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In this study, we undertook an extensive investigation to determine how CypB PPIase activity affects preadipocyte differentiation and lipid metabolism. Our findings revealed that inhibition of CypB's PPIase activity suppressed the expression of crucial proteins involved in adipocyte differentiation and induced changes in proteins regulating the cell cycle. Furthermore, we clarified the impact of CypB's PPIase activity on lipid metabolism via the AKT/mTOR signaling pathway. Additionally, we demonstrated the involvement of CypB's PPIase activity in lipid metabolism through the XBP1s pathway. These discoveries offer invaluable insights for devising innovative therapeutic strategies aimed at treating and averting obesity and its related health complications. Targeting CypB's PPIase activity may emerge as a promising avenue for addressing obesity-related conditions. Furthermore, our research opens up opportunities for creating new therapeutic strategies by enhancing our comprehension of the processes involved in cellular endoplasmic reticulum stress.
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Células 3T3-L1 , Adipocitos , Diferenciación Celular , Metabolismo de los Lípidos , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Proteína 1 de Unión a la X-Box , Proteína 1 de Unión a la X-Box/metabolismo , Animales , Ratones , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Adipocitos/metabolismo , Adipogénesis , Estrés del Retículo Endoplásmico/fisiologíaRESUMEN
Background: Although obesity is known to be related to allergic diseases, few studies have investigated the prevalence of allergic diseases in individuals with obesity, especially during the COVID-19 pandemic. Thus, this study aimed to analyze national trends of allergic diseases among individuals with obesity and sociodemographic factors. Methods: This study used data from the Korea National Health and Nutrition Examination Survey to examine the prevalence of allergic diseases among individuals with obesity in South Korea from 2005 to 2021. A nationally representative sample of 118,275 participants aged over 2 years or above was divided into six groups for analysis. This study used weighted multivariate regression analysis to examine the estimates of related factors. It assessed the weighted odds ratios or ß-coefficients for these factors across different categories, including age, sex, region of residence, education level, household income, and body mass index for the entire population. Results: All allergic diseases showed a general upward trend from 2005 to 2021, but each disease showed different prevalence trends when compared by age. Before the pandemic, those aged ≤39 years had an increasing trend for asthma and AD, but those aged ≥40 years had a decreasing trend. For asthma, ß-coefficients were 0.629 (95 % CI, 0.299 to 0.958) for 19-39 years, -0.245 (-0.450 to -0.040) for 40-59 years, and -0.668 (-1.024 to -0.313) for ≥60 years. For AD, ß-coefficients were 2.514 (1.258-3.769) in those aged 2-18 years, 0.630 (0.173-1.086) in those aged 19-39 years, -0.458 (-0.648 to -0.268) in those aged 40-59 years, and -0.253 (-0.454 to -0.052) in those aged ≥60 years. However, for both asthma and AD, there were no significant changes in prevalence during the pandemic. In the case of AR, trends were different from those of asthma and AD. Before the pandemic, AR showed an increasing trend in those aged ≤39 years and those aged ≥40 years: ß-coefficients were 3.067 (2.344-3.790) in 19-39 years, 2.051 (1.609-2.493) in 40-59 years, and 1.173 (0.820-1.526) in ≥60 years. During the pandemic, there was an increasing trend only among those aged 40-59, with no significant changes in other age groups: ß-coefficients were 1.438 (0.065-2.811) in 40-59 years. Conclusions: From 2005 to 2021, all allergic diseases (asthma, AD, and AR) increased overall, but with different age-related trends. No significant link was found between COVID-19 and allergic diseases, possibly due to preventive measures like mask-wearing and social distancing. Anxiety about accessing healthcare during the pandemic likely contributed to a decline in allergy diagnoses, highlighting the need for comprehensive strategies to manage and prevent allergic diseases.
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The heat shock response is an evolutionarily conserved mechanism that protects cells or organisms from the harmful effects of various stressors such as heat, chemicals toxins, UV radiation, and oxidizing agents. The heat shock response triggers the expression of a specific set of genes and proteins known as heat shock genes/proteins or molecular chaperones, including HSP100, HSP90, HSP70, HSP60, and small HSPs. Heat shock proteins (HSPs) play a crucial role in thermotolerance and aiding in protecting cells from harmful insults of stressors. HSPs are involved in essential cellular functions such as protein folding, eliminating misfolded proteins, apoptosis, and modulating cell signaling. The stress response to various environmental insults has been extensively studied in organisms from prokaryotes to higher organisms. The responses of organisms to various environmental stressors rely on the intensity and threshold of the stress stimuli, which vary among organisms and cellular contexts. Studies on heat shock proteins have primarily focused on HSP70, HSP90, HSP60, small HSPs, and ubiquitin, along with their applications in human biology. The current review highlighted a comprehensive mechanism of heat shock response and explores the function of heat shock proteins in stress management, as well as their potential as therapeutic agents and diagnostic markers for various diseases.
