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1.
Blood ; 136(6): 749-754, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32548640

RESUMO

Several studies demonstrate that hemolysis and free heme in circulation cause endothelial barrier dysfunction and are associated with severe pathological conditions such as acute respiratory distress syndrome, acute chest syndrome, and sepsis. However, the precise molecular mechanisms involved in the pathology of heme-induced barrier disruption remain to be elucidated. In this study, we investigated the role of free heme in the endothelial barrier integrity and mechanisms of heme-mediated intracellular signaling of human lung microvascular endothelial cells (HLMVECs). Heme, in a dose-dependent manner, induced a rapid drop in the endothelial barrier integrity of HLMVECs. An investigation into barrier proteins revealed that heme primarily affected the tight junction proteins zona occludens-1, claudin-1, and claudin-5, which were significantly reduced after heme exposure. The p38MAPK/HSP27 pathway, involved in the regulation of endothelial cytoskeleton remodeling, was also significantly altered after heme treatment, both in HLMVECs and mice. By using a knockout (KO) mouse for MKK3, a key regulator of the p38MAPK pathway, we showed that this KO effectively decreased heme-induced endothelial barrier dysfunction. Taken together, our results indicate that targeting the p38MAPK pathway may represent a crucial treatment strategy in alleviating hemolytic diseases.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Heme/farmacologia , MAP Quinase Quinase 3/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Antígenos CD/análise , Caderinas/análise , Permeabilidade Capilar/fisiologia , Células Cultivadas , Claudinas/análise , Células Endoteliais/fisiologia , Proteínas de Choque Térmico HSP27/fisiologia , Proteínas de Choque Térmico/fisiologia , Hemólise , Humanos , Pulmão/irrigação sanguínea , MAP Quinase Quinase 3/deficiência , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Knockout , Microvasos/citologia , Chaperonas Moleculares/fisiologia , Junções Íntimas/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/análise , Proteínas Quinases p38 Ativadas por Mitógeno
2.
Int J Environ Health Res ; 32(6): 1403-1417, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33573386

RESUMO

Chronic Obstructive Pulmonary Disease (COPD) is attributable to household air pollution and is known to increase the Disability Adjusted Life Years (DALYs), morbidity and mortality and women are most susceptible groups for the exposure. In order to understand the global risk among women with COPD due to exposure of household air pollutants, an evidence-based systematic review and meta-analysis was conducted. Meta regression analysis was carried out to identify potential sources of heterogeneity. The summary estimates of the included studies showed higher prevalence of COPD due to biomass fuel exposure in women. Clinical diagnosis has shown more risk of COPD prevalence compared to diagnosis based on spirometer test alone. However, the data between included studies for both clinical and spirometry-based studies showed higher heterogeneity. The present meta-data analysis has shown that household air pollutants may be a factor associated with increased risk of COPD in women.


Assuntos
Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Poluição do Ar , Doença Pulmonar Obstrutiva Crônica , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/análise , Poluição do Ar em Ambientes Fechados/efeitos adversos , Poluição do Ar em Ambientes Fechados/análise , Biomassa , Feminino , Humanos , Masculino , Prevalência , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fatores de Risco
3.
Mol Pharm ; 17(2): 604-621, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31904978

