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Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.
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Trastorno del Espectro Autista , Modelos Animales de Enfermedad , Edaravona , Estrés Oxidativo , Ácido Valproico , Animales , Ácido Valproico/farmacología , Ácido Valproico/administración & dosificación , Edaravona/farmacología , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/inducido químicamente , Femenino , Estrés Oxidativo/efectos de los fármacos , Masculino , Administración Oral , Embarazo , Ratas , Ratas Sprague-Dawley , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/administración & dosificación , Depuradores de Radicales Libres/uso terapéutico , Relación Dosis-Respuesta a Droga , Conducta Estereotipada/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Interacción Social/efectos de los fármacosRESUMEN
The high rate of relapse to compulsive methamphetamine (MA)-taking and seeking behaviors after abstinence constitutes a major obstacle to the treatment of MA addiction. Perineuronal nets (PNNs), essential components of the extracellular matrix, play a critical role in synaptic function, learning, and memory. Abnormalities in PNNs have been closely linked to a series of neurological diseases, such as addiction. However, the exact role of PNNs in MA-induced related behaviors remains elusive. Here, we established a MA-induced conditioned place preference (CPP) paradigm in female mice and found that the number and average optical density of PNNs increased significantly in the medial prefrontal cortex (mPFC) of mice during the acquisition, extinction, and reinstatement stages of CPP. Notably, the removal of PNNs in the mPFC via chondroitinase ABC (ChABC) before extinction training not only facilitated the extinction of MA-induced CPP and attenuated the relapse of extinguished MA preference but also significantly reduced the activation of c-Fos in the mPFC. Similarly, the ablation of PNNs in the mPFC before reinstatement markedly lessened the reinstatement of MA-induced CPP, which was accompanied by the decreased expression of c-Fos in the mPFC. Collectively, our results provide more evidence for the implication of degradation of PNNs in facilitating extinction and preventing relapse of MA-induced CPP, which indicate that targeting PNNs may be an effective therapeutic option for MA-induced CPP memories.
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Extinción Psicológica , Metanfetamina , Ratones Endogámicos C57BL , Corteza Prefrontal , Animales , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Metanfetamina/farmacología , Femenino , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Ratones , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/fisiología , Red Nerviosa/efectos de los fármacos , Red Nerviosa/metabolismo , Condroitina ABC Liasa/farmacologíaRESUMEN
Excessive or inappropriate fear responses can lead to anxiety-related disorders, such as post-traumatic stress disorder (PTSD). Studies have shown that microglial activation occurs after fear conditioning and that microglial inhibition impacts fear memory. However, the role of microglia in fear memory recall remains unclear. In this study, we investigated the activated profiles of microglia after the recall of remote-cued fear memory and the role of activated microglia in the extinction of remote-cued fear in adult male C57BL/6 mice. The results revealed that the expression of the microglia marker Iba1 increased in the medial prefrontal cortex (mPFC) at 10 min and 1 h following remote-cued fear recall, which was accompanied by amoeboid morphology. Inhibiting microglial activation through PLX3397 treatment before remote fear recall did not affect recall, reconsolidation, or regular extinction but facilitated recall-extinction and mitigated spontaneous recovery. Moreover, our results demonstrated reduced co-expression of Iba1 and postsynaptic density protein 95 (PSD95) in the mPFC, along with decreases in the p-PI3K/PI3K ratio, p-Akt/Akt ratio, and KLF4 expression after PLX3397 treatment. Our results suggest that microglial activation after remote fear recall impedes fear extinction through the pruning of synapses in the mPFC, accompanied by alterations in the expression of the PI3K/AKT/KLF4 pathway. This finding can help elucidate the mechanism involved in remote fear extinction, contributing to the theoretical foundation for the intervention and treatment of PTSD.