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Proteínas de Choque Térmico , Respuesta al Choque Térmico , Humanos , Proteínas de Choque Térmico/metabolismo , AnimalesRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition characterized by lipid accumulation in hepatocytes with low alcohol consumption. The development of sterile inflammation, which occurs in response to a range of cellular stressors or injuries, has been identified as a major contributor to the pathogenesis of NAFLD. Recent studies of the pathogenesis of NAFLD reported the newly developed roles of damage-associated molecular patterns (DAMPs). These molecules activate pattern recognition receptors (PRRs), which are placed in the infiltrated neutrophils, dendritic cells, monocytes, or Kupffer cells. DAMPs cause the activation of PRRs, which triggers a number of immunological responses, including the generation of cytokines that promote inflammation and the localization of immune cells to the site of the damage. This review provides a comprehensive overview of the impact of DAMPs and PRRs on the development of NAFLD.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/etiología , Macrófagos del Hígado , Monocitos , Neutrófilos , InflamaciónRESUMEN
Two synthetic phenylethylamines, N-methyl-1-(naphthalen-2-yl)propan-2-amine (MNA) and 1-phenyl-2-pyrrolidinylpentane (prolintane), are being abused by people seeking hallucinogens for pleasure. These new psychotropic substances may provoke problems because there is no existing information about their toxicity and pharmacological behaviors. Therefore, we evaluated the safety of nerves and cardiovascular systems by determining toxicity after MNA and prolintane drugs administrations to mice and rat. Consequently, side effects such as increased spontaneous motion and body temperature were observed in oral administration of MNA. In addition, both substances reduced motor coordination levels. The IHC tests were conducted to see whether the immune response also shows abnormalities in brain tissue compared to the control group. It has been confirmed that the length of allograft inflammatory factor 1(IBA-1), an immune antibody known as microglia marker, has been shortened. We identified that a problem with the contact between synapses and neurons might be possibly produced. In the assessment of the cardiac toxicity harmfulness, no substances have been confirmed to be toxic to myocardial cells, but at certain concentrations, they have caused the QT prolongation, an indicator of ventricular arrhythmia. In addition, the hERG potassium channel, the biomarker of the QT prolongation, has been checked for inhibition. The results revealed that the possibility of QT prolongation through the hERG channel could not be excluded, and the two substances can be considered toxic that may cause ventricular arrhythmia. In sum, this study demonstrated that the possibility of toxicity in MNA and prolintane compounds might bring many harmful effects on nerves and hearts.
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Cardiotoxicidad , Alucinógenos , Síndrome de QT Prolongado , Síndromes de Neurotoxicidad , Fenetilaminas , Animales , Ratones , Ratas , Cardiotoxicidad/etiología , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Alucinógenos/toxicidad , Síndrome de QT Prolongado/inducido químicamente , Miocitos Cardíacos/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Fenetilaminas/toxicidadRESUMEN
Ketone bodies (KBs), such as acetoacetate and ß-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.
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Lesiones Encefálicas , Dieta Cetogénica , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Humanos , Cuerpos Cetónicos , Neuroprotección , Fármacos Neuroprotectores/uso terapéutico , Infarto CerebralRESUMEN
The ketone bodies (KBs) ß-hydroxybutyrate and acetoacetate are important alternative energy sources for glucose during nutrient deprivation. KBs synthesized by hepatic ketogenesis are catabolized to acetyl-CoA through ketolysis in extrahepatic tissues, followed by the tricarboxylic acid cycle and electron transport chain for ATP production. Ketogenesis and ketolysis are regulated by the key rate-limiting enzymes, 3-hydroxy-3-methylglutaryl-CoA synthase 2 and succinyl-CoA:3-oxoacid-CoA transferase, respectively. KBs participate in various cellular processes as signaling molecules. KBs bind to G protein-coupled receptors. The most abundant KB, ß-hydroxybutyrate, regulates gene expression and other cellular functions by inducing post-translational modifications. KBs protect tissues by regulating inflammation and oxidative stress. Recently, interest in KBs has been increasing due to their potential for treatment of various diseases such as neurological and cardiovascular diseases and cancer. Cancer cells reprogram their metabolism to maintain rapid cell growth and proliferation. Dysregulation of KB metabolism also plays a role in tumorigenesis in various types of cancer. Targeting metabolic changes through dietary interventions, including fasting and ketogenic diets, has shown beneficial effects in cancer therapy. Here, we review current knowledge of the molecular mechanisms involved in the regulation of KB metabolism and cellular signaling functions, and the therapeutic potential of KBs and ketogenic diets in cancer.
