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1.
Protein Sci ; 33(6): e5004, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38723164

RESUMEN

Dysregulation of RNA splicing processes is intricately linked to tumorigenesis in various cancers, especially breast cancer. Cdc2-like kinase 2 (CLK2), an oncogenic RNA-splicing kinase pivotal in breast cancer, plays a significant role, particularly in the context of triple-negative breast cancer (TNBC), a subtype marked by substantial medical challenges due to its low survival rates. In this study, we employed a structure-based virtual screening (SBVS) method to identify potential CLK2 inhibitors with novel chemical structures for treating TNBC. Compound 670551 emerged as a novel CLK2 inhibitor with a 50% inhibitory concentration (IC50) value of 619.7 nM. Importantly, Compound 670551 exhibited high selectivity for CLK2 over other protein kinases. Functionally, this compound significantly reduced the survival and proliferation of TNBC cells. Results from a cell-based assay demonstrated that this inhibitor led to a decrease in RNA splicing proteins, such as SRSF4 and SRSF6, resulting in cell apoptosis. In summary, we identified a novel CLK2 inhibitor as a promising potential treatment for TNBC therapy.


Asunto(s)
Inhibidores de Proteínas Quinasas , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/genética , Femenino , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Simulación del Acoplamiento Molecular , Proliferación Celular/efectos de los fármacos
2.
Sci Rep ; 14(1): 6903, 2024 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-38519566

RESUMEN

A Go endgame database consists of optimal game values and moves for every legal arrangement of no more than S pieces on an N by N board. This paper describes methods for constructing such databases when 1 < N ≤ 5 and S = N 2 . When cycles of plies with lengths greater than 4 are encountered, two rules, one allowing cycles and the other disallowing them, are implemented. Observations and knowledge are obtained for these endgames, which may elucidate the fundamental properties of the popular game Go. First, the optimal game values are different when N is even and odd, regardless of whether the repetition of positions is allowed. When N is odd, the first player can occupy the whole board, while this is not the case when N is even. Second, allowing cycles makes the first and second players equal in strength when N is even, whereas the first player always dominates when N is odd. Using the state-of-the-art open-source deep learning Go engine KataGo to correctly solve a given position as an indicator, factors affecting level of difficulty are found, including the distributions of the optimal game values among all legal plies and the cardinality and values of the true optimal plies. A simple formula is designed that works on more than 10% of the positions so that positions with a given level of difficulty can be found with a high probability.

3.
Biomed Pharmacother ; 162: 114667, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37037092

RESUMEN

Prostate cancer is a prevalent malignancy among men globally, and androgen deprivation therapy is the conventional first-line treatment for metastatic prostate cancer. While androgen deprivation therapy is efficacious in castration-sensitive prostate cancer, it remains less effective in castration-resistant cases. Transcriptional dysregulation is a well-established hallmark of cancer, and targeting proteins involved in transcriptional regulation, such as cyclin-dependent kinase 8 (CDK8), has become an attractive therapeutic strategy. CDK8, a nuclear serine-threonine kinase, is a key component of the mediator complex and plays a critical role in transcriptional regulation. Recent studies have highlighted the promising role of CDK8 as a target in the treatment of metastatic prostate cancer. Our study assessed the efficacy of a novel CDK8 inhibitor, E966-0530-45418, which exhibited potent CDK8 inhibition (IC50 of 129 nM) and high CDK8 selectivity. Treatment with E966-0530-45418 significantly inhibited prostate cancer cell migration and epithelial-to-mesenchymal transition (EMT) at both the RNA and protein levels. Further mechanistic analysis indicated that E966-0530-45418 suppresses prostate cancer metastasis by decreasing CDK8 activity and inhibiting TGF-ß1-mediated Smad3/RNA polymerase II linker phosphorylation and Akt/GSK3ß/ß-catenin signaling. The results in animal model also showed that E966-0530-45418 exhibited anti-metastatic properties in vivo. Our study demonstrated that E966-0530-45418 has great therapeutic potential in the treatment of metastatic prostate cancer.