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Extinción Psicológica , Miedo , Factor 4 Similar a Kruppel , Recuerdo Mental , Ratones Endogámicos C57BL , Microglía , Corteza Prefrontal , Animales , Miedo/fisiología , Miedo/psicología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiología , Masculino , Microglía/metabolismo , Extinción Psicológica/fisiología , Recuerdo Mental/fisiología , Ratones , Proteínas de Microfilamentos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Homólogo 4 de la Proteína Discs Large/metabolismo , Estimulación Acústica/efectos adversos , Transducción de SeñalRESUMEN
Aphis gossypii Glover, a widespread insect, presents a substantial danger to global agriculture. Lambda-cyhalothrin is a pyrethroid insecticide that has been widely studied for its effects on arthropods. Studies have reported that sublethal doses of insecticides can produce various consequences on arthropod reproduction. Hence, the objective of this research was to examine the potential effects of a sublethal dose of lambda-cyhalothrin (LC30, 1.15 mg/L) on A. gossypii, for which we created life tables and conducted qPCR analysis. Adult longevity, fecundity, net reproductive rate (R0), body length, width, weight, and the expression of vitellogenin (Vg) and vitellogenin receptor (VgR) genes were not significantly altered by lambda-cyhalothrin treatment at LC30 concentration in the F0 generation of A. gossypii adults. The intrinsic rate of increase (r) and finite rates of increase (λ) decreased significantly, while the mean generation time (T) increased. In addition, Vg and VgR gene expression levels were significantly higher in the F1 and F2 generations, whereas body length, width, and weight were notably reduced. The developmental duration, longevity, r, and λ did not differ significantly from those of the control group. Thus, the sublethal and intergenerational stimulatory effects of lambda-cyhalothrin were observed in A. gossypii, and the alterations in Vg and VgR in A. gossypii were strongly associated with sublethal effects. The results of this research offer valuable knowledge regarding the indirect impacts of lambda-cyhalothrin on A. gossypii, which can be utilized as a theoretical foundation for the prudent utilization of insecticides to combat this pest and devise strategies for managing resistance.
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BACKGROUND: Myocardial infarction is a common perioperative complication, and blood flow restoration causes ischemia/reperfusion injury (IRI). Dexmedetomidine (DEX) pretreatment can protect against cardiac IRI, but the mechanism is still insufficiently understood. METHODS: In vivo, myocardial ischemia/reperfusion (30 minutes/120 minutes) was induced via ligation and then reperfusion of the left anterior descending coronary artery (LAD) in mice. Intravenous infusion of 10 µg/kg DEX was performed 20 minutes before ligation. Moreover, the α2-adrenoreceptor antagonist Yohimbine and STAT3 inhibitor Stattic were applied 30 minutes ahead of DEX infusion. In vitro, hypoxia/reoxygenation (H/R) with DEX pretreatment for 1 hour was performed in isolated neonatal rat cardiomyocytes. In addition, Stattic was applied before DEX pretreatment. RESULTS: In the mouse cardiac ischemia/reperfusion model, DEX pretreatment lowered the serum creatine kinase-MB isoenzyme (CK-MB) levels (2.47 ± 0.165 vs 1.55 ± 0.183; P < .0001), downregulated the inflammatory response ( P ≤ .0303), decreased 4-hydroxynonenal (4-HNE) production and cell apoptosis ( P = .0074), and promoted the phosphorylation of STAT3 (4.94 ± 0.690 vs 6.68 ± 0.710, P = .0001), which could be blunted by Yohimbine and Stattic. The bioinformatic analysis of differentially expressed mRNAs further confirmed that STAT3 signaling might be involved in the cardioprotection of DEX. Upon H/R treatment in isolated neonatal rat cardiomyocytes, 5 µM DEX pretreatment improved cell viability ( P = .0005), inhibited reactive oxygen species (ROS) production and calcium overload (both P ≤ .0040), decreased cell apoptosis ( P = .0470), and promoted STAT3 phosphorylation at Tyr705 (0.102 ± 0.0224 vs 0.297 ± 0.0937; P < .0001) and Ser727 (0.586 ± 0.177 vs 0.886 ± 0.0546; P = .0157), which could be abolished by Stattic. CONCLUSIONS: DEX pretreatment protects against myocardial IRI, presumably by promoting STAT3 phosphorylation via the α2-adrenoreceptor in vivo and in vitro.
