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1.
Life Sci ; 305: 120786, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35809664

RESUMO

AIM: Urinary glycoproteins such as Tamm Horsfall Protein (THP) and Osteopontin (OPN) are well established key regulators of renal stone formation. Additionally, recent revelations have highlighted the influence of Endoplasmic Reticulum (ER) and mitochondria of crucial importance in nephrolithiasis. However, till date conclusive approach highlighting the influence of ER stress on urinary glycoproteins and chaperone in nephrolithiasis remains elusive. Therefore, the present study was focussed on deciphering the possible effect of 4-PBA mitigating ER stress on urinary glycoproteins and calnexin (chaperone) with emphasis on interlinking calcium homeostasis in hyperoxaluric rats. MATERIAL AND METHODS: Post 9 days of treatment, animals were sacrificed, and renal tissues were investigated for urinary glycoproteins, calnexin, calcium homeostasis, ER environment, redox status, and mitochondrial linkage. KEY FINDINGS: 4-PBA appreciably reversed the altered levels of THP, OPN, and calnexin observed along with curtailing the disrupted calcium homeostasis when assessed for SERCA activity and intra-cellular calcium levels. Additionally, significant improvement in the perturbed ER environment as verified by escalated ER stress markers, disturbed protein folding-aggregation-degradation (congo red assay) pathway, and redox status was found post 4-PBA intervention. Interestingly, linkage of ER stress and mitochondria was established under hyperoxaluric conditions when assessed for protein levels of VDAC1 and GRP75. SIGNIFICANCE: 4-PBA treatment resulted in rectifying the repercussions of ER-mitochondrial caused distress when assessed for protein folding/aggregation/degradation events along with disturbed calcium homeostasis. The present study advocates the necessity to adopt a holistic vision towards hyperoxaluria with emphasis on glycoproteins and ER environment.


Assuntos
Hiperoxalúria , Cálculos Renais , Animais , Butilaminas , Cálcio/metabolismo , Calnexina/metabolismo , Calnexina/farmacologia , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Glicoproteínas/metabolismo , Homeostase , Cálculos Renais/etiologia , Cálculos Renais/metabolismo , Mitocôndrias/metabolismo , Chaperonas Moleculares/metabolismo , Ratos
2.
Phys Chem Chem Phys ; 24(30): 18427-18434, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35881619

RESUMO

Hydroxyaromatic compounds (ArOHs) have a wide range of applications in catalytic synthesis and biological processes due to their increased acidity upon photo-excitation. The proton transfer of ArOHs via the excited singlet state has been extensively studied. However, there has still been a debate on the unique type of ArOH that can undergo an ultrafast intersystem crossing. The nitro group in p-nitrophenylphenol (NO2-Bp-OH) enhances the spin-orbit coupling between excited singlet states and the triplet manifold, enabling ultrafast intersystem crossing and the formation of the long-lived lowest excited triplet state (T1) with a high yield. In this work, we used time-resolved transient absorption to investigate the excited state proton transfer of NO2-Bp-OH in its T1 state to t-butylamine, methanol, and ethanol. The T1 state of the deprotonated form NO2-Bp-O- was first observed and identified in the case of t-butylamine. Kinetic analysis demonstrates that the formation of the hydrogen-bonded complex with methanol and ethanol as proton acceptors involves their trimers. The alcohol oligomer size required in the excited state proton transfer process is dependent on the excited acidity of photoacid.


Assuntos
Aminas , Prótons , Aminas/química , Butilaminas , Etanol , Cinética , Metanol , Dióxido de Nitrogênio
3.
Curr Microbiol ; 79(7): 190, 2022 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-35556178

RESUMO

This study reports, for the first time, morphological transition from yeast-like to filamentous form, normally associated with pathogenicity/increased protein secretion, in Pichia pastoris SMD1168 strain. The response was recorded in response to nutritional and environmental cues. The factors affecting this switch were extracellular pH (under nitrogen starvation conditions), carbon and nitrogen source under nitrogen- and carbon-limiting conditions respectively. Under nitrogen-limiting conditions, addition of fructose and sucrose in the culture medium induced filamentous morphology in a segregated form whereas addition of galactose led to a mixture of yeast and the filamentous form of the cells. Under carbon-limiting conditions, isoleucine and proline forced a filamentous form whereas glycine, valine, alanine and phenylalanine promoted yeast-like morphology. Similar dimorphic shift was also displayed by a recombinant methanol slow utilizing (Muts) strain (SMD-GCSF Muts) producing human granulocyte colony-stimulating factor in response to change in the initial inoculum level. Analysis of the extracellular metabolome by GC-MS indicated that several amino acids (leucine, proline, tyrosine), carboxylic acids (phenylacetic-, propanoic acid), alcohols and butylamine were present at different levels in the culture broth of the two morphological forms. High accumulation of proline and butylamine was seen in the extracellular culture filtrate of the filamentous form of the yeast. Presence of quorum-sensing molecules (phenylethyl alcohol, dodecanol) suggested complex network of pathways involved in this morphological transition.