Asunto(s)
Quinasa 8 Dependiente de Ciclina , Neoplasias de la Próstata , Animales , Humanos , Masculino , Antagonistas de Andrógenos , Andrógenos , Línea Celular Tumoral , Quinasa 8 Dependiente de Ciclina/antagonistas & inhibidores , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Transducción de Señal , Metástasis de la Neoplasia
4.
Sci Rep ; 13(1): 5033, 2023 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-36977737

RESUMEN

Dysregulated consolidation of emotional memories is a core feature of posttraumatic stress disorder (PTSD). Brain Derived Neurotrophic Factor (BDNF) influences synaptic plasticity and emotional memory consolidation. The BDNF Val66Met polymorphism has been associated with PTSD risk and memory deficits respectively, although findings have been inconsistent, potentially due to a failure to control for important confounds such as sex, ethnicity, and the timing/extent of previous trauma experiences. Furthermore, very little research has examined the impact of BDNF genotypes on emotional memory in PTSD populations. This study investigated the interaction effects of Val66Met and PTSD symptomatology in an emotional recognition memory task in 234 participants divided into healthy control (n = 85), trauma exposed (TE: n = 105) and PTSD (n = 44) groups. Key findings revealed impaired negative recognition memory in PTSD compared to control and TE groups and in participants with the Val/Met compared to the Val/Val genotype. There was a group × genotype interaction showing no Met effect in the TE group despite significant effects in PTSD and controls. Results suggest that people previously exposed to trauma who do not develop PTSD may be protected from the BDNF Met effect, however more research is needed to replicate findings and to explore the epigenetic and neural processes involved.


Asunto(s)
Trastornos por Estrés Postraumático , Humanos , Factor Neurotrófico Derivado del Encéfalo/genética , Emociones , Genotipo , Trastornos de la Memoria , Polimorfismo de Nucleótido Simple , Trastornos por Estrés Postraumático/genética
5.
Behav Res Ther ; 159: 104222, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36327524

RESUMEN

Sleep has been found to play a key role in fear conditioning, extinction learning and extinction recall, and sleep disturbances are linked to many mental disorders including post-traumatic stress disorder (PTSD). Previous studies examining associations between sleep and fear or extinction processes primarily focused on objectively measured sleep architecture. Little research has so far focused on subjective sleep measures and particularly in clinical populations, which often experience subjectively poor sleep, including PTSD. Here we investigated whether subjective sleep disturbance, sleep onset latency, wake after sleep onset or sleep efficiency were related to fear conditioning, extinction learning or extinction recall in a large sample of individuals with a range of PTSD symptom severity (n = 248). Overall, we did not find that subjective sleep was associated with fear conditioning or extinction processes. However, exploratory analyses examining the moderating effect of sex found that shorter sleep onset latency and greater sleep efficiency were associated with improved extinction recall in women with higher PTSD symptom severity. This suggests that less time falling asleep and longer time asleep while in bed may be protective in highly symptomatic women against the commonly observed impaired extinction recall in PTSD. More studies are needed to explore sex-specific effects further.


Asunto(s)
Trastornos por Estrés Postraumático , Femenino , Humanos , Masculino , Trastornos por Estrés Postraumático/complicaciones , Extinción Psicológica , Caracteres Sexuales , Miedo , Recuerdo Mental , Sueño
6.
Neurosci Biobehav Rev ; 130: 529-542, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34517034

RESUMEN

Anxiety and stress-related disorders are more prevalent in women and associated with negative emotional memory consolidation as well as impaired fear extinction recall. Recent research has identified a role of gonadal steroid hormones in influencing emotional memories and fear extinction, however most individual studies have small samples and employed various protocols. A systematic review and meta-analysis were conducted on studies that examined sex hormones (estrogen, progesterone, testosterone, allopregnanolone, dehydroepiandrosterone) on four aspects of memory, namely, intentional recall (k = 13), recognition memory (k = 7), intrusive memories (k = 9), and extinction recall (k = 11). The meta-analysis on natural cycling women revealed that progesterone level was positively associated with negative recall and negative intrusive memories, and this effect on intentional recall was enhanced under stress induction. Estradiol level was positively associated with extinction recall. This study reveals an important role of progesterone and estradiol in influencing emotional memory consolidation. It highlights the need to control for these hormonal effects and examine progesterone and estradiol concurrently across all menstrual phases in future emotional memory paradigms.


