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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.
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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.
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Citocinas , Reposicionamento de Medicamentos , Inibidores de Histona Desacetilases , Imunidade Inata , Infecções por Mycobacterium não Tuberculosas , Imunidade Inata/efeitos dos fármacos , Humanos , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Inibidores de Histona Desacetilases/farmacologia , Citocinas/metabolismo , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Micobactérias não Tuberculosas/efeitos dos fármacos , Micobactérias não Tuberculosas/imunologia , Mycobacterium/imunologia , Mycobacterium/efeitos dos fármacosRESUMO
Babesiosis is a growing concern due to the increased prevalence of this infectious disease caused by Babesia protozoan parasites, affecting various animals and humans. With rising worries over medication side effects and emerging drug resistance, there is a notable shift towards researching babesiacidal agents. Antimicrobial peptides, specifically cathelicidins known for their broad-spectrum activity and immunomodulatory functions, have emerged as potential candidates. Aquiluscidin, a cathelicidin from Crotalus aquilus, and its derivative Vcn-23, have been of interest due to their previously observed antibacterial effects and non-hemolytic activity. This work aimed to characterize the effect of these peptides against three Babesia species. Results showed Aquiluscidin's significant antimicrobial effects on Babesia species, reducing the B. bigemina growth rate and exhibiting IC50 values of 14.48 and 20.70 µM against B. ovata and B. bovis, respectively. However, its efficacy was impacted by serum presence in culture, and it showed no inhibition against a B. bovis strain grown in serum-supplemented medium. Conversely, Vcn-23 did not demonstrate babesiacidal activity. In conclusion, Aquiluscidin shows antibabesia activity in vitro and its efficacy is affected by the presence of serum in the culture medium. Nevertheless, this peptide represents a candidate for further investigation of its antiparasitic properties and provides insights into potential alternatives for the treatment of babesiosis.
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PM2.5 and arsenic are two of the most hazardous substances for humans that coexist worldwide. Independently, they might cause multiple organ damage. However, the combined effect of PM2.5 and arsenic has not been studied. Here, we used an animal model of simultaneous exposure to arsenic and PM2.5. Adult Wistar rats were exposed to PM2.5, As, or PM2.5 + As and their corresponding control groups. After 7, 14, and 28 days of exposure, the animals were euthanized and serum, lungs, kidneys, and hearts were collected. Analysis performed showed high levels of lung inflammation in all experimental groups, with an additive effect in the coexposed group. Besides, we observed cartilaginous metaplasia in the hearts of all exposed animals. The levels of creatine kinase, CK-MB, and lactate dehydrogenase increased in experimental groups. Tissue alterations might be related to oxidative stress through increased GPx and NADPH oxidase activity. The findings of this study suggest that exposure to arsenic, PM2.5, or coexposure induces high levels of oxidative stress, which might be associated with lung inflammation and heart damage. These findings highlight the importance of reducing exposure to these pollutants to protect human health.
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During the COVID-19 pandemic, a considerable proportion of patients developed a severe condition that included respiratory failure, shock, or multiple organ dysfunction. Acute Kidney Injury (AKI) has been recognized as a possible cause of severe COVID-19 development. Given this, this study investigates the occurrence and consequences of AKI in Mexican patients to contribute to better knowledge and management of this problem. Methods: Using a retrospective observational cohort methodology, we investigated 313 cases from a cohort of 1019 patients diagnosed with COVID-19 at the IMSS Zacatecas General Hospital of Zone No. 1 in 2020. The prevalence of AKI was determined using the AKIN criteria based on serum creatinine levels and a detailed review of demographic characteristics, medical history, comorbidities, and clinical development. Results: The data showed a 25.30% prevalence of AKI among patients infected with severe COVID-19. Remarkably, these patients with AKI exhibited an advanced age (>65 years), arterial hypertension, a higher number of white blood cells during admission and the hospital stay, and elevated levels of C-reactive protein, serum creatinine, and blood urea nitrogen (BUN). Clinically, patients with AKI had signs of prostration, pneumonia, and the requirement for ventilatory assistance when compared to those without AKI. Finally, those diagnosed with AKI and COVID-19 had a 74% death rate. Relative risk analyses indicated that age (>65 years), arterial hypertension, high creatinine levels, endotracheal intubation, and pneumonia are associated with the development of AKI. On the other hand, among the protective factors against AKI, high hemoglobin levels and the consumption of statins during COVID-19 were found. Conclusions: The findings of this study underscore the significance of promptly identifying and effectively managing AKI to potentially alleviate the negative consequences of this complication within the Mexican population during COVID-19.
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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.