Assuntos
Pichia , Saccharomyces cerevisiae , Butilaminas/metabolismo , Carbono/metabolismo , Humanos , Nitrogênio/metabolismo , Pichia/genética , Pichia/metabolismo , Prolina/metabolismo , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomycetales , Caracteres Sexuais
4.
Cell Death Dis ; 13(4): 345, 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35418110

RESUMO

Neutrophils are the dominant leukocytes in circulation and the first responders to infection and inflammatory cues. While the roles of neutrophils in driving inflammation have been widely recognized, the contribution of neutrophils in facilitating inflammation resolution is under-studied. Here, through single-cell RNA sequencing analysis, we identified a subpopulation of neutrophils exhibiting pro-resolving characteristics with greater Cd200r and Cd86 expression at the resting state. We further discovered that 4-PBA, a peroxisomal stress-reducing agent, can potently train neutrophils into the resolving state with enhanced expression of CD200R, CD86, as well as soluble pro-resolving mediators Resolvin D1 and SerpinB1. Resolving neutrophils trained by 4-PBA manifest enhanced phagocytosis and bacterial-killing functions. Mechanistically, the generation of resolving neutrophils is mediated by the PPARγ/LMO4/STAT3 signaling circuit modulated by TLR4 adaptor molecule TRAM. We further demonstrated that genetic deletion of TRAM renders the constitutive expansion of resolving neutrophils, with an enhanced signaling circuitry of PPARγ/LMO4/STAT3. These findings may have profound implications for the effective training of resolving neutrophils with therapeutic potential in the treatment of both acute infection as well as chronic inflammatory diseases.


Assuntos
Neutrófilos , Serpinas , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Butilaminas , Humanos , Inflamação/metabolismo , Proteínas com Domínio LIM/metabolismo , Neutrófilos/metabolismo , PPAR gama/metabolismo , Fagocitose , Serpinas/metabolismo
5.
J Bone Miner Res ; 37(4): 675-686, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34997935

RESUMO

Osteogenesis imperfecta (OI) is a genetically heterogenous disorder most often due to heterozygosity for mutations in the type I procollagen genes, COL1A1 or COL1A2. The disorder is characterized by bone fragility leading to increased fracture incidence and long-bone deformities. Although multiple mechanisms underlie OI, endoplasmic reticulum (ER) stress as a cellular response to defective collagen trafficking is emerging as a contributor to OI pathogenesis. Herein, we used 4-phenylbutiric acid (4-PBA), an established chemical chaperone, to determine if treatment of Aga2+/- mice, a model for moderately severe OI due to a Col1a1 structural mutation, could attenuate the phenotype. In vitro, Aga2+/- osteoblasts show increased protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation protein levels, which improved upon treatment with 4-PBA. The in vivo data demonstrate that a postweaning 5-week 4-PBA treatment increased total body length and weight, decreased fracture incidence, increased femoral bone volume fraction (BV/TV), and increased cortical thickness. These findings were associated with in vivo evidence of decreased bone-derived protein levels of the ER stress markers binding immunoglobulin protein (BiP), CCAAT/-enhancer-binding protein homologous protein (CHOP), and activating transcription factor 4 (ATF4) as well as increased levels of the autophagosome marker light chain 3A/B (LC3A/B). Genetic ablation of CHOP in Aga2+/- mice resulted in increased severity of the Aga2+/- phenotype, suggesting that the reduction in CHOP observed in vitro after treatment is a consequence rather than a cause of reduced ER stress. These findings suggest the potential use of chemical chaperones as an adjunct treatment for forms of OI associated with ER stress. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Osteogênese Imperfeita , Animais , Butilaminas , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Camundongos , Chaperonas Moleculares/metabolismo , Mutação , Osteoblastos/metabolismo , Osteogênese , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/metabolismo , Fenótipo
6.
J Neurochem ; 160(2): 218-233, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34816436

