of the regulator InvF, a transcriptional regulator of the AraC/XylS family. InvF needs to interact with the chaperone SicA to activate transcription of SPI-1 genes including sicA, sopB, sptP, sopE, sopE2, and STM1239. InvF very likely acts as a classical activator; however, whether InvF interacts with the RNA polymerase alpha subunit RpoA has not been determined. Results from this study confirm the interaction between InvF with SicA and reveal that both proteins interact with the RNAP alpha subunit. Thus, our study further supports that the InvF/SicA complex acts as a classical activator. Additionally, we showed for the first time an interaction between a chaperone of T3SS effectors (SicA) and the RNAP.
Assuntos
Proteínas de Ligação a DNA , Salmonella typhimurium , Humanos , Salmonella typhimurium/metabolismo , Proteínas de Ligação a DNA/genética , Transativadores/genética , Transativadores/metabolismo , Proteínas de Bactérias/metabolismo , Fatores de Transcrição/metabolismo , Chaperonas Moleculares/metabolismo , Regulação Bacteriana da Expressão GênicaRESUMO
We designed and synthesized five new 5-nitrothiazole-NSAID chimeras as analogues of nitazoxanide, using a DCC-activated amidation. Compounds 1-5 were tested in vitro against a panel of five protozoa: 2 amitochondriates (Giardia intestinalis, Trichomonas vaginalis) and 3 kinetoplastids (Leishmania mexicana, Leishmania amazonensis and Trypanosoma cruzi). All chimeras showed broad spectrum and potent antiprotozoal activities, with IC50 values ranging from the low micromolar to nanomolar order. Compounds 1-5 were even more active than metronidazole and nitazoxanide, two marketed first-line drugs against giardiasis. In particular, compound 4 (an indomethacin hybrid) was one of the most potent of the series, inhibiting G. intestinalis growth in vitro with an IC50 of 0.145µM. Compound 4 was 38-times more potent than metronidazole and 8-times more active than nitazoxanide. The in vivo giardicidal effect of 4 was evaluated in a CD-1 mouse model obtaining a median effective dose of 1.709µg/kg (3.53nmol/kg), a 321-fold and 1015-fold increase in effectiveness after intragastric administration over metronidazole and nitazoxanide, respectively. Compounds 1 and 3 (hybrids of ibuprofen and clofibric acid), showed potent giardicidal activities in the in vitro as well as in the in vivo assays after oral administration. Therefore, compounds 1-5 constitute promising drug candidates for further testing in experimental chemotherapy against giardiasis, trichomoniasis, leishmaniasis and even trypanosomiasis infections.
Assuntos
Antiprotozoários/química , Antiprotozoários/uso terapêutico , Giardia lamblia/efeitos dos fármacos , Giardíase/tratamento farmacológico , Tiazóis/química , Tiazóis/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Desenho de Fármacos , Feminino , Humanos , Leishmania/efeitos dos fármacos , Camundongos , Nitrocompostos , Infecções por Protozoários/tratamento farmacológico , Tiazóis/síntese química , Tiazóis/farmacologia , Trichomonas vaginalis/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacosRESUMO
CONTEXT: Corticosteroid withdrawal may reduce insulin resistance; however, it could also influence pancreatic autoantibody profile in simultaneous pancreas-kidney (SPK) transplant patients. OBJECTIVE: To evaluate the effect of corticosteroid withdrawal on glucose metabolism and anti-glutamic acid decarboxylase (GAD) antibody titers in SPK patients with type 1 diabetes after 12 months of follow-up. DESIGN: In this retrospective study, fasting glucose and glycated hemoglobin (A1c) were compared before and after 3, 6, and 12 months of corticosteroid withdrawal in 80 SPK patients. In addition, weight, anti-GAD, and C-peptide levels were compared before and after withdrawal. Finally, fasting and postglucose, insulin, and C-peptide levels were compared before and after withdrawal in 25 patients undergoing oral glucose tolerance test (OGTT). RESULTS: Fasting glucose levels did not change during corticosteroid discontinuation. After 12 months, A1c slightly increased from 4.6% (0.4%) to 4.8% (0.6%) (P < .01) and C-peptide decreased from 2.8 (1.1) ng/mL to 2.4 (1.3) ng/mL (P <. 01). In patients submitted to OGTT, glucose, insulin, and C-peptide levels did not change. There was no alteration in the proportion of anti-GAD positive tests (41% vs 45%). Anti-GAD titers remained stable or decreased in 70% of positive patients. CONCLUSION: Corticosteroid withdrawal has no significant effect on glucose metabolism and on anti-GAD profile among SPK patients.
