RESUMO
NLRP6 is important in host defense by inducing functional outcomes including inflammasome activation and interferon production. Here, we show that NLRP6 undergoes liquid-liquid phase separation (LLPS) upon interaction with double-stranded RNA (dsRNA) in vitro and in cells, and an intrinsically disordered poly-lysine sequence (K350-354) of NLRP6 is important for multivalent interactions, phase separation, and inflammasome activation. Nlrp6-deficient or Nlrp6K350-354A mutant mice show reduced inflammasome activation upon mouse hepatitis virus or rotavirus infection, and in steady state stimulated by intestinal microbiota, implicating NLRP6 LLPS in anti-microbial immunity. Recruitment of ASC via helical assembly solidifies NLRP6 condensates, and ASC further recruits and activates caspase-1. Lipoteichoic acid, a known NLRP6 ligand, also promotes NLRP6 LLPS, and DHX15, a helicase in NLRP6-induced interferon signaling, co-forms condensates with NLRP6 and dsRNA. Thus, LLPS of NLRP6 is a common response to ligand stimulation, which serves to direct NLRP6 to distinct functional outcomes depending on the cellular context.
Assuntos
Inflamassomos/metabolismo , Vírus de RNA/fisiologia , Receptores de Superfície Celular/metabolismo , Sequência de Aminoácidos , Animais , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Hepatócitos/virologia , Intestinos/virologia , Proteínas Intrinsicamente Desordenadas/química , Lipopolissacarídeos/metabolismo , Fígado/virologia , Camundongos , Polilisina/metabolismo , Ligação Proteica , RNA de Cadeia Dupla/metabolismo , Receptores de Superfície Celular/química , Transdução de Sinais , Ácidos Teicoicos/metabolismoRESUMO
Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.
Assuntos
Neoplasias Encefálicas/genética , Carcinogênese/genética , Glioma/genética , Histonas/genética , Interneurônios/metabolismo , Mutação/genética , Células-Tronco Neurais/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Neoplasias Encefálicas/patologia , Carcinogênese/patologia , Linhagem da Célula , Reprogramação Celular/genética , Cromatina/metabolismo , Embrião de Mamíferos/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Glioma/patologia , Histonas/metabolismo , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Gradação de Tumores , Oligodendroglia/metabolismo , Regiões Promotoras Genéticas/genética , Prosencéfalo/embriologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transcrição Gênica , Transcriptoma/genéticaRESUMO
Mycobacterial genomes encode multiple adenylyl cyclases and cAMP effector proteins, underscoring the diverse ways these bacteria utilize cAMP. We identified universal stress proteins, Rv1636 and MSMEG_3811 in Mycobacterium tuberculosis and Mycobacterium smegmatis, respectively, as abundantly expressed, novel cAMP-binding proteins. Rv1636 is secreted via the SecA2 secretion system in M. tuberculosis but is not directly responsible for the efflux of cAMP from the cell. In slow-growing mycobacteria, intrabacterial concentrations of Rv1636 were equivalent to the concentrations of cAMP present in the cell. In contrast, levels of intrabacterial MSMEG_3811 in M. smegmatis were lower than that of cAMP and therefore, overexpression of Rv1636 increased levels of "bound" cAMP. While msmeg_3811 could be readily deleted from the genome of M. smegmatis, we found that the rv1636 gene is essential for the viability of M. tuberculosis and is dependent on the cAMP-binding ability of Rv1636. Therefore, Rv1636 may function to regulate cAMP signaling by direct sequestration of the second messenger. This is the first evidence of a "sponge" for any second messenger in bacterial signaling that would allow mycobacterial cells to regulate the available intrabacterial "free" pool of cAMP.
