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Ovarian cancer is the leading cause of death from female gynecological cancers. Cisplatin (DDP) is a first-line drug for ovarian cancer treatment. Due to DDP resistance, there is an urgent need for novel therapeutic drugs with improved antitumor activity. AMPK-mediated metabolic regulatory pathways are related to tumor drug resistance. Our study aimed to determine the relationship between reversing DDP resistance with the anthraquinone derivative KA-4s and regulating AMPK energy metabolism in ovarian cancer. The results showed that KA-4s inhibited the proliferation of ovarian cancer cells. The combination of KA-4s with DDP effectively promoted drug-resistant ovarian cancer cell apoptosis and inhibited cell migration and invasion. Moreover, KA-4s decreased the intracellular ATP level and increased the calcium ion level, leading to AMPK phosphorylation. Further studies suggested that the AMPK signaling pathway may be involved in the mechanism through which KA-4s reduce drug resistance. KA-4s inhibited mitochondrial respiration and glycolysis; downregulated the glucose metabolism-related proteins GLUT1 and GLUT4; the lipid metabolism-related proteins SREBP1 and SCD1; and the drug resistance-related proteins P-gp, MRP1, and LRP. The inhibitory effect of KA-4s on GLUT1 was confirmed by the application of the GLUT1 inhibitor BAY-876. KA-4s combined with DDP significantly increased the expression of p-AMPK and reduced the expression of P-gp. In a xenograft model of ovarian cancer, treatment with KA-4s combined with DDP reduced energy metabolism and drug resistance, inducing tumor apoptosis. Consequently, KA-4s might be evaluated as a new agent for enhancing the chemotherapeutic efficacy of treatment for ovarian cancer.
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Genetic epilepsy with febrile seizures plus (GEFS+) is a genetic epilepsy syndrome characterized by a marked hereditary tendency inherited as an autosomal dominant trait. Patients with GEFS+ may develop typical febrile seizures (FS), while generalized tonic-clonic seizures (GTCSs) with fever commonly occur between 3 months and 6 years of age, which is generally followed by febrile seizure plus (FS+), with or without absence seizures, focal seizures, or GTCSs. GEFS+ exhibits significant genetic heterogeneity, with polymerase chain reaction, exon sequencing, and single nucleotide polymorphism analyses all showing that the occurrence of GEFS+ is mainly related to mutations in the gamma-aminobutyric acid type A receptor gamma 2 subunit (GABRG2) gene. The most common mutations in GABRG2 are separated in large autosomal dominant families, but their pathogenesis remains unclear. The predominant types of GABRG2 mutations include missense (c.983A â T, c.245G â A, p.Met199Val), nonsense (R136*, Q390*, W429*), frameshift (c.1329delC, p.Val462fs*33, p.Pro59fs*12), point (P83S), and splice site (IVS6+2T â G) mutations. All of these mutations types can reduce the function of ion channels on the cell membrane; however, the degree and mechanism underlying these dysfunctions are different and could be linked to the main mechanism of epilepsy. The γ2 subunit plays a special role in receptor trafficking and is closely related to its structural specificity. This review focused on investigating the relationship between GEFS+ and GABRG2 mutation types in recent years, discussing novel aspects deemed to be great significance for clinically accurate diagnosis, anti-epileptic treatment strategies, and new drug development.
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Mutación , Receptores de GABA-A , Convulsiones Febriles , Humanos , Receptores de GABA-A/genética , Convulsiones Febriles/genética , Mutación/genética , Epilepsia/genética , AnimalesRESUMEN
Silicosis is a chronic fibroproliferative lung disease caused by long-term inhalation of crystalline silica dust, characterized by the proliferation of fibroblasts and pulmonary interstitial fibrosis. Currently, there are no effective treatments available. Recent research suggests that the Integrin ß1/ILK/PI3K signaling pathway may be associated with the pathogenesis of silicosis fibrosis. In this study, we investigated the effects of Echistatin (Integrin ß1 inhibitor) and BYL-719 (PI3K inhibitor) on silicosis rats at 28 and 56 days after silica exposure. Histopathological analysis of rat lung tissue was performed using H&E staining and Masson staining. Immunohistochemistry, Western blotting, and qRT-PCR were employed to assess the expression of markers associated with epithelial-mesenchymal transition (EMT), fibrosis, and the Integrin ß1/ILK/PI3K pathway in lung tissue. The results showed that Echistatin, BYL 719 or their combination up-regulated the expression of E-cadherin and down-regulated the expression of Vimentin and extracellular matrix (ECM) components, including type I and type III collagen. The increase of Snail, AKT and ß-catenin in the downstream Integrin ß1/ILK/PI3K pathway was inhibited. These results indicate that Echistatin and BYL 719 can inhibit EMT and pulmonary fibrosis by blocking different stages of Integrinß1 /ILK/PI3K signaling pathway. This indicates that the Integrin ß1/ILK/PI3K signaling pathway is associated with silica-induced EMT and may serve as a potential therapeutic target for silicosis.