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Dexmedetomidina , Isquemia Miocárdica , Daño por Reperfusión Miocárdica , Daño por Reperfusión , Animales , Ratones , Ratas , Apoptosis , Forma MB de la Creatina-Quinasa , Dexmedetomidina/farmacología , Modelos Animales de Enfermedad , Hipoxia , Daño por Reperfusión Miocárdica/prevención & control , Miocardio , Transducción de Señal , Receptores Adrenérgicos alfaRESUMEN
Methamphetamine (Meth), a commonly used central nervous system stimulant, is highly addictive. Currently, there is no effective treatment for Meth dependence and abuse, although cell adhesion molecules (CAMs) have been shown to play an important role in the formation and remodeling of synapses in the nervous system while also being involved in addictive behavior. Contactin 1 (CNTN1) is a CAM that is widely expressed in the brain; nevertheless, its role in Meth addiction remains unclear. Therefore, in the present study, we established mouse models of single and repeated Meth exposure and subsequently determined that CNTN1 expression in the nucleus accumbens (NAc) was upregulated in mice following single or repeated Meth exposure, whereas CNTN1 expression in the hippocampus was not significantly altered. Intraperitoneal injection of the dopamine receptor 2 antagonist haloperidol reversed Meth-induced hyperlocomotion and upregulation of CNTN1 expression in the NAc. Additionally, repeated Meth exposure also induced conditioned place preference (CPP) in mice and upregulated the expression levels of CNTN1, NR2A, NR2B, and PSD95 in the NAc. Using an AAV-shRNA-based approach to specifically silence CNTN1 expression in the NAc via brain stereotaxis reversed Meth-induced CPP and decreased the expression levels of NR2A, NR2B, and PSD95 in the NAc. These findings suggest that CNTN1 expression in the NAc plays an important role in Meth-induced addiction, and the underlying mechanism may be related to the expression of synapse-associated proteins in the NAc. The results of this study improved our understanding of the role of cell adhesion molecules in Meth addiction.
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Trastornos Relacionados con Anfetaminas , Estimulantes del Sistema Nervioso Central , Metanfetamina , Ratones , Animales , Metanfetamina/farmacología , Núcleo Accumbens , Contactina 1/metabolismo , Estimulantes del Sistema Nervioso Central/farmacología , Encéfalo/metabolismo , Trastornos Relacionados con Anfetaminas/metabolismoRESUMEN
The integrated device for energy supply and sensing (IDESS) is a potential candidate for relieving the energy and space burdens caused by the rising integration degrees of microsystems. In this article, we propose a force sensor based on an interdigital supercapacitor (IDTSC). The capacitance and internal resistance of the IDTSC change under external loads, resulting in a transient current fluctuation at a constant bias voltage, which can be used to sense external force/acceleration. The IDTSC showed a specific energy and specific power of 4.16 Wh/kg and 22.26 W/kg (at 0.1 A/g), respectively, which could maintain an essential energy supply. According to the simulation analysis, the designed IDTSC's current response exhibited good linearity with the external force. In addition, benefiting from its light weight and the applied gel electrolytes, the IDTSC showed good high-g impact sensing performance (from 9.9 × 103× g to 3.2 × 104× g). This work demonstrated the feasibility of realizing an integrated energy supply and force-sensing device by empowering energy storage devices with sensing capabilities.
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Aceleración , Electricidad , Capacidad Eléctrica , Simulación por ComputadorRESUMEN
ABSTRACT: Background: Dexmedetomidine (DEX) attenuates intestinal I/R injury, but its mechanism of action remains to be further elucidated. Protein disulfide isomerase A3 (PDIA3) has been reported as a therapeutic protein for the prevention and treatment of intestinal I/R injury. This study was to investigate whether PDIA3 is involved in intestinal protection of DEX and explore the underlying mechanisms. Methods: The potential involvement of PDIA3 in DEX attenuation of intestinal I/R injury was tested in PDIA3 Flox/Flox mice and PDIA3 conditional knockout (cKO) in intestinal epithelium mice subjected to 45 min of superior mesenteric artery occlusion followed by 4 h of reperfusion. Furthermore, the α2-adrenergic receptor (α2-AR) antagonist, yohimbine, was administered in wild-type C57BL/6N mice intestinal I/R model to investigate the role of α2-AR in the intestinal protection conferred by DEX. Results: In the present study, we identified intestinal I/R-induced obvious inflammation, endoplasmic reticulum (ER) stress-dependent apoptosis, and oxidative stress, and all the aforementioned changes were improved by the administration of DEX. PDIA3 cKO in the intestinal epithelium have reversed the protective effects of DEX. Moreover, yohimbine also reversed the intestinal protection of DEX and downregulated the messenger RNA and protein levels of PDIA3. Conclusion: DEX prevents PDIA3 decrease by activating α2-AR to inhibit intestinal I/R-induced inflammation, ER stress-dependent apoptosis, and oxidative stress in mice.