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Mycobacterium tuberculosis , Tuberculose , Vitamina D , Humanos , Vitamina D/uso terapêutico , Vitamina D/administração & dosagem , Tuberculose/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Ensaios Clínicos como Assunto , Animais , Antituberculosos/uso terapêutico , Antituberculosos/administração & dosagem , Vitaminas/uso terapêutico , Vitaminas/administração & dosagemRESUMO
Introduction: Metabolic syndrome (MetS) is a pathophysiological condition defined by a set of metabolic alterations such as hypertriglyceridemia, hyperglycemia, hypertension, low HDL-c levels, and visceral obesity. Its presence identifies people with an increased risk of developing cardiovascular diseases and type 2 diabetes; however, the lack of practical and reliable methods for its diagnosis limits the identification of people with this condition. In this sense, the objective of this study was to analyze the diagnostic utility of markers derived from the lipid profile [triglyceride-glucose (TyG) index and the ratios total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-c), triglyceride (TG)/HDL-c, low-density lipoprotein cholesterol/HDL-c, fasting blood glucose (FBG)/HDL-c, and white blood cell/HDL-c] in the determination of MetS. Methods: A retrospective study was designed that included 619 individuals. A logistic regression model was used to evaluate the associations of the different markers with MetS, and the cutoff points of the markers were determined through an analysis of receiver operating characteristic curves and the Youden Index. Results: A positive and significant association was observed between all markers and the presence of MetS. The cutoff values for the markers that best predicted MetS were TyG ≥ 4.8 (sensitivity = 91.4%, specificity = 74.3%), TC/HDL-c ≥ 3.7 (sensitivity = 74.3%, specificity = 75.7%), TG/HDL-c ≥ 3.3 (sensitivity = 82.5%, specificity = 84.0%), and FBG/HDL-c ≥ 2.0 (sensitivity = 85.1%, specificity = 79.7%). Conclusion: Our study demonstrated the diagnostic relevance of the different markers in detecting MetS, suggesting that these ratios may be useful in clinical practice for the opportune and accurate diagnosis of MetS.
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Metformin (MET) and atorvastatin (ATO) are promising treatments for COVID-19. This review explores the potential of MET and ATO, commonly prescribed for diabetes and dyslipidemia, respectively, as versatile medicines against SARS-CoV-2. Due to their immunomodulatory and antiviral capabilities, as well as their cost-effectiveness and ubiquitous availability, they are highly suitable options for treating the virus. MET's effect extends beyond managing blood sugar, impacting pathways that can potentially decrease the severity and fatality rates linked with COVID-19. It can partially block mitochondrial complex I and stimulate AMPK, which indicates that it can be used more widely in managing viral infections. ATO, however, impacts cholesterol metabolism, a crucial element of the viral replicative cycle, and demonstrates anti-inflammatory characteristics that could modulate intense immune reactions in individuals with COVID-19. Retrospective investigations and clinical trials show decreased hospitalizations, severity, and mortality rates in patients receiving these medications. Nevertheless, the journey from observing something to applying it in a therapeutic setting is intricate, and the inherent diversity of the data necessitates carefully executed, forward-looking clinical trials. This review highlights the requirement for efficacious, easily obtainable, and secure COVID-19 therapeutics and identifies MET and ATO as promising treatments in this worldwide health emergency.
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We sought to evaluate the effect of endodontic-causative microorganisms of primary infections on mononuclear cells such as CD14+, CD4+, CD8+, CD19+ and Tregs Foxp3+. Facultative anaerobic microorganisms were isolated from radicular conducts and peripheral blood samples, which were taken from patients with primary infections. Cellular cultures were performed with peripheral blood mononuclear cells (PBMC) with and without Actinomyces spp. and Streptococcus spp. during 48, 72, and 96 h of contact in culture (concentration 5 × 105 cells/well) in a round plate bound with 48 wells. Later, PBMC was collected for analysis by flow cytometry, with the monoclonal antibodies αCD14, αCD4, αCD8, αCD19 and αFoxp3, and acquired using an FACSCanto II cytometer. The supernatant of cellular cultures was analyzed for the quantification of inflammatory cytokines. Data analysis was performed in FlowJo v10.8.2 and FCAPArray software, and statistical analysis was performed using GraphPad v5.0. software. We observed an increase in the percentage of CD14+ cells in patients at different hours of cellular culture in the presence of both Actinomyces spp. and Streptococcus spp. microorganisms, compared to healthy controls. This study demonstrates the role played by the innate immune system in the pathogeny of endodontic primary infections, explaining the effects that generate the more common microorganisms in this oral pathology.