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Transición Epitelial-Mesenquimal , Integrina beta1 , Fosfatidilinositol 3-Quinasas , Proteínas Serina-Treonina Quinasas , Fibrosis Pulmonar , Transducción de Señal , Dióxido de Silicio , Silicosis , Animales , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Integrina beta1/metabolismo , Integrina beta1/genética , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/patología , Masculino , Dióxido de Silicio/toxicidad , Silicosis/metabolismo , Silicosis/patología , Silicosis/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Pulmón/patología , Pulmón/efectos de los fármacos , Ratas Sprague-DawleyRESUMEN
We aimed to assess the temporal epidemiological trends in tuberculosis (TB) by use of an advanced Theta method. The TB incidence data from Tianjin, Heilongjiang, Hubei, and Guangxi provinces in China, spanning January 2005 to December 2019, were extracted. We then constructed and compared various modeling approaches, including the seasonal autoregressive integrated moving average (SARIMA) model, the Theta model, the standard Theta model (STM), the dynamic optimized Theta model (DOTM), the dynamic standard Theta model (DSTM), and the optimized Theta model (OTM). During 2005-2019, these four provinces recorded a total of 2,068,399 TB cases. Analyses indicated that TB exhibited seasonality, with prominent peaks in spring and winter, and a slight downward trend was seen in incidence. In the Tianjin forecast, the OTM consistently demonstrated superior performance with the lowest values across metrics, including mean absolute deviation (0.159), mean absolute percentage error (7.032), root mean square error (0.21), mean error rate (0.068), and root mean square percentage error (0.093), compared with those of SARIMA (0.397, 16.654, 0.436, 0.169, and 0.179, respectively), Theta (0.166, 7.248, 0.231, 0.071, and 0.102, respectively), DOTM (0.169, 7.341, 0.234, 0.072, and 0.102, respectively), DSTM (0.169, 7.532, 0.203, 0.072, and 0.092, respectively), and STM (0.165, 7.218, 0.231, 0.070, and 0.101, respectively). Similar results were also observed in the other provinces, emphasizing the effectiveness of the OTM in estimating TB trends. Thus, the OTM may serve as a beneficial and effective tool for estimating the temporal epidemiological trends of TB.