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Dexmedetomidina , Animales , Ratones , Dexmedetomidina/farmacología , Dexmedetomidina/uso terapéutico , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Proteína Disulfuro Isomerasas/genética , Proteína Disulfuro Isomerasas/farmacología , Ratones Endogámicos C57BL , Apoptosis , Yohimbina/farmacología , Inflamación/tratamiento farmacológicoRESUMEN
In order to solve the problem of seismic performance of prefabricated concrete shear walls connected with ultra-high performance cement-based composite (UHPC) after short lap of steel bars, the author proposes a cement-based composite nanomaterial in the prefabricated thin-walled lightweight application in steel structure composite wall. In order to explore the influence of the axial compression ratio on its seismic performance, 1 is a cast-in-place shear wall with a design axial compression ratio of 0.2, and 3 is a prefabricated shear wall with a design axial compression ratio of 0.2, 0.33, and 0.47, respectively, all the specimens were mainly damaged by shear compression. The test results show that the cracking loads of specimens PW2 and PW3 are increased by 17.04% and 38.81%, respectively, the yield load is increased by 27.74% and 50.28%, respectively, and the peak load is increased by 25.29% and 48.4%, respectively. Conclusion. With the increase of the axial compression ratio, the crack resistance and bearing capacity of the specimens are significantly improved.
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Influx of activated neutrophils into the lungs is the histopathologic hallmark of acute lung injury (ALI) after intestinal ischemia/reperfusion (I/R). Neutrophils can release DNA and granular proteins to form cytotoxic neutrophil extracellular traps (NETs), which promotes bystander tissue injury. However, whether NETs are responsible for the remote ALI after intestinal I/R and the mechanisms underlying the dissemination of harmful gut-derived mediators to the lungs are unknown. In the C57BL/6J mouse intestinal I/R model, DNase I-mediated degradation and protein arginine deiminase 4 (PAD4) inhibitor-mediated inhibition of NET treatments reduced NET formation, tissue inflammation, and pathological injury in the lung. High-mobility group protein B1 (HMGB1) blocking prevented NET formation and protected against tissue inflammation, as well as reduced cell apoptosis and improved survival rate. Moreover, recombinant human HMGB1 administration further drives NETs and concurrent tissue toxic injury, which in turn can be reversed by neutrophil deletion via anti-Ly6G Ab i.p. injection. Furthermore, global MyD88 deficiency regulated NET formation and alleviated the development of ALI induced by intestinal I/R. Thus, HMGB1 released from necroptotic enterocytes caused ALI after intestinal I/R by inducing NET formation. Targeting NETosis and the HMGB1 pathway might extend effective therapeutic strategies to minimize intestinal I/R-induced ALI.