Asunto(s)
Consolidación de la Memoria , Estradiol , Extinción Psicológica , Miedo , Femenino , Hormonas Esteroides Gonadales , Humanos , Ciclo Menstrual , Progesterona
7.
Behav Res Ther ; 145: 103942, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34340176

RESUMEN

Brain-derived neurotropic factor (BDNF) is a potent regulator of memory processes and is believed to influence the consolidation of fear extinction memories. No previous human study has tested the effect of unstimulated BDNF on fear extinction recall, and no study has tested the association between plasma BDNF levels and psychophysiological responding during an extinction paradigm. We tested the association between fear responses during a 2-day differential conditioning, extinction and extinction recall paradigm and Val66Met genotype in a group of healthy participants (N = 191). There were no group differences during habituation or acquisition. Met allele carriers compared to Val homozygotes displayed higher responses to the CS + compared to the CS- during extinction learning and had higher responding to both the CS+ and CS- during extinction recall. Plasma levels of BDNF protein that were collected in a sub-sample of the group (n = 56) moderated the effect of Met allele presence, such that lower BDNF level was associated with higher skin conductance response in the Met but not Val group to the CS+ during extinction learning and to both the CS+ and CS- during extinction recall. The current results extend previous observations of a Val66Met effect during fear extinction learning to extinction recall and show for the first time that these effects are moderated by plasma BDNF level.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Extinción Psicológica , Miedo , Encéfalo , Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Respuesta Galvánica de la Piel , Genotipo , Humanos
8.
Depress Anxiety ; 38(10): 1087-1099, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34151472

RESUMEN

BACKGROUND: The endocannabinoid system is gaining increasing attention as a favorable target for improving posttraumatic stress disorder (PTSD) treatments. Exposure therapy is the gold-standard treatment for PTSD, and fear extinction learning is a key concept underlying successful exposure. METHODS: This study examined the role of genetic endocannabinoid polymorphisms in a fear extinction paradigm with PTSD compared to healthy participants (N = 220). Participants provided saliva for genotyping, completed a fear conditioning and extinction task, with blood samples taken before and after the task (n = 57). Skin conductance was the outcome and was analyzed using mixed models. RESULTS: Results for cannabinoid receptor type 1 polymorphisms suggested that minor alleles of rs2180619 and rs1049353 were associated with poorer extinction learning in PTSD participants. The minor allele of the fatty acid amide hydrolase (FAAH) polymorphism rs324420 was associated with worse extinction in PTSD participants. Subanalysis of healthy participants (n = 57) showed the FAAH rs324420 genotype effect was dependent on plasma arachidonoyl ethanolamide (AEA) level, but not oleoylethanolamide or 2-arachidonoyl glycerol. Specifically, higher but not lower AEA levels in conjunction with the minor allele of FAAH rs324420 were associated with better extinction learning. CONCLUSIONS: These findings provide translational evidence that cannabinoid receptor 1 and AEA are involved in extinction learning in humans. FAAH rs324420's effect on fear extinction is moderated by AEA plasma level in healthy controls. These findings imply that FAAH inhibitors may be effective for targeting anxiety in PTSD, but this effect needs to be explored further in clinical populations.


