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Aging is characterized as the process of functional decline in an organism from adulthood, often marked by a progressive loss of cellular function and systemic deterioration of multiple tissues. Among the numerous molecular, cellular, and systemic hallmarks associated with aging, mitochondrial dysfunction is considered one of the pivotal factors that initiates the aging process. During aging, mitochondria undergo varying degrees of damage, resulting in impaired energy production and disruption of the homeostatic regulation of mitochondrial quality control systems, which in turn affects cellular energy metabolism and results in cellular dysfunction, accelerating the aging process. AMP-activated protein kinase (AMPK) and the mechanistic target of rapamycin complex 1 (mTORC1) are two central kinase complexes responsible for sensing intracellular nutrient levels, regulating metabolic homeostasis, modulating aging and play a crucial role in maintaining the homeostatic balance of mitochondria. Our previous studies found that the novel compound tetramethylpyrazine nitrone (TBN) can protect mitochondria via the AMPK/mTOR pathway in many animal models, extending healthy lifespan through the Nrf2 signaling pathway in nematodes. Building upon this foundation, we have posited a reasonable hypothesis, TBN can improve mitochondrial function to delay aging by regulating the AMPK/mTORC1 signaling pathway. This study focuses on the C. elegans, exploring the impact and underlying mechanisms of TBN on aging and mitochondrial function (especially the mitochondrial quality control system) during the aging process. The present studies demonstrated that TBN extends lifespan of wild-type nematodes and is associated with the AMPK/mTORC1 signaling pathway. TBN elevated ATP and NAD+ levels in aging nematodes while orchestrating mitochondrial biogenesis and mitophagy. Moreover, TBN was observed to significantly enhance normal activities during aging in C. elegans, such as mobility and pharyngeal pumping, concurrently impeding lipofuscin accumulation that were closely associated with AMPK and mTORC1. This study not only highlights the delayed effects of TBN on aging but also underscores its potential application in strategies aimed at improving mitochondrial function via the AMPK/mTOR pathway in C. elegans.
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Proteínas Quinases Ativadas por AMP , Envelhecimento , Caenorhabditis elegans , Alvo Mecanístico do Complexo 1 de Rapamicina , Mitocôndrias , Pirazinas , Transdução de Sinais , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Pirazinas/farmacologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento/metabolismo , Envelhecimento/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Óxidos de Nitrogênio/metabolismoRESUMO
Aggregation of α-synuclein (α-syn) and α-syn cytotoxicity are hallmarks of sporadic and familial Parkinson's disease (PD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent enhancement of the expression of the 20S proteasome core particles (20S CPs) and regulatory particles (RPs) increases proteasome activity, which can promote α-syn clearance in PD. Activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) may reduce oxidative stress by strongly inducing Nrf2 gene expression. In the present study, tetramethylpyrazine nitrone (TBN), a potent-free radical scavenger, promoted α-syn clearance by the ubiquitin-proteasome system (UPS) in cell models overexpressing the human A53T mutant α-syn. In the α-syn transgenic mice model, TBN improved motor impairment, decreased the products of oxidative damage, and down-regulated the α-syn level in the serum. TBN consistently up-regulated PGC-1α and Nrf2 expression in tested models of PD. Additionally, TBN similarly enhanced the proteasome 20S subunit beta 8 (Psmb8) expression, which is linked to chymotrypsin-like proteasome activity. Furthermore, TBN increased the mRNA levels of both the 11S RPs subunits Pa28αß and a proteasome chaperone, known as the proteasome maturation protein (Pomp). Interestingly, specific siRNA targeting of Nrf2 blocked TBN's effects on Psmb8, Pa28αß, Pomp expression, and α-syn clearance. In conclusion, TBN promotes the clearance of α-syn via Nrf2-mediated UPS activation, and it may serve as a potentially disease-modifying therapeutic agent for PD.