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Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/metabolismo , Trampas Extracelulares/genética , Proteína HMGB1/genética , Neutrófilos/inmunología , Neutrófilos/metabolismo , Daño por Reperfusión/etiología , Daño por Reperfusión/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Apoptosis/genética , Biomarcadores , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Proteína HMGB1/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/deficiencia , Daño por Reperfusión/patologíaRESUMEN
Drinking behavior in rodents is characterized by stereotyped, rhythmic licking movement, which is regulated by the basal ganglia. It is unclear how direct and indirect pathways control the lick bout and individual spout contact. We find that inactivating D1 and D2 receptor-expressing medium spiny neurons (MSNs) in the ventrolateral striatum (VLS) oppositely alters the number of licks in a bout. D1- and D2-MSNs exhibit different patterns of lick-sequence-related activity and different phases of oscillation time-locked to the lick cycle. On the timescale of a lick cycle, transient inactivation of D1-MSNs during tongue protrusion reduces spout contact probability, whereas transiently inactivating D2-MSNs has no effect. On the timescale of a lick bout, inactivation of D1-MSNs (D2-MSNs) causes rate increase (decrease) in a subset of basal ganglia output neurons that decrease firing during licking. Our results reveal the distinct roles of D1- and D2-MSNs in regulating licking at both coarse and fine timescales.
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Conducta Animal , Neuronas Dopaminérgicas/fisiología , Conducta de Ingestión de Líquido , Vías Nerviosas/fisiología , Sustancia Negra/fisiología , Estriado Ventral/fisiología , Potenciales de Acción , Animales , Neuronas Dopaminérgicas/metabolismo , Técnicas In Vitro , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Movimiento , Inhibición Neural , Vías Nerviosas/metabolismo , Optogenética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Conducta Estereotipada , Sustancia Negra/metabolismo , Factores de Tiempo , Lengua/inervación , Estriado Ventral/metabolismoRESUMEN
Conversion of glial cells into functional neurons represents a potential therapeutic approach for replenishing neuronal loss associated with neurodegenerative diseases and brain injury. Previous attempts in this area using expression of transcription factors were hindered by the low conversion efficiency and failure of generating desired neuronal types in vivo. Here, we report that downregulation of a single RNA-binding protein, polypyrimidine tract-binding protein 1 (Ptbp1), using in vivo viral delivery of a recently developed RNA-targeting CRISPR system CasRx, resulted in the conversion of Müller glia into retinal ganglion cells (RGCs) with a high efficiency, leading to the alleviation of disease symptoms associated with RGC loss. Furthermore, this approach also induced neurons with dopaminergic features in the striatum and alleviated motor defects in a Parkinson's disease mouse model. Thus, glia-to-neuron conversion by CasRx-mediated Ptbp1 knockdown represents a promising in vivo genetic approach for treating a variety of disorders due to neuronal loss.
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Neurogénesis/fisiología , Neuroglía/metabolismo , Células Ganglionares de la Retina/metabolismo , Animales , Sistemas CRISPR-Cas/fisiología , Diferenciación Celular/fisiología , Células Cultivadas , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Modelos Animales de Enfermedad , Dopamina/metabolismo , Regulación de la Expresión Génica/genética , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades del Sistema Nervioso/metabolismo , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismo , Proteína de Unión al Tracto de Polipirimidina/genética , Proteína de Unión al Tracto de Polipirimidina/metabolismo , Células Ganglionares de la Retina/fisiologíaRESUMEN
Fifteen known amaryllidaceae alkaloids were isolated from the bulbs of Lycoris radiata. Some of the compounds and lycoricidine derivatives had been screened for the activities against tobacco mosaic virus (TMV) by the conventional half-leaf method. Lycoricidine derivatives were also carried out the assay of effect on systemic infection of TMV by western-blot and RT-PCR analysis. The tested compounds showed moderate inactivation effect, whereas the lycoricidine derivatives showed good protective effect. The protective inhibitory activity of compounds L1 (N-methyl-2,3,4-trimethoxylycoricidine) (60.8%) and L3 (N-methyl-2-methoxy-3,4-acetonidelycoricidine) (62.0%) was almost similar to the positive control, Ningnanmycin (66.4%). RT-PCR and Western-blot analysis displayed that compounds L1, L3, L5 (N-allyl-2,3,4-triallyloxylycoricidine) exhibited antiviral activity, which was evidenced by reducing TMV-CP gene replication and TMV-CP protein expression. Additionally, defensive enzyme activities confirmed that compound L1 could increase the activity of PAL, POD, SOD to improve disease resistance of tobacco.