Assuntos
Proteínas de Bactérias , AMP Cíclico , Mycobacterium tuberculosis , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , AMP Cíclico/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Viabilidade Microbiana , Mycobacterium smegmatis/metabolismo , Mycobacterium smegmatis/genética , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/genética , Ligação ProteicaRESUMO
Latent tuberculosis, caused by dormant Mycobacterium tuberculosis (Mtb), poses a threat to global health through the incubation of undiagnosed infections within the community. Dormant Mtb, which is phenotypically tolerant to antibiotics, accumulates triacylglycerol (TAG) utilizing fatty acids obtained from macrophage lipid droplets. TAG is vital to mycobacteria, serving as a cell envelope component and energy reservoir during latency. TAG synthesis occurs by sequential acylation of glycerol-3-phosphate, wherein the second acylation step is catalyzed by acylglycerol-3-phosphate acyltransferase (AGPAT), resulting in the production of phosphatidic acid (PA), a precursor for the synthesis of TAG and various phospholipids. Here, we have characterized a putative acyltransferase of Mtb encoded by Rv3816c. We found that Rv3816c has all four characteristic motifs of AGPAT, exists as a membrane-bound enzyme, and functions as 1-acylglycerol-3-phosphate acyltransferase. The enzyme could transfer the acyl group to acylglycerol-3-phosphate (LPA) from monounsaturated fatty acyl-coenzyme A of chain length 16 or 18 to produce PA. Complementation of Escherichia coli PlsC mutant in vivo by Rv3816c confirmed that it functions as AGPAT. Its active site mutants, H43A and D48A, were incapable of transferring the acyl group to LPA in vitro and were not able to rescue the growth defect of E. coli PlsC mutant in vivo. Identifying Rv3816c as AGPAT and comparing its properties with other AGPAT homologs is not only a step toward understanding the TAG biosynthesis in mycobacteria but has the potential to explore it as a drug target.
Assuntos
Mycobacterium tuberculosis , Triglicerídeos , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Triglicerídeos/biossíntese , Triglicerídeos/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferase/metabolismo , 1-Acilglicerol-3-Fosfato O-Aciltransferase/genética , Glicerol-3-Fosfato O-Aciltransferase/metabolismo , Glicerol-3-Fosfato O-Aciltransferase/genética , Aciltransferases/metabolismo , Aciltransferases/genética , Acilação , Ácidos Graxos/metabolismo , Ácidos Graxos/biossíntese , Ácidos Fosfatídicos/metabolismo , Ácidos Fosfatídicos/biossíntese , Acil Coenzima A/metabolismoRESUMO
BACKGROUND: Rhinovirus (RV) infections can progress from the upper (URT) to lower (LRT) respiratory tract in immunocompromised individuals, causing high rates of fatal pneumonia. Little is known about how RV evolves within hosts during infection. METHODS: We sequenced RV complete genomes from 12 hematopoietic cell transplant patients with infection for up to 190 days from both URT (nasal wash, NW) and LRT (bronchoalveolar lavage, BAL). Metagenomic and amplicon next-generation sequencing were used to track the emergence and evolution of intrahost single nucleotide variants (iSNVs). RESULTS: Identical RV intrahost populations in matched NW and BAL specimens indicated no genetic adaptation is required for RV to progress from URT to LRT. Coding iSNVs were 2.3-fold more prevalent in capsid over nonstructural genes. iSNVs modeled were significantly more likely to be found in capsid surface residues, but were not preferentially located in known RV-neutralizing antibody epitopes. Newly emergent, genotype-matched iSNV haplotypes from immunocompromised individuals in 2008-2010 could be detected in Seattle-area community RV sequences in 2020-2021. CONCLUSIONS: RV infections in immunocompromised hosts can progress from URT to LRT with no specific evolutionary requirement. Capsid proteins carry the highest variability and emergent mutations can be detected in other, including future, RV sequences.