RESUMO

N-ethyl-pentylone (NEP), also known as 'ephylone' and N-ethylnorpentylone, has been identified as one of the most recent novel psychostimulants to emerge into the illicit drug market and it has been associated with some intoxications and even fatalities. However, little is known about the consequences of its repeated consumption as well as the role of the monoaminergic system in such consequences. Thus, the aim of our study was to investigate the neurochemical profile and the behavioural effects after both acute and repeated NEP exposure. Male OF1 mice were acutely (1, 3, 10 mg/kg, i.p.) or repeatedly (1, 3, 10 mg/kg, i.p., 5 days, twice/day) exposed to NEP, and anxiety-like behaviour, aggressiveness, social interaction, depressive-like symptoms, body temperature, changes in monoaminergic enzymes and neurotransmitters levels as well as ΔFosB in striatum and prefrontal cortex (PFC) from post-mortem tissue were analysed short after drug-exposure or during drug-withdrawal. Acute administration of NEP induced anxiolytic effects but also an aggressive behaviour and social exploration deficits in mice, which persist during NEP-withdrawal. Moreover, NEP induced hyperthermia as well as depressive-like symptoms after repeated administrations that may be related to the decrease in serotonin and noradrenaline levels observed in striatum and PFC. Finally, the long-term increase in ΔFosB levels in striatum after NEP chronic exposure points to a high risk of dependence. Altogether indicates that NEP consumption induces different neurological and neuropsychiatric disorders accompanied by changes in the monoaminergic system, posing a threat to public health.


Assuntos
Comportamento Animal/efeitos dos fármacos , Benzodioxóis/toxicidade , Butilaminas/toxicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Animais , Masculino , Camundongos
7.
Artigo em Inglês | MEDLINE | ID: mdl-34610469

RESUMO

Trans fatty acids (TFA) in food can cause liver inflammation. Activation of NOD-like receptor protein-3 (NLRP3) inflammasome is a key factor in the regulation of inflammation. Accumulating evidence suggests that ERS-induced NLRP3 inflammasome activation underlies the pathological basis of various inflammatory diseases, but the precise mechanism has not been fully elucidated. Therefore, this paper focused on TFA, represented by elaidic acid (EA), to investigate the mechanism of liver inflammation. Levels of mRNA and protein were detected by RT-qPCR and Western blotting, the release of proinflammatory cytokines was measured by ELISA, and intracellular Ca2+ levels were determined by flow cytometer using Fluo 4-AM fluorescent probes. Our research indicated that EA induced the endoplasmic reticulum stress (ERS) response in Kupffer cells (KCs), accompanied by the activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which resulted in NLRP3 inflammasome formation, and eventually increased the release of inflammatory factors. NLRP3 inflammasome activation was inhibited when KCs were pretreated with ERS inhibitors (4-PBA) and MAPK selective inhibitors. Furthermore, when ERS was blocked, the MAPK pathway was inhibited.


Assuntos
Inflamação/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Ácidos Oleicos/farmacologia , Ácidos Graxos trans/farmacologia , Animais , Butilaminas/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Humanos , Inflamassomos/genética , Inflamação/tratamento farmacológico , Inflamação/patologia , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Sistema de Sinalização das MAP Quinases , Ratos , Ácidos Graxos trans/metabolismo
8.
Vet Med Sci ; 8(2): 781-791, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34904397

RESUMO

BACKGROUND: Management and control of metabolic disorders in sheep around parturition is important. and various researchers have suggested different managerial solutions. Butaphosphan and cyanocobalamin are widely used for curing metabolic disorders resulting from poor nutrition, inadequate management or diseases. OBJECTIVES: It was hypothesised that butaphosphan and cyanocobalamin could improve the metabolism of ewes around parturition. METHODS: Twenty-eight clinically healthy 3-year-old pregnant Afshari ewes from 21 days before parturition were enrolled into four equal groups: control (Ctrl), B+C1, B+C2 and B+C3. The Ctrl group only received intravenous normal saline and B+C1, B+C2 and B+C3 ewes, respectively, received an intravenous combination of 10% butaphosphan and 0.005% cyanocobalamin at 2, 4 and 6 ml/ewe, on Days 19-21, 10-12 and 1-3 before parturition. Blood samples were taken from all the ewes on Days 21, 12 and 3 before lambing at parturition day and on days 3, 12 and 21 after parturition. A body condition score of all the ewes was assessed at blood sampling days, and lambs born from the ewes were weighed at birth and every 2 weeks up to 3 months. Serum concentrations of glucose, cortisol, non-esterified fatty acids, beta-hydroxy butyric acid, triglyceride, cholesterol, high-, low- and very-low-density lipoproteins, aspartate aminotransferase and alanine aminotransferase were measured. RESULTS: This drug combination decreased circulating glucose, cortisol, lipid profile and hepatic enzymes via dose-dependent manner, 6 ml of this drug compound/ewe was more potent than 4 and 2 ml/ewe. The lambs' weight from mothers receiving 6 ml of this combination was significantly higher than those of the others. CONCLUSIONS: It may be suggested that the intravenous administration of 6 ml/ewe of this combination for 3 consecutive days in three states before parturition had prophylactic effects on metabolic disorders of ewes and enhanced the lambs weight gain after birth.