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Leucócitos Mononucleares , Monócitos , Humanos , Actinomyces , Citocinas/metabolismo , Interleucina-12/metabolismo , Interleucina-8/metabolismo , Leucócitos Mononucleares/metabolismo , Monócitos/metabolismo , Streptococcus/metabolismoRESUMO
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.
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Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Humanos , Rifampina/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Histona DesacetilasesRESUMO
Tuberculosis is among the infectious diseases with the highest mortality and morbidity worldwide, behind the COVID-19 pandemic. It can affect any organ, although the respiratory infection is the most common. The correct activation of the immune response eliminates or contain the bacteria; however, the active disease is progressive and must be treated under strict supervision. Treatment for tuberculosis is prolonged and consists of a combination of several antibiotics associated with a wide variety of adverse effects. These effects are the main cause of therapeutic abandonment, which facilitates the appearance of drug-resistant strains. Hence the importance of developing new therapeutic strategies to reduce the dose of the drug or its administration time. To achieve these objectives, the use of nano-vehicles, which are controlled and directed drug release systems, has been proposed. Specifically, liposomes are formulations that have advantages when administered by the respiratory route since they facilitate the reach of the respiratory mucosa and the lungs, which are the main organs affected by tuberculosis. This review analyzes the use of nano-vehicles as effective drug delivery systems and the formulations under study. Perspectives for the application of nanotechnology in the development of new pharmacological treatments for tuberculosis are also proposed.
La tuberculosis se ubica entre las enfermedades infecciosas con mayor mortalidad y morbilidad a nivel mundial, por detrás de la actual pandemia de COVID-19. Puede afectar a cualquier órgano, aunque la principal forma de infección es respiratoria. La correcta activación de la respuesta inmune logra eliminar o contener a la bacteria en un estado de latencia; sin embargo, la enfermedad activa es progresiva y debe ser tratada bajo estricta supervisión. El tratamiento para la tuberculosis es prolongado y consiste en una combinación de varios antifímicos; por lo tanto, se asocia a la aparición de una gran diversidad de efectos adversos. Estos efectos son la principal causa de abandono terapéutico, que a su vez facilita la aparición de cepas farmacorresistentes. De ahí la importancia de desarrollar nuevas estrategias terapéuticas con el objetivo de disminuir la dosis del fármaco o bien su tiempo de administración. Para lograr estos objetivos se ha propuesto el uso de nanovehículos, que son sistemas de liberación de fármacos controlados y dirigidos. Específicamente, los liposomas son formulaciones que presentan ventajas al ser administrados por vía respiratoria, ya que esta facilita el alcance a la mucosa respiratoria y a los pulmones, que es el principal órgano afectado en la infección por tuberculosis. En la presente revisión se analiza el uso de nanovehículos como sistemas efectivos de entrega de fármacos, así como las formulaciones que se encuentran en estudio. También se proponen perspectivas para la aplicación de la nanotecnología en el desarrollo de nuevos tratamientos farmacológicos para la tuberculosis.
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COVID-19 , Tuberculose , Humanos , Lipossomos/uso terapêutico , Antituberculosos/uso terapêutico , Antituberculosos/farmacologia , Pandemias , Tuberculose/tratamento farmacológicoRESUMO
Tobacco consumption increases the susceptibility to develop infectious diseases such as tuberculosis (TB). Nicotine (Nc) is the main component of cigarette smoke with immunomodulatory properties, however, its effect on Mycobacterium tuberculosis (Mtb) has been scarcely investigated. The present study evaluated the effect of nicotine on the growth of Mtb and on the induction of virulence-related genes. Mycobacteria were exposed to different concentrations of nicotine then Mtb growth was evaluated. Subsequently, the expression of the virulence-related genes lysX, pirG, fad26, fbpa, ompa, hbhA, esxA, esxB, hspx, katG, lpqh, and caeA was evaluated by RT-qPCR. The effect of nicotine on intracellular Mtb was also evaluated. The results showed that nicotine promotes the growth of Mtb both extracellularly and intracellularly and increases the expression of genes related to virulence. In summary, nicotine promotes the growth of Mtb and the expression of virulence-related genes that could be correlated with the increased the risk of smokers developing TB.
