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1.
Artículo en Inglés | MEDLINE | ID: mdl-39243350

RESUMEN

Probiotics, postbiotics, and n-3 polyunsaturated fatty acids (PUFA) have antidepressant-like effects. However, the underlying mechanisms of the dopaminergic pathway are unclear. The present study investigated the hypothesis that probiotics and postbiotics combined with n-3 PUFA synergistically improve depression by modulating the dopaminergic pathway through the brain-gut axis. Rats were randomly divided into seven groups: non-chronic mild stress (CMS) with n-6 PUFA, and CMS with n-6 PUFA, n-3 PUFA, probiotics, postbiotics, probiotics combined with n-3 PUFA, and postbiotics combined with n-3 PUFA. Probiotics, postbiotics, and n-3 PUFA improved depressive behaviors, decreased blood concentrations of interferon-γ, and interleukin-1ß, and increased the brain and gut concentrations of short chain fatty acids and dopamine. Moreover, probiotics, postbiotics, and n-3 PUFA increased the brain and gut expression of glucocorticoid receptor and tyrosine hydroxylase; brain expression of l-type amino acid transporter 1 and dopamine receptor (DR) D1; and gut expression of DRD2. The expression of phosphorylated protein kinase A/protein kinase A and phosphorylated cAMP response element-binding protein/cAMP response element-binding protein increased in the brain, however, decreased in the gut by the supplementation of probiotics, postbiotics, and n-3 PUFA. There was synergistic effect of probiotics and postbiotics combined with n-3 PUFA on the depressive behaviors and dopaminergic pathway in blood, brain, and gut. Moreover, no significant difference in the dopaminergic pathways between the probiotics and postbiotics was observed. In conclusion, probiotics and postbiotics, combined with n-3 PUFA have synergistic antidepressant-like effects on the dopaminergic pathway through the brain-gut axis in rats exposed to CMS.

2.
Nutr Res Pract ; 18(1): 33-45, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38352207

RESUMEN

BACKGROUND/OBJECTIVES: Onion, particularly onion peel, is a quercetin-rich food with, anti-inflammatory and immunomodulatory effects. However, the effect of onion peel extract (OPE) in humans is unclear. Thus, the present study aimed to investigate whether OPE improves natural killer (NK) cell activity and cytokine concentration in a randomized double-blind placebo-controlled trial. SUBJECTS/METHODS: Eighty participants aged 19-64 yrs old with a white blood cell count of 4,000-10,000 cells/µL, symptoms of upper respiratory infection at least once within the previous 12 mon, and perceived stress scale (PSS) over 14 were included. Participants were randomly assigned to take either 1,000 mg/day OPE or a placebo for 8 weeks. RESULTS: Compliance were 87.4 ± 8.6% and 86.9 ± 79.0% in OPE and placebo groups. Compared to the placebo, OPE supplementation improved "Hoarseness" (P = 0.038) of the Wisconsin Upper Respiratory Symptom Survey (WURSS)-21 symptom, and stress scores (P = 0.001; 0.021) of PSS. Supplementation of OPE had no significant effect on NK cell activity and concentrations of cytokines such as interleukin (IL)-2, IL-6, IL-12, IL-1ß, interferon-γ, and tumor necrosis factor-α. At baseline, the WURSS-21 symptom and PSS score (P = 0.024; 0.026) were higher in the OPE group than the placebo group. Among participants with higher than median WURSS-21 symptom score, OPE supplementation increased NK cell activity (P = 0.038). Supplementation of OPE had no significant effects on safety measurements and adverse events. CONCLUSIONS: The present study suggested that OPE supplementation improves NK cell activity in participants with moderate upper respiratory symptoms without any significant adverse effects. Trial Registration: ClinicalTrials.gov Identifier: NCT05666752.

3.
Sensors (Basel) ; 23(12)2023 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-37420635

RESUMEN

This paper presents a novel computational integral imaging reconstruction (CIIR) method using elemental image blending to eliminate the normalization process in CIIR. Normalization is commonly used in CIIR to address uneven overlapping artifacts. By incorporating elemental image blending, we remove the normalization step in CIIR, leading to decreased memory consumption and computational time compared to those of existing techniques. We conducted a theoretical analysis of the impact of elemental image blending on a CIIR method using windowing techniques, and the results showed that the proposed method is superior to the standard CIIR method in terms of image quality. We also performed computer simulations and optical experiments to evaluate the proposed method. The experimental results showed that the proposed method enhances the image quality over that of the standard CIIR method, while also reducing memory usage and processing time.