Assuntos
Hidrocortisona , Parto , Administração Intravenosa/veterinária , Animais , Butilaminas , Feminino , Glucose/farmacologia , Hidrocortisona/farmacologia , Ácidos Fosfínicos , Gravidez , Ovinos , Vitamina B 12/farmacologia , Aumento de Peso
9.
Neuropharmacology ; 203: 108880, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34774549

RESUMO

Impairment in various aspects of cognition is recognized as an important non-motor symptom of Parkinson's disease (PD). Mild cognitive impairment in PD (PD-MCI) is common in non-demented PD patients and is often associated with severity of motor symptoms, disease duration and increasing age. Further, PD-MCI can have a significant negative effect on performance of daily life activities and may be a harbinger of development of PD dementia. Thus, there is significant interest in developing therapeutic strategies to ameliorate cognitive deficits in PD and improve cognitive functioning of PD patients. However, due to significant questions that remain regarding the pathophysiology of cognitive dysfunction in PD, remediation of cognitive dysfunction in PD has proven difficult. In this paper, we will focus on PD-MCI and will review some of the current therapeutic approaches being taken to try to improve cognitive functioning in patients with PD-MCI.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Butilaminas/administração & dosagem , Colinérgicos/administração & dosagem , Ensaios Clínicos como Assunto/métodos , Disfunção Cognitiva/psicologia , Dopaminérgicos/administração & dosagem , Humanos , Testes Neuropsicológicos , Doença de Parkinson/psicologia , Serotoninérgicos/administração & dosagem , Resultado do Tratamento
10.
Clin Sci (Lond) ; 135(23): 2643-2658, 2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34796904

RESUMO

Acute kidney injury (AKI)-related fibrosis is emerging as a major driver of chronic kidney disease (CKD) development. Aberrant kidney recovery after AKI is multifactorial and still poorly understood. The accumulation of indoxyl sulfate (IS), a protein-bound uremic toxin, has been identified as a detrimental factor of renal fibrosis. However, the mechanisms underlying IS-related aberrant kidney recovery after AKI is still unknown. The present study aims to elucidate the effects of IS on tubular damage and its involvement in the pathogenesis of AKI-to-CKD transition. Our results showed that serum IS started to accumulate associated with the downregulation of tubular organic anion transporter but not observed in the small-molecule uremic toxins of the unilateral ischemia-reperfusion injury (UIRI) without a contralateral nephrectomy model. Serum IS is positively correlated with renal fibrosis and binding immunoglobulin protein (BiP) and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) expression induction in the UIRI with a contralateral nephrectomy model (UIRI+Nx). To evaluate the effects of IS in the AKI-to-CKD transition, we administered indole, a precursor of IS, at the early stage of UIRI. Our results demonstrated IS potentiates renal fibrosis, senescence-associated secretory phenotype (SASP), and activation of endoplasmic reticulum (ER) stress, which is attenuated by synergistic AST-120 administration. Furthermore, we clearly demonstrated that IS exposure potentiated hypoxia-reperfusion (H/R) induced G2/M cell cycle arrest, epithelial-mesenchymal transition (EMT) and aggravated ER stress induction in vitro. Finally, the ER chemical chaperon, 4-phenylbutyric acid (4-PBA), successfully reversed the above-mentioned AKI-to-CKD transition. Taken together, early IS elimination in the early stage of AKI is likely to be a useful strategy in the prevention and/or treatment of the AKI-to-CKD transition.


Assuntos
Injúria Renal Aguda/sangue , Carbono/uso terapêutico , Indicã/antagonistas & inibidores , Nefroesclerose/prevenção & controle , Óxidos/uso terapêutico , Insuficiência Renal Crônica/prevenção & controle , Injúria Renal Aguda/complicações , Animais , Butilaminas , Carbono/farmacologia , Avaliação Pré-Clínica de Medicamentos , Indicã/sangue , Indicã/isolamento & purificação , Camundongos Endogâmicos C57BL , Nefroesclerose/sangue , Nefroesclerose/etiologia , Óxidos/farmacologia , Insuficiência Renal Crônica/etiologia , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/etiologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos
11.
ChemMedChem ; 16(23): 3588-3599, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34519427

RESUMO

Three analogues of To042, a tocainide-related lead compound recently reported for the treatment of myotonia, were synthesized and evaluated in vitro as skeletal muscle sodium channel blockers possibly endowed with enhanced use-dependent behavior. Patch-clamp experiments on hNav1.4 expressed in HEK293 cells showed that N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine, the aryloxyalkyl bioisostere of To042, exerted a higher use-dependent block than To042 thus being able to preferentially block the channels in over-excited membranes while preserving healthy tissue function. It also showed the lowest active transport across BBB according to the results of P-glycoprotein (P-gp) interacting activity evaluation and the highest cytoprotective effect on HeLa cells. Quantum mechanical calculations and dockings gave insights on the most probable conformation of the aryloxyalkyl bioisostere of To042 in solution and the target residues involved in the binding, respectively. Both approaches indicated the conformations that might be adopted in both the unbound and bound state of the ligand. Overall, N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine exhibits an interesting toxico-pharmacological profile and deserves further investigation.