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Fator 2 Relacionado a NF-E2 , Complexo de Endopeptidases do Proteassoma , Pirazinas , Humanos , Animais , Camundongos , Fator 2 Relacionado a NF-E2/genética , alfa-Sinucleína/genética , Camundongos Transgênicos , UbiquitinasRESUMO
Tetramethylpyrazine nitrone (TBN), a novel derivative of tetramethylpyrazine (TMP) designed and synthesized by our group, possesses multi-functional mechanisms of action and displays broad protective effects in vitro and in animal models of age-related brain disorders such as stroke, Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's disease (PD). In the present report, we investigated the effects of TBN on aging, specifically on muscle aging and the associated decline of motor functions. Using a D-galactose-induced aging mouse model, we found that TBN could reverse the levels of several senescence and aging markers including p16, p21, ceramides, and telomere length and increase the wet-weight ratio of gastrocnemius muscle tissue, demonstrating its efficacy in ameliorating muscle aging. Additionally, the pharmacological effects of TBN on motor deficits (gait analysis, pole-climbing test and grip strength test), muscle fibrosis (hematoxylin & eosin (HE), Masson staining, and αSMA staining), inflammatory response (IL-1ß, IL-6, and TNF-α), and mitochondrial function (ATP, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were also confirmed in the D-galactose-induced aging models. Further experiments demonstrated that TBN alleviated muscle aging and improved the decline of age-related motor deficits through an AMPK-dependent mechanism. These findings highlight the significance of TBN as a potential anti-aging agent to combat the occurrence and development of aging and age-related diseases.
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Galactose , Fármacos Neuroprotetores , Pirazinas , Camundongos , Animais , Proteínas Quinases Ativadas por AMP , Fármacos Neuroprotetores/farmacologia , Envelhecimento , Transdução de Sinais , Músculo EsqueléticoRESUMO
INTRODUCTION: Parkinson's disease (PD) is common neurodegenerative disease where oxidative stress and mitochondrial dysfunction play important roles in its progression. Tetramethylpyrazine nitrone (TBN), a potent free radical scavenger, has shown protective effects in various neurological conditions. However, the neuroprotective mechanisms of TBN in PD models remain unclear. OBJECTIVES: We aimed to investigate TBN's neuroprotective effects and mechanisms in PD models. METHODS: TBN's neuroprotection was initially measured in MPP+/MPTP-induced PD models. Subsequently, a luciferase reporter assay was used to detect peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) promoter activity. Effects of TBN on antioxidant damage and the PGC-1α/Nuclear factor erythroid-2-related factor 2 (Nrf2) pathway were thoroughly investigated. RESULTS: In MPP+-induced cell model, TBN (30-300 µM) increased cell survival by 9.95 % (P < 0.05), 16.63 % (P < 0.001), and 24.09 % (P < 0.001), respectively. TBN enhanced oxidative phosphorylation (P < 0.05) and restored PGC-1α transcriptional activity suppressed by MPP+ (84.30 % vs 59.03 %, P < 0.01). In MPTP-treated mice, TBN (30 mg/kg) ameliorated motor impairment, increased striatal dopamine levels (16.75 %, P < 0.001), dopaminergic neurons survival (27.12 %, P < 0.001), and tyrosine hydroxylase expression (28.07 %, P < 0.01). Selegiline, a positive control, increased dopamine levels (15.35 %, P < 0.001) and dopaminergic neurons survival (25.34 %, P < 0.001). Additionally, TBN reduced oxidative products and activated the PGC-1α/Nrf2 pathway. PGC-1α knockdown diminished TBN's neuroprotective effects, decreasing cell viability from 73.65 % to 56.87 % (P < 0.001). CONCLUSION: TBN has demonstrated consistent effectiveness in MPP+-induced midbrain neurons and MPTP-induced mice. Notably, the therapeutic effect of TBN in mitigating motor deficits and neurodegeneration is superior to selegiline. The neuroprotective mechanisms of TBN are associated with activation of the PGC-1α/Nrf2 pathway, thereby reducing oxidative stress and maintaining mitochondrial function. These findings suggest that TBN may be a promising therapeutic candidate for PD, warranting further development and investigation.