Assuntos
Infecções por Enterovirus , Transplante de Células-Tronco Hematopoéticas , Humanos , Proteínas do Capsídeo/genética , Capsídeo , Rhinovirus/genética , MutaçãoRESUMO
The virulence of Mycobacterium tuberculosis (M. tuberculosis) is related to many factors, including intracellular survival, cell wall permeability, and cell envelope proteins. However, the biological function of the M. tuberculosis membrane protein Rv1476 remains unclear. To investigate the potential role played by Rv1476, we constructed an Rv1476 overexpression strain and found that overexpression of Rv1476 enhanced the intracellular survival of M. tuberculosis, while having no impact on the growth rate in vitro. Stress experiments demonstrated that the Rv1476 overexpression strain displayed increased susceptibility to different stresses compared to the wild-type strain. Transcriptome analysis showed that Rv1476 overexpression causes changes in the transcriptome of THP-1 cells, and differential genes are mainly enriched in cell proliferation, fatty acid degradation, cytokine-cytokine receptor interaction, and immune response pathways. Rv1476 overexpression inhibited the expression of some anti-tuberculosis-related genes, such as CCL1, IL15, IL16, ISG15, GBP5, IL23, ATG2A, IFNß, and CSF3. Altogether, we conclude that Rv1476 may play a critical role for M. tuberculosis in macrophage survival.
RESUMO
Tuberculosis is a highly lethal bacterial disease worldwide caused by Mycobacterium tuberculosis (Mtb). Caespitate is a phytochemical isolated from Helichrysum caespititium, a plant used in African traditional medicine that shows anti-tubercular activity, but its mode of action remains unknown. It is suggested that there are four potential targets in Mtb, specifically in the H37Rv strain: InhA, MabA, and UGM, enzymes involved in the formation of Mtb's cell wall, and PanK, which plays a role in cell growth. Two caespitate conformational structures from DFT conformational analysis in the gas phase (GC) and in solution with DMSO (CS) were selected. Molecular docking calculations, MM/GBSA analysis, and ADME parameter evaluations were performed. The docking results suggest that CS is the preferred caespitate conformation when interacting with PanK and UGM. In both cases, the two intramolecular hydrogen bonds characteristic of caespitate's molecular structure were maintained to achieve the most stable complexes. The MM/GBSA study confirmed that PanK/caespitate and UGM/caespitate were the most stable complexes. Caespitate showed favorable pharmacokinetic characteristics, suggesting rapid absorption, permeability, and high bioavailability. Additionally, it is proposed that caespitate may exhibit antibacterial and antimonial activity. This research lays the foundation for the design of anti-tuberculosis drugs from natural sources, especially by identifying potential drug targets in Mtb.
RESUMO
Mycobacterium tuberculosis (Mtb) genome possesses a unique family called Proline-Glutamate/Proline-Proline-Glutamate (PE/PPE) gene family, exclusive to pathogenic mycobacterium. Some of these proteins are known to play role in virulence and immune response modulation, but many are still uncharacterized. This study investigated the role of C-terminal region of Rv1039c (PPE15) in inducing mitochondrial perturbations and macrophage apoptosis. Our in-silico studies revealed the disordered, coiled, and hydrophobic C-terminal region in Rv1039c has similarity with C-terminal of mitochondria-targeting pro-apoptotic host proteins. Wild type Rv1039c and C-terminal deleted Rv1039c (Rv1039c-/-Cterm) recombinant proteins were purified and their M. smegmatis knock-in strains were constructed which were used for in-vitro experiments. Confocal microscopy showed localization of Rv1039c to mitochondria of PMA-differentiated THP1 macrophages; and reduced mitochondrial membrane depolarization and production of mitochondrial superoxides were observed in response to Rv1039c-/-Cterm in comparison to full-length Rv1039c. The C-terminal region of Rv1039c was found to activate caspases 3, 7 and 9 along with upregulated expression of pro-apoptotic genes like Bax and Bim. Rv1039c-/-Cterm also reduced the Cytochrome-C release from the mitochondria and the expression of AnnexinV/PI positive and TUNEL positive cells as compared to Rv1039c. Additionally, Rv1039c was observed to upregulate the TLR4-NF-κB-TNF-α signalling whereas the same was downregulated in response to Rv1039c-/-Cterm. These findings suggested that the C-terminal region of Rv1039c is a molecular mimic of pro-apoptotic host proteins which induce mitochondria-dependent macrophage apoptosis and evoke host immune response. These observations enhance our understanding about the role of PE/PPE proteins at host-pathogen interface.