Assuntos
Butilaminas/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo , Éteres Fenílicos/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Antioxidantes/síntese química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/toxicidade , Butilaminas/síntese química , Butilaminas/metabolismo , Butilaminas/toxicidade , Células HEK293 , Células HeLa , Humanos , Mexiletina/farmacologia , Simulação de Acoplamento Molecular , Éteres Fenílicos/síntese química , Éteres Fenílicos/metabolismo , Éteres Fenílicos/toxicidade , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/toxicidade
12.
J Neurosci Res ; 99(10): 2573-2591, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34197000

RESUMO

Glutamate excitotoxicity and endoplasmic reticulum (ER) recently have been found to be instrumental in the pathogenesis of various neurodegenerative diseases. However, the paucity of literature deciphering the inter-linkage among glutamate receptors, behavioral alterations, and ER demands thorough exploration. Reckoning the aforesaid concerns, a prospective study was outlined to delineate the influence of ER stress inhibition via 4-phenylbutyric acid (PBA) on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) excitotoxicity-induced behavioral aspects and possible ER stress-glutamate linkage. Male SD rats were randomly divided into four groups namely sham (surgical control+vehicle, group 1), AMPA-induced excitotoxic group 2 receive a single intra-hippocampal injection of 10 mM AMPA, group 3 received AMPA along with PBA (i.p, 100 mg/kg body weight) for 15 days, and group 4 received PBA alone. Behavioral analyses were performed prior to the sacrifice of animals and hippocampus was extracted thereafter for further analysis. AMPA-induced excitotoxicity exhibited significant impairment of locomotion as well as cognitive functions. The levels of neurotransmitters such as dopamine, homo vanillic acid (HVA), norepinephrine, and serotonin were reduced accompanied by reduced expression of GLUR1 and GLUR4 (glutamate receptor) as well as loss of neurons in different layers of hippocampus. ER stress markers were upregulated upon AMPA excitotoxicity. However, chemical chaperone PBA supplementation remarkably mitigated the behavioral alterations along with expression of glutamate and ER stress intermediates/markers in AMPA excitotoxic animals. Therefore, the present exploration convincingly emphasizes the significance of ER stress and its inhibition via PBA in combating cognitive impairment as well as improving locomotion in excitotoxic animals.


Assuntos
Butilaminas/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/prevenção & controle , Estresse do Retículo Endoplasmático/fisiologia , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/toxicidade , Animais , Butilaminas/uso terapêutico , Disfunção Cognitiva/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley
13.
Hum Exp Toxicol ; 40(12_suppl): S39-S48, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34219543

RESUMO

BACKGROUND: Benzonatate is a commonly prescribed medication that can be lethal in acute overdose of a small number of capsules. OBJECTIVE: This was a systematic review to describe the course of severe poisoning and deaths from benzonatate supplemented with the National Poison Data System (NPDS) fatalities module. METHODS: The NPDS was queried from 2000 to 2018 for benzonatate fatalities. Pubmed, Cochrane, Embase, and Google Scholar were searched for combinations of benzonatate and "poisoning," "overdose," and "toxicity." References of relevant articles were searched for additional publications. Articles were included if they described the clinical course of at least one patient suffering from benzonatate poisoning and available in English. Dual independent review and extraction were performed. RESULTS: Seventeen cases from NPDS and 19 published reports met the inclusion criteria resulting in 36 cases, mostly (28/36) self-harm ingestions. Most patients were young [17 (11-29), median (IQR)] and female (22). Onset of toxicity was rapid at <5 min (9). Most common symptoms included cardiac arrest (29), seizures (24), and dysrhythmias (24). Treatments included intubation (26), cardiopulmonary resuscitation (28), vasopressors (20) and others. Return of spontaneous circulation was achieved in 23/28 patients, but most had significant neurologic deficits or other end organ damage and 5 survived with a good neurologic outcome. CONCLUSION AND RELEVANCE: Overdose ingestions of benzonatate can cause significant toxicity with a rapid onset. Interventions performed were generally supportive in nature. Duration of directly toxic effects is short, but dramatic with neurologic devastation and resuscitated patients often still have a poor outcome.