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Aerobic granulation is an emerging process in wastewater treatment that has the potential to accelerate sedimentation of the microbial biomass during secondary treatment. Aerobic granulation has been difficult to achieve in the continuous flow reactors (CFRs) used in modern wastewater treatment plants. Recent research has demonstrated that the alternation of nutrient-abundant (feast) and nutrient-limiting (famine) conditions is able to promote aerobic granulation in a CFR. In this study, we conducted a metagenomic analysis with the objective of characterizing the bacterial composition of the granular biomass developed in three simulated plug flow reactors (PFRs) with different feast-to-famine ratios. Phylogenetic analyses revealed a clear distinction between the bacterial composition of aerobic granules in the pilot simulated PFRs as compared with conventional activated sludge. Larger and denser granules, showing improved sedimentation properties, were observed in the PFR with the longest famine time and were characterized by a greater proportion of bacteria producing abundant extracellular polymeric substances (EPS). Functional metagenomic analysis based on KEGG pathways indicated that the large and dense aerobic granules in the PFR with the longest famine time showed increased functionalities related to secretion systems and quorum sensing, which are characteristics of bacteria in biofilms and aerobic granules. This study contributes to a further understanding of the relationship between aerobic granule morphology and the bacterial composition of the granular biomass.
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Hepatitis C virus (HCV) infection is one of the major factors to trigger a sustained hepatic inflammatory response and hence hepatocellular carcinoma (HCC), but direct-acting-antiviral (DAAs) was not efficient to suppress HCC development. Heat shock protein 90 kDa (HSP90) is highly abundant in different types of cancers, and especially controls protein translation, endoplasmic reticulum stress, and viral replication. In this study we investigated the correlation between the expression levels of HSP90 isoforms and inflammatory response marker NLRP3 in different types of HCC patients as well as the effect of a natural product celastrol in suppression of HCV translation and associated inflammatory response in vivo. We identified that the expression level of HSP90ß isoform was correlated with that of NLRP3 in the liver tissues of HCV positive HCC patients (R2 = 0.3867, P < 0.0101), but not in hepatitis B virus-associated HCC or cirrhosis patients. We demonstrated that celastrol (3, 10, 30 µM) dose-dependently suppressed the ATPase activity of both HSP90α and HSP90ß, while its anti-HCV activity was dependent on the Ala47 residue in the ATPase pocket of HSP90ß. Celastrol (200 nM) halted HCV internal ribosomal entry site (IRES)-mediated translation at the initial step by disrupting the association between HSP90ß and 4EBP1. The inhibitory activity of celastrol on HCV RNA-dependent RNA polymerase (RdRp)-triggered inflammatory response also depended on the Ala47 residue of HSP90ß. Intravenous injection of adenovirus expressing HCV NS5B (pAde-NS5B) in mice induced severe hepatic inflammatory response characterized by significantly increased infiltration of immune cells and hepatic expression level of Nlrp3, which was dose-dependently ameliorated by pretreatment with celastrol (0.2, 0.5 mg/kg, i.p.). This study reveals a fundamental role of HSP90ß in governing HCV IRES-mediated translation as well as hepatic inflammation, and celastrol as a novel inhibitor of HCV translation and associated inflammation by specifically targeting HSP90ß, which could be developed as a lead for the treatment of HSP90ß positive HCV-associated HCC.
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Carcinoma Hepatocelular , Hepatite C , Neoplasias Hepáticas , Camundongos , Animais , Hepacivirus , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Proteínas de Choque Térmico , Proteína 3 que Contém Domínio de Pirina da Família NLR , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Proteínas de Choque Térmico HSP90/metabolismo , Inflamação/tratamento farmacológicoRESUMO
Renal anemia is one of the most common complications of chronic kidney disease and diabetic kidney disease. Despite the progress made in recent years, there is still an urgent unmet clinical need for renal anemia treatment. In this research, we investigated the efficacy and mechanism of action of the novel tetramethylpyrazine nitrone (TBN). Animal models of anemia including the streptozotocin (STZ)-induced spontaneously hypertensive rats (SHR) and the cisplatin (CDDP)-induced C57BL/6J mice are established to study the TBN's effects on expression of hypoxia-inducible factor and erythropoietin. To explore the mechanism of TBN's therapeutic effect on renal anemia, cobalt chloride (CoCl2) is used in Hep3B/HepG2 cells to simulate a hypoxic environment. TBN is found to increase the expression of hypoxia-inducible factor HIF-1α and HIF-2α under hypoxic conditions and reverse the reduction of HIFs expression caused by saccharate ferric oxide (SFO). TBN also positively regulates the AMPK pathway. TBN stimulates nuclear transcription and translation of erythropoietin by enhancing the stability of HIF-1α expression. TBN has a significant regulatory effect on several major biomarkers of iron homeostasis, including ferritin, ferroportin (FPN), and divalent metal transporter-1 (DMT1). In conclusion, TBN regulates the AMPK/mTOR/4E-BP1/HIFs pathway, and activates the hypoxia-inducible factor and regulates iron homeostasis to improve renal anemia.