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Tuberculosis , Humanos , Incidencia , China/epidemiología , Tuberculosis/epidemiología , Modelos Estadísticos , Estaciones del AñoRESUMEN
BACKGROUND: Interrupted time series (ITS) analysis is a growing method for assessing intervention impacts on diseases. However, it remains unstudied how the COVID-19 outbreak impacts gonorrhea. This study aimed to evaluate the effect of COVID-19 on gonorrhea and predict gonorrhea epidemics using the ITS-autoregressive integrated moving average (ARIMA) model. METHODS: The number of gonorrhea cases reported in China from January 2005 to September 2022 was collected. Statistical descriptions were applied to indicate the overall epidemiological characteristics of the data, and then the ITS-ARIMA was established. Additionally, we compared the forecasting abilities of ITS-ARIMA with Bayesian structural time series (BSTS), and discussed the model selection process, transfer function, check model fitting, and interpretation of results. RESULT: During 2005-2022, the total cases of gonorrhea were 2,165,048, with an annual average incidence rate of 8.99 per 100,000 people. The highest incidence rate was 14.2 per 100,000 people in 2005 and the lowest was 6.9 per 100,000 people in 2012. The optimal model was ARIMA (0,1, (1,3)) (0,1,1)12 (Akaike's information criterion = 3293.93). When predicting the gonorrhea incidence, the mean absolute percentage error under the ARIMA (16.45%) was smaller than that under the BSTS (22.48%). The study found a 62.4% reduction in gonorrhea during the first-level response, a 46.47% reduction during the second-level response, and an increase of 3.6% during the third-level response. The final model estimated a step change of - 2171 (95% confidence interval [CI] - 3698 to - 644) cases and an impulse change of - 1359 (95% CI - 2381 to - 338) cases. Using the ITS-ARIMA to evaluate the effect of COVID-19 on gonorrhea, the gonorrhea incidence showed a temporary decline before rebounding to pre-COVID-19 levels in China. CONCLUSION: ITS analysis is a valuable tool for gauging intervention effectiveness, providing flexibility in modelling various impacts. The ITS-ARIMA model can adeptly explain potential trends, autocorrelation, and seasonality. Gonorrhea, marked by periodicity and seasonality, exhibited a downward trend under the influence of COVID-19 intervention. The ITS-ARIMA outperformed the BSTS, offering superior predictive capabilities for the gonorrhea incidence trend in China.
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COVID-19 , Gonorrea , Humanos , COVID-19/epidemiología , Modelos Estadísticos , Factores de Tiempo , Teorema de Bayes , Gonorrea/epidemiología , China/epidemiología , Incidencia , PredicciónRESUMEN
OBJECTIVE: Hepatitis C presents a profound global health challenge. The impact of COVID-19 on hepatitis C, however, remain uncertain. This study aimed to ascertain the influence of COVID-19 on the hepatitis C epidemic trend in Henan Province. METHODS: We collated the number of monthly diagnosed cases in Henan Province from January 2013 to September 2022. Upon detailing the overarching epidemiological characteristics, the interrupted time series (ITS) analysis using autoregressive integrated moving average (ARIMA) models was employed to estimate the hepatitis C diagnosis rate pre and post the COVID-19 emergence. In addition, we also discussed the model selection process, test model fitting, and result interpretation. RESULTS: Between January 2013 and September 2022, a total of 267,968 hepatitis C cases were diagnosed. The yearly average diagnosis rate stood at 2.42/100,000 persons. While 2013 witnessed the peak diagnosis rate at 2.97/100,000 persons, 2020 reported the least at 1.7/100,000 persons. The monthly mean hepatitis C diagnosed numbers culminated in 2291 cases. The optimal ARIMA model chosen was ARIMA (0,1,1) (0,1,1)12 with AIC = 1459.58, AICc = 1460.19, and BIC = 1472.8; having coefficients MA1=-0.62 (t=-8.06, P < 0.001) and SMA1=-0.79 (t=-6.76, P < 0.001). The final model's projected step change was - 800.0 (95% confidence interval [CI] -1179.9 ~ -420.1, P < 0.05) and pulse change was 463.40 (95% CI 191.7 ~ 735.1, P < 0.05) per month. CONCLUSION: The measures undertaken to curtail COVID-19 led to a diminishing trend in the diagnosis rate of hepatitis C. The ARIMA model is a useful tool for evaluating the impact of large-scale interventions, because it can explain potential trends, autocorrelation, and seasonality, and allow for flexible modeling of different types of impacts.