RESUMO
Multidrug-resistant tuberculosis (MDR-TB) patients not cured at the time of stopping treatment are exposed to Minimum Inhibitory Concentration (MIC) and sub-MIC levels for many months after discontinuing bedaquiline (BDQ) or clofazimine (CFZ) treatment. In vitro cultures treated with BDQ and CFZ sub-MIC concentrations clearly showed enrichment in the Rv0678 mutant population, demonstrating that pre-existing Rv0678 mutants can be selected by sub-MIC concentrations of BDQ and CFZ if not protected by an alternative MDR-TB treatment.
Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Mycobacterium tuberculosis/genética , Clofazimina/farmacologia , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Diarilquinolinas/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Testes de Sensibilidade MicrobianaRESUMO
Right ventricular failure (RVF) is a major cause of early mortality after heart transplantation (HT). Isoproterenol (Iso) has chronotropic, inotropic, and vasodilatory properties, which might improve right ventricle function in this setting. We aimed to investigate the hemodynamic effects of isoproterenol on patients with post-HT RVF. We conducted a 1-yr retrospective observational study including patients receiving isoproterenol (Iso) and dobutamine for early RVF after HT. A comprehensive multiparametric hemodynamic evaluation was performed successively three times: no isoproterenol, low doses: 0.025 µg/kg/min, and high doses: 0.05 µg/kg/min (henceforth, respectively, called no Iso, low Iso, and high Iso). From June 2022 to June 2023, 25 patients, median [interquartile range (IQR) 25-75] age 54 [38-61] yr, were included. Before isoproterenol was introduced, all patients received dobutamine, and 15 (60%) were on venoarterial extracorporeal membrane oxygenation (VA-ECMO). Isoproterenol significantly increased heart rate from 84 [77-99] (no Iso) to 91 [88-106] (low Iso) and 102 [90-122] beats/min (high Iso, P < 0.001). Similarly, cardiac index rose from 2.3 [1.4-3.1] to 2.7 [1.8-3.4] and 3 [1.9-3.7] L/min/m2 (P < 0.001) with a concomitant increase in indexed stroke volume (28 [17-34] to 31 [20-34] and 33 [23-35] mL/m2, P < 0.05). Effective pulmonary arterial elastance and pressures were not modified by isoproterenol. Pulmonary vascular resistance (PVR) tended to decrease from 2.9 [1.4-3.6] to 2.3 [1.3-3.5] wood units (WU), P = 0.06. Right ventricular ejection fraction/systolic pulmonary artery pressure (sPAP) evaluating right ventricle-pulmonary artery (RV-PA) coupling increased after isoproterenol from 0.8 to 0.9 and 1%·mmHg-1 (P = 0.001). In conclusion, in post-HT RVF, isoproterenol exhibits chronotropic and inotropic effects, thereby improving RV-PA coupling and resulting in a clinically relevant increase in the cardiac index.NEW & NOTEWORTHY This study offers a detailed and comprehensive hemodynamic investigation at the bedside, illustrating the favorable impact of isoproterenol on right ventricular-pulmonary arterial coupling and global hemodynamics. It elucidates the physiological effects of an underused inotropic strategy in a critical clinical scenario. By enhancing cardiac hemodynamics, isoproterenol has the potential to expedite right ventricular recovery and mitigate primary graft dysfunction, thereby reducing the duration of mechanical support and intensive care unit stay posttransplantation.
Assuntos
Transplante de Coração , Hemodinâmica , Isoproterenol , Artéria Pulmonar , Disfunção Ventricular Direita , Função Ventricular Direita , Humanos , Isoproterenol/farmacologia , Transplante de Coração/efeitos adversos , Pessoa de Meia-Idade , Masculino , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Feminino , Função Ventricular Direita/efeitos dos fármacos , Estudos Retrospectivos , Adulto , Hemodinâmica/efeitos dos fármacos , Idoso , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/etiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Dobutamina/farmacologia , Resultado do Tratamento , Frequência Cardíaca/efeitos dos fármacos , Recuperação de Função Fisiológica , Cardiotônicos/farmacologiaRESUMO
The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles.