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Sepsis is a life-threatening organ dysfunction with devastating consequences, prominent among which is lung damage. Memantine, an N-methyl-D-aspartic acid receptor (NMDAR) antagonist, is able to alleviate acute lung injury (ALI). Nitric oxide (NO) suppresses NLRP3 inflammasome activation against lipopolysaccharide (LPS)-induced septic shock. MN-08, a novel nitrate derivative of memantine, possesses both the ability to antagonize NMDAR and release NO. In the present study, we aimed to investigate the protective effects of MN-08 against LPS-induced systemic inflammation and septic lung injury in mice, and to explore the underlying mechanisms of MN-08 in LPS-induced mice and THP-1 macrophages. MN-08 significantly increased the survival rate of septic mice, alleviated LPS-induced sepsis in mice via improving systemic inflammatory response syndrome and immune dysfunction, and attenuated pulmonary injury and inflammatory infiltration. More importantly, the therapeutic benefit of MN-08 for sepsis was greater than that of memantine and dexamethasone. Mechanistically, MN-08 exerted anti-inflammatory activity through inhibiting nuclear translocation of NF-κB, activation of the MAPK signaling pathway and the signaling transduction of STAT3/NF-κB. In addition, MN-08 suppressed NLRP3 inflammasome activation. Taken together, our studies demonstrate that MN-08 may be a promising therapeutic agent for sepsis-induced acute lung injury.
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Lesão Pulmonar Aguda , Sepse , Animais , Camundongos , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Inflamassomos/metabolismo , Lipopolissacarídeos , Pulmão , Memantina/farmacologia , Memantina/uso terapêutico , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Nitratos/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismoRESUMO
SKN-1, the ortholog of mammalian Nrf2 proteins, is a transcription factor that plays an important role in oxidative stress resistance and longevity. Similar to other defense systems, the Nrf2-mediated stress response is compromised in aging and neurodegenerative diseases. Our previous studies demonstrated that tetramethylpyrazine nitrone (TBN), a derivative of tetramethylpyrazine armed with a potent free radical-scavenging nitrone moiety, exerted multifunctional neuroprotection in neurological and other diseases. However, the ability of TBN to extend a healthy lifespan and its underlying mechanisms of action are not yet clear. C. elegans have become a popular animal model in aging research. Herein, we demonstrate that TBN can extend the lifespan, promote age-associated health indicators, and restore mitochondrial function in C. elegans. TBN also significantly reduced ROS levels and superoxide accumulation in C. elegans. We show that TBN-mediated lifespan extension is SKN-1dependent. The present study provides valuable insights into the mechanisms by which TBN inhibits aging via the Nrf2/SKN-1 pathway in C. elegans.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Proteínas de Ligação a DNA/metabolismo , Longevidade/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Pirazinas , Transdução de Sinais , Fatores de Transcrição/metabolismoRESUMO
Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure, but therapeutic options for nephroprotection are limited. Oxidative stress plays a key role in the pathogenesis of DKD. Our previous studies demonstrated that tetramethylpyrazine nitrone (TBN), a novel nitrone derivative of tetramethylpyrazine with potent free radical-scavenging activity, exerted multifunctional neuroprotection in neurological diseases. However, the effect of TBN on DKD and its underlying mechanisms of action are not yet clear. Herein, we performed streptozotocin-induced rat models of DKD and found that TBN administrated orally twice daily for 6 weeks significantly lowered urinary albumin, N-acetyl-ß-D-glycosaminidase, cystatin C, malonaldehyde, and 8-hydroxy-2'-deoxyguanosine levels. TBN also ameliorated renal histopathological changes. More importantly, in a nonhuman primate model of spontaneous stage III DKD, TBN increased the estimated glomerular filtration rate, decreased serum 3-nitrotyrosine, malonaldehyde and 8-hydroxy-2'-deoxyguanosine levels, and improved metabolic abnormalities. In HK-2 cells, TBN increased glycolytic and mitochondrial functions. The protective mechanism of TBN might involve the activation of AMPK/PGC-1α-mediated downstream signaling pathways, thereby improving mitochondrial function and reducing oxidative stress in the kidneys of DKD rodent models. These results support the clinical development of TBN for the treatment of DKD.