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Mycobacterium tuberculosis , Tuberculose , Humanos , Mycobacterium tuberculosis/genética , Virulência/genética , Nicotina/farmacologia , Fatores de Virulência/genética , Fatores de Virulência/metabolismoRESUMO
Mycobacterium tuberculosis (Mtb) is one of the most important infectious agents worldwide and causes more than 1.5 million deaths annually. To make matters worse, the drug resistance among Mtb strains has risen substantially in the last few decades. Nowadays, it is not uncommon to find patients infected with Mtb strains that are virtually resistant to all antibiotics, which has led to the urgent search for new molecules and therapies. Over previous decades, several studies have demonstrated the efficiency of antimicrobial peptides to eliminate even multidrug-resistant bacteria, making them outstanding candidates to counterattack this growing health problem. Nevertheless, the complexity of the Mtb cell wall makes us wonder whether antimicrobial peptides can effectively kill this persistent Mycobacterium. In the present review, we explore the complexity of the Mtb cell wall and analyze the effectiveness of antimicrobial peptides to eliminate the bacilli.
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Mycobacterium tuberculosis , Humanos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Antituberculosos/química , Peptídeos Antimicrobianos , Farmacorresistência Bacteriana Múltipla , Parede Celular/químicaRESUMO
PURPOSE: Conventional therapies and surgery remain the standard treatment for breast cancer. However, combating the eventual development of metastasis is still a challenge. Newcastle disease virus (NDV) is one of the various species of viruses under clinical evaluation as a vector for oncolytic, gene-, and immune-stimulating therapies. The purpose of this study was to evaluate the antitumor activity of a recombinant NDV (rNDV-P05) in a breast cancer murine model. METHODS: Tumors were induced by injecting the cellular suspension (4T1 cell line) subcutaneously. The virus strain P05 was applied three times at intervals of seven days, starting seven days after tumor induction, and was completed 21 days later. Determination of tumor weight, spleen index, and lung metastasis were done after sacrificing the mice. Serum levels of interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, and TNF-related apoptosis-inducing ligand (TRAIL) were quantified by enzyme-linked immunosorbent assay. CD8+ infiltrated cells were analyzed by immunofluorescence. RESULTS: rNDV-P05 showed a route-of-administration-dependent effect, demonstrating that the systemic administration of the virus significantly reduces the tumor mass and volume, spleen index, and abundance of metastatic clonogenic colonies in lung tissue, and increases the inhibition rate of the tumor. The intratumoral administration of rNDV-P05 was ineffective for all the parameters evaluated. Antitumor and antimetastatic capability of rNDV-P05 is mediated, at least partially, through its immune-stimulatory effect on the upregulation of TNF-α, TRAIL, IFN-α, and IFN-γ, and its ability to recruit CD8+ T cells into tumor tissue. CONCLUSION: Systemic treatment with rNDV-P05 decreases the tumoral parameters in the breast cancer murine model.
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Background: Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2) are chronic degenerative diseases with complex molecular processes that are potentially interconnected. The aim of this work was to predict the potential molecular links between AD and DM2 from different sources of biological information. Materials and Methods: In this work, data mining of nine databases (DisGeNET, Ensembl, OMIM, Protein Data Bank, The Human Protein Atlas, UniProt, Gene Expression Omnibus, Human Cell Atlas, and PubMed) was performed to identify gene and protein information that was shared in AD and DM2. Next, the information was mapped to human protein-protein interaction (PPI) networks based on experimental data using the STRING web platform. Then, gene ontology biological process (GOBP) and pathway analyses with EnrichR showed its specific and shared biological process and pathway deregulations. Finally, potential biomarkers and drug targets were predicted with the Metascape platform. Results: A total of 1,551 genes shared in AD and DM2 were identified. The highest average degree of nodes within the PPI was for DM2 (average = 2.97), followed by AD (average degree = 2.35). GOBP for AD was related to specific transcriptional and translation genetic terms occurring in neurons cells. The GOBP and pathway information for the association AD-DM2 were linked mainly to bioenergetics and cytokine signaling. Within the AD-DM2 association, 10 hub proteins were identified, seven of which were predicted to be present in plasma and exhibit pharmacological interaction with monoclonal antibodies in use, anticancer drugs, and flavonoid derivatives. Conclusion: Our data mining and analysis strategy showed that there are a plenty of biological information based on experiments that links AD and DM2, which could provide a rational guide to design further diagnosis and treatment for AD and DM2.
