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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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Heterozygous autosomal dominant mutations in the CXCR4 gene cause WHIM syndrome, a severe combined immunodeficiency disorder. The mutations primarily affect the C-terminal region of the CXCR4 chemokine receptor, specifically several potential phosphorylation sites critical for agonist (CXCL12)-mediated receptor internalization and desensitization. Mutant receptors have a prolonged residence time on the cell surface, leading to hyperactive signaling that is responsible for some of the symptoms of WHIM syndrome. Recent studies have shown that the situation is more complex than originally thought, as mutant WHIM receptors and CXCR4 exhibit different dynamics at the cell membrane, which also influences their respective cellular functions. This review examines the functional mechanisms of CXCR4 and the impact of WHIM mutations in both physiological and pathological conditions.
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Mutação , Doenças da Imunodeficiência Primária , Receptores CXCR4 , Transdução de Sinais , Verrugas , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Humanos , Doenças da Imunodeficiência Primária/genética , Verrugas/genética , Animais , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Trombocitopenia/genética , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismoRESUMO
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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Here we report the characterization of 17T2, a SARS-CoV-2 pan-neutralizing human monoclonal antibody isolated from a COVID-19 convalescent individual infected during the first pandemic wave. 17T2 is a class 1 VH1-58/κ3-20 antibody, derived from a receptor binding domain (RBD)-specific IgA+ memory B cell, with a broad neutralizing activity against former and new SARS-CoV-2 variants, including XBB.1.16 and BA.2.86 Omicron subvariants. Consistently, 17T2 demonstrates in vivo prophylactic and therapeutic activity against Omicron BA.1.1 infection in K18-hACE2 mice. Cryo-electron microscopy reconstruction shows that 17T2 binds the BA.1 spike with the RBD in "up" position and blocks the receptor binding motif, as other structurally similar antibodies do, including S2E12. Yet, unlike S2E12, 17T2 retains its neutralizing activity against all variants tested, probably due to a larger RBD contact area. These results highlight the impact of small structural antibody changes on neutralizing performance and identify 17T2 as a potential candidate for future clinical interventions.
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Anticorpos Monoclonais , COVID-19 , Humanos , Animais , Camundongos , SARS-CoV-2 , Microscopia Crioeletrônica , Anticorpos Monoclonais Humanizados , Anticorpos Neutralizantes , Anticorpos Antivirais , Glicoproteína da Espícula de Coronavírus/genéticaRESUMO
J-domain proteins tune the specificity of Hsp70s, engaging them in precise functions. Despite their essential role, the structure and function of many J-domain proteins remain largely unknown. We explore human DNAJA2, finding that it reversibly forms highly-ordered, tubular structures that can be dissociated by Hsc70, the constitutively expressed Hsp70 isoform. Cryoelectron microscopy and mutational studies reveal that different domains are involved in self-association. Oligomer dissociation into dimers potentiates its interaction with unfolded client proteins. The J-domains are accessible to Hsc70 within the tubular structure. They allow binding of closely spaced Hsc70 molecules that could be transferred to the unfolded substrate for its cooperative remodelling, explaining the efficient recovery of DNAJA2-bound clients. The disordered C-terminal domain, comprising the last 52 residues, regulates its holding activity and productive interaction with Hsc70. These in vitro findings suggest that the association equilibrium of DNAJA2 could regulate its interaction with client proteins and Hsc70.
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Proteínas de Choque Térmico HSP70 , Polímeros , Humanos , Microscopia Crioeletrônica , Proteínas de Choque Térmico HSP40 , MutaçãoRESUMO
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
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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p38γ and p38δ (p38γ/p38δ) regulate inflammation, in part by controlling tumor progression locus 2 (TPL2) expression in myeloid cells. Here, we demonstrate that TPL2 protein levels are dramatically reduced in p38γ/p38δ-deficient (p38γ/δ-/-) cells and tissues without affecting TPL2 messenger ribonucleic acid (mRNA) expression. We show that p38γ/p38δ posttranscriptionally regulates the TPL2 amount at two different levels. p38γ/p38δ interacts with the TPL2/A20 Binding Inhibitor of NF-κB2 (ABIN2)/Nuclear Factor κB1p105 (NF-κB1p105) complex, increasing TPL2 protein stability. Additionally, p38γ/p38δ regulates TPL2 mRNA translation by modulating the repressor function of TPL2 3' Untranslated region (UTR) mediated by its association with aconitase-1 (ACO1). ACO1 overexpression in wild-type cells increases the translational repression induced by TPL2 3'UTR and severely decreases TPL2 protein levels. p38δ binds to ACO1, and p38δ expression in p38γ/δ-/- cells fully restores TPL2 protein to wild-type levels by reducing the translational repression of TPL2 mRNA. This study reveals a unique mechanism of posttranscriptional regulation of TPL2 expression, which given its central role in innate immune response, likely has great relevance in physiopathology.