Assuntos
Modelos Animais de Doenças , Insuficiência Cardíaca , Mitocôndrias Cardíacas , Animais , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Masculino , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/genética , Proteômica , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/genética , Disfunção Ventricular Direita/patologia , Função Ventricular Direita , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/patologia , Ratos , Função Ventricular Esquerda , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/genética , Transcriptoma , Ratos Sprague-Dawley , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genéticaRESUMO
Resolvin (Rv) and lipoxin (Lx) play important regulative roles in the development of several inflammation-related diseases. The dysregulation of their metabolic network is believed to be closely related to the occurrence and development of asthma. The Hyssopus Cuspidatus Boriss extract (SXCF) has long been used as a treatment for asthma, while the mechanism of anti-inflammatory and anti-asthma action targeting Rv and Lx has not been thoroughly investigated. In this study, we aimed to investigate the effects of SXCF on Rv, Lx in ovalbumin (OVA)-sensitized asthmatic mice. The changes of Rv, Lx before and after drug administration were analyzed based on high sensitivity chromatography-multiple response monitoring (UHPLC-MRM) analysis and multivariate statistics. The pathology exploration included behavioral changes of mice, IgE in serum, cytokines in BALF, and lung tissue sections stained with H&E. It was found that SXCF significantly modulated the metabolic disturbance of Rv, Lx due to asthma. Its modulation effect was significantly better than that of dexamethasone and rosmarinic acid which is the first-line clinical medicine and the main component of Hyssopus Cuspidatus Boriss, respectively. SXCF is demonstrated to be a potential anti-asthmatic drug with significant disease-modifying effects on OVA-induced asthma. The modulation of Rv and Lx is a possible underlying mechanism of the SXCF effects.
Assuntos
Antiasmáticos , Asma , Lipoxinas , Camundongos , Animais , Lipoxinas/farmacologia , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/metabolismo , Antiasmáticos/efeitos adversos , Pulmão/metabolismo , Citocinas/metabolismo , Extratos Vegetais/farmacologia , Camundongos Endogâmicos BALB C , Modelos Animais de DoençasRESUMO
Isonicotinohydrazide is the first-line medication in the prevention and treatment of tuberculosis. Antitubercular, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial activity, anticancer, antineoplastic activity, and anti-HIV activity are all demonstrated by drugs with a pyrimidine ring. The current study focuses on the synthesis of N-(4-(substituted-phenyl)-6-(substituted-aryl) pyrimidin-2-yl)-2-(2-isonicotinoylhydrazinyl) acetamide from isonicotinohydrazide. Newly synthesized compounds were characterized by spectral studies (IR, 1 H-NMR, 13 C-NMR, and mass spectroscopy). They were screened for their antituberculosis, antimalarial, and antiprotozoal activities and compared with standard drugs. Molecular docking of isonicotinohydrazide-bearing pyrimidine motifs was also done for some of the active compounds.
Assuntos
Antimaláricos , Simulação de Acoplamento Molecular , Antituberculosos/farmacologia , Antibacterianos/farmacologia , Isoniazida , Pirimidinas/química , Acetamidas , Relação Estrutura-Atividade , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: A relatively common complication of COVID -19 infection is arrhythmia. There is limited information about myocardial deformation and heart rate variability (HRV) in symptomatic post COVID patients presented by ventricular arrhythmia. AIM OF THE STUDY: Our goal was to assess 2D-ventricular strain and heart rate variability indices (evaluated by ambulatory ECG monitoring) in post-COVID-19 patients suffering from ventricular arrhythmia. METHODS: The current observational case-control study performed on 60 patients one month after they had recovered from the COVID-19 infection. Thirty healthy volunteers served as the control group. Each participant had a full medical history review, blood tests, a 12-lead