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Dieta Cetogénica , Neoplasias , Humanos , Ácido 3-Hidroxibutírico , Cuerpos Cetónicos/metabolismo , Transducción de Señal , Neoplasias/tratamiento farmacológicoRESUMEN
The use of many benzodiazepines is controlled worldwide due to their high likelihood of abuse and potential adverse effects. Flubromazepam-a designer benzodiazepine-is a long-acting gamma-aminobutyric acid subtype A receptor agonist. There is currently a lack of scientific evidence regarding the potential for flubromazepam dependence or other adverse effects. This study aimed to evaluate the dependence potential, and cardiotoxicity via confirmation of the QT and RR intervals which are the factors on the electrical properties of the heart of flubromazepam in rodents. Using a conditioned place preference test, we discovered that mice treated intraperitoneally with flubromazepam (0.1 mg/kg) exhibited a significant preference for the flubromazepam-paired compartment, suggesting a potential for flubromazepam dependence. In addition, we observed several cardiotoxic effects of flubromazepam; 100-µM flubromazepam reduced cell viability, increased RR intervals but not QT intervals in the electrocardiography measurements, and considerably inhibited potassium channels in a human ether-à-go-go-related gene assay. Collectively, these findings suggest that flubromazepam may have adverse effects on psychological and cardiovascular health, laying the foundation for further efforts to list flubromazepam as a controlled substance at both national and international levels.
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Two new psychoactive substances (NPSs) classified as phenethylamines, namely 2-((2-(4-Iodo-2,5-dimethoxyphenyl)ethylamino)methyl)phenol (25I-NBOH) and 2-(((2-(4-chloro-2,5-dimethoxyphenyl)ethyl)amino)methyl)phenol (25C-NBOH), are being abused by people seeking recreational hallucinogens. These NPSs may cause serious health problems as their adverse effects are not known in most cases. Therefore, in the present study, we evaluated the cardiotoxicity of 25I-NBOH and 25C-NBOH using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, rat electrocardiography (ECG), Langendorff test, and human ether-a-go-go-related gene (hERG) assay. Furthermore, we analyzed the expression levels of p21 CDC42/RAC1-activated kinase 1 (PAK1), which is known to play various roles in the cardiovascular system. In the MTT assay, treatment with 25I-NBOH or 25C-NBOH dramatically decreased viability of H9c2 cardiomyocytes. Meanwhile, these two compounds significantly increased QT intervals and RR intervals in the rat ECG measurement. 25I-NBOH down-regulated the PAK1 protein expression in rat primary cardiomyocytes as well as H9c2 cells. However, 25C-NBOH had no effect on the PAK1 expression in H9c2 cells. In an in-depth study, 25I-NBOH inhibited potassium channels in the hERG assay, but in ex vivo test, the substance did not affect the left ventricular developed pressure (LVDP) and heart rate of the isolated rat hearts. Taken together, these results suggest that both 25I-NBOH and 25C-NBOH may have adverse cardiovascular effect. Further investigation would be needed to determine which factors mainly influence the relationship between PAK1 expression and cardiotoxicity.