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Aconitato Hidratase , MAP Quinase Quinase Quinases , Proteína Quinase 12 Ativada por Mitógeno , Proteína Quinase 13 Ativada por Mitógeno , Aconitato Hidratase/genética , Aconitato Hidratase/metabolismo , Regulação da Expressão Gênica , Imunidade Inata , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Proteína Quinase 12 Ativada por Mitógeno/genética , Proteína Quinase 12 Ativada por Mitógeno/metabolismo , Proteína Quinase 13 Ativada por Mitógeno/genética , Proteína Quinase 13 Ativada por Mitógeno/metabolismo , RNA Mensageiro/genéticaRESUMO
Chemokine receptor nanoscale organization at the cell membrane is orchestrated by the actin cytoskeleton and influences cell responses. Using single-particle tracking analysis we show that CXCR4R334X, a truncated mutant chemokine receptor linked to WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis), fails to nanoclusterize after CXCL12 stimulation, and alters the lateral mobility and spatial organization of CXCR4 when coexpressed. These findings correlate with multiple phalloidin-positive protrusions in cells expressing CXCR4R334X, and their inability to correctly sense chemokine gradients. The underlying mechanisms involve inappropriate actin cytoskeleton remodeling due to the inadequate ß-arrestin1 activation by CXCR4R334X, which disrupts the equilibrium between activated and deactivated cofilin. Overall, we provide insights into the molecular mechanisms governing CXCR4 nanoclustering, signaling and cell function, and highlight the essential scaffold role of ß-arrestin1 to support CXCL12-mediated actin reorganization and receptor clustering. These defects associated with CXCR4R334X expression might contribute to the severe immunological symptoms associated with WHIM syndrome.
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Doenças da Imunodeficiência Primária , Receptores CXCR4 , Verrugas , Fatores de Despolimerização de Actina/metabolismo , Membrana Celular/metabolismo , Movimento Celular , Humanos , Mutação , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Imagem Individual de Molécula , Verrugas/genética , Verrugas/metabolismoRESUMO
Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines, and its dysfunction leads to DA deficiency and parkinsonisms. Inhibition by catecholamines and reactivation by S40 phosphorylation are key regulatory mechanisms of TH activity and conformational stability. We used Cryo-EM to determine the structures of full-length human TH without and with DA, and the structure of S40 phosphorylated TH, complemented with biophysical and biochemical characterizations and molecular dynamics simulations. TH presents a tetrameric structure with dimerized regulatory domains that are separated 15 Å from the catalytic domains. Upon DA binding, a 20-residue α-helix in the flexible N-terminal tail of the regulatory domain is fixed in the active site, blocking it, while S40-phosphorylation forces its egress. The structures reveal the molecular basis of the inhibitory and stabilizing effects of DA and its counteraction by S40-phosphorylation, key regulatory mechanisms for homeostasis of DA and TH.
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Dopamina/farmacologia , Inibidores Enzimáticos/farmacologia , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Tirosina 3-Mono-Oxigenase/química , Sequência de Aminoácidos , Domínio Catalítico , Catecolaminas/metabolismo , Microscopia Crioeletrônica , Dopamina/química , Dopamina/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Modelos Moleculares , Fosforilação , Ligação Proteica , Domínios Proteicos , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Dendritic cells (DCs) are the most potent antigen-presenting cells, and their function is essential to configure adaptative immunity and avoid excessive inflammation. DCs are predicted to play a crucial role in the clinical evolution of the infection by the severe acute respiratory syndrome (SARS) coronavirus (CoV)-2. DCs interaction with the SARS-CoV-2 Spike protein, which mediates cell receptor binding and subsequent fusion of the viral particle with host cell, is a key step to induce effective immunity against this virus and in the S protein-based vaccination protocols. Here we evaluated human DCs in response to SARS-CoV-2 S protein, or to a fragment encompassing the receptor binding domain (RBD) challenge. Both proteins increased the expression of maturation markers, including MHC molecules and costimulatory receptors. DCs interaction with the SARS-CoV-2 S protein promotes activation of key signaling molecules involved in inflammation, including MAPK, AKT, STAT1, and NFκB, which correlates with the expression and secretion of distinctive proinflammatory cytokines. Differences in the expression of ACE2 along the differentiation of human monocytes to mature DCs and inter-donor were found. Our results show that SARS-CoV-2 S protein promotes inflammatory response and provides molecular links between individual variations and the degree of response against this virus.
