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1.
Pulm Pharmacol Ther ; 85: 102300, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38723942

RESUMEN

Over the past few decades, there has been extensive research on the use of vitamin D as an adjunctive therapy in the treatment and prevention of tuberculosis. In vitro studies have provided valuable insights into the mechanisms by which vitamin D activates the immune response to combat Mycobacterium tuberculosis. These encouraging findings have spurred clinical investigations globally to assess the effectiveness of vitamin D as a preventive measure and as an adjunctive treatment for tuberculosis. However, the results from these clinical studies have been contradictory, with some demonstrating clear efficacy while others report only modest or no activity. In this review, we aim to analyze the clinical studies on vitamin D and examine the possible discrepancies observed in their outcomes.


Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Vitamina D , Humanos , Vitamina D/uso terapéutico , Vitamina D/administración & dosificación , Tuberculosis/tratamiento farmacológico , Mycobacterium tuberculosis/efectos de los fármacos , Ensayos Clínicos como Asunto , Animales , Antituberculosos/uso terapéutico , Antituberculosos/administración & dosificación , Vitaminas/uso terapéutico , Vitaminas/administración & dosificación
2.
Can J Microbiol ; 70(7): 252-261, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38855942

RESUMEN

Non-tuberculosis infections in immunocompromised patients represent a cause for concern, given the increased risks of infection, and limited treatments available. Herein, we report that molecules for binding to the catalytic site of histone deacetylase (HDAC) inhibit its activity, thus increasing the innate immune response against environmental mycobacteria. The action of HDAC inhibitors (iHDACs) was explored in a model of type II pneumocytes and macrophages infection by Mycobacterium aurum. The results show that the use of 1,3-diphenylurea increases the expression of the TLR-4 in M. aurum infected MDMs, as well as the production of defb4, IL-1ß, IL-12, and IL-6. Moreover, we observed that aminoacetanilide upregulates the expression of TLR-4 together with TLR-9, defb4, CAMP, RNase 6, RNase 7, IL-1ß, IL-12, and IL-6 in T2P. Results conclude that the tested iHDACs selectively modulate the expression of cytokines and antimicrobial peptides that are associated with reduction of non-tuberculous mycobacteria infection.


Asunto(s)
Citocinas , Reposicionamiento de Medicamentos , Inhibidores de Histona Desacetilasas , Inmunidad Innata , Infecciones por Mycobacterium no Tuberculosas , Inmunidad Innata/efectos de los fármacos , Humanos , Infecciones por Mycobacterium no Tuberculosas/inmunología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Inhibidores de Histona Desacetilasas/farmacología , Citocinas/metabolismo , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Micobacterias no Tuberculosas/efectos de los fármacos , Micobacterias no Tuberculosas/inmunología , Mycobacterium/inmunología , Mycobacterium/efectos de los fármacos
3.
Mem Inst Oswaldo Cruz ; 118: e230143, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38126492

RESUMEN

BACKGROUND: Tuberculosis (TB) is a major public health problem, which has been aggravated by the alarming growth of drug-resistant tuberculosis. Therefore, the development of a safer and more effective treatment is needed. OBJECTIVES: The aim of this work was repositioning and evaluate histone deacetylases (HDAC) inhibitors- based drugs with potential antimycobacterial activity. METHODS: Using an in silico pharmacological repositioning strategy, three molecules that bind to the catalytic site of histone deacetylase were selected. Pneumocytes type II and macrophages were infected with Mycobacterium tuberculosis and treated with pre-selected HDAC inhibitors (HDACi). Subsequently, the ability of each of these molecules to directly promote the elimination of M. tuberculosis was evaluated by colony-forming unit (CFU)/mL. We assessed the expression of antimicrobial peptides and respiratory burst using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). FINDINGS: Aminoacetanilide (ACE), N-Boc-1,2-phenylenediamine (N-BOC), 1,3-Diphenylurea (DFU), reduce bacillary loads in macrophages and increase the production of ß-defensin-2, LL-37, superoxide dismutase (SOD) 3 and inducible nitric oxide synthase (iNOS). While only the use of ACE in type II pneumocytes decreases the bacterial load through increasing LL-37 expression. Furthermore, the use of ACE and rifampicin inhibited the survival of intracellular multi-drug resistance M. tuberculosis. MAIN CONCLUSIONS: Our data support the usefulness of in silico approaches for drug repositioning to provide a potential adjunctive therapy for TB.