Asunto(s)
Cannabinoides , Endocannabinoides , Extinción Psicológica , Miedo , Humanos , Aprendizaje
9.
Behav Res Ther ; 142: 103875, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34052606

RESUMEN

Low levels of estradiol in women have been associated with impaired fear extinction recall, with suggestions this may promote the return of fear and heighten the female vulnerability for anxiety disorders. A particularly important measure for the return of fear is reinstatement, but no human studies to date have examined the impact of estradiol on fear reinstatement. Forty-two healthy females completed a differential fear conditioning, extinction and reinstatement task with skin conductance response (SCR) amplitude indexing level of conditioned fear. Saliva samples were taken to measure estradiol and progesterone. To examine fear reinstatement, SCR amplitude was compared between the last trial of the late extinction phase to the first re-extinction trial following the unsignaled presentation of two aversive electric shocks. No significant effects of estradiol were found for acquisition of fear conditioning or fear extinction learning. Lower estradiol predicted a significantly larger generalized SCR amplitude at re-extinction (post-reinstatement) in women. This provides novel evidence suggesting a protective role of estradiol in potentially reducing the relapse of fear following re-exposure to aversive stimuli, although further research is necessary in clinical populations to clarify this effect.


Asunto(s)
Extinción Psicológica , Miedo , Condicionamiento Clásico , Estradiol , Femenino , Humanos , Saliva
10.
Behav Sleep Med ; 19(2): 178-191, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-31986908

RESUMEN

Background: PTSD is characterised by severe sleep disturbances, which is increasingly recognised to in many cases consist of similar symptomology to sleep disorders such as REM Behaviour Disorder (RBD). The present study aimed to investigate whether different aspects of sleep quality influence intrusive memory development and whether PTSD status moderates this relationship. Participants and Methods: 34 PTSD, 52 trauma-exposed (TE) and 42 non-trauma exposed (NTE) participants completed an emotional memory task, where they viewed 60 images (20 positive, 20 negative and 20 neutral) and, two days later, reported how many intrusive memories they had of each valence category. Participants also completed three measures of sleep quality: the Pittsburgh Sleep Quality Index, the REM Behaviour Disorder Screening Questionnaire and total hours slept before each session. Results: The PTSD group reported poorer sleep quality than both TE and NTE groups on all three measures, and significantly more negative intrusive memories than the NTE group. Mediation analyses revealed that self-reported RBD symptomology before the second session mediated the relationship between PTSD status and intrusive memories. Follow-up moderation analyses revealed that self-reported RBD symptomology before the second session was only a significant predictor of intrusion in the PTSD group, though with a small effect size. Conclusions: These findings suggest that RBD symptomology is an indicator of consolidation of intrusive memories in PTSD but not trauma-exposed or healthy participants, which supports the relevance of characterising RBD in PTSD.


Asunto(s)
Recuerdo Mental , Trastorno de la Conducta del Sueño REM/psicología , Autoinforme , Trastornos por Estrés Postraumático/psicología , Adulto , Emociones , Humanos , Masculino , Sueño , Adulto Joven
11.
Br J Ophthalmol ; 104(9): 1266-1270, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-31831505

RESUMEN

BACKGROUND: We evaluated the surgical outcomes of vitrectomy with non-fovea-sparing internal limiting membrane (ILM) peeling for myopic foveoschisis with a follow-up of at least 3 years. METHODS: In this retrospective study, 32 consecutive eyes with high myopia with or without foveal detachment underwent vitrectomy and centripetal, non-fovea-sparing ILM peeling with gas tamponade for myopic foveoschisis. Outcome measures were visual acuity (VA) and optical coherence tomography findings. RESULTS: Mean axial length was 29.39±1.92 mm; mean follow-up was 42.66 (±8.29) months. Foveoschisis and foveal detachment completely resolved in all eyes postoperatively. Mean central foveal thickness (CFT) improved significantly from 631.88±191.72 to 232.65±69.67 µm, and mean best-corrected visual acuity improved significantly from 0.90 (Snellen equivalent (SE), 20/160)±0.43 logarithm of minimum angle of resolution (logMAR) to 0.43 (SE, 20/54)±0.29 logMAR (both p<0.001; two-tailed, paired t-test). Eyes with foveal detachment (n=10) at baseline had thicker preoperative CFT (737.8±239.83 vs 583.73±147.78 µm; p=0.033) but thinner postoperative CFT (188.20±31.52 vs 252.86±73.29 µm; p=0.012). Eyes without foveal detachment at baseline had significantly better postoperative VA (0.33 (SE, 20/43)±0.18 vs 0.65 (SE, 20/86)±0.37 logMAR; p=0.002). No macular hole or other complications occurred during follow-up. CONCLUSION: Centripetal, non-fovea-sparing ILM peeling with gas tamponade may achieve myopic foveoschisis resolution and vision improvement without macular hole formation during at least 3-year follow-up.