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Células Dendríticas/patologia , Células Dendríticas/virologia , Receptores Virais/metabolismo , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Moléculas de Adesão Celular/metabolismo , Diferenciação Celular , Citocinas/biossíntese , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Inflamação/patologia , Lectinas Tipo C/metabolismo , Domínios Proteicos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Superfície Celular/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Doadores de TecidosRESUMO
Resumen: México fue pionero en establecer catálogos para identificar y hacer asequibles insumos médicos para la atención de su población, incluyendo medicamentos, instrumental, equipos y material de curación. Hace medio siglo, en 1971, surgió en el Instituto Mexicano del Seguro Social la iniciativa del llamado Cuadro Básico, que se constituyó como una herramienta fundamental para el funcionamiento de las instituciones públicas de salud, con la cual se establecieron listados de insumos con probada eficacia y seguridad, con claves administrativas asignadas que permitieron su adquisición ordenada. En 2020 se llevó a cabo la transición del Cuadro Básico y Catálogo al Compendio Nacional de Insumos para la Salud, el cual recuperó el espíritu original de sus creadores como un documento vivo y en constante evolución, respaldado por una metodología rigurosa para la revisión de los insumos que se incluyen, basada en la evaluación de su efectividad, seguridad y calidad, y en criterios farmacoeconómicos y consensos interinstitucionales.
Abstract: Mexico pioneered the creation of catalogs for identification and access of the medical commodities necessary for public healthcare, including medicines, medical equipment and wound dressing supplies. Fifty years ago, in 1971, the Instituto Mexicano del Seguro Social started the initiative of the Basic Scheme (Cuadro básico), that became a fundamental tool for provision of healthcare in the public institutions through the establishment of listings of medical supplies with proved safety and efficacy, assigning administrative codes that allowed an orderly acquisition. On 2020, the Basic Scheme and Catalog underwent a transition towards the National Compendium of Health Commodities (Compendio Nacional de Insumos para la Salud), recovering the original spirit of their creators as a live document in constant evolution, supported by a rigorous methodology for the assessment of the medical commodities included, based on evaluations of effectiveness, safety and quality, pharmacoeconomic criteria and interinstitutional consensus.
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OBJECTIVE: To generate a value set for the Mexican adult general population to support and facilitate the inclusion of quality-adjusted life years (QALYs) into the health technology assessment process of the Mexican healthcare authorities. METHODS: A representative sample of the Mexican adult population stratified by age, sex and socio-economic status was used. Following version 2.0 of the EuroQol EQ-5D-5L valuation protocol, trained interviewers guided participants in completing composite time trade-off (cTTO) and discrete-choice experiment (DCE) tasks included in the EQ-VT software. Generalized least squares, Tobit and Bayesian models were used for cTTO data. The choice of value set model was based on criteria that included: theoretical considerations, parsimony, logical ordering of coefficients, and statistical significance. RESULTS: Based on quality control criteria and interviewer judgment, 1000 out of 1032 participants provided useable responses. Participants' demographic characteristics were similar to the 2010 Mexican Population Census and followed the socioeconomic structure defined by the Mexican Association of Marketing Research and Public Opinion Agencies (AMAI). The predicted index values in the final cTTO model (a heteroscedastic censored model with Bayesian estimation) ranged from - 0.5960 to 1, with 19.7% of all predicted health state scores less than 0 (i.e., worse than dead). CONCLUSION: This study has generated the first value set representing the stated preferences of the Mexican adult population for use in estimating QALYs. The resulting EQ-5D-5L value set is technically robust and will facilitate health economic analyses as well as quality-of-life studies.