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Cardiopatías/inducido químicamente , Miocitos Cardíacos/efectos de los fármacos , Fenetilaminas/toxicidad , Psicotrópicos/toxicidad , Compuestos de Amonio Cuaternario/toxicidad , Animales , Células CHO , Línea Celular , Cricetulus , Reducción Gradual de Medicamentos , Canal de Potasio ERG1/genética , Canal de Potasio ERG1/metabolismo , Electrocardiografía , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Estructura Molecular , Fenetilaminas/administración & dosificación , Compuestos de Amonio Cuaternario/administración & dosificación , Ratas , Ratas Sprague-Dawley , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismoRESUMEN
Abuse of new psychoactive substances is an emerging social problem. Several phenethylamines are internationally controlled substances as they are likely to be abused and have adverse effects. Phenethylamine analog 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25I-NBOMe) has been reported as one of the most commonly abused psychoactive substance. However, the cardiotoxicity of this compound has not been extensively evaluated. Thus, in this study, we investigated the adverse cardiovascular effects of 25I-NBOMe, related to p21 (CDC42/RAC)-activated kinase 1 (PAK1). The cardiotoxicity of 25I-NBOMe was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, live/dead cytotoxicity assay, PAK1/CDC42 kinase assay, and in vivo electrocardiography (ECG). Also, we analyzed the expression level of PAK1, which is known to play key roles in the cardiovascular system. In the MTT assay, cell viability of 25I-NBOMe-treated H9c2 cells or primary cardiomyocytes of ICR mice decreased in a concentration-dependent manner. Results from the in vitro cytotoxicity assay in cardiomyocytes showed that 25I-NBOMe decreased the viability of H9c2 rat cardiomyocytes, and TC50 of 25I-NBOMe was found to be 70.4 µM. We also observed that 25I-NBOMe reduced PAK1 activity in vitro. Surface ECG measurement revealed that intravenous injection of 25I-NBOMe (doses of 1.0 and 3.0 mg/kg, corresponding to serum concentrations of 18.1 and 28.6 ng/mL, respectively) prolonged the QTc interval in SD rats. Furthermore, treatment with 25I-NBOMe downregulated the expression of PAK1 in the hearts of SD rats and H9c2 cells. In summary, our findings indicate that PAK1-related adverse effects of 25I-NBOMe can cause toxicity to cardiomyocytes and induce an abnormal ECG pattern in animals.
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Dimetoxifeniletilamina , Roedores , Animales , Dimetoxifeniletilamina/análogos & derivados , Dimetoxifeniletilamina/farmacología , Ratones , Ratones Endogámicos ICR , Miocitos Cardíacos , Fenetilaminas/toxicidad , Ratas , Ratas Sprague-DawleyRESUMEN
Triclosan (TCS) is an antibacterial and antifungal agent used in many consumer products and exhibits a chemical structure similar to non-steroidal estrogen, which is known to induce endocrine disruption. Triclosan has been found in human plasma, urine, and breast milk, and the safety of TCS-containing products has been disputed. Although studies attempted to determine the estrogenic activity of TCS, no clear results have emerged. The aim of the present study was to examine estrogenic activity of TCS using an in vitro E-screen assay and an in vivo uterotrophic assay. The in vitro E-screen assay demonstrated that TCS significantly enhanced proliferation of MCF-7 breast cancer cells, although not in a concentration-dependent manner. The in vivo uterotrophic results showed no significant change in the weight of uteri obtained from TCS-administered Sprague-Dawley rats. Further, to understand the estrogenic activity attributed to TCS at the molecular level, gene-expression profiling of uterus samples was performed from both TCS- or estrogen-treated rats and the genes and cellular processes affected by TCS or estrogen were compared. Data demonstrated that both the genes and cellular processes affected by TCS or estrogen were significantly similar, indicating the possibility that TCS-mediated estrogenic activity occurred at the global transcriptome level. In conclusion, in vitro and gene-profiling results suggested that TCS exhibited estrogenic activity.
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Antiinfecciosos Locales/efectos adversos , Disruptores Endocrinos/efectos adversos , Estrógenos/efectos adversos , Triclosán/efectos adversos , Animales , Femenino , Humanos , Células MCF-7 , Ratas , Ratas Sprague-Dawley , Útero/efectos de los fármacosRESUMEN
The Wnt/ß-catenin signaling pathway is involved in breast cancer and Myxococcus fulvus KYC4048 is a myxobacterial strain that can produce a variety of bioactive secondary metabolites. Although a previous study revealed that KYC4048 metabolites exhibit anti-proliferative effects on breast cancer, the biochemical mechanism involved in their effects remains unclear. In the present study, KYC4048 metabolites were separated into polar and non-polar (ethyl acetate and n-hexane) fractions via liquid-liquid extraction. The effects of these polar and non-polar KYC4048 metabolites on the viability of breast cancer cells were then determined by MTT assay. Expression levels of Wnt/ß-catenin pathway proteins were determined by Western blot analysis. Cell cycle and apoptosis were measured via fluorescence-activated cell sorting (FACS). The results revealed that non-polar KYC4048 metabolites induced cell death of breast cancer cells and decreased expression levels of WNT2B, ß-catenin, and Wnt target genes (c-Myc and cyclin D1). Moreover, the n-hexane fraction of non-polar KYC4048 metabolites was found most effective in inducing apoptosis, necrosis, and cell cycle arrest, leading us to conclude that it can induce apoptosis of breast cancer cells through the Wnt/ß-catenin pathway. These findings provide evidence that the n-hexane fraction of non-polar KYC4048 metabolites can be developed as a potential therapeutic agent for breast cancer via inhibition of the Wnt/ß-catenin pathway.