Asunto(s)
Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis , Humanos , Rifampin/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Histona Desacetilasas
4.
Tuberculosis (Edinb) ; 148: 102548, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39068772

RESUMEN

Research suggests that both tuberculosis (TB) and type 2 diabetes mellitus (T2DM) have an immuno-endocrine imbalance characterized by dysregulated proinflammatory molecules and hormone levels (high cortisol/DHEA ratio), impeding an effective immune response against Mycobacterium tuberculosis (Mtb) driven by cytokines, antimicrobial peptides (AMPs), and androgens like DHEA. Insulin, sulfonylurea derivatives, and metformin are commonly used glucose-lowering drugs in patients suffering from TB and T2DM. For this comorbidity, metformin is an attractive target to restore the immunoendocrine mechanisms dysregulated against Mtb. This study aimed to assess whether metformin influences cortisol and DHEA synthesis in adrenal cells and if these hormones influence the expression of proinflammatory cytokines and AMPs in Mtb-infected macrophages. Our results suggest that metformin may enhance DHEA synthesis while maintaining cortisol homeostasis. In addition, supernatants from metformin-treated adrenal cells decreased mycobacterial loads in macrophages, which related to rising proinflammatory cytokines and AMP expression (HBD-2 and 3). Intriguingly, we find that HBD-3 and LL-37 can modulate steroid synthesis in adrenal cells with diminished levels of cortisol and DHEA, highlighting the importance of crosstalk communication between adrenal hormones and these effectors of innate immunity. We suggest that metformin's effects can promote innate immunity against Mtb straight or through modulation of corticosteroid hormones.


Asunto(s)
Citocinas , Deshidroepiandrosterona , Hidrocortisona , Macrófagos , Metformina , Mycobacterium tuberculosis , Metformina/farmacología , Humanos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Macrófagos/inmunología , Mycobacterium tuberculosis/efectos de los fármacos , Hidrocortisona/metabolismo , Deshidroepiandrosterona/farmacología , Citocinas/metabolismo , Inmunidad Innata/efectos de los fármacos , Células THP-1 , Interacciones Huésped-Patógeno , Células Cultivadas , Hipoglucemiantes/farmacología , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/microbiología , Mediadores de Inflamación/metabolismo
5.
Peptides ; 140: 170527, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33744370

RESUMEN

Infectious diseases are an important growing public health problem, which perspective has worsened due to the increasing number of drug-resistant strains in the last few years. Although diverse solutions have been proposed, one viable solution could be the use of immune system modulators. The induction of the immune response can be increased by histone deacetylase inhibitors (iHDAC), which in turn modulate the chromatin and increase the activation of different cellular pathways and nuclear factors such as STAT3, HIF-1α NF-kB, C/EBPα and, AP-1. These pathways are capable to promote several immune response-related molecules including those with antimicrobial properties such as antimicrobial peptides (AMPs) that lead to the elimination of pathogens including multi drug-resistant strains.


Asunto(s)
Antiinfecciosos/farmacología , Catelicidinas/metabolismo , Enfermedades Transmisibles/tratamiento farmacológico , Defensinas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Animales , Enfermedades Transmisibles/microbiología , Enfermedades Transmisibles/patología , Resistencia a Múltiples Medicamentos , Humanos
6.
Peptides ; 142: 170580, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34033876

RESUMEN

Tuberculosis (TB) is the leading cause of death by a single infectious agent, Mycobacterium tuberculosis (Mtb). Alveolar macrophages and respiratory epithelial cells are the first cells exposed to Mtb during the primary infection, once these cells are activated, secrete cytokines and antimicrobial peptides that are associated with the Mtb contention and elimination. Vitamins are micronutrients that function as boosters on the innate immune system, however, is unclear whether they have any protective activity during Mtb infection. Thus, we investigated the role of vitamin A (retinoic acid), vitamin C (ascorbic acid), vitamin D (calcitriol), and vitamin E (alfa-tocopherol) as inductors of molecules related to mycobacterial infection in macrophages and epithelial cells. Our results showed that retinoic acid promotes the expression of pro- and anti-inflammatory molecules such as Thymic stromal lymphopoietin (TSLP), ß-defensin-2, IL-1ß, CCL20, ß-defensin-3, Cathelicidin LL-37, TGF-ß, and RNase 7, whereas calcitriol, ascorbic acid, and α-tocopherol lead to an anti-inflammatory response. Treatment of Mtb-infected epithelial cells and macrophage-like cells with the vitamins showed a differential response, where calcitriol reduced Mtb in macrophages, while retinoic acid reduced infection in epithelial cells. Thereby, we propose that a combination of calcitriol and retinoic acid supplementation can drive the immune response, and promotes the Mtb elimination by increasing the expression of antimicrobial peptides and cytokines, while simultaneously modulating inflammation.