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Qualidade de Vida , Adulto , Teorema de Bayes , Humanos , Anos de Vida Ajustados por Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
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.
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Peptídeos Antimicrobianos/farmacologia , Brônquios/efeitos dos fármacos , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Tretinoína/farmacologia , Tuberculose/tratamento farmacológico , Antineoplásicos/farmacologia , Autofagia , Brônquios/metabolismo , Brônquios/microbiologia , Brônquios/patologia , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/microbiologia , Macrófagos/patologia , Tuberculose/metabolismo , Tuberculose/microbiologia , Tuberculose/patologiaRESUMO
Epidemiological studies have associated long-term exposure to environmental air pollution particulate matter (PM) with the development of diverse health problems. They include infectious respiratory diseases related to the deregulation of some innate immune response mechanisms, such as the host defense peptides' expression. Herein, we evaluated in BALB/c mice the effect of long-standing exposure (60 days) to urban-PM from the south of Mexico City, with aerodynamic diameters below 2.5 µm (PM2.5) and 10 µm (PM10) on the lung's gene expression and production of three host defense peptides (HDPs); murine beta-defensin-3, -4 (mBD-3, mBD-4) and cathelin-related antimicrobial peptide (CRAMP). We also evaluated mRNA levels of Il1b and Il10, two cytokines related to the expression of host defense peptides. Exposure to PM2.5 and PM10 differentially induced lung inflammation, being PM2.5, which caused higher inflammation levels, probably associated with a differential deposition on the airways, that facilitate the interaction with alveolar macrophages. Inflammation levels were associated with an early upregulation of the three HDPs assessed and an increment in Il1b mRNA levels. Interestingly, after 28 days of exposure, Il10 mRNA upregulation was observed and was associated with the downregulation of HDPs and Il1b mRNA levels. The upregulation of Il10 mRNA and suppression of HDPs might facilitate microbial colonization and the development of diseases associated with long-term exposure to PM.
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Poluentes Atmosféricos/toxicidade , Catelicidinas/metabolismo , Interleucina-1beta/metabolismo , Material Particulado/toxicidade , Pneumonia/patologia , beta-Defensinas/metabolismo , Animais , Catelicidinas/genética , Interleucina-1beta/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/etiologia , Pneumonia/metabolismo , beta-Defensinas/genéticaRESUMO
The toll-like receptor (TLR) family comprises both cell-surface and intracellular receptors that recognize different types of pathogen-associated molecular patterns (PAMPs) leading to the production of pro-inflammatory cytokines and subsequent development of adaptive immunity. TLR2 is a cell-surface receptor initially thought to act as a bacterial sentinel but also shown to recognize a number of viral glycoproteins. In this study, we sought to characterize the role of TLR2 in the activation of the immune response by peste des petits ruminants virus (PPRV), a morbillivirus of the Paramixoviridae family that causes an acute, highly contagious disease in goats and sheep. Using human embryonic kidney (HEK) 293 cells stably expressing human (h)TLR2 but lacking any other TLR, we found that PPRV induces IL-8 production in a dose-dependent manner. That activation is only observed in cells expressing hTLR2 and is greatly reduced when the receptor is blocked by pretreatment with specific antibody. We identified hemagglutinin (H) as the viral protein responsible of TLR2 activation by performing the same assays with purified recombinant mammalian-expressed H protein. Exogenous addition of recombinant H protein to cell culture induces high levels of interleukin (IL)-8 only in TLR2-expressing cells. Moreover, H engagement on TLR2 in the monocytic cell line THP-1 activates extracellular-signal-regulated kinase (ERK) signaling. Stimulation of primary ovine dendritic cells with either inactivated PPRV or purified recombinant H protein results in transcription of pro-inflammatory cytokines and the secretion of the Th1-polarizing cytokine IL-12. The role of these host immune mechanisms in the control of PPR is discussed.