Assuntos
Corticosteroides/administração & dosagem , Autoanticorpos , Glucose/metabolismo , Transplante de Rim , Transplante de Pâncreas , Glicemia , Diabetes Mellitus Tipo 1 , Seguimentos , Humanos , Insulina , Estudos RetrospectivosRESUMO
For the treatment of chronic ocular diseases such as glaucoma, continuous instillations of eye drops are needed. However, frequent administrations of hypotensive topical formulations can produce adverse ocular surface effects due to the active substance or other components of the formulation, such as preservatives or other excipients. Thus the development of unpreserved formulations that are well tolerated after frequent instillations is an important challenge to improve ophthalmic chronic topical therapies. Furthermore, several components can improve the properties of the formulation in terms of efficacy. In order to achieve the mentioned objectives, we have developed formulations of liposomes (150-200 nm) containing components similar to those in the tear film and loaded with the hypotensive melatonin analog 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT, 100 µM). These formulations were combined with mucoadhesive (sodium hyaluronate or carboxymethylcellulose) or amphiphilic block thermosensitive (poloxamer) polymers to prolong the hypotensive efficacy of the drug. In rabbit eyes, the decrease of intraocular pressure with 5-MCA-NAT-loaded liposomes that were dispersed with 0.2% sodium hyaluronate, 39.1±2.2%, was remarkably higher compared to other liposomes formulated without or with other bioadhesive polymers, and the effect lasted more than 8 hours. According to the results obtained in the present work, these technological strategies could provide an improved modality for delivering therapeutic agents in patients with glaucoma.
Assuntos
Adesivos/química , Química Farmacêutica/métodos , Lipossomos/química , Melatonina/análogos & derivados , Polímeros/química , Triptaminas/química , Triptaminas/farmacologia , Animais , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Pressão Intraocular/efeitos dos fármacos , Masculino , Concentração Osmolar , Tamanho da Partícula , Coelhos , Lágrimas/química , Lágrimas/efeitos dos fármacos , Triptaminas/efeitos adversos , ViscosidadeRESUMO
Nuestro país posee una alta prevalencia e incidencia de casos de tuberculosis (para el año 2012 se registró una morbilidad de 105,2 casos por 100 000 habitantes).En el tratamiento de esta patología pueden desencadenarse numerosas reacciones adversas de índole heterogénea, siendo preponderantes las neuropsiquiátricas, por la polifarmacia antibiótica requerida y otros posibles factores de riesgo del usuario. A partir de un caso de psicosis desencadenada por cicloserina en un paciente con tuberculosis multidrogorresistente, revisamos la literatura pertinente y recomendamos la ponderación individualizada del retiro de la medicación desencadenante del efecto adverso, respecto a la necesidad de mantener la cobertura antibiótica imprescindible y adecuada.
Our country has a high prevalence of tuberculosis (morbidity in year 2012 was 105,2 cases per 100 000 people). In the treatment of this disease, a high number of diverse drug-related side-effects, with prevalent neuropsychiatric type, can be developed, because of the antibiotic polypharmacy required and other possible risk factors. From a case of cycloserine-induced psychosis, in a patient with multidrug-resistant tuberculosis, we review the relevant literature and recommend individualized consideration on the withdrawal of the side-effect trigger medication versus the need to maintain the essential and appropriate antibiotic coverage.