surface electrocardiogram (ECG), 24-h ambulatory ECG monitoring, and an echo-Doppler examination to evaluate the left ventricular (LV) dimensions, tissue Doppler velocities, and 2D-speckle tracking echocardiography (2D-STE) for both the LV and right ventricular (RV) strain. RESULTS: Symptomatic post-COVID patients with monomorphic premature ventricular contractions (PVCs) showed a substantial impairment of LV/RV systolic and diastolic functions, LV/RV myocardial performance (MPI) with reduced indices of HRV. Patients with higher versus lower ventricular burden had poorer functional status, higher levels of inflammatory biomarkers and reduced parameters of HRV (New York Heart Association (NYHA) class: 2.1 ± 0.9 vs. 1.5 ± 0.6, p < 0.001, C-reactive protein (CRP): 13.3 ± 4.1 vs. 8.3 ± 5.9 mg/L, p < 0.0001, low frequency/high frequency (LF/HF): 3.6 ± 2.4 vs. 2.2 ± 1.2, p < 0.002, the root mean square of the difference between successive normal intervals (rMSSD): 21.8 ± 4.7 vs. 29.3 ± 14.9 ms, p < 0.039 and the standard deviation of the RR interval (SDNN): 69.8 ± 19.1 vs.108.8 ± 37.4 ms, p < 0.0001). The ventricular burden positively correlated with neutrophil/lymphocyte ratio (NLR) (r = 0.33, p < 0.001), CRP (r = 0.60, p < 0.0001), while it negatively correlated with LV-global longitudinal strain (GLS) (r = -0.38, p < 0.0001), and RV-GLS (r = -0.37, p < 0.0001). CONCLUSIONS: Patients with post-COVID symptoms presented by ventricular arrhythmia had poor functional status. Patients with post-COVID symptoms and ventricular arrhythmia had subclinical myocardial damage, evidenced by speckle tracking echocardiography while having apparently preserved LV systolic function. The burden of ventricular arrhythmia in post-COVID patients significantly correlated with increased inflammatory biomarkers and reduced biventricular strain.
Assuntos
COVID-19 , Eletrocardiografia Ambulatorial , Frequência Cardíaca , Complexos Ventriculares Prematuros , Humanos , COVID-19/complicações , COVID-19/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Complexos Ventriculares Prematuros/fisiopatologia , Complexos Ventriculares Prematuros/diagnóstico , Complexos Ventriculares Prematuros/etiologia , Adulto , Função Ventricular Esquerda , Ecocardiografia Doppler , Valor Preditivo dos Testes , SARS-CoV-2 , Função Ventricular DireitaRESUMO
BACKGROUND: Atrial septal defects (ASD) are the most common type of adult congenital heart disease (ACHD) associated with a high risk developing of pulmonary arterial hypertension (PAH). ASD closure is not recommended in patients with PAH and Pulmonary Vascular Resistance (PVR) ≥ 5 Wood Unit (WU). Noninvasive methods have been proposed to measure PVR; however, their accuracy remains low. Right Ventricle (RV) - Pulmonary Artery (PA) coupling is defined as the ability of the RV to adapt to high-resistance conditions. Tricuspid Annular Plane Systolic Excursion (TAPSE)/estimated pulmonary artery systolic pressure (ePASP) calculation using echocardiography is a noninvasive technique that has been proposed as a surrogate equation to evaluate RV-PA coupling. Currently, no research has demonstrated a relationship between RV-PA coupling and PVR in patients with ASD. METHODS: The study participants were consecutive eligible patients with ASD who underwent right heart catheterization (RHC) and echocardiography at Hasan Sadikin General Hospital, Bandung. Both the procedures were performed on the same day. RV-PA Coupling, defined as TAPSE/ePASP > 0.31, was assessed using echocardiography. The PVR was calculated during RHC using the indirect Fick method. RESULTS: There were 58 patients with ASD underwent RHC and echocardiography. Among them, 18 had RV/PA Coupling and 40 had RV/PA Uncoupling. The PVR values were significantly different between the two groups (p = 0.000). Correlation test between TAPSE/ePASP with PVR showed moderate negative correlation (r= -0.502, p = 0.001). TAPSE/ePASP ≤ 0.34 is the cutoff point to predict PVR > 5 WU with sensitivity of 91.7% and specificity 63.6%. CONCLUSION: This study showed a moderate negative correlation between TAPSE/ePASP and PVR. TAPSE/ePASP ≤ 0.34 could predict PVR > 5 WU with good sensitivity.