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Hemaglutininas Virais/imunologia , Imunidade Inata/efeitos dos fármacos , Vírus da Peste dos Pequenos Ruminantes/genética , Vírus da Peste dos Pequenos Ruminantes/imunologia , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Animais , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/virologia , Células HEK293 , Hemaglutininas Virais/genética , Hemaglutininas Virais/farmacologia , Humanos , Ovinos , Transdução de Sinais/efeitos dos fármacos , Células THP-1RESUMO
México fue pionero en establecer catálogos para identificar y hacer asequibles insumos médicos para la atención de su población, incluyendo medicamentos, instrumental, equipos y material de curación. Hace medio siglo, en 1971, surgió en el Instituto Mexicano del Seguro Social la iniciativa del llamado Cuadro Básico, que se constituyó como una herramienta fun-damental para el funcionamiento de las instituciones públicas de salud, con la cual se establecieron listados de insumos con probada eficacia y seguridad, con claves administrativas asignadas que permitieron su adquisición ordenada. En 2020 se llevó a cabo la transición del Cuadro Básico y Catálogo al Compendio Nacional de Insumos para la Salud, el cual recuperó el espíritu original de sus creadores como un do-cumento vivo y en constante evolución, respaldado por una metodología rigurosa para la revisión de los insumos que se incluyen, basada en la evaluación de su efectividad, seguridad y calidad, y en criterios farmacoeconómicos y consensos interinstitucionales.
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Aggregation and accumulation of amyloid beta (Aß) are believed to play a key role in the pathogenesis of Alzheimer's disease (AD). We previously reported that Thioredoxin-80 (Trx80), a truncated form of Thioredoxin-1, prevents the toxic effects of Aß and inhibits its aggregation in vitro. Trx80 levels were found to be dramatically reduced both in the human brain and cerebrospinal fluid of AD patients. In this study, we investigated the effect of Trx80 expression using in vivo and in vitro models of Aß pathology. We developed Drosophila melanogaster models overexpressing either human Trx80, human Aß42, or both Aß42/Trx80 in the central nervous system. We found that Trx80 expression prevents Aß42 accumulation in the brain and rescues the reduction in life span and locomotor impairments seen in Aß42 expressing flies. Also, we show that Trx80 induces autophagosome formation and reverses the inhibition of Atg4b-Atg8a/b autophagosome formation pathway caused by Aß42. These effects were also confirmed in human neuroblastoma cells. These results give insight into Trx80 function in vivo, suggesting its role in the autophagosome biogenesis and thus in Aß42 degradation. Our findings put Trx80 on the spotlight as an endogenous agent against Aß42-induced toxicity in the brain suggesting that strategies to enhance Trx80 levels in neurons could potentially be beneficial against AD pathology in humans.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Doença de Alzheimer/genética , Animais , Drosophila melanogaster , Humanos , Lisossomos , Fragmentos de Peptídeos , Tiorredoxinas/genéticaRESUMO
INTRODUCTION: The use of probiotics has been broadly popularized due to positive effects in the attenuation of aberrant immune responses such as asthma. Allergic asthma is a chronic respiratory disease characterized by airway inflammation and remodelling. OBJECTIVE: This study was aimed to evaluate the effect of oral administration of Lactococcus lactis NZ9000 on asthmatic airway inflammation and lung tissue remodelling in rats and its relation to the maintenance of an adequate intestinal barrier. METHODS: Wistar rats were ovalbumin (OVA) sensitized and challenged and orally treated with L. lactis. Lung inflammatory infiltrates and cytokines were measured, and remodelling was evaluated. Serum OVA-specific immunoglobulin (Ig) E levels were assessed. We also evaluated changes on intestinal environment and on systemic immune response. RESULTS: L. lactis diminished the infiltration of proinflammatory leucocytes, mainly eosinophils, in the bronchoalveolar compartment, decreased lung IL-4 and IL-5 expression, and reduced the level of serum allergen-specific IgE. Furthermore, L. lactis prevented eosinophil influx, collagen deposition, and goblet cell hyperplasia in lung tissue. In the intestine, L. lactis-treated asthmatic rats increased Peyer's patch and goblet cell quantity and mRNA expression of IgA, MUC-2, and claudin. Additionally, intestinal morphological alterations were normalized by L. lactis administration. Splenocyte proliferative response to OVA was abolished, and serum levels of transforming growth factor (TGF)-ß were increased by L. lactis treatment. CONCLUSIONS: These findings suggest that L. lactis is a potential candidate for asthma prevention, and the effect is mediated by the improvement of intestinal barrier function and systemic TGF-ß production.