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Polydatin is the major active ingredient of Polygonum cuspidatum Sieb. Et Zucc. A recent study indicated that polydatin could protect against substantia nigra dopaminergic degeneration in rodent models associated with Parkinson's disease. However, mechanisms that underlie the neuroprotection of polydatin have not been fully elucidated. In the current study, the neuroprotective effects and detailed mechanisms of action of polydatin were investigated in Parkinson's disease-related cellular models. Polydatin dose- and time-dependently prevented neurotoxicity caused by 1-methyl-4-phenylpyridinium ion (MPP+) in primary cerebellar granule neurons. Moreover, we found that polydatin enhanced the activity of the transcription factor myocyte enhancer factor 2D (MEF2D) at both basal and pathological conditions using luciferase reporter gene assay. Additionally, western blot analysis revealed that polydatin could downregulate glycogen synthase kinase 3ß (GSK3ß), which is a negative regulator of MEF2D. Molecular docking simulations finally suggested an interaction between polydatin and a hydrophobic pocket within GSK3ß. All these results suggest that polydatin prevents MPP+-induced neurotoxicity via enhancing MEF2D through the inhibition of GSK3ß and that treatment with polydatin is worthy of further anti-Parkinson's disease study in future.
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1-Metil-4-fenilpiridínio/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Glucosídeos/farmacologia , Herbicidas/toxicidade , Fármacos Neuroprotetores/farmacologia , Estilbenos/farmacologia , Animais , Animais Recém-Nascidos , Sobrevivência Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Fatores de Transcrição MEF2/metabolismo , Células PC12 , Ratos , Ratos Sprague-DawleyRESUMO
Alzheimer's disease (AD) is a leading cause of dementia in elderly individuals and therapeutic options for AD are very limited. Over-activation of N-methyl-D-aspartate (NMDA) receptors, amyloid ß (Aß) aggregation, a decrease in cerebral blood flow (CBF), and downstream pathological events play important roles in the disease progression of AD. In the present study, MN-08, a novel memantine nitrate, was found to inhibit Aß accumulation, prevent neuronal and dendritic spine loss, and consequently attenuate cognitive deficits in 2-month-old APP/PS1 transgenic mice (for a 6-month preventative course) and in the 8-month-old triple-transgenic (3×Tg-AD) mice (for a 4-month therapeutic course). In vitro, MN-08 could bind to and antagonize NMDA receptors, inhibit the calcium influx, and reverse the dysregulations of ERK and PI3K/Akt/GSK3ß pathway, subsequently preventing glutamate-induced neuronal loss. In addition, MN-08 had favorable pharmacokinetics, blood-brain barrier penetration, and safety profiles in rats and beagle dogs. These findings suggest that the novel memantine nitrate MN-08 may be a useful therapeutic agent for AD.