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COVID-19 , Hepatitis C , Humanos , Análisis de Series de Tiempo Interrumpido , Incidencia , COVID-19/epidemiología , Hepatitis C/epidemiología , Hepacivirus , Predicción , China/epidemiología , Modelos EstadísticosRESUMEN
Objective: This study aims to investigate the impact of vagus nerve stimulation (VNS) on the connectivity and small-world metrics of brain functional networks during seizure periods. Methods: Ten refractory epilepsy patients underwent video encephalographic monitoring before and after VNS treatment. The 2-min electroencephalogram segment containing the ictal was selected for each participant, resulting in a total of 20 min of seizure data. The weighted phase lag index (wPLI) and small-world metrics were calculated for the whole frequency band and different frequency bands (delta, theta, alpha, beta, and gamma). Finally, the relevant metrics were statistically analyzed, and the false discovery rate was used to correct for differences after multiple comparisons. Results: In the whole band, the wPLI was notably enhanced, and the network metrics, including degree (D), clustering coefficient (CC), and global efficiency (GE), increased, while characteristic path length (CPL) decreased (P < 0.01). In different frequency bands, the wPLI between the parieto-occipital and frontal regions was significantly strengthened in the delta and beta bands, while the wPLI within the frontal region and between the frontal and parieto-occipital regions were significantly reduced in the beta and gamma bands (P < 0.01). In the low-frequency band (<13 Hz), the small-world metrics demonstrated significantly increased CC, D, and GE, with a significantly decreased CPL, indicating a more efficient network organization. In contrast, in the gamma band, the GE decreased, and the CPL increased, suggesting a shift toward less efficient network organization. Conclusion: VNS treatment can significantly change the wPLI and small-world metrics. These findings contribute to a deeper understanding of the impact of VNS therapy on brain networks and provide objective indicators for evaluating the efficacy of VNS.
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Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumour that occurs in the superficial tissue of extremities of children and young adults. A painless mass in the deep dermis and subcutaneous tissue is the main clinical manifestation. AFH also occurs infrequently in the central nervous system and is relatively common in the cranium. However, spinal canal AFH has not been described yet. We report a rare case of AFH in the cervical canal of a 20-year-old male patient. Microsurgical gross total resection of the tumour was performed, and the diagnosis was confirmed by postoperative pathology. To our knowledge, this is the first case of AFH in the spinal canal.
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Histiocitoma Fibroso Benigno , Histiocitoma Fibroso Maligno , Masculino , Niño , Adulto Joven , Humanos , Adulto , Histiocitoma Fibroso Benigno/diagnóstico por imagen , Histiocitoma Fibroso Benigno/cirugía , Histiocitoma Fibroso Maligno/diagnóstico por imagen , Histiocitoma Fibroso Maligno/cirugíaRESUMEN
Silicosis is an occupational lung disease that results from long-term inhalation of free silica dust, the expression is sustained inflammation response, fibroblast hyperplasia, and excessive collagen deposit, bringing about pulmonary interstitial fibrosis. Wnt signaling pathway exists in various kinds of eukaryotic cells, is a highly conservative signaling pathway in biological evolution, and participates in cell proliferation, differentiation, migration, and polarity of physiological activity, such as in embryonic development, organ morphology, and tumor. In addition, it plays an important role in the progress of fibrosis disease. At present, studies related to silicosis are increasing, but the pathogenesis of silicosis still is not clear. In recent years, more and more studies have suggested that the Wnt signaling pathway could participate in the pathogenesis of silicosis fibrosis. In the study, we explored the mechanism of the Wnt signaling pathway in the pathogenesis of silicosis fibrosis and evaluated the effect of XAV-939 treatment epithelial-mesenchymal transformation (EMT) induced by silica. In addition, the results showed that EMT and activation of the Wnt signaling pathway would occur after stimulation of silica or TGF-ß1. However, after treatment with the Wnt signaling pathway inhibitor XAV-939, EMT was reversed and the expression of the ß-catenin decreased. These results suggested that the Wnt signaling pathway is associated with EMT induced by silica and it could be a potential target for the treatment of silicosis.