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Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Myxococcus/química , Vía de Señalización Wnt/efectos de los fármacos , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Ciclina D1 , Glicoproteínas , Humanos , Células MCF-7 , Proteínas Proto-Oncogénicas c-myc , Proteínas Wnt , beta CateninaRESUMEN
Hepatocellular carcinoma (HCC) is the fifth common types of cancer with poor prognosis in the world. Honokiol (HNK), a natural biphenyl compound derived from the magnolia plant, has been reported to exert anticancer effects, but its mechanism has not been elucidated exactly. In the present study, HNK treatment significantly suppressed the migration ability of HepG2 and Hep3B human hepatocellular carcinoma. The treatment reduced the expression levels of the genes associated with cell migration, such as S100A4, MMP-2, MMP-9 and Vimentin. Interestingly, treatment with HNK significantly reduced the expression level of Cyclophilin B (CypB) which stimulates cancer cell migration. However, overexpressed CypB abolished HNK-mediated suppression of cell migration, and reversed the apoptotic effects of HNK. Altogether, we concluded that the suppression of migration activities by HNK was through down-regulated CypB in HCC. These finding suggest that HNK may be a promising candidate for HCC treatment via regulation of CypB.
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Compuestos de Bifenilo/farmacología , Carcinoma Hepatocelular/genética , Movimiento Celular/efectos de los fármacos , Ciclofilinas/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Lignanos/farmacología , Neoplasias Hepáticas/genética , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Ciclofilinas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Animal models of human diseases are crucial experimental tools to investigate the mechanisms involved in disease pathogenesis and to develop new therapies. In spite of the numerous animal models currently available that reproduce several neuropathological features of Parkinson disease (PD), it is challenging to have one that consistently recapitulates human PD conditions in both motor behaviors and biochemical pathological outcomes. Given that, we have implemented a new paradigm to expose rats to a chronic low dose of paraquat (PQ), using osmotic minipumps and characterized the developed pathologic features over time. The PQ exposure paradigm used lead to a rodent model of PD depicting progressive nigrostriatal dopaminergic neurodegeneration, characterized by a 41% significant loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc), a significant decrease of 18% and 40% of dopamine levels in striatum at week 5 and 8, respectively, and a significant 1.5-fold decrease in motor performance. We observed a significant increase of microglia activation state, sustained levels of α-synucleinopathy and increased oxidative stress markers in the SNpc. In summary, this is an explorative study that allowed to characterize an improved PQ-based rat model that recapitulates cardinal features of PD and may represent an attractive tool to investigate several mechanisms underlying the various aspects of PD pathogenesis as well as for the validation of the efficacy of new therapeutic approaches that targets different mechanisms involved in PD neurodegeneration.
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Paraquat , Enfermedad de Parkinson , Animales , Cuerpo Estriado , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas , Paraquat/toxicidad , Porción Compacta de la Sustancia Negra , Ratas , Sustancia NegraRESUMEN
Two synthetic tryptamines, namely [3-[2-(diethylamino)ethyl]-1H-indol-4-yl] acetate (4-AcO-DET) and 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol (4-HO-MET), are abused by individuals seeking recreational hallucinogens. These new psychoactive substances (NPSs) can cause serious health problems because their adverse effects are mostly unknown. In the present study, we evaluated the cardiotoxicity of 4-AcO-DET and 4-HO-MET using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, electrocardiography (ECG), and the human ether-a-go-go-related gene (hERG) assay. In addition, we analyzed the expression level of p21 (CDC42/RAC)-activated kinase 1 (PAK1), which is known to play various roles in the cardiovascular system. In the MTT assay, 4-AcO-DET- and 4-HO-MET-treated H9c2 cells proliferated in a concentration-dependent manner. Moreover, both substances increased QT intervals (as determined using ECG) in Sprague-Dawley rats and inhibited potassium channels (as verified by the hERG assay) in Chinese hamster ovary cells. However, there was no change in PAK1 expression. Collectively, the results indicated that 4-AcO-DET and 4-HO-MET might cause adverse effects on the cardiovascular system. Further studies are required to confirm the relationship between PAK1 expression and cardiotoxicity. The findings of the present study would provide science-based evidence for scheduling the two NPSs.