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The purpose of this study was to evaluate the cerebral protection of salvianolic acid B (Sal B) against cerebral I/R injury and investigate the underlying mechanism. As shown by 2,3,5-Triphenyltetrazolium chloride (TTC) staining and magnetic resonance imaging (MRI) analyses, Sal B significantly reduced cerebral infarct size, and accompanied with improved neurobehavioral functions as indicated by the modified Bederson score and Longa five-point scale. Sal B decreased the production of reactive oxygen species (pâ¯<â¯.05, nâ¯=â¯10). The data of Western blotting and reverse transcription quantitative real time polymerase chain reaction (qRT-PCR) analyses showed that the expression of GFAP, Iba1, IL-1ß, IL-6, TNF-α and Cleaved-caspase 3 was significantly reduced by Sal B in I/R injured brain tissues as compared to corresponding controls (pâ¯<â¯.05, nâ¯=â¯10). Over activation of astrocytes and microglia were inhibited by Sal B as shown by immunostaining of GFAP and Iba 1. These data suggest that Sal B has neural protective effects against I/R-induced cerebral injury and could be an effective candidate for further development of clinical therapy.
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Benzofuranos/uso terapéutico , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/etiología , Infarto de la Arteria Cerebral Media/complicaciones , Fármacos Neuroprotectores/uso terapéutico , Reperfusión/efectos adversos , Animales , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Caspasa 3/genética , Caspasa 3/metabolismo , Infarto Cerebral/etiología , Infarto Cerebral/prevención & control , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismoRESUMEN
The well-known traditional Chinese medicine formula Pien Tze Huang (PZH) has long been used to treat various malignancies, including colorectal cancer (CRC). It was recently reported that PZH possesses the ability to overcome multidrug resistance in CRC cells. In the present study, a 5-fluorouracil (5-FU) resistant human CRC cell line (HCT-8/5-FU) was used to further evaluate the effect of PZH on chemotherapy (chemo)-resistance and investigate the mechanisms through which this occurs. The results identified that PZH significantly reduced the viability and cell density of HCT-8/5-FU cells in a dose- and time-dependent manner (P<0.05). PZH inhibited cell survival, reduced the proportion of cells in S-phase, and suppressed the expression of pro-proliferative proteins cyclin D1 and cyclin-dependent kinase 4. In addition, PZH treatment induced nuclear condensation and fragmentation, activated caspase-9 and -3 and increased the pro-apoptotic Bcl-2-associated X protein/B-cell lymphoma 2 protein ratio. Furthermore, PZH treatment upregulated the expression of microRNA-22 (miR-22) and downregulated the expression of c-Myc (a target gene of miR-22). In conclusion, the findings from the present study suggest that PZH can overcome chemo-resistance in cancer cells, likely through increasing miR-22 expression, and by reversing the imbalance between levels of proliferation and apoptosis.
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We report a new circular DNA virus identified from a Chinese jujube tree showing mosaic-like symptoms. The genome of this virus is 7194 bp in length and contains five putative open reading frames (ORFs), all on the plus-strand of the genome. The genomic organization, primer binding sites and the sizes of the ORFs were similar to those reported for other badnaviruses (family Caulimoviridae), except for ORF3, which was split into ORF3a and ORF3b with a 70-nt intergenic region. Furthermore, this new virus shares low nucleotide sequence identity (<50%) with other members of the family Caulimoviridae. Consequently, we propose this virus as a new member of the family Caulimoviridae and refer to it as jujube mosaic-associated virus (JuMaV).