RESUMO

Acute myeloid leukemia (AML) is a malignant disorder of hematopoietic progenitor cells with a poor prognosis of 26% of patients surviving 5 years after diagnosis. Poor bioavailability and solubility are significant factors limiting the efficacy of chemopreventive agents. In AML, the epigenetic regulator polycomb group of protein member EZH2 is highly expressed and is essential for the survival of leukemic cells. An EZH2-specific inhibitor, EPZ011989, encapsulated in human serum albumin nanoparticles (HSANPs) was synthesized for the first time via the desolvation method. The noncovalent interactions between EPZ011989 and HSANPs in nanocomposites facilitating the efficient loading and sustainable release of the drug showed enhanced cellular uptake and nuclear localization of EPZ011989-loaded HSANPs in human AML cell lines. The reduction of cell viability, colony formation inhibition, cell cycle arrest at the G2/M phase, and cell proliferation assay promoting apoptosis through the loss of mitochondrial homeostasis exerting antileukemic activity were evident. The real-time polymerase chain reaction (PCR) and western blot-based studies showed that the present nanoformulation reduces the level of PcG proteins, including EZH2, BMI-1, etc. This downregulation is associated with reduced H3K27me3 and H2AK119ub modifications conferring chromatin compaction. The immunoprecipitation study showed the physical interaction of EZH2 and c-Myb can be linked to the regulation of leukemogenesis. Further investigation revealed the mechanism of EZH2 and c-Myb downregulation via ubiquitination and proteasomal degradation pathway, confirmed by using proteasome inhibitor, suggesting the key role of proteasomal degradation machinery. Moreover, c-Myb interacted with the EZH2 promoter, which is evident by the chromatin immunoprecipitation assay and siRNA silencing. Furthermore, the formulation of EPZ011989 in HSANPs improved its biodistribution in vivo and showed excellent aqueous dispersibility and biocompatibility. In vivo studies further showed that EPZ011989-loaded HSANPs reduce the expression of CD11b+ and CD45+ markers in immunophenotyping from peripheral blood and bone marrow in engrafted nude mice. Targeted depletion of EZH2 alleviated the disease progression in nude mice and prolonged their survival. The findings provide valuable experimental evidence for the targeted epigenetic therapy of AML. The present results demonstrate an epigenetic regulation-based superior antileukemic therapy.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Epigênese Genética/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Nanopartículas/administração & dosagem , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myb/genética , Animais , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células HL-60 , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Albumina Sérica Humana/química , Distribuição Tecidual , Transfecção , Células U937 , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nanomedicine ; 24: 102088, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31476446

RESUMO

Posttranslational modification and agglomeration of α-synuclein (α-Syn), mitochondrial dysfunction, oxidative stress and loss of dopaminergic neurons are hallmark of Parkinson's disease (PD). This paper evaluates neuroprotection efficacy of nature inspired biocompatible polydopamine nanocarrier for metformin delivery (Met encapsulated PDANPs) by crossing blood brain barrier in in vitro, 3D and in vivo experimental PD models. The neuroprotective potential was arbitrated by downregulation of phospho-serine 129 (pSer129) α-Syn, with reduction in oxidative stress, prevention of apoptosis and anti-inflammatory activities. The neuroprotective mechanism proved novel interaction of epigenetic regulator EZH2 mediated ubiquitination and proteasomal degradation of aggregated pSer129 α-Syn. In summary, this study divulges the neuroprotective role of Met loaded PDANPs by reversing the neurochemical deficits by confirming an epigenetic mediated nanotherapeutic approach for the PD prevention.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Metformina , Modelos Biológicos , Nanoestruturas , Doença de Parkinson/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , alfa-Sinucleína/metabolismo , Linhagem Celular Tumoral , Humanos , Indóis/química , Indóis/farmacologia , Metformina/química , Metformina/farmacologia , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Polímeros/química , Polímeros/farmacologia
5.
J Neurochem ; 148(2): 238-251, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30308090

RESUMO

Brain-derived neurotrophic factor (BDNF) which is primarily associated with neuronal survivability, differentiation and synaptic plasticity has been reported to mediate neurodegeneration in hypoxia through its p75 Neurotrophin receptors (p75NTR). The molecular events promoting BDNF-mediated pro-death signalling in hypoxia, however, still remain an enigma. This study attempts towards deciphering the signalling cascades involved in alteration of BDNF isoforms and its cognate receptor subtypes leading to neurodegeneration in hypoxia. Adult Sprague-Dawley rats were exposed to global hypobaric hypoxia simulating an altitude of 7620 m at standard temperature and humidity. Chronic hypoxic exposure for 7 days resulted in higher expression of pro-BDNF and alteration in N-linked glycosylation in hippocampus along with increased expression of endoplasmic reticulum stress markers viz., glucose-regulated protein (Grp78), calnexin and changes in the endoplasmic reticulum morphology. Our findings reveal enriched expression of p75NTR in lipid rafts and higher expression of tyrosine receptor kinase ß (Trkß) in non-raft regions following hypoxic exposure. Further investigations on membrane properties revealed decline in membrane fluidity along with increased cholesterol oxidation resulting in reduced translocation of Trkß from non-raft to raft regions. Supplementation of vitamin E during hypoxic exposure on the other hand reduced cholesterol oxidation and increased translocation of Trkß from non-raft to raft regions and promoted neuronal survival. Hence, our findings suggest a novel mechanism of cholesterol oxidation-induced alteration in raft dynamics which is promotes p75 receptor-mediated death signalling in hippocampal neurons during chronic hypoxia.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colesterol/metabolismo , Hipocampo/fisiopatologia , Hipóxia/fisiopatologia , Degeneração Neural/fisiopatologia , Animais , Apoptose/fisiologia , Hipocampo/metabolismo , Masculino , Microdomínios da Membrana/metabolismo , Microdomínios da Membrana/patologia , Proteínas do Tecido Nervoso , Neurônios/metabolismo , Neurônios/patologia , Oxirredução , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Fatores de Crescimento , Receptores de Fator de Crescimento Neural/metabolismo , Transdução de Sinais/fisiologia
7.
Am J Respir Cell Mol Biol ; 59(3): 334-345, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29652520