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Transición Epitelial-Mesenquimal , Fibrosis Pulmonar , Silicosis , Humanos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibrosis , Fibrosis Pulmonar/inducido químicamente , Dióxido de Silicio/toxicidad , Silicosis/metabolismo , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
Background: Dravet syndrome (DS) is a severe epileptic encephalopathy mainly caused by haploinsufficiency of the gene SCN1A, which encodes the voltage-gated sodium channel NaV1. 1 in the brain. While SCN1A mutations are known to be the primary cause of DS, other genes that may cause DS are poorly understood. Several genes with pathogenic mutations result in DS or DS-like phenotypes, which may require different drug treatment approaches. Therefore, it is urgent for clinicians, especially epilepsy specialists to fully understand these genes involved in DS in addition to SCN1A. Particularly for healthcare providers, a deep understanding of these pathogenic genes is useful in properly selecting and adjusting drugs in a more effective and timely manner. Objective: The purpose of this study was to identify genes other than SCN1A that may also cause DS or DS-like phenotypes. Methods: A comprehensive search of relevant Dravet syndrome and severe myoclonic epilepsy in infancy was performed in PubMed, until December 1, 2021. Two independent authors performed the screening for potentially eligible studies. Disagreements were decided by a third, more professional researcher or by all three. The results reported by each study were narratively summarized. Results: A PubMed search yielded 5,064 items, and other sources search 12 records. A total of 29 studies published between 2009 and 2021 met the inclusion criteria. Regarding the included articles, seven studies on PCDH19, three on SCN2A, two on SCN8A, five on SCN1B, two on GABRA1, three on GABRB3, three on GABRG2, and three on STXBP1 were included. Only one study was recorded for CHD2, CPLX1, HCN1 and KCNA2, respectively. It is worth noting that a few articles reported on more than one epilepsy gene. Conclusion: DS is not only identified in variants of SCN1A, but other genes such as PCDH19, SCN2A, SCN8A, SCN1B, GABRA1, GABRB3, GABRG2, KCNA2, CHD2, CPLX1, HCN1A, STXBP1 can also be involved in DS or DS-like phenotypes. As genetic testing becomes more widely available, more genes associated with DS and DS-like phenotypes may be identified and gene-based diagnosis of subtypes of phenotypes in this spectrum may improve the management of these diseases in the future.
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BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a hereditary monogenic peripheral nerve disease. Variants in the gene encoding myelin protein zero (MPZ) lead to CMT, and different variants have different clinical phenotypes. A variant site, namely, c.389A > G (p.Lys130Arg), in the MPZ gene has been found in Chinese people. The pathogenicity of this variant has been clarified through pedigrees, and peripheral blood-related functional studies have been conducted. METHOD: Whole-exome sequencing and Sanger sequencing were used to detect the c.389A > G (p.Lys130Arg) variant in the MPZ gene in family members of the proband. Physical examination was performed in the case group to assess the clinical characteristics of MPZ site variants. The expression of MPZ and phosphorylated MPZ in the blood of 12 cases and 12 randomly selected controls was compared by RT-qPCR, Western blotting, and ELISA. RESULTS: The proband and 12 of her family members presented the AG genotype with different clinical manifestations. The expression of MPZ mRNA in the case group was increased compared with that in the control group, and the levels of MPZ and phosphorylated MPZ in peripheral blood were higher than those in normal controls. CONCLUSION: The heterozygous genotype of the c.389A > G (p.Lys130Arg) variant in the MPZ gene mediated the increase in MPZ and phosphorylated MPZ levels in peripheral blood and was found to be involved with CMT.
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Enfermedad de Charcot-Marie-Tooth , Proteína P0 de la Mielina , Enfermedad de Charcot-Marie-Tooth/genética , China , Femenino , Humanos , Mutación , Proteína P0 de la Mielina/genética , Proteína P0 de la Mielina/metabolismo , FenotipoRESUMEN
Epilepsy comorbidities and antiepileptic drugs (AEDs) are currently the main limitations of epilepsy treatment. Semaglutide is a glucagon like peptide1 analogue that has entered the market as a new onceweekly drug for type II diabetes. The aim of the present study was to investigate the functions of semaglutide in epilepsy and inflammation models, in order to investigate its potential mechanism. In vitro, an inflammation model was established using lipopolysaccharide (LPS) and nigericin stimulation in BV2 cells. In vivo, chronic epilepsy model mice were generated using a pentylenetetrazole (PTZ) kindling method. BV2 cell proliferation was assessed using the Cell Counting Kit8. The effects of semaglutide on NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and inflammatory cytokine secretion were determined using western blotting (WB) and ELISA. A lactate dehydrogenase (LDH) assay kit was used to detect the effect of semaglutide on LDH release. Electrocorticography and the modified Racine scale were used to assess seizure severity. Cognitive function was evaluated with behavioral assessment. Morphological changes in the hippocampus were observed with Nissl staining. Double immunofluorescence staining for NeuN and Iba1, WB and immunofluorescence analysis of apoptosisrelated proteins were used to evaluate neuronal apoptosis. The NLRP3 inflammasome was assessed by reverse transcriptionquantitative PCR, WB and immunofluorescence staining, and inflammatory cytokine release was evaluated by WB analysis in the hippocampus of C57/BL6J model mouse. Semaglutide attenuated the LPS and nigericininduced inflammatory response and LDH release by blocking NLRP3 inflammasome activation in BV2 cells. Moreover, semaglutide decreased seizure severity, alleviated hippocampal neuronal apoptosis, ameliorated cognitive dysfunction, blocked NLRP3 inflammasome activation and decreased inflammatory cytokine secretion in PTZkindled mice. These results indicated that semaglutide reduced seizure severity, exerted neuroprotective effects and ameliorated cognitive dysfunction, possibly via inhibition of NLRP3 inflammasome activation and inflammatory cytokine secretion. Semaglutide may therefore be a novel, promising adjuvant therapeutic for epilepsy and its associated comorbidities.