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Doença de Alzheimer/tratamento farmacológico , Memantina/uso terapêutico , Animais , Modelos Animais de Doenças , Memantina/farmacologia , Camundongos , Camundongos TransgênicosRESUMO
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are serious neurodegenerative diseases. Although their pathogenesis is unclear, the abnormal accumulation of TAR DNA-binding protein of 43 kDa (TDP-43) is a pathological feature that exists in almost all patients. Thus far, there is no drug that can cure ALS/FTLD. Tetramethylpyrazine nitrone (TBN) is a derivative of tetramethylapyrazine, derived from the traditional Chinese medicine Ligusticum chuanxiong, which has been widely proven to have therapeutic effects on models of various neurodegenerative diseases. TBN is currently under clinical investigation for several indications including a Phase II trial of ALS. Here, we explored the therapeutic effect of TBN in an ALS/FTLD mouse model. We injected the TDP-43 M337V virus into the striatum of mice unilaterally and bilaterally, and then administered 30 mg/kg TBN intragastrically to observe changes in behavior and survival rate of mice. The results showed that in mice with unilateral injection of TDP-43M337V into the striatum, TBN improved motor deficits and cognitive impairment in the early stages of disease progression. In mice with bilateral injection of TDP-43M337V into the striatum, TBN not only improved motor function but also prolonged survival rate. Moreover, we show that its therapeutic effect may be through activation of the Akt/mTOR/GSK-3ß and AMPK/PGC-1α/Nrf2 signaling pathways. In summary, TBN is a promising agent for the treatment of ALS/FTLD.
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Esclerose Lateral Amiotrófica , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , CamundongosRESUMO
[Figure: see text].
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Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Remodelação Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Doadores de Óxido Nítrico/uso terapêutico , RatosRESUMO
T-006, a small-molecule compound derived from tetramethylpyrazine (TMP), has potential for the treatment of neurological diseases. In order to investigate the effect of T-006 prophylactic treatment on an Alzheimer's disease (AD) model and identify the target of T-006, we intragastrically administered T-006 (3 mg/kg) to Alzheimer's disease (AD) transgenic mice (APP/PS1-2xTg and APP/PS1/Tau-3xTg) for 6 and 8 months, respectively. T-006 improved cognitive ability after long-term administration in two AD mouse models and targeted mitochondrial-related protein alpha-F1-ATP synthase (ATP5A). T-006 significantly reduced the expression of phosphorylated-tau, total tau, and APP while increasing the expression of synapse-associated proteins in 3xTg mice. In addition, T-006 modulated the JNK and mTOR-ULK1 pathways to reduce both p-tau and total tau levels. Our data suggested that T-006 mitigated cognitive decline primarily by reducing the p-tau and total tau levels in 3xTg mice, supporting further investigation into its development as a candidate drug for AD treatment.
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Doença de Alzheimer/tratamento farmacológico , Transtornos Cognitivos/tratamento farmacológico , Hidrazonas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Pirazinas/uso terapêutico , Proteínas tau/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Autofagia/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Aprendizagem da Esquiva , Modelos Animais de Doenças , Donepezila/farmacologia , Donepezila/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Hidrazonas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Memantina/farmacologia , Memantina/uso terapêutico , Camundongos , Camundongos Transgênicos , Teste do Labirinto Aquático de Morris , Fármacos Neuroprotetores/farmacologia , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Pirazinas/farmacologia , Distribuição Aleatória , Reconhecimento Psicológico , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of upper and lower motor neurons that results in skeletal muscle atrophy, weakness and paralysis. Oxidative stress plays a key role in the pathogenesis of ALS, including familial forms of the disease arising from mutation of the gene coding for superoxide dismutase (SOD1). We have used the SOD1G93A ALS mouse model to investigate the efficacy of 2-[[(1,1-dimethylethyl)oxidoimino]-methyl]-3,5,6-trimethylpyrazine (TBN), a novel tetramethylpyrazine derivative armed with a powerful free-radical scavenging nitrone moiety. TBN was administered to mice by intraperitoneal or intragastric injection after the onset of motor deficits. TBN slowed the progression of motor neuron disease as evidenced by improved motor performance, reduced spinal motor neuron loss and the associated glial response, and decreased skeletal muscle fiber denervation and fibrosis. TBN treatment activated mitochondrial antioxidant activity through the PGC-1α/Nrf2/HO-1 pathway and decreased the expression of human SOD1. These findings suggest that TBN holds promise as a therapeutic agent for ALS.