Asunto(s)
Membrana Basal/cirugía , Endotaponamiento , Miopía/cirugía , Desprendimiento de Retina/cirugía , Retinosquisis/cirugía , Vitrectomía , Adulto , Anciano , Femenino , Fluorocarburos/administración & dosificación , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Miopía/diagnóstico , Miopía/fisiopatología , Posición Prona , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/fisiopatología , Retinosquisis/diagnóstico , Retinosquisis/fisiopatología , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Agudeza Visual/fisiología , Adulto Joven
12.
Psychoneuroendocrinology ; 109: 104416, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31472433

RESUMEN

Women are at least twice as susceptible to developing post-traumatic stress disorder (PTSD) compared to men. Although most research seeking to explain this discrepancy has focussed on the role of oestradiol during fear extinction learning, the role of progesterone has been overlooked, despite relatively consistent findings being reported concerning the role of progesterone during consolidation of emotional and intrusive memories. In this review article, we outline literature supporting the role of progesterone on memory formation, with particular emphasis on potential memory-enhancing properties of progesterone when subjects are placed under stress. It is possible that progesterone directly and indirectly exerts memory-enhancing effects at the time of trauma, which is an effect that may not be necessarily captured during non-stressful paradigms. We propose a model whereby progesterone's steroidogenic relationship to cortisol and brain-derived neurotrophic factor in combination with elevated oestradiol may enhance emotional memory consolidation during trauma and therefore present a specific vulnerability to PTSD formation in women, particularly during the mid-luteal phase of the menstrual cycle.


Asunto(s)
Hormonas Esteroides Gonadales/metabolismo , Trastornos por Estrés Postraumático/metabolismo , Trastornos por Estrés Postraumático/psicología , Adulto , Emociones/fisiología , Estradiol/metabolismo , Estrógenos/metabolismo , Miedo/psicología , Femenino , Hormonas Esteroides Gonadales/fisiología , Humanos , Hidrocortisona/metabolismo , Aprendizaje/fisiología , Masculino , Memoria/fisiología , Consolidación de la Memoria/fisiología , Ciclo Menstrual/psicología , Progesterona/metabolismo , Caracteres Sexuales
13.
PLoS One ; 13(12): e0208575, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30521618

RESUMEN

BACKGROUND: A key mechanism thought to underlie Posttraumatic Stress Disorder (PTSD) is enhanced emotional memory consolidation. Recent evidence in healthy controls revealed that women have greater negative memory consolidation following stress relative to men. This study examined emotional memory consolidation in women and men with PTSD, and in trauma-exposed and non-trauma controls to test the hypothesis that emotionally negative memory consolidation would be greater in women with PTSD. METHOD: One hundred and forty-seven men and women (47 with PTSD, 49 trauma-exposed controls, and 51 non-trauma controls) completed an emotional memory task where they looked at negative, neutral and positive images from the International Affective Picture System (IAPS). Delayed recall and an intrusive memory diary were completed two days later. RESULTS: Women displayed greater recall, and reported more negative intrusive memories than men. A gender x group interaction effect showed that both women with PTSD and trauma-exposed women reported more intrusive memories than women without trauma exposure or men. CONCLUSION: This study provided preliminary evidence of sex differences in intrusive memories in those with PTSD as well as those with a history of trauma exposure. Future research should include measures of sex hormones to further examine sex differences on memory consolidation in the context of trauma exposure and PTSD.