Asunto(s)
Algoritmos , Procesamiento de Imagen Asistido por Computador , Artefactos , Visión Ocular
4.
J Nutr Biochem ; 116: 109326, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36963732

RESUMEN

N-3 polyunsaturated fatty acids (PUFA) and probiotics have antidepressant-like effects, but the underlying mechanisms are unclear. We hypothesized that n-3 PUFA combined with live and dead probiotics synergistically improves depression by modulating the hypothalamic-pituitary-adrenal (HPA) axis and serotonergic pathways through the brain-gut axis. Rats were randomly divided into seven groups (n = 8/group): nonchronic mild stress (CMS) with n-6 PUFA, CMS with n-3 PUFA, n-6 PUFA, live probiotics, dead probiotics, n-3 PUFA, and live probiotics, and n-3 PUFA and dead probiotics. Diets of n-6 and n-3 PUFA and oral supplementation of live and dead probiotics were provided for 12 weeks, and CMS was performed for the last 5 weeks. N-3 PUFA and probiotics improved depressive behaviors and modulated the brain and gut HPA axis by synergistically increasing glucocorticoid receptor expression and decreasing corticotropin-releasing factor expression and blood levels of adrenocorticotropic hormone and corticosterone. N-3 PUFA and probiotics upregulated the brain serotonergic pathway through serotonin levels and expression of brain-derived neurotrophic factor, phosphorylated cAMP response binding protein, and 5-hydroxytryptamine 1A receptor while downregulating the gut serotonergic pathway. Furthermore, n-3 PUFA and probiotics increased the abundance of Ruminococcaceae, brain and gut short chain fatty acid levels, and occludin expression while decreasing the expression of tumor necrosis factor-α, interleukin-1ß, and prostaglandin E2 and blood lipopolysaccharides levels. There was no significant difference between the live and dead probiotics. In conclusion, n-3 PUFA and probiotics had synergistic antidepressant-like effects on the HPA axis and serotonergic pathways of the brain and gut through the brain-gut axis.


Asunto(s)
Ácidos Grasos Omega-3 , Probióticos , Ratas , Animales , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-3/metabolismo , Depresión/terapia , Depresión/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Eje Cerebro-Intestino , Sistema Hipófiso-Suprarrenal/fisiología , Antidepresivos/farmacología , Antidepresivos/uso terapéutico
5.
Contemp Clin Trials ; 126: 107108, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36724841

RESUMEN

BACKGROUND: Oxiracetam may have a modest effect on preventing cognitive decline. Exercise can also enhance cognitive function. This trial aims to investigate the effect of oxiracetam on post-stroke cognitive impairment and explore whether this effect is modified by exercise. Furthermore, the mechanisms that mediate this effect will be investigated through a neural network analysis. METHODS: This is a multicenter, randomized, double-blind, placebo-controlled phase IV trial. Patients who complained of cognitive decline 3 months after stroke and had a high risk of cognitive decline were eligible. Patients were randomly assigned to receive either 800 mg of oxiracetam or placebo twice daily for 36 weeks. After randomization, a predetermined exercise protocol was provided to each participant, and the degree of physical activity was assessed using wrist actigraphy at 4, 12, 24, and 36 weeks. Resting-state functional MRI was obtained in baseline and 36-week follow-up. Co-primary endpoints are changes in the Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes. Secondary endpoints include changes in the NINDS-CSN VCIHS-Neuropsychology Protocol, Euro QoL, patient's global assessment, and functional network connectivity. If there is a significant difference in physical activity between the two groups, the interaction effect between physical activity and the treatment group will be examined. A total of 500 patients were enrolled from February 2018, and the last patient's final follow-up was completed in September 2022. CONCLUSION: This trial is meaningful not only to prove the efficacy of oxiracetam, but also evaluate whether exercise can modify the effects of medication and how cognitive function can be restored. Trial registrationhttp://cris.nih.go.kr (KCT0005137).