RESUMO

Although hemolytic anemia-associated pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are more common than the prevalence of idiopathic PAH alone, the role of hemolysis in the development of PAH is poorly characterized. We hypothesized that hemolysis independently contributes to PAH pathogenesis via endothelial barrier dysfunction with resulting perivascular edema and inflammation. Plasma samples from patients with and without PAH (both confirmed by right heart catheterization) were used to measure free hemoglobin (Hb) and its correlation with PAH severity. A sugen (50 mg/kg)/hypoxia (3 wk)/normoxia (2 wk) rat model was used to elucidate the role of free Hb/heme pathways in PAH. Human lung microvascular endothelial cells were used to study heme-mediated endothelial barrier effects. Our data indicate that patients with PAH have increased levels of free Hb in plasma that correlate with PAH severity. There is also a significant accumulation of free Hb and depletion of haptoglobin in the rat model. In rats, perivascular edema was observed at early time points concomitant with increased infiltration of inflammatory cells. Heme-induced endothelial permeability in human lung microvascular endothelial cells involved activation of the p38/HSP27 pathway. Indeed, the rat model also exhibited increased activation of p38/HSP27 during the initial phase of PH. Surprisingly, despite the increased levels of hemolysis and heme-mediated signaling, there was no heme oxygenase-1 activation. This can be explained by observed destabilization of HIF-1a during the first 2 weeks of PH regardless of hypoxic conditions. Our data suggest that hemolysis may play a significant role in PAH pathobiology.


Assuntos
Hemoglobinas/metabolismo , Hemólise/fisiologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Pulmão/irrigação sanguínea , Adulto , Idoso , Animais , Modelos Animais de Doenças , Feminino , Humanos , Hipóxia/complicações , Pneumopatias/patologia , Masculino , Pessoa de Meia-Idade , Ratos , Remodelação Vascular/fisiologia
8.
PLoS Pathog ; 12(11): e1005943, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27812211

RESUMO

Leptospirosis causes significant morbidity and mortality worldwide; however, the role of the host immune response in disease progression and high case fatality (>10-50%) is poorly understood. We conducted a multi-parameter investigation of patients with acute leptospirosis to identify mechanisms associated with case fatality. Whole blood transcriptional profiling of 16 hospitalized Brazilian patients with acute leptospirosis (13 survivors, 3 deceased) revealed fatal cases had lower expression of the antimicrobial peptide, cathelicidin, and chemokines, but more abundant pro-inflammatory cytokine receptors. In contrast, survivors generated strong adaptive immune signatures, including transcripts relevant to antigen presentation and immunoglobulin production. In an independent cohort (23 survivors, 22 deceased), fatal cases had higher bacterial loads (P = 0.0004) and lower anti-Leptospira antibody titers (P = 0.02) at the time of hospitalization, independent of the duration of illness. Low serum cathelicidin and RANTES levels during acute illness were independent risk factors for higher bacterial loads (P = 0.005) and death (P = 0.04), respectively. To investigate the mechanism of cathelicidin in patients surviving acute disease, we administered LL-37, the active peptide of cathelicidin, in a hamster model of lethal leptospirosis and found it significantly decreased bacterial loads and increased survival. Our findings indicate that the host immune response plays a central role in severe leptospirosis disease progression. While drawn from a limited study size, significant conclusions include that poor clinical outcomes are associated with high systemic bacterial loads, and a decreased antibody response. Furthermore, our data identified a key role for the antimicrobial peptide, cathelicidin, in mounting an effective bactericidal response against the pathogen, which represents a valuable new therapeutic approach for leptospirosis.