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Disfunción Cognitiva/tratamiento farmacológico , Péptidos Similares al Glucagón/farmacología , Inflamasomas/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Pentilenotetrazol/farmacología , Convulsiones/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Disfunción Cognitiva/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inflamasomas/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Fármacos Neuroprotectores/farmacología , Convulsiones/metabolismoRESUMEN
Exendin-4 (Ex4), a long-lasting glucagon-like peptide-1 analog, was reported to exert favourable actions on inhibiting cocaine-associated rewarding and reinforcing effects of drug in animal models of addiction. However, the therapeutic potential of different dose of GLP-1 receptor agonist Ex4 in different behavioral paradigms and the underlying pharmacological mechanisms of action are incompletely understood. Herein, we firstly investigated the effects of Ex4 on cocaine-induced condition place preference (CPP) as well as extinction and reinstatement in male C57BL/6J mice. Additionally, we sought to elucidate the underlying pharmacological mechanism of these actions of Ex4. The paradigm of cocaine-induced CPP was established using 20 mg/kg cocaine or saline alternately during conditioning, while the reinstatement paradigm was modeled using 10 mg/kg cocaine on the reinstatement day. Different dose of Ex4 was administrated intraperitoneally either during conditioning or during extinction state or only on the test day. To elucidate the molecular mechanism underlying the potential effects of Ex4 on maladaptive behaviors of cocaine, the TLR4-related inflammation within the hippocampus was observed by immunofluorescence staining, and the expression levels of toll-like receptor 4 (TLR4), tumor necrosis factor (TNF)-α, and interleukin (IL)-1ß were detected by Western blotting. As a consequence, systemic administration of different dose of Ex4 was sufficient to inhibit the acquisition and expression of cocaine-induced CPP, facilitate the extinction of cocaine-associated reward and attenuate reinstatement of cocaine-induced behavior. Furthermore, Ex4 treatment diminished expression levels of TLR4, TNF-α, and IL-1ß, which were up-regulated by cocaine exposure. Altogether, our results indicated that Ex4 effectively ameliorated cocaine-induced behaviors likely through neurobiological mechanisms partly attributable to the inhibition of TLR4, TNF-α and IL-1ß in mice. Consequently, our findings improved our understanding of the efficacy of Ex4 for the amelioration of cocaine-induced behavior and suggested that Ex4 may be applied as a drug candidate for cocaine addiction.