Assuntos
Antitussígenos/envenenamento , Butilaminas/envenenamento , Centros de Controle de Intoxicações , Humanos
14.
Front Immunol ; 12: 674316, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122432

RESUMO

Endoplasmic reticulum (ER) stress that disrupts ER function can occur in response to a wide variety of cellular stress factors leads to the accumulation of unfolded and misfolded proteins in the ER. Many studies have shown that ER stress amplified inflammatory reactions and was involved in various inflammatory diseases. However, little is known regarding the role of ER stress in hyperoxia-induced acute lung injury (HALI). This study investigated the influence of ER stress inhibitor, 4-phenyl butyric acid (4-PBA), in mice with HALI. Treatment with 4-PBA in the hyperoxia groups significantly prolonged the survival, decreased lung edema, and reduced the levels of inflammatory mediators, lactate dehydrogenase, and protein in bronchoalveolar lavage fluid, and increased claudin-4 protein expression in lung tissue. Moreover, 4-PBA reduced the ER stress-related protein expression, NF-κB activation, and apoptosis in the lung tissue. In in vitro study, 4-PBA also exerted a similar effect in hyperoxia-exposed mouse lung epithelial cells (MLE-12). However, when claudin-4 siRNA was administrated in mice and MLE-12 cells, the protective effect of 4-PBA was abrogated. These results suggested that 4-PBA protected against hyperoxia-induced ALI via enhancing claudin-4 expression.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Butilaminas/farmacologia , Claudina-4/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Lesão Pulmonar Aguda/etiologia , Animais , Hiperóxia/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regulação para Cima
15.
J Dairy Sci ; 104(8): 9205-9226, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34024600

RESUMO

Dairy cows in modern production systems are at risk to develop metabolic disorders during the transition period. Reasons for individual differences in susceptibility, as well as the underlying pathomechanisms, are still only partially understood. The development of metaphylactic treatment protocols is needed. In this context, an on-farm prospective 3-fold blinded randomized study involving 80 German Holstein cows was performed throughout 1 yr. The trial involved a thorough recording of the production and clinical traits, clinical chemistry, and liver biopsies and blood and urine sampling at d 14 (mean: 12 d, range: 1-26 d) antepartum (AP), and d 7 (7, 4-13) and 28 (28, 23-34) postpartum (PP) for metabolomics analyses. Two groups received a treatment with butaphosphan and cyanocobalamin (BCC) at either the dosage recommended by the manufacturer or the double dosage (5 or 10 mL/100 kg of body weight 10% butaphosphan and 0.005% cyanocobalamin (Catosal, Bayer Animal Health), n = 20 in each group, parity: 4.2 ± 2.0 and 3.4 ± 1.3, respectively (mean ± SD)] and one group a placebo treatment (NaCl 0.9%, n = 40, parity: 4.0 ± 1.9). The animals were treated at 6 time points (7, 6, and 5 d AP, and 1, 2, and 3 d PP) via intravenous injection. Mass spectroscopy-based targeted metabolomics analysis of blood plasma and liver samples were performed using the AbsoluteIDQ p180 kit (Biocrates Life Sciences), whereas the urine samples were analyzed by nuclear magnetic resonance spectroscopy. Statistical analysis was performed using multivariate [partial least squares discriminant analysis (PLS-DA)] and univariate methods (linear mixed model). Multivariate data analysis (PLS-DA plots) of the liver metabolome revealed 3 different metabotypes (A = medium, B = minor, C = large alterations in liver metabolome profile between AP and PP status). Metabotype B animals were characterized by higher PP lipomobilization (stronger PP body condition decrease and higher blood bilirubin, fatty acids, gamma-glutamyltransferase, and triglyceride levels) and a higher occurrence of transition cow diseases, compared with the animals in metabotype C. Analysis of the feeding data showed that the period of metabotype B animals (calving in a distinct time frame) was characterized by a decreased grass silage quality. The PP liver metabolome of the metabotype C animals was characterized by higher concentrations of AA, acylcarnitines, lysoPC and sphingomyelins compared with metabotype B. For the metaphylactic treatment with BCC a dose-dependent effect was confirmed, differing between the metabotypes. In all matrices and metabotypes at various time points significant treatment effects were observed, with different profiles in clinical chemistry and as well in metabolomics data. The most clear-cut treatment effect was observed in metabotype B in the liver at 7 d PP, characterized by an increase in several acylcarnitines and phosphatidylcholines, indicating a more efficient influx and oxidation of fatty acids in mitochondria and thereby an increase in energy supply and more efficient triglyceride export in the liver. The results from the liver metabolomics analysis support the application of an indication-based metaphylactic treatment with BCC.