Assuntos
Peptídeos Catiônicos Antimicrobianos/imunologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Leptospirose/imunologia , Animais , Brasil , Análise por Conglomerados , Cricetinae , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Mesocricetus , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Risco , Catelicidinas
9.
Respir Res ; 19(1): 69, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29685148

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease; however, the mechanisms directly involved in triggering and the progression of PAH are not clear. Based on previous studies that demonstrated a possible role of mitochondrial dysfunction in the pathogenesis of PAH, we investigated the effects of chronic inhibition of mitochondrial function in vivo in healthy rodents. METHODS: Right ventricle systolic pressure (RVSP) was measured in female rats at baseline and up to 24 days after inhibition of mitochondrial respiratory Complex III, induced by Antimycin A (AA, 0.35 mg/kg, given three times starting at baseline and then days 3 and 6 as a bolus injection into the right atrial chamber). RESULTS: Rodents exposed to AA demonstrated sustained increases in RVSP from days 6 through 24. AA-exposed rodents also possessed a progressive increase in RV end-diastolic pressure but not RV hypertrophy, which may be attributed to either early stages of PAH development or to reduced RV contractility due to inhibition of myocardial respiration. Protein nitration levels in plasma were positively correlated with PAH development in AA-treated rats. This finding was strongly supported by results obtained from PAH humans where plasma protein nitration levels were correlated with markers of PAH severity in female but not male PAH patients. Based on previously reported associations between increased nitric oxide production levels with female gender, we speculate that in females with PAH mitochondrial dysfunction may represent a more deleterious form, in part, due to an increased nitrosative stress development. Indeed, the histological analysis of AA treated rats revealed a strong perivascular edema, a marker of pulmonary endothelial damage. Finally, AA treatment was accompanied by a severe metabolic shift toward glycolysis, a hallmark of PAH pathology. CONCLUSIONS: Chronic mitochondrial dysfunction induces the combination of vascular damage and metabolic reprogramming that may be responsible for PAH development. This mechanism may be especially important in females, perhaps due to an increased NO production and nitrosative stress development.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Glicólise/fisiologia , Hipertensão Pulmonar/metabolismo , Pulmão/metabolismo , Mitocôndrias/metabolismo , Vasoconstrição/fisiologia , Animais , Antimicina A/toxicidade , Feminino , Glicólise/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/fisiopatologia , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Mitocôndrias/efeitos dos fármacos , Monocrotalina/toxicidade , Ratos , Ratos Sprague-Dawley , Vasoconstrição/efeitos dos fármacos , Disfunção Ventricular Direita/induzido quimicamente , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/fisiopatologia
10.
Nanotechnology ; 28(36): 365102, 2017 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-28820142

RESUMO

Melatonin (MEL) has promising medicinal value as an anticancer agent in a variety of malignancies, but there are difficulties in achieving a therapeutic dose due to its short half-life, low bioavailability, poor solubility and extensive first-pass metabolism. In this study chitosan/tripolyphosphate (TPP) nanoparticles were prepared by an ionic gelation method to overcome the therapeutic challenges of melatonin and to improve its anticancer efficacy. Characterization of the melatonin-loaded chitosan (MEL-CS) nanoformulation was performed using transmission and scanning electron microscopies, dynamic light scattering, Fourier transform infrared spectroscopy, Raman spectroscopy and x-ray diffraction. In vitro release, cellular uptake and efficacy studies were tested for their enhanced anticancer potential in human U87MG glioblastoma cells. Confocal studies revealed higher cellular uptake of MEL-CS nanoparticles and enhanced anticancer efficacy in human malignant glioblastoma cancer cells than in healthy non-malignant human HEK293T cells in mono- and co-culture models. Our study has shown for the first time that MEL-CS nanocomposites are therapeutically more effective as compared to free MEL at inducing functional anticancer efficacy in the human brain tumour U87MG cell line.

11.
Adv Exp Med Biol ; 967: 105-137, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29047084

RESUMO

The generation of reactive oxygen species (ROS) plays an important role for the maintenance of cellular processes and functions in the body. However, the excessive generation of oxygen radicals under pathological conditions such as acute lung injury (ALI) and its most severe form acute respiratory distress syndrome (ARDS) leads to increased endothelial permeability. Within this hallmark of ALI and ARDS, vascular microvessels lose their junctional integrity and show increased myosin contractions that promote the migration of polymorphonuclear leukocytes (PMNs) and the transition of solutes and fluids in the alveolar lumen. These processes all have a redox component, and this chapter focuses on the role played by ROS during the development of ALI/ARDS. We discuss the origins of ROS within the cell, cellular defense mechanisms against oxidative damage, the role of ROS in the development of endothelial permeability, and potential therapies targeted at oxidative stress.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Animais , Antioxidantes/metabolismo , Permeabilidade Capilar , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Humanos , Modelos Biológicos , Oxirredução , Estresse Oxidativo , Síndrome do Desconforto Respiratório/fisiopatologia , Transdução de Sinais
12.
Am J Physiol Lung Cell Mol Physiol ; 306(7): L604-19, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24487387