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Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/metabolismo , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Pirazinas/uso terapêutico , Animais , Feminino , Força da Mão/fisiologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Pirazinas/farmacologia , Superóxido Dismutase-1/biossíntese , Superóxido Dismutase-1/genéticaRESUMO
Free ammonia (FA) inhibition has been taken advantage as a strategy to suppress the growth of nitrite-oxidizing bacteria (NOB) in aerobic granules stabilized in a continuous upflow airlift reactor to achieve partial nitritation. However, after nearly 18 months of continuous exposure of aerobic granules to FA in the reactor, the FA inhibition of NOB was proven ineffective, and the partial nitritation gradually shifted to partial nitrification even though the long-term granule structural stability remained excellent under the continuous-flow mode. The extent of NOB resistance to FA inhibition was quantified based on the kinetic response of NOB to various FA concentrations in the form of an uncompetitive inhibition coefficient. It was confirmed that the NOB immobilized in larger granules under longer term exposure to FA tend to become more resistant to FA. Thereby, it was concluded that NOB can develop strong resistance to FA after continuous exposure, and thus, FA inhibition is not a reliable strategy to achieve partial nitritation in mainstream wastewater treatment. PRACTITIONER POINTS: Nitrifying aerobic granules can remain structurally stable in continuous-flow bioreactors. NOB developed free ammonia resistance after 6-month continuous exposure. Larger aerobic granules tended to develop stronger free ammonia resistance. Free ammonia inhibition is not a reliable strategy for mainstream anammox.
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Nitritos , Esgotos , Amônia , Bactérias , Reatores Biológicos , Nitrificação , Nitrogênio/análise , OxirreduçãoRESUMO
Plug flow reactors (PFRs) made of multiple completely stirred tank reactors (CSTRs) in series were used to cultivate aerobic granules in real domestic wastewater. Theoretically, changing the number of CSTR chambers in series will change the nature of plug flow, and thus alter the pattern of the feast/famine condition and impact the aerobic granulation progress. Therefore, PFRs were operated in 4-, 6-, and 8-chamber mode under the same gravity selection pressure (a critical settling velocity of 9.75 m h-1) and hydraulic retention time (6.5 h) until steady states were reached to evaluate the effect of the feast/famine condition on continuous flow aerobic granulation. The sludge particle size, circularity, settleability, specific gravity, zone settling velocity, and extracellular polymeric substance contents were analyzed to evaluate the role that a feast/famine regime plays in aerobic granulation. It was found that aerobic granulation failed whenever the feast/famine ratio was greater than 0.5. The results support a conclusion that the feast/famine condition is likely a prerequisite for continuous flow aerobic granulation.
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Reatores Biológicos , Eliminação de Resíduos Líquidos , Aerobiose , Matriz Extracelular de Substâncias Poliméricas , EsgotosRESUMO
Plug flow reactors (PFRs) approximated by the connection of multiple completely stirred tank reactors (CSTRs) in series were used to achieve continuous flow aerobic granulation in real domestic wastewater. This study revealed, possibly for the first time, that the morphology and characteristics of aerobic granular sludge transformed in the course of a mixed liquor flow through a PFR. The feast zone, located at the front end of the PFR, can quickly develop filamentous structure on the surface of aerobic granular sludge which later disappeared in the famine zone at the back end of the PFR. Detention time from the front to the back end of the PFR was only 6.5 h. During this period the observed sludge morphological change led to sludge settleability fluctuation as much as 66% in zone settling velocity, 16% in specific gravity, and 40% in settled sludge volume. Further analysis revealed these types of sludge morphologies and characteristics were closely related to the specific substrate removal rate profiles of the PFR, i.e., the feast zone might have encouraged filamentous bacteria to extend outward into the bulk solution for soluble substrate, and the famine zone appeared to play an essential role in solidifying the structure of granular sludge structure prior to subjecting it to the gravity selection pressure. It can be inferred from this study that the lack of a famine zone in aerobic granulation reactors can loosen the granule structure and in turn deteriorate granule settleability. For a PFR, a famine zone following the feast zone is essential for maintaining the structural integrity of aerobic granular sludge in a continuous flow wastewater treatment system.