Assuntos
Lactação , Metaboloma , Animais , Butilaminas , Bovinos , Dieta/veterinária , Feminino , Fígado , Metabolômica , Leite , Ácidos Fosfínicos , Período Pós-Parto , Gravidez , Estudos Prospectivos , Vitamina B 12
16.
J Dairy Sci ; 104(8): 9227-9244, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34024602

RESUMO

The aims of this study were to evaluate histopathologic changes during the transition period, describe the histopathological features of the metabotypes identified in Part I (Schären et al., 2021b), and investigate effects of a metaphylactic treatment with butaphosphan and cyanocobalamin (BCC) on the liver parenchyma. Eighty German Holstein cows (mean 305-d production: 10,957 kg, range: 6,480-15,193 kg; mean lactation number: 3.9, range: 2-9) from a commercial dairy farm in Saxony, Germany, were enrolled in a randomized, prospective, triple-blinded study. Two groups received a treatment with BCC (5 or 10 mL/100 kg of body weight 10% butaphosphan and 0.005% cyanocobalamin, Catosal, Bayer Animal Health, n = 20 each) and one group a placebo treatment (NaCl 0.9%, n = 40). Liver biopsy specimens were collected 14 d antepartum (AP) and 7, 28, and 42 d postpartum (PP), routinely processed for histologic examination, and stained with hematoxylin and eosin, Sudan III, periodic acid-Schiff, and picrosirius red stains. The sections were assessed for fat and glycogen content and degenerative, inflammatory, fibrotic, and proliferative changes. The statistical analysis included the effects of the sampling day, the lactation number, the treatment, and the metabotype (A = medium, B = minor, C = large alterations in the liver metabolome profile between AP and PP status). There was mild to moderate fat infiltration in the liver of 37% of cows in the last 2 wk AP, and moderate to severe fat infiltration in 66% of cows in the first days PP. The degree of fat infiltration increased from 2 wk AP until the end of the first week PP, and then decreased until the end of the study period, at which time about 25% of cows had moderate to severe fatty infiltration. Lipidosis was positively correlated with the severity of liver cell degeneration, and negatively correlated with the degree of glycogen deposits. Complete glycogen depletion of hepatocytes was not observed in cows, even in the presence of severe hepatic lipidosis. Moderate to severe lymphocytic hepatitis was seen in 39% of cows throughout the study period, and cows with lactation numbers 5 or greater had perisinusoidal fibrosis more often than younger cows. Severe fibrosis and cirrhosis of the liver did not occur. Metabotype B animals exhibited a higher chance of fatty infiltration, lower glycogen storage, and perisinusoidal fibrosis and for this metabotype positive correlations were calculated between increased fat deposition in the liver and marked glycogen depletion, and increased degenerative, inflammatory, fibrotic, and proliferative changes of hepatic tissue. For the treatment with BCC, no significant effect was observed. In summary, during the transition period, the liver of dairy cows is characterized by fat accumulation and glycogen depletion and histologic signs of hepatitis and hepatocyte degeneration. These histomorphologic changes were accentuated in animals exhibiting little alterations in their liver metabolome profile across the transition period (metabotype B) and support the assumption of a decreased grass silage quality as a causative factor.


Assuntos
Lactação , Período Pós-Parto , Animais , Butilaminas , Bovinos , Dieta/veterinária , Feminino , Alemanha , Fígado , Metabolômica , Leite , Ácidos Fosfínicos , Estudos Prospectivos , Vitamina B 12
17.
Commun Biol ; 4(1): 569, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980979

RESUMO

Following the FDA-approval of the hematopoietic stem cell (HSC) mobilizer plerixafor, orally available and potent CXCR4 antagonists were pursued. One such proposition was AMD11070, which was orally active and had superior antagonism in vitro; however, it did not appear as effective for HSC mobilization in vivo. Here we show that while AMD11070 acts as a full antagonist, plerixafor acts biased by stimulating ß-arrestin recruitment while fully antagonizing G protein. Consequently, while AMD11070 prevents the constitutive receptor internalization, plerixafor allows it and thereby decreases receptor expression. These findings are confirmed by the successful transfer of both ligands' binding sites and action to the related CXCR3 receptor. In vivo, plerixafor exhibits superior HSC mobilization associated with a dramatic reversal of the CXCL12 gradient across the bone marrow endothelium, which is not seen for AMD11070. We propose that the biased action of plerixafor is central for its superior therapeutic effect in HSC mobilization.


Assuntos
Benzilaminas/farmacologia , Ciclamos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Receptores CXCR4/metabolismo , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacologia , Animais , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Benzilaminas/metabolismo , Butilaminas/metabolismo , Butilaminas/farmacologia , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Ciclamos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Feminino , Fator Estimulador de Colônias de Granulócitos , Células HEK293 , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Preparações Farmacêuticas/metabolismo , Receptores CXCR3/efeitos dos fármacos , Receptores CXCR3/metabolismo , Receptores CXCR4/efeitos dos fármacos , beta-Arrestinas/efeitos dos fármacos , beta-Arrestinas/metabolismo
18.
Clin Toxicol (Phila) ; 59(12): 1270-1273, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33855924