Asunto(s)
Consolidación de la Memoria , Trastornos por Estrés Postraumático/fisiopatología , Femenino , Humanos , Masculino , Factores Sexuales , Estrés Psicológico
14.
J Chin Med Assoc ; 80(8): 503-507, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28601626

RESUMEN

BACKGROUND: To report our 3-year experience of 23-gauge transconjunctival sutureless vitrectomy (TSV) for acute postoperative endophthalmitis at a tertiary referral center in southern Taiwan. METHODS: This retrospective chart review study included 19 patients with acute postoperative endophthalmitis who underwent 23-gauge TSV from January 2011 to January 2015 at Kaohsiung Veterans General Hospital, Taiwan. Bacterial and fungal cultures from aqueous samples, vitreous samples, or both were performed. RESULTS: Nineteen patients (12 male; 7 female) were included. The mean age was 72.4 ± 8.29 years. Acute postoperative endophthalmitis was noted in 18 patients after cataract surgery and in 1 patient after 23-gauge vitrectomy for a rhegmatogenous retinal detachment. Upon presentation, visual acuity was less than hand movement for 80% of the patients. Chief complaints included blurred vision (19 patients, 100%), followed by pain (10 patients, 52.6%) and red eye (4 patients, 21%). All patients were administered an intravitreal injection (IVI) of antibiotics and 23-gauge TSV, and the average number of IVIs was 2.68 ± 1.73 (1-9 IVIs). The interval between their initial eye symptoms and vitrectomy was 4.11 ± 4.73 days (0-2 days), and the interval between diagnosis with endophthalmitis and a vitrectomy was 1.11 ± 1.52 days (0-6 days). The final visual acuity was no light perception for 1 patient (5.3%), between 6/60 and 6/12 for 8 patients (42.1%), and 6/12 or better for 9 patients (47.4%). No retinal detachment or hypotony was noted postoperatively in any case. CONCLUSION: 23-gauge vitrectomy is safe and effective for the management of acute postoperative endophthalmitis. Early diagnosis and treatment with 23-gauge vitrectomy may provide a good visual outcome.


Asunto(s)
Endoftalmitis/cirugía , Complicaciones Posoperatorias/cirugía , Técnicas de Sutura , Vitrectomía/métodos , Enfermedad Aguda , Anciano , Anciano de 80 o más Años , Conjuntiva/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Agudeza Visual
15.
Eur J Med Chem ; 134: 13-23, 2017 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-28395150

RESUMEN

A series of 4,5-indolyl-N-hydroxyphenylacrylamides, as HDAC inhibitors, has been synthesized and evaluated in vitro and in vivo. 4-Indolyl compounds 13 and 17 functions as potent inhibitors of HDAC1 (IC50 1.28 nM and 1.34 nM) and HDAC 2 (IC50 0.90 and 0.53 nM). N-Hydroxy-3-{4-[2-(1H-indol-4-yl)-ethylsulfamoyl]-phenyl}-acrylamide (13) inhibited the human cancer cell growth of PC3, A549, MDA-MB-231 and AsPC-1 with a GI50 of 0.14, 0.25, 0.32, and 0.24 µM, respectively. In in vivo evaluations bearing prostate PC3 xenografts nude mice model, compound 13 suppressed tumor growth with a tumor growth inhibition (TGI) of 62.2%. Immunohistochemistry of protein expressions, in PC-3 xenograft model indicated elevated acetyl-histone 3 and prominently inhibited HDAC2 protein expressions. Therefore, compound 13 could be a suitable lead for further investigation and the development of selective HDAC 2 inhibitors as potent anti-cancer compounds.