RESUMO

Sepsis is a systemic inflammatory response to infection and a major cause of death worldwide. Because specific therapies to treat sepsis are limited, and underlying pathogenesis is unclear, current medical care remains purely supportive. Therefore targeted therapies to treat sepsis need to be developed. Although an important mediator of sepsis is thought to be mitochondrial dysfunction, the underlying molecular mechanism is unclear. Modulation of mitochondrial processes may be an effective therapeutic strategy in sepsis. Here, we investigated the role of the kinase MKK3 in regulation of mitochondrial function in sepsis. Using clinically relevant animal models, we examined mitochondrial function in primary mouse lung endothelial cells exposed to LPS. MKK3 deficiency reduces lethality of sepsis in mice and by lowering levels of lung and mitochondrial injury as well as reactive oxygen species. Furthermore, MKK3 deficiency appeared to simultaneously increase mitochondrial biogenesis and mitophagy through the actions of Sirt1, Pink1, and Parkin. This led to a more robust mitochondrial network, which we propose provides protection against sepsis. We also detected higher MKK3 activation in isolated peripheral blood mononuclear cells from septic patients compared with nonseptic controls. Our findings demonstrate a critical role for mitochondria in the pathogenesis of sepsis that involves a previously unrecognized function of MKK3 in mitochondrial quality control. This mitochondrial pathway may help reveal new diagnostic markers and therapeutic targets against sepsis.


Assuntos
Lesão Pulmonar/etiologia , MAP Quinase Quinase 3/sangue , MAP Quinase Quinase 3/deficiência , Mitocôndrias/fisiologia , Mitofagia , Sepse/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Animais , Células Endoteliais/metabolismo , Feminino , Humanos , Lipopolissacarídeos , Pulmão/metabolismo , MAP Quinase Quinase 3/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Proteínas Quinases/metabolismo , Sepse/complicações , Sirtuína 1/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo
13.
Nutr Neurosci ; 17(4): 164-71, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24257078

RESUMO

OBJECTIVE: Decalepis hamiltonii roots are traditionally consumed as general vitalizer and used in ayurvedic medicine preparations. We have isolated/characterized potent antioxidants from the aqueous extract of the root of this plant. In this study, we examined the antioxidant potential of the aqueous extract of the roots of D. hamiltonii (DHAE) against hexachlorocyclohexane (HCH)-induced oxidative stress in four major regions of the rat brain. METHODS: The antioxidant activity of the standardized DHAE with known antioxidant constituents was tested against HCH-induced oxidative stress in the major brain regions of 60-day-old adult male Wistar rats. RESULTS: Pretreatment of rats with multiple doses of DHAE, 50 and 100 mg/kg body weight (b.w.), for 7 consecutive days significantly prevented the HCH-induced (single dose -500 mg/kg b.w.) increase in lipid peroxidation, reduction in glutathione, and altered antioxidant enzyme activities viz. superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase in major rat brain regions viz. cortex, cerebellum, midbrain, and brain stem. DHAE, per se, elevated the antioxidant status of the rat brain. DISCUSSION: DHAE shows protective action against HCH-induced oxidative stress in rat brain regions. The protective effect of DHAE could be ascribed to the isolated/characterized antioxidant compounds which could be prospective novel nutraceuticals.