Asunto(s)
Péptidos Antimicrobianos/farmacología , Bronquios/efectos de los fármacos , Citocinas/metabolismo , Células Epiteliales/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Tretinoina/farmacología , Tuberculosis/tratamiento farmacológico , Antineoplásicos/farmacología , Autofagia , Bronquios/metabolismo , Bronquios/microbiología , Bronquios/patología , Células Cultivadas , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Células Epiteliales/patología , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/microbiología , Macrófagos/patología , Tuberculosis/metabolismo , Tuberculosis/microbiología , Tuberculosis/patología
7.
Arch Med Res ; 51(4): 327-335, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32229156

RESUMEN

BACKGROUND: Diabetic foot ulcers (DFUs) are one of the main complications in patients with type 2 diabetes mellitus (DM2), previous studies have reported that DM2 patients have lower production of host defense peptides (HDP). AIM OF THE STUDY: To investigate the expression of RNase 7, cathelicidin, HBD-2, and psoriasin in biopsies obtained from DM2 patients with or without DFU. METHODS: Biopsies from DFU patients grade 3 according to Wagner's classification, from diabetic patients without ulcer and from healthy donors were obtained. qPCR, immunohistochemistry and cell line cultures were performed. To assess whether L-isoleucine, calcitriol, phenyl butyrate, metformin, glyburide or insulin induced RNase 7, keratinocytes were stimulated, and RNase 7 expression was evaluated. RESULTS: Our data showed that RNase 7 levels were decreased in both diabetic groups when were compared with skin from healthy donors. Since most of the DM2 patients are treated with drugs to reduce glycemia, we investigated whether glyburide, metformin or insulin were able to induce any change regarding RNase 7 production. Results showed that metformin reduces the expression of RNase 7 in in vitro treated keratinocytes, suggesting that the chronic use of metformin should be evaluated in DFU patients, whereas calcitriol, phenyl butyrate and L-isoleucine did not increase the RNase 7 production. CONCLUSIONS: Due RNase 7 has antimicrobial activity, its downregulation can make prone to DM2 patients to develop infections and impaired wound healing.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Pie Diabético/genética , Metformina/efectos adversos , Ribonucleasas/metabolismo , Cicatrización de Heridas/efectos de los fármacos , Adulto , Enfermedad Crónica , Regulación hacia Abajo , Femenino , Humanos , Masculino , Persona de Mediana Edad
8.
Mem. Inst. Oswaldo Cruz ; 118: e230143, 2023. tab, graf
Artículo en Inglés | LILACS-Express | LILACS | ID: biblio-1529018

RESUMEN

BACKGROUND Tuberculosis (TB) is a major public health problem, which has been aggravated by the alarming growth of drug-resistant tuberculosis. Therefore, the development of a safer and more effective treatment is needed. OBJECTIVES The aim of this work was repositioning and evaluate histone deacetylases (HDAC) inhibitors- based drugs with potential antimycobacterial activity. METHODS Using an in silico pharmacological repositioning strategy, three molecules that bind to the catalytic site of histone deacetylase were selected. Pneumocytes type II and macrophages were infected with Mycobacterium tuberculosis and treated with pre-selected HDAC inhibitors (HDACi). Subsequently, the ability of each of these molecules to directly promote the elimination of M. tuberculosis was evaluated by colony-forming unit (CFU)/mL. We assessed the expression of antimicrobial peptides and respiratory burst using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) FINDINGS Aminoacetanilide (ACE), N-Boc-1,2-phenylenediamine (N-BOC), 1,3-Diphenylurea (DFU), reduce bacillary loads in macrophages and increase the production of β-defensin-2, LL-37, superoxide dismutase (SOD) 3 and inducible nitric oxide synthase (iNOS). While only the use of ACE in type II pneumocytes decreases the bacterial load through increasing LL-37 expression. Furthermore, the use of ACE and rifampicin inhibited the survival of intracellular multi-drug resistance M. tuberculosis. MAIN CONCLUSIONS Our data support the usefulness of in silico approaches for drug repositioning to provide a potential adjunctive therapy for TB.

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