RESUMO

INTRODUCTION: Acute toxicity caused by New Psychoactive Substances (NPS) has created a significant burden for Emergency Departments (EDs). Here we report characteristics of people presenting with toxicity after exposure to the synthetic cathinone N-ethylpentylone (NEP). METHODS: Adults presenting to hospital with severe acute toxicity after suspected NPS use were recruited between March 2015 and October 2020. Clinical features were recorded using consistent methodology and biological samples analysed using liquid chromatography-tandem mass-spectrometry. RESULTS: NEP was detected in at least one sample from 9 of 893 patients recruited during the period of study, all presenting between 2016 and 2019 and 8 presenting in southern England. Commonly reported clinical features included tachycardia (6), agitation (6), confusion (6), mydriasis (5), hallucinations (4), acidosis (3) and elevated creatine kinase (3). Co-used drugs, detected in 6 patients, may have contributed to these features, but agitation and hallucinations were also reported in all 3 patients without analytical evidence of co-use. CONCLUSIONS: NEP was detected infrequently in episodes of drug toxicity in the UK between 2016 and 2019, especially in southern England. Clinical characteristics of toxicity are similar to those of other cathinones, although co-use of other drugs is common and may contribute to the features observed.


Assuntos
Benzodioxóis , Butilaminas , Adulto , Alcaloides , Humanos , Psicotrópicos/toxicidade , Reino Unido/epidemiologia
19.
Aging (Albany NY) ; 13(8): 11135-11149, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33819187

RESUMO

Myocardial infarction (MI) is one of the leading causes of death. Wilms' tumor 1-associating protein (WTAP), one of the components of the m6A methyltransferase complex, has been shown to affect gene expression via regulating mRNA modification. Although WTAP has been implicated in various diseases, its role in MI is unclear. In this study, we found that hypoxia/reoxygenation (H/R) time-dependently increased WTAP expression, which in turn promoted endoplasmic reticulum (ER) stress and apoptosis, in human cardiomyocytes (AC16). H/R effects on ER stress and apoptosis were all blocked by silencing of WTAP, promoted by WTAP overexpression, and ameliorated by administration of ER stress inhibitor, 4-PBA. We then investigated the underlying molecular mechanism and found that WTAP affected m6A methylation of ATF4 mRNA to regulate its expression, and that the inhibitory effects of WTAP on ER stress and apoptosis were ATF4 dependent. Finally, WTAP's effects on myocardial I/R injury were confirmed in vivo. WTAP promoted myocardial I/R injury through promoting ER stress and cell apoptosis by regulating m6A modification of ATF4 mRNA. These findings highlight the importance of WTAP in I/R injury and provide new insights into therapeutic strategies for MI.


Assuntos
Fator 4 Ativador da Transcrição/genética , Proteínas de Ciclo Celular/metabolismo , Infarto do Miocárdio/complicações , Traumatismo por Reperfusão Miocárdica/genética , Fatores de Processamento de RNA/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Butilaminas/farmacologia , Butilaminas/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Linhagem Celular , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Metilação , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Fatores de Processamento de RNA/antagonistas & inibidores , Fatores de Processamento de RNA/genética , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
20.
Oxid Med Cell Longev ; 2021: 6492879, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833850

RESUMO

Inflammation plays a key role in intervertebral disc degeneration (IDD). The association between inflammation and endoplasmic reticulum (ER) stress has been observed in many diseases. However, whether ER stress plays an important role in IDD remains unclear. Therefore, this study is aimed at investigating the expression of ER stress in IDD and at exploring the underlying mechanisms of IDD, ER stress, and inflammation. The expression of ER stress was activated in nucleus pulposus cells from patients who had IDD (D-NPCs) compared with patients without IDD (N-NPCs); and both the proliferation and synthesis capacity were decreased by inducer tunicamycin (Tm) and proinflammatory cytokines. Pretreatment of NPCs with 4-phenyl butyric acid (4-PBA) prevented the inflammatory cytokine-induced upregulation of unfolded protein response- (UPR-) related proteins and recovered cell synthetic ability. Furthermore, proinflammatory cytokine treatment significantly upregulated the expression of inositol-requiring protein 1 (IRE1-α) and protein kinase RNA-like ER kinase (PERK), but not activating transcription factor 6 (ATF6). Finally, knockdown of IRE1-α and PERK also restored the biological activity of NPCs. Our findings identified that IRE1-α and PERK might be the potential targets for IDD treatment, which may help illustrate the underlying mechanism of ER stress in IDD.


Assuntos
Endorribonucleases/metabolismo , Degeneração do Disco Intervertebral/metabolismo , Resposta a Proteínas não Dobradas , eIF-2 Quinase/metabolismo , Adolescente , Adulto , Anti-Inflamatórios/farmacologia , Butilaminas/farmacologia , Células Cultivadas , Feminino , Humanos , Interleucina-1beta/farmacologia , Masculino , Pessoa de Meia-Idade , Núcleo Pulposo/efeitos dos fármacos , Núcleo Pulposo/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Tunicamicina/farmacologia
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