Assuntos
Antioxidantes/farmacologia , Hexaclorocicloexano/toxicidade , Inseticidas/toxicidade , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Apocynaceae/química , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Ayurveda , Raízes de Plantas/química , Ratos , Ratos Wistar
14.
Mol Microbiol ; 85(6): 1148-65, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22780904

RESUMO

Host-generated oxidative stress is considered one of the main mechanisms constraining Mycobacterium tuberculosis (Mtb) growth. The redox-sensing mechanisms in Mtb are not completely understood. Here we show that WhiB4 responds to oxygen (O2) and nitric oxide (NO) via its 4Fe-4S cluster and controls the oxidative stress response in Mtb. The WhiB4 mutant (MtbΔwhiB4) displayed an altered redox balance and a reduced membrane potential. Microarray analysis demonstrated that MtbΔwhiB4 overexpresses the antioxidant systems including alkyl hydroperoxidase (ahpC-ahpD) and rubredoxins (rubA-rubB). DNA binding assays showed that WhiB4 [4Fe-4S] cluster is dispensable for DNA binding. However, oxidation of the apo-WhiB4 Cys thiols induced disulphide-linked oligomerization, DNA binding and transcriptional repression, whereas reduction reversed the effect. Furthermore, WhiB4 binds DNA with a preference for GC-rich sequences. Expression analysis showed that oxidative stress repressed whiB4 and induced antioxidants in Mtb, while their hyper-induction was observed in MtbΔwhiB4. MtbΔwhiB4 showed increased resistance to oxidative stress in vitro and enhanced survival inside the macrophages. Lastly, MtbΔwhiB4 displayed hypervirulence in the lungs of guinea pigs, but showed a defect in dissemination to their spleen. These findings suggest that WhiB4 systematically calibrates the activation of oxidative stress response in Mtb to maintain redox balance, and to modulate virulence.


Assuntos
Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Viabilidade Microbiana , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidade , Estresse Oxidativo , Estresse Fisiológico , Animais , Proteínas de Bactérias/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Deleção de Genes , Perfilação da Expressão Gênica , Cobaias , Pulmão/microbiologia , Macrófagos/imunologia , Macrófagos/microbiologia , Análise em Microsséries , Óxido Nítrico/toxicidade , Oxidantes/toxicidade , Oxigênio/toxicidade , Baço/microbiologia , Virulência , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
15.
Rev Environ Health ; 28(2-3): 117-28, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24192498

RESUMO

Ultrafine particles (UfPs, PM<0.1) are constituents of urban ambient air aerosol. We have reviewed literature on UfPs in urban ambient air and their health perspectives. Generally traffic-linked and of anthropogenic origin, these are toxicants and a health risk factor for urban subjects. UfPs occur in single and agglomerate forms. Studies on the number concentrations of UfPs show tens of thousand times greater levels in urban aerosol than in nonurban aerosol. These nanosize pollutants seem to have more aggressive implications than other respirable fractions of urban aerosol. In literature, it is hypothesized that a chronic exposure to their high number concentrations and their vast surface area, transporting various toxicants, injure tissues or cells and induce inflammation or, eventually, adverse health effects. UfPs are deposited deep in the tissues, translocate, and skip the innate clearance mechanisms. After retention for a long time, these can infiltrate into the interstitium and permeate cells. Traffic-linked UfPs have been found to be toxic to the respiratory, cardiovascular, and nervous systems. At the molecular level, UfPs influence signaling cascade, actin-cytoskeleton pathway, immunoregulation, reactive oxygen species generation to trigger histaminic response, mast cell activation, and pro-inflammatory changes; their mutagenic and carcinogenic effects are also tacit in view of the carcinogenic potential of diesel exhaust in humans. The molecular changes are proposed to be the subclinical effects that manifest disease exacerbations or the predisposition of subjects to pathologies after exposure to UfP. A legislatively regulated monitoring of UfP-contaminated urban ambient air environment is also endorsed to reduce the disease load or its exacerbation that is growing in diesel exhaust (a human carcinogen)-polluted urban areas.


Assuntos
Cidades , Tamanho da Partícula , Material Particulado/efeitos adversos , Material Particulado/química , Humanos
16.
Hepatology ; 54(1): 153-63, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21520201