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Mutations in the GABRG2 gene encoding the γ-aminobutyric acid (GABA) A receptor gamma 2 subunit are associated with genetic epilepsy with febrile seizures plus, febrile seizures plus, febrile seizures, and other symptoms of epilepsy. However, the mechanisms underlying Gabrg2-mediated febrile seizures are poorly understood. Here, we used the Cre/loxP system to generate conditional knockout (CKO) mice with deficient Gabrg2 in the hippocampus and neocortex. Heterozygous CKO mice (Gabrg2fl/wtCre+) exhibited temperature-dependent myoclonic jerks, generalised tonic-clonic seizures, increased anxiety-like symptoms, and a predisposition to induce seizures. Cortical electroencephalography showed the hyperexcitability in response to temperature elevation in Gabrg2fl/wtCre+ mice, but not in wild-type mice. Gabrg2fl/wtCre+ mice exhibited spontaneous seizures and susceptibility to temperature-induced seizures. Loss of neurons were observed in cortical layers V-VI and hippocampus of Gabrg2fl/wtCre+ mice. Furthermore, the latency of temperature- or pentylenetetrazol-induced seizures were significantly decreased in Gabrg2fl/wtCre+ mice compared with wild-type mice. In summary, Gabrg2fl/wtCre+ mice with Gabrg2 deletion in the neocortex and hippocampus reproduce many features of febrile seizures and therefore provide a novel model to further understand this syndrome at the cellular and molecular level.
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Receptores de GABA-A/metabolismo , Convulsiones Febriles/genética , Convulsiones/genética , Animales , Humanos , Masculino , Ratones , Mutación , Neocórtex , Convulsiones/fisiopatología , Convulsiones Febriles/fisiopatología , TemperaturaRESUMEN
At present, effective therapeutic drugs for triplenegative breast cancer (TNBC) are lacking due to the absence of identified or available targets. Therefore, the present study aimed to identify key molecular targets and a specific targeted therapeutic drug to aid with the development of novel therapeutic strategies for TNBC. Based on the high expression of EGFR and Rac1 in TNBC and inspired by a novel antitumor strategy termed combitargeting, novel anthraquinonequinazoline hybrid 7B was synthesized to simultaneously target EGFR and Rac1. It was hypothesized that hybrid 7B may possess enhanced potency compared with its parent compounds. Breast cancer cell viability was detected by performing MTT assays. Flow cytometry was conducted to detect the effects of hybrid 7B on the cell cycle, apoptosis and the mitochondrial outer membrane potential. Ultrastructural alterations were observed by transmission electron microscopy. Cell invasion and migration were assessed by performing Transwell and woundhealing assays, respectively. The expression levels of epithelialmesenchymal transition (EMT) markers and metastasisrelated proteins were detected by western blotting. Compared with Rhein and gefitinib, hybrid 7B displayed superior antiproliferative activity in MDAMB231 cells with an IC50 value of 2.31 µM, which was 14fold higher compared with the EGFR tyrosine kinase inhibitor gefitinib. Further experiments demonstrated that hybrid 7B significantly reduced the mitochondrial membrane potential, enhanced MDAMB231 cell apoptosis and induced cell cycle arrest at the G2/M phase compared with the control group. Typical morphological alterations of apoptotic cells were observed in hybrid 7Btreated MDAMB231 and MCF7 cells. Compared with the control group, hybrid 7B significantly inhibited MDAMB231 cell invasion and migration by downregulating Rac1, EGFR, matrix metalloproteinases, snail family transcriptional repressor 1, Vimentin and ßcatenin protein expression levels, and upregulating Ecadherin protein expression levels. The present study demonstrated that hybrid 7B inhibited TNBC cell migration and invasion by reversing EMT and targeting EGFR and Rac1; therefore, hybrid 7B may serve as a promising therapeutic agent for TNBC.