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Caulimoviridae/genética , Genoma Viral , Virus del Mosaico/genética , Ziziphus/virología , FilogeniaRESUMEN
BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare malignancy of the serosal membranes of the abdominal cavity. This cancer is ultimately fatal in almost all afflicted individuals; however, there is marked variability in its clinical behavior: Some patients die rapidly, and others survive for many years. In the current study, the authors investigated the molecular nature of MPM to obtain insights into the heterogeneity of its clinical behavior and to identify new therapeutic targets for intervention. METHODS: Fresh pretreatment tumor samples were collected from 41 patients with MPM who underwent surgical cytoreduction and received regional intraoperative chemotherapy perfusion. From those samples, gene expression analyses were performed. The major cellular pathways that were identified in this cancer were inhibited using a pathway-specific inhibitor. RESULTS: Unsupervised clustering of genes identified 2 distinct groups of patients with significantly different survivals (Group A: median survival, 24 months; Group B: median survival, 69.5 months; P = .035). Phosphoinositide-3-kinase (PI3K) and the closely interacting mammalian target of rapamycin (mTOR) signaling pathways were overexpressed predominantly in the poor survival group; and the genes of these pathways, phosphoinositide-3-kinase, catalytic, α polypeptide (PIK3CA) and rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR), were highly significantly predictive of shortened patient survival in Group A. The role of these pathways in MPM tumor progression was also investigated by treating 2 MPM cell lines with BEZ235, a dual-class PI3K and mTOR inhibitor, and the authors observed significant inhibition of downstream cell signaling and cell proliferation. CONCLUSIONS: Taken together, the results from this study revealed that, based on gene expression profiles, there were 2 distinct patient groups with significantly different survival and that targeting the PI3K and mTOR signaling pathways may have significant therapeutic value in patients with MPM.
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Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Mesotelioma/metabolismo , Mesotelioma/mortalidad , Neoplasias Peritoneales/metabolismo , Neoplasias Peritoneales/mortalidad , Serina-Treonina Quinasas TOR/metabolismo , Adolescente , Adulto , Anciano , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de las Quinasa Fosfoinosítidos-3 , Transducción de Señal , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
The accumulation of heat shock protein 70 (Hsp70) generally occurs in plants infected with viruses. However, the effect of Hsp70 accumulation on plant viral infection and pathogenesis remains elusive. In this study, the expression of six Hsp70 genes was found to be induced by the four diverse RNA viruses, Tobacco mosaic virus, Potato virus X (PVX), Cucumber mosaic virus and Watermelon mosaic virus, in Nicotiana benthamiana. Heat treatment enhanced the accumulation and systemic infection of these viruses. Similar results were obtained for viral infection in plants heterologously expressing an Arabidopsis cytoplasmic Hsp70 through either a PVX vector or Agrobacterium infiltration. In contrast, viral infection was compromised in cytoplasmic NbHsp70c-1 gene-silenced plants. These data demonstrate that the cytoplasmic Hsp70s can enhance the infection of N. benthamiana by diverse viruses.
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Citoplasma/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP70 de Choque Térmico/fisiología , Nicotiana/virología , Arabidopsis/genética , Western Blotting , Cucumovirus/patogenicidad , Cucumovirus/fisiología , Proteínas HSP70 de Choque Térmico/genética , Calor , Virus del Mosaico/patogenicidad , Virus del Mosaico/fisiología , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/fisiología , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/metabolismo , Plantas Modificadas Genéticamente/virología , Potexvirus/patogenicidad , Potexvirus/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Nicotiana/genética , Nicotiana/metabolismo , Virus del Mosaico del Tabaco/patogenicidad , Virus del Mosaico del Tabaco/fisiologíaRESUMEN
OBJECTIVES/HYPOTHESIS: The objectives of this study were to delineate methods for the development of primary squamous cell carcinoma (SCCHN) xenografts and to define human leukocyte antigen (HLA), melanoma-associated antigen (MAGE)-A3, and human papilloma virus (HPV) 16 antigenic expression in resultant cellular products. STUDY DESIGN: Prospective experimental model. METHODS: Freshly isolated SCCHN xenografts were established in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice using a variety of methods. Resultant tumors were analyzed for expression patterns of HLA-A, MAGE-A3, and HPV 16. Appropriate controls were included to ensure the presence of human RNA. RESULTS: Three xenografts were successfully established and passaged in vivo. Characterization of the resultant products revealed that one was positive for HLA-A2 at both the DNA and protein levels. One of the tumor lines expressed MAGE-A3, whereas none expressed HPV 16. CONCLUSIONS: Freshly isolated SCCHN can be used to generate primary xenografts. Characterization of select patterns of protein expression in established xenografts is a precursor to the development of a mouse model for SCCHN using tumor bearing animals reconstituted with autologous patient leukocytes.