RESUMO

UNLABELLED: Chronic alcohol-induced liver disease results in inflammation, steatosis, and increased oxidative and nitrosative damage to the mitochondrion. We hypothesized that targeting an antioxidant to the mitochondria would prevent oxidative damage and attenuate the steatosis associated with alcoholic liver disease. To test this we investigated the effects of mitochondria-targeted ubiquinone (MitoQ) (5 and 25 mg/kg/day for 4 weeks) in male Sprague-Dawley rats consuming ethanol using the Lieber-DeCarli diet with pair-fed controls. Hepatic steatosis, 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE), hypoxia inducible factor α (HIF1α), and the activity of the mitochondrial respiratory chain complexes were assessed. As reported previously, ethanol consumption resulted in hepatocyte ballooning, increased lipid accumulation in the form of micro and macrovesicular steatosis, and induction of cytochrome P450 2E1 (CYP2E1). MitoQ had a minor effect on the ethanol-dependent decrease in mitochondrial respiratory chain proteins and their activities; however, it did decrease hepatic steatosis in ethanol-consuming animals and prevented the ethanol-induced formation of 3-NT and 4-HNE. Interestingly, MitoQ completely blocked the increase in HIF1α in all ethanol-fed groups, which has previously been demonstrated in cell culture models and shown to be essential in ethanol-dependent hepatosteatosis. CONCLUSION: These results demonstrate the antioxidant capacity of MitoQ in alleviating alcohol-associated mitochondrial reactive oxygen species (ROS) and several downstream effects of ROS/RNS (reactive nitrogen species) production such as inhibiting protein nitration and protein aldehyde formation and specifically ROS-dependent HIF1α stabilization.


Assuntos
Antioxidantes/farmacologia , Etanol/efeitos adversos , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/prevenção & controle , Mitocôndrias Hepáticas/efeitos dos fármacos , Compostos Organofosforados/farmacologia , Ubiquinona/análogos & derivados , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antioxidantes/uso terapêutico , Citocromo P-450 CYP2E1/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Transporte de Elétrons/efeitos dos fármacos , Transporte de Elétrons/fisiologia , Fígado Gorduroso/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Mitocôndrias Hepáticas/fisiologia , Compostos Organofosforados/uso terapêutico , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico
17.
Mol Cell Biochem ; 364(1-2): 1-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22198290

RESUMO

Natural compounds with free-radical scavenging activity have potential role in maintaining human health and preventing diseases. In this study, we report the antioxidant and cytoprotective properties of 14-aminotetradecanoic acid (ATDA) isolated from the Decalepis hamiltonii roots. ATDA is a potent scavenger of superoxide (O(2) (•-)), hydroxyl ((•)OH), nitric oxide ((•)NO), and lipid peroxide (LOO(•)) physiologically relevant free radicals with IC(50) values in nM (36-323) range. ATDA also exhibits concentration-dependent secondary antioxidant activities like reducing power, metal-chelating activity, and inhibition of protein carbonylation. Further, ATDA at nM concentration prevented CuSO(4)-induced human LDL oxidation. ATDA demonstrated cytoprotective activity in primary hepatocytes and Ehrlich ascites tumor cells against oxidative stress inducing xenobiotics apart from the in vitro free-radical scavenging activity. The mechanism of cytoprotective action involved maintaining the intracellular glutathione, scavenging of reactive oxygen species, and inhibition of lipid peroxidation. It is suggested that ATDA is a novel bioactive molecule with potential health implications.


Assuntos
Antioxidantes/farmacologia , Apocynaceae , Citoproteção , Sequestradores de Radicais Livres/farmacologia , Ácido Mirístico/farmacologia , Extratos Vegetais/farmacologia , Animais , Antioxidantes/química , Apocynaceae/química , Sequestradores de Radicais Livres/química , Glutationa/química , Humanos , Peróxido de Hidrogênio/química , Peroxidação de Lipídeos/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Ácido Mirístico/química , Óxido Nítrico/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Raízes de Plantas/química , Carbonilação Proteica/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/química , Superóxidos/química , Xenobióticos/toxicidade
18.
PLoS One ; 17(11): e0275245, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36383519

RESUMO

We conducted the first profitability comparison study across health care industries in the United States, using the DuPont Analysis framework. The combination of Return on Equity (ROE) and ROE volatility was used to provide a comprehensive "risk-return" approach for profitability comparison. Based on the 2010-2019 financial disclosures of 1,231 publicly traded health care companies in the U.S. that reported positive assets and equity, we estimated the industry-specific fixed effects on ROE and its three components-profit margin, asset utilization, and financial leverage-for ten industries in the health care sector, classified by the Global Industry Classification Standard (GICS). For each industry, we also estimated its fixed effects on ROE volatility. We found that the pharmaceuticals industry and biotechnology industry have lower ROE-mainly driven by their relatively low profit margin and low assets utilization-and higher ROE volatility than other health care industries. We also found that the health care facilities industry relies most on debt financing. This study demonstrates a holistic approach for profitability comparison across industries.