Assuntos
Cateterismo Cardíaco , Comunicação Interatrial , Artéria Pulmonar , Resistência Vascular , Função Ventricular Direita , Humanos , Comunicação Interatrial/fisiopatologia , Comunicação Interatrial/diagnóstico por imagem , Comunicação Interatrial/complicações , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/diagnóstico por imagem , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Pressão Arterial , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/diagnóstico por imagem , Valor Preditivo dos TestesRESUMO
INTRODUCTION: As an infectious disease, tuberculosis (TB) poses a serious threat to public health. Although amikacin (AMK) is an important antibiotic for the treatment of drug-resistant TB, its resistance mechanisms are not fully understood. METHODS: To investigate the role of Rv3737 gene on AMK drug susceptibility, a Mycobacterium tuberculosis (M.tb) Rv3737 knockout strain (H37Rvâ³Rv3737) and a Mycobacterium smegmatis (M.sm) Rv3737 overexpressing strain (Msm/pMV261-Rv3737) were used to detect their minimal inhibitory concentrations (MICs) in this study. RESULTS: The AMK MICs of Rv3737 knockout and overexpressing strains were 4-fold lower and 2-fold higher than those of the wild-type and empty plasmid strains, respectively. The results of clinical isolates showed that no Rv3737 gene mutation was found to be associated with AMK susceptibility, while the rrs A1401G mutation remained the main mechanism of high level of AMK resistance (MIC>32 µg/ml). There was a positive correlation between Rv3737 mRNA expression level and AMK MIC. In the isolates with low-level AMK resistance (MIC = 4 µg/ml) without rrs A1401G mutation, the expression level of Rv3737 gene was significantly higher than those of susceptible isolates. CONCLUSIONS: In this study, the Rv3737 gene was reported for the first time for its effect on AMK susceptibility in M.tb. Although the rrs A1401G mutation remains the main reason of high-level AMK resistance, high expression of the Rv3737 gene was associated with low-level AMK resistance in clinical isolates.
Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Amicacina/farmacologia , Amicacina/uso terapêutico , Canamicina/farmacologia , Capreomicina/farmacologia , Capreomicina/uso terapêutico , Farmacorresistência Bacteriana Múltipla/genética , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Mutação , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Testes de Sensibilidade MicrobianaRESUMO
Chronic thromboembolic pulmonary hypertension (CTEPH) results from an incomplete resolution of acute pulmonary embolism, leading to occlusive organized thrombi, vascular remodeling, and associated microvasculopathy with pulmonary hypertension (PH). A definitive CTEPH diagnosis requires PH confirmation by right-heart catheterization and evidence of chronic thromboembolic pulmonary disease on imaging studies. Surgical removal of the organized fibrotic material by pulmonary endarterectomy (PEA) under deep hypothermic circulatory arrest represents the treatment of choice. One-third of patients with CTEPH are not deemed suitable for surgical treatment, and medical therapy or interventional balloon pulmonary angioplasty presents alternative treatment options. Pulmonary endarterectomy in patients with technically operable disease significantly improves symptoms, functional capacity, hemodynamics, and quality of life. Perioperative mortality is <2.5% in expert centers where a CTEPH multidisciplinary team optimizes patient selection and ensures the best preoperative optimization according to individualized risk assessment. Despite adequate pulmonary artery clearance, patients might be prone to perioperative complications, such as right ventricular maladaptation, airway bleeding, or pulmonary reperfusion injury. These complications can be treated conventionally, but extracorporeal membrane oxygenation has been included in their management recently. Patients with residual PH post-PEA should be considered for medical or percutaneous interventional therapy.