Asunto(s)
Acrilamidas/química , Acrilamidas/uso terapéutico , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Acrilamidas/farmacología , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/antagonistas & inhibidores , Histona Desacetilasa 2/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Indoles/química , Indoles/farmacología , Indoles/uso terapéutico , Masculino , Ratones , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Próstata/efectos de los fármacos , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Ensayos Antitumor por Modelo de Xenoinjerto
16.
J Affect Disord ; 217: 246-251, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28437761

RESUMEN

BACKGROUND: Considerable research has revealed impaired fear extinction to be a significant predictor of PTSD. Fear extinction is also considered the primary mechanism of exposure therapy, and a critical factor in PTSD recovery. The cognitive theory of PTSD proposes that symptoms persist due to excessive negative appraisals about the trauma and its sequelae. Research has not yet examined the relationship between fear extinction and negative appraisals in PTSD. METHODS: A cross-sectional sample of participants with PTSD (n =21), and trauma-exposed controls (n =33) underwent a standardized differential fear conditioning and extinction paradigm, with skin conductance response (SCR) amplitude serving as the index of conditioned responses. The Posttraumatic Cognitions Inventory (PTCI) was used to index catastrophic negative appraisals. RESULTS: Participants with PTSD demonstrated a slower decrease in overall SCR responses during extinction and greater negative appraisals compared to the group. A moderation analysis revealed that both negative trauma-relevant appraisals and fear extinction learning were independently associated with PTSD symptoms, but there was no moderation interaction. LIMITATIONS: The current study was limited by a modest sample size, leading to the inclusion of participants with subclinical PTSD symptoms. Further, the current study only assessed fear extinction learning; including a second day extinction recall task may show alternative effects. CONCLUSIONS: These findings indicate that negative appraisals and fear extinction did not interact, but had independent relationships with PTSD symptoms. Here we show for the first time in an experimental framework that negative appraisals and fear extinction play separate roles in PTSD symptoms.


Asunto(s)
Extinción Psicológica , Miedo/psicología , Trastornos por Estrés Postraumático/psicología , Adulto , Condicionamiento Clásico , Estudios Transversales , Femenino , Humanos , Masculino , Recuerdo Mental/fisiología , Pruebas Neuropsicológicas
17.
Sci Rep ; 7: 46149, 2017 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-28387244

RESUMEN

Patients with ovarian cancer are typically diagnosed at an advanced stage, resulting in poor prognosis since there are currently no effective early-detection screening tests for women at average-risk for ovarian cancer. Here, we investigated the effects of MT-6, a derivative of moscatilin, in ovarian cancer cells. Our investigation showed that MT-6 inhibited the proliferation and viability of ovarian cancer cells with submicromolar IC50 values. MT-6-treated SKOV3 cells showed significant cell cycle arrest at G2/M phase, followed by an increase in the proportion of cells in a sub-G1 phase. In addition, MT-6 induced a concentration-dependent increase in mitotic markers, mitotic kinases, cell cycle regulators of G2/M transition, and apoptosis-related markers in ovarian cancer cells. MT-6 treatment also induced mitochondrial membrane potential loss, JNK activation, and DR5 expression. Cotreatment of cells with the JNK inhibitor SP600125 considerably attenuated MT-6-induced apoptosis, mitochondria membrane potential loss, DR5 upregulation, and suppression of cell viability. MT-6 also inhibited tumor growth in an SKOV3 xenograft model without significant body weight loss. Together, our findings suggest that MT-6 is a potent anticancer agent with tumor-suppressive activity in vitro and in vivo that could be further investigated for ovarian cancer therapy in the future.