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Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Humanos , Doença de Alzheimer/genética , Diabetes Mellitus Tipo 2/genética , Mapas de Interação de Proteínas/genética , Biologia Computacional , Bases de Dados FactuaisRESUMO
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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The aim of this study was to analyze molecules associated with regulatory immune response in unvaccinated, recovered COVID-19 patients with and without diabetes mellitus (DM) and hypertension (HTN). We determined anti-SARS-CoV-2 nucleocapsid IgG in plasma by electrochemiluminescence immunoassay. The levels of sCD40, TGF-ß, IL-10, and sCTLA-4 were assessed by ELISA in the serum of the subjects, as well as in healthy donors. We observed that only half of the subjects in the non-comorbid group produced antibodies, whereas all subjects in comorbid groups were IgG-positive for the anti-SARS-CoV-2 nucleocapsid. High levels of sCTL-4 were observed in the non-comorbid group, and the level of IL-10 was observed to increase in seropositive subjects without comorbidities. TGF-ß concentration was similar in all groups studied. Finally, sCD40 decreased in the comorbid group. In conclusion, our results suggest that comorbidities such as DM and HTN alter the production of co-stimulatory inhibitory molecules sCTLA-4 and sCD40 in subjects recovering from mild COVID-19. The alterations observed here were independent of seropositivity, suggesting an effective humoral immune response against COVID-19 separate from the levels of co-stimulatory inhibitory molecules.
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An infectious process into the uterine cavity represents a major endangered condition that compromises the immune privilege of the maternal-fetal unit and increases the risk for preterm birth (PTB) and premature rupture of membranes (PROM). Fetal membranes are active secretors of antimicrobial peptides (AMP), which limit bacterial growth, such as Escherichia coli. Nevertheless, the antibacterial responses displayed by chorioamniotic membranes against a choriodecidual E. coli infection have been briefly studied. The objective of this research was to characterize the profile of synthesis, activity, and spatial distribution of a broad panel of AMPs produced by fetal membranes in response to E. coli choriodecidual infection. Term human chorioamniotic membranes were mounted in a two independent compartment model in which the choriodecidual region was infected with live E. coli (1 × 105 CFU/mL). Amnion and choriodecidual AMP tissue levels and TNF-α and IL-1ß secretion were measured by the enzyme-linked immunosorbent assay. The passage of bacterium through fetal membranes and their effect on structural continuity was followed for 24 h. Our results showed that E. coli infection caused a progressive mechanical disruption of the chorioamniotic membranes and an activated inflammatory environment. After the challenge, the amnion quickly (2-4 h) induced production of human beta defensins (HBD)-1, HBD-2, and LL-37. Afterwards (8-24 h), the amnion significantly produced HBD-1, HBD-2, HNP-1-3, S100A7, sPLA2, and elafin, whereas the choriodecidua induced LL-37 synthesis. Therefore, we noticed a temporal- and tissue-specific pattern regulation of the synthesis of AMPs by infected fetal membranes. However, fetal membranes were not able to contain the collagen degradation or the bacterial growth and migration despite the battery of produced AMPs, which deeply increases the risk for PTB and PROM. The mixture of recombinant HBDs at low concentrations resulted in increased bactericidal activity compared to each HBD alone in vitro, encouraging further research to study AMP combinations that may offer synergy to control drug-resistant infections in the perinatal period.
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Infecções por Escherichia coli , Nascimento Prematuro , beta-Defensinas , Feminino , Humanos , Recém-Nascido , Gravidez , beta-Defensinas/metabolismo , Escherichia coli/metabolismo , Infecções por Escherichia coli/metabolismo , Membranas Extraembrionárias/metabolismo , Imunidade Inata , Nascimento Prematuro/metabolismoRESUMO
Tobacco consumption is related to an increased risk to develop tuberculosis. Antimicrobial peptides are essential molecules in the response to Mycobacterium tuberculosis (Mtb) because of their direct antimicrobial activity. The aim of this study was to demonstrate that nicotine enters into Mtb infected epithelial cells and associates with the mycobacteria inducing genes related to antimicrobial peptides resistance. Epithelial cells were infected with virulent Mtb, afterwards cells were stimulated with nicotine. The internalization of nicotine was followed using electron and confocal microscopy. The lysX expression was evaluated isolating mycobacterial RNA and submitted to RT-PCR analysis. Our results indicated that nicotine promotes Mtb growth in a dose-dependent manner in infected cells. We also reported that nicotine induces lysX expression. In conclusion, nicotine associates to intracellular mycobacteria promoting intracellular survival.
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Mycobacterium tuberculosis , Tuberculose , Peptídeos Antimicrobianos , Humanos , Macrófagos , Mycobacterium tuberculosis/genética , Nicotina/farmacologiaRESUMO
The term host defense peptides arose at the beginning to refer to those peptides that are part of the host's immunity. Because of their broad antimicrobial capacity and immunomodulatory activity, nowadays, they emerge as a hope to combat resistant multi-drug microorganisms and emerging viruses, such as the case of coronaviruses. Since the beginning of this century, coronaviruses have been part of different outbreaks and a pandemic, and they will be surely part of the next pandemics, this review analyses whether these peptides and their derivatives are ready to be part of the treatment of the next coronavirus pandemic.