Assuntos
Angioplastia com Balão , Hipertensão Pulmonar , Embolia Pulmonar , Tromboembolia , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/cirurgia , Qualidade de Vida , Doença Crônica , Embolia Pulmonar/complicações , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/cirurgia , Artéria Pulmonar/cirurgia , Angioplastia com Balão/métodos , Período Perioperatório , Endarterectomia/métodosRESUMO
Children with COVID-associated multisystem inflammatory syndrome (MIS-C) may develop severe disease. We explored the association of admission echocardiographic and laboratory parameters with MIS-C disease severity. This retrospective, single center study of consecutive MIS-C patients (4/2020-12/2021) excluded those with preexisting cardiomyopathy, congenital heart disease, or prior cardiotoxic therapy. Our hypothesis was that worse admission echocardiographic and laboratory parameters were associated with more severe disease based on vasoactive medication use. Univariable and multivariable logistic regression models assessed the association between vasoactive medication use and baseline variables. Of 118 MIS-C patients, median age was 7.8 years (IQR 4.6, 11.8), 48% received vasoactive medication. Higher admission brain natriuretic peptide [OR 1.07 (95% CI 1.02,1.14), p = 0.019], C-reactive protein [OR 1.08 (1.03,1.14), p = 0.002], troponin [OR 1.05 (1.02,1.1), p = 0.015]; lower left ventricular ejection fraction [LVEF, OR 0.96 (0.92,1), p = 0.042], and worse left atrial reservoir strain [OR 0.96 (0.92,1), p = 0.04] were associated with vasoactive medication use. Only higher CRP [OR 1.07 (1.01, 1.11), p = 0.034] and lower LVEF [0.91 (0.84,0.98), p = 0.015] remained independently significant. Among those with normal admission LVEF (78%, 92/118), 43% received vasoactive medication and only higher BNP [OR 1.09 (1.02,1.19), p = 0.021 per 100 pg/mL] and higher CRP [OR 1.07 (1.02,1.14), p = 0.013] were associated with use of vasoactive medication. Nearly half of all children admitted for MIS-C subsequently received vasoactive medication, including those admitted with a normal LVEF. Similarly, admission strain parameters were not discriminatory. Laboratory markers of systemic inflammation and cardiac injury may better predict early MIS-C disease severity.
Assuntos
Ecocardiografia , Função Ventricular Esquerda , Criança , Humanos , Volume Sistólico , Estudos Retrospectivos , Peptídeo Natriurético Encefálico , Gravidade do PacienteRESUMO
In pursuit of potential chemotherapeutic alternates to combat severe tuberculosis infections, novel heterocyclic templates derived from clinically approved anti-TB drug isoniazid and isatin have been synthesized that demonstrate potent inhibitory action against Mycobacterium tuberculosis, and compound 4i with nitrophenyl motif exhibited the highest anti-TB efficacy with a MIC value of 2.54 µM/ml. Notably, the same nitro analog 4i shows the best antioxidant efficacy among all the synthesized compounds with an IC50 value of 37.37 µg/ml, suggesting a synergistic influence of antioxidant proficiency on the anti-TB action. The titled compounds exhibit explicit binding affinity with the InhA receptor. The befitting biochemical reactivity and near-appropriate pharmacokinetic proficiency of the isoniazid conjugates is reflected in the density functional theory (DFT) studies and ADMET screening. The remarkable anti-TB action of the isoniazid cognates with marked radical quenching ability may serve as a base for developing multi-target medications to confront drug-resistant TB pathogens. Keywords Isoniazid . Isatin . H37Rv . Antituberculosis . Antioxidant . Molecular Docking.
RESUMO
With the rise of multidrug-resistant tuberculosis, the imperative for an alternative and superior treatment regimen, incorporating novel mechanisms of action, has become crucial. In pursuit of this goal, we have developed and synthesized a new series of rhodanine-linked enamine-carbohydrazide derivatives, exploring their potential as inhibitors of mycobacterial carbonic anhydrase. The findings reveal their efficacy, displaying notable selectivity toward the mycobacterial carbonic anhydrase 2 (mtCA 2) enzyme. While exhibiting moderate activity against human carbonic anhydrase isoforms, this series demonstrates promising selectivity, positioning these compounds as potential antitubercular agents. Compound 6d was the best one from the series with a Ki value of 9.5 µM toward mtCA 2. Most of the compounds displayed moderate to good inhibition against the Mtb H37Rv strain; compound 11k showed a minimum inhibitory concentration of 1 µg/mL. Molecular docking studies revealed that compounds 6d and 11k show metal coordination with the zinc ion, like classical CA inhibitors.