Asunto(s)
Apoptosis/efectos de los fármacos , Compuestos de Bencilo/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Mitosis/efectos de los fármacos , Neoplasias Ováricas/patología , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Desnudos , Receptores de Muerte Celular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Eur J Med Chem ; 122: 92-101, 2016 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-27344487

RESUMEN

This study reports the design and synthesis of 2-(phenylsulfonyl)quinoline N-hydroxyacrylamides (8a-k). Structure-activity relationship studies focusing on regio-effect of N-hydroxyacrylamide moiety and influence of the sulfonyl linker revealed that N-hydroxy-3-[3-(quinoline-2-sulfonyl)-phenyl]-acrylamide (8f) showed remarkable enzymatic and cellular activity. The GI50 values of 8f for HL-60, HCT116, PC-3, and A549 cells were found to be 0.29, 0.08, 0.15, and 0.27 µM, respectively. The compounds are therefore more potent than FDA approved PXD-101 and SAHA. They also have an effect on the acetylation degree of histone H3 and α-tubulin. In in vivo studies, 8f showed marked inhibition of the growth of HCT116 xenografts.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Quinolinas/química , Quinolinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Histonas/metabolismo , Humanos , Masculino , Ratones , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Depress Anxiety ; 33(3): 203-10, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26744059

RESUMEN

BACKGROUND: Prior research has demonstrated that time-of-day may play an important role in the extinction of conditioned fear, with extinction better learned earlier in the day rather than later. Impaired fear extinction memory is widely considered a key mechanism of posttraumatic stress disorder (PTSD). The relationship between fear extinction and PTSD symptoms may be moderated by hours-since-waking. METHOD: In the present experiment, we examined whether hours-since-waking would moderate fear extinction learning ability in a clinical PTSD sample (n = 15), compared to trauma-exposed (n = 33) and nonexposed controls (n = 22). Participants completed a standardized differential fear conditioning and extinction paradigm, providing skin conductance response measures to quantify conditioned responding. RESULTS: Mixed-model analysis of variance revealed a PTSD-specific impairment in extinction learning ability in the late extinction phase. A moderation analysis showed that hours-since-waking was a significant moderator of the relationship between impaired late extinction and PTSD symptoms. Specifically, we found that participants with higher PTSD symptoms demonstrated poorer fear extinction learning ability as they were awake for longer. CONCLUSIONS: The results of the current study add to a growing literature indicating deficits in fear extinction learning in PTSD samples, compared to trauma-exposed and nonexposed controls. These results support previous findings that fear extinction is impaired later in the day, and extends this to a clinical sample, suggesting that exposure-therapy may be optimized by scheduling sessions in the morning.


Asunto(s)
Extinción Psicológica/fisiología , Miedo/fisiología , Trastornos por Estrés Postraumático/fisiopatología , Adolescente , Adulto , Miedo/clasificación , Femenino , Respuesta Galvánica de la Piel/fisiología , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto Joven
20.
Arch Insect Biochem Physiol ; 89(2): 111-26, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25781309

RESUMEN

We described the cDNA cloning of two antimicrobial peptides (AMPs), cecropin (BdCec), and attacin C (BdAttC), from the oriental fruit fly, Bactrocera dorsalis (Hendel), a serious insect pest of fruit trees. Using rapid amplification of cDNA ends, fragments encompassing the entire open reading frames of BdCec and BdAttC were cloned and sequenced. The complete 425 bp cDNA of BdCec encodes a protein of 64 amino acids with a predicted molecular weight of 6.84 kDa. The 931 bp cDNA of BdAttC encodes a protein of 239 residues with a predicted molecular weight of 24.97 kDa. Real-time quantitative RT-PCR demonstrated that the developmental transcription profiles of BdCec and BdAttC were similar in each larvae, pupae, and adults. The constitutive expression levels of both AMPs were high in the first-instar and late third-instar larvae, suggesting that their antimicrobial activity is active in the newly hatched larvae and just before pupation. The basal expression levels were not significant different in adult fat bodies. The expression of BdCec and BdAttC was upregulated after bacterial challenge in adult fat bodies. The ratio of inducible expression to constitutive expression was lower in males compared to females.


Asunto(s)
Cecropinas/metabolismo , Proteínas de Insectos/metabolismo , Tephritidae/metabolismo , Secuencia de Aminoácidos , Animales , Cuerpo Adiposo/metabolismo , Femenino , Regulación de la Expresión Génica , Masculino , Datos de Secuencia Molecular , Filogenia , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido
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