Assuntos
Indústria Farmacêutica , Setor de Assistência à Saúde , Estados Unidos
19.
J Immunotoxicol ; 19(1): 61-73, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35901199

RESUMO

Nickel titanium (NiTi, or Nitinol) alloy is used in several biomedical applications, including cardiac, peripheral vascular, and fallopian tube stents. There are significant biocompatibility issues of metallic implants to nickel ions and nano-/micro-sized alloy particles. Our laboratories have recently shown that microscale CoCr wear particles from metal-on-metal hips crosslink with the innate immune signaling Toll-like receptor 4 (TLR4), prompting downstream signaling that results in interleukin (IL)-1ß and IL-8 gene expression. In vivo, NiTi alloy can also generate wear particles on the nanoscale (NP) that have thus far not been studied for their potential to induce inflammation and angiogenesis that can, in turn, contribute to implant (e.g. stent) failure. Earlier studies by others demonstrated that nickel could induce contact hypersensitivity by crosslinking the human, but not the mouse, TLR4. In the present work, it is demonstrated that NiCl2 ions and NiTi nanoparticles induce pro-inflammatory and pro-angiogenic cytokine/chemokine expression in human endothelial and monocyte cell lines in vitro. These observations prompt concerns about potential mechanisms for stent failure. The data here showed a direct correlation between intracellular uptake of Ni2+ and generation of reactive oxygen species. To determine a role for nickel and NiTi nanoparticles in inducing angiogenesis in vivo, 1-cm silicone angioreactors were implanted subcutaneously into athymic (T-cell-deficient) nude mice. The angioreactors contained Matrigel (a gelatinous protein mixture that resembles extracellular matrix) in addition to one of the following: PBS (negative control), VEGF/FGF-2 (positive control), NiCl2, or NiTi NP. The implantation of angioreactors represents a potential tool for quantification of angiogenic potentials of medical device-derived particles and ions in vivo. By this approach, NiTi NP were found to be markedly angiogenic, while Ni2+ was less-so. The angioreactors may provide a powerful tool to examine if debris shed from medical devices may promote untoward biological effects.


Assuntos
Nanopartículas Metálicas , Níquel , Ligas , Animais , Humanos , Inflamação , Íons , Camundongos , Camundongos Nus , Nanopartículas , Níquel/farmacologia , Titânio/efeitos adversos , Receptor 4 Toll-Like
20.
J Colloid Interface Sci ; 606(Pt 2): 2024-2037, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34749449

RESUMO

The remediation of non-reactive phosphate pollutants in the aquatic system is essential for protecting the ecological niche. In this work, a highly robust protein nanoparticles networked rare-earth metal carbonate-grafted bio-composite membrane (abbreviated as REMC) was fabricated via chemical crosslinking of three-dimensional (3D) hierarchical lanthanum carbonate (mREM) and casein nanoparticles (CsNPs) for selective rejection of non-reactive phosphates. The main components of the REMC membrane are mREM and CsNPs, which were prepared via SDS/CTAB templated homogeneous precipitation and the coacervation/desolvation hybrid method, respectively. The active lanthanum ion (La3+) on the 3D spherulitic surface of mREM exhibited excellent phosphate adsorption capacity (maximum adsorption capacity was 358 mg.g-1) across a wide pH range and in a multi-ionic environment. A series of batch testing and characterizations revealed that the active La3+ and dominating phosphate centers in the REMC membrane framework enable non-enzymatic phosphatase-like activity, cleaving the phosphate ester bond of organic phosphates and releasing free phosphate anions. These released phosphate ions are retained in the REMC membrane via an ion exchange mechanism, where they contribute to improved phosphate removal capacities. Furthermore, CsNPs have a dual function in the membrane, acting as a matrix in the REMC membrane framework and contributing to phosphate ion sequestrations in a synergistic manner. The catalysis of para-nitrophenyl phosphates (pNPP) to paranitrophenol (pNP) in a sequential dephosphorylation by REMC offers an estimate of reaction kinetics and elucidates the underlying mechanism of improved phosphate selectivity in a multi-ionic environment. Furthermore, phosphate specificity, homogeneous binding capacity, reusability, and visual observation of REMC membrane saturation binding direct it's useful economic, industrial applications in aqueous phosphate contaminant removal, which could be beneficial for the active recovery of the aquatic ecosystem.


Assuntos
Lantânio , Poluentes Químicos da Água , Adsorção , Catálise , Ecossistema , Concentração de Íons de Hidrogênio , Troca Iônica , Cinética , Organofosfatos , Fosfatos
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