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Antraquinonas/farmacología , Quinazolinas/farmacología , Neoplasias de la Mama Triple Negativas/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Antraquinonas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Transición Epitelial-Mesenquimal/efectos de los fármacos , Receptores ErbB/química , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Modelos Moleculares , Simulación del Acoplamiento Molecular , Metástasis de la Neoplasia , Quinazolinas/química , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Proteína de Unión al GTP rac1/químicaRESUMEN
Background: SCN1A is one of the most common epilepsy genes. About 80% of SCN1A gene mutations cause Dravet syndrome (DS), which is a severe and catastrophic epileptic encephalopathy. More than 1,800 mutations have been identified in SCN1A. Although it is known that SCN1A is the main cause of DS and genetic epilepsy with febrile seizures plus (GEFS+), there is a dearth of information on the other related diseases caused by mutations of SCN1A. Objective: The aim of this study is to systematically review the literature associated with SCN1A and other non-DS-related disorders. Methods: We searched PubMed and SCOPUS for all the published cases related to gene mutations of SCN1A until October 20, 2021. The results reported by each study were summarized narratively. Results: The PubMed and SCOPUS search yielded 2,889 items. A total of 453 studies published between 2005 and 2020 met the final inclusion criteria. Overall, 303 studies on DS, 93 on GEFS+, three on Doose syndrome, nine on the epilepsy of infancy with migrating focal seizures (EIMFS), six on the West syndrome, two on the Lennox-Gastaut syndrome (LGS), one on the Rett syndrome, seven on the nonsyndromic epileptic encephalopathy (NEE), 19 on hemiplegia migraine, six on autism spectrum disorder (ASD), two on nonepileptic SCN1A-related sudden deaths, and two on the arthrogryposis multiplex congenital were included. Conclusion: Aside from DS, SCN1A also causes other epileptic encephalopathies, such as GEFS+, Doose syndrome, EIMFS, West syndrome, LGS, Rett syndrome, and NEE. In addition to epilepsy, hemiplegic migraine, ASD, sudden death, and arthrogryposis multiplex congenital can also be caused by mutations of SCN1A.
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Recently we read a paper in Investigational New Drugs "An orally antitumor chalcone hybrid inhibited HepG2 cells growth and migration as the tubulin binding agent". Chalcone hybrid 9, a novel chalcone derivative, may be a promising agent for the treatment of hepatocellular carcinoma. However, there are some problems in this paper that are worthy of comment. Human hepatocellular carcinoma HepG2 cells from Shanghai Research Science Limited Company could generate xenograft in nude mice and chalcone hybrid 9 suppressed the growth of HepG2 tumor. However, according to the description of cell bank of Chinese Academy of Science and ATCC, HepG2 cells are no tumorigenic. Similarly, our lab also confirmed that HepG2 cells cannot demonstrate tumorigenic ability in nude mice. Therefore, this discrepancy raised our concern about HepG2 xenograft in the paper.
Asunto(s)
Carcinoma Hepatocelular , Chalcona , Chalconas , Neoplasias Hepáticas , Animales , Proliferación Celular , Chalcona/farmacología , China , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Ratones , Ratones Desnudos , Tubulina (Proteína)RESUMEN
Deep brain stimulation (DBS) modulates the neuronal activity in specific brain circuits and has been recently considered as a promising intervention for refractory addiction. The insula cortex is the hub of interoception and is known to be involved in different aspects of substance use disorder. In the present study, we investigate the effects of continuous high frequency DBS in the anterior insula (AI) on drug-seeking behaviors and examined the molecular mechanisms of DBS action in morphine-addicted rats. Sprague-Dawley rats were trained to the morphine-conditioned place preference (CPP, day 1-8) followed by bilaterally implanted with DBS electrodes in the AI (Day 10) and recovery (Day 10-15). Continuous high-frequency (HF) -DBS (130 Hz, 150 µA, 90 µs) was applied during withdrawal (Day 16-30) or extinction sessions. CPP tests were conducted on days 16, 30, 40 during withdrawal session and several rats were used for proteomic analysis on day 30. Following the complete extinction, morphine-CPP was reinstated by a priming dose of morphine infusion (2 mg/kg). The open field and novel objective recognition tests were also performed to evaluate the DBS side effect on the locomotion and recognition memory. Continuous HF-DBS in the AI attenuated the expression of morphine-CPP post-withdrawal (Day 30), but morphine addictive behavior relapsed 10 days after the cessation of DBS (Day 40). Continuous HF-DBS reduced the period to full extinction of morphine-CPP and blocked morphine priming-induced recurrence of morphine addiction. HF-DBS in the AI had no obvious effect on the locomotor activity and novel objective recognition and did not cause anxiety-like behavior. In addition, our proteomic analysis identified eight morphine-regulated proteins in the AI and their expression levels were reversely changed by HF-DBS. Continuous HF-DBS in the bilateral anterior insula prevents the relapse of morphine place preference after withdrawal, facilitates its extinction, blocks the reinstatement induced by morphine priming and reverses the expression of morphine-regulated proteins. Our findings suggest that manipulation of insular activity by DBS could be a potential intervention to treat substance use disorder, although future research is warranted.