Asunto(s)
Disfunción Cognitiva , Accidente Cerebrovascular , Humanos , Calidad de Vida , Disfunción Cognitiva/tratamiento farmacológico , Pirrolidinas/uso terapéutico , Método Doble Ciego , Resultado del Tratamiento
6.
Neurol Sci ; 44(6): 2087-2095, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36759490

RESUMEN

INTRODUCTION: This study is to explore the long-term functional outcome of antihypertensive medication-naïve, untreated hypertension (HTN) patients with acute ischemic stroke compared to those with no prior HTN and those with treated HTN. PATIENTS AND METHODS: We analyzed a prospectively collected stroke registry of all patients with acute ischemic stroke consecutively admitted to Incheon St. Mary's Hospital. Patients who received reperfusion therapy were excluded. Long-term functional outcomes were assessed at a 3-month follow-up visit using the modified Rankin Scale. RESULTS: A total of 1044 patients was enrolled. Compared to patients with no or treated HTN, those with untreated HTN had higher odds for more favorable outcomes (adjusted odds ratio (OR): 1.7 [95% CI: 1.0-2.7, p = 0.050*] and 1.7 [95% CI: 1.0-2.8, p = 0.047*], respectively) when the stroke was large vessel atherosclerosis (LAA)/cardioembolic (CE) with large vessel occlusion/stenosis. However, no such association was observed when there was no large vessel occlusion or stenosis, in total patients, or if the index stroke was related to SVO. In untreated HTN patients with LAA/CE and large vessel occlusion/stenosis compared to patients in the lowest mean arterial pressure quartile (< 96.7 mmHg), patients in the second and third highest quartiles had higher odds of favorable outcomes. CONCLUSIONS: Patients with untreated HTN had significantly more favorable outcomes at 3 months after ischemic stroke compared to those with no or treated HTN when the stroke was LAA/CE with large vessel occlusion/stenosis. Untreated HTN patients also showed an association between higher MAP and favorable outcomes.


Asunto(s)
Aterosclerosis , Isquemia Encefálica , Hipertensión , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular Isquémico/complicaciones , Isquemia Encefálica/complicaciones , Isquemia Encefálica/terapia , Constricción Patológica , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular/complicaciones , Pronóstico , Hipertensión/complicaciones , Hipertensión/epidemiología , Resultado del Tratamiento
7.
Int J Neurosci ; 133(11): 1271-1284, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35575757

RESUMEN

OBJECTIVE: To evaluate predictors for intracerebral hemorrhage (ICH) and 1-month mortality after intravenous (IV) or intraarterial (IA) recanalization therapy for major cerebral artery occlusion in Korean patients. METHODS: From 2011 to 2015, we prospectively gathered data from consecutive patients treated with IV/IA recanalization within 8 h of symptoms in a single center. The effects of demographic, clinical, laboratory, and radiological factors on ICH within 2 weeks were assessed, as well as 1-month mortality. RESULTS: From a total of 183 patients, symptomatic intracerebral hemorrhage (SICH) occurred in 32 patients (17.5%), and asymptomatic ICH occurred in 37 patients (20.2%). The mortality rate at 1 month in ICH patients was 37.7%. The international normalized ratio (INR) (OR, 4.9; 95% CI, 1.03-23.4; p = 0.046), glucose (OR, 1.119 per mmol/L; 95% CI, 1.015-1.233; p = 0.023), medium-volume infarct (15-69.9 mL) (OR, 2.62; 95% CI, 1.1-6.26; p = 0.03), large-volume infarct (≥70 mL) (OR, 5.54; 95% CI, 2.1-14.6; p = 0.001), and angioplasty or stenting (OR, 6.29; 95% CI, 1.71-23.22; p = 0.006) were predictors of any ICH. Hyperlipidemia or statin medication (OR, 4.17; 95% CI, 1.38-12.59; p = 0.011), INR (OR, 7.13; 95% CI, 0.94-54.22 p = 0.058), and large-volume infarct (≥70 mL) (OR, 7.96; 95% CI, 2.31-27.39; p = 0.001) were predictors of SICH. Hypertension (OR, 5.77; 95% CI, 1.43-23.3; p = 0.014), initial NIHSS score (OR, 1.09; 95% CI, 1.01-1.18; p = 0.27), and SICH (OR, 15.7; 95% CI, 4.04-61.08; p < 0.001) were predictors of 1-month mortality. CONCLUSION: INR and glucose may be strong modifiable predictors of critical ICH leading to death after IV/IA recanalization therapy in acute cerebral artery occlusion.

8.
Korean J Intern Med ; 37(6): 1176-1185, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36375488

RESUMEN

BACKGROUND/AIMS: Acute upper gastrointestinal (UGI) bleeding is a significant emergency situation with a mortality rate of 2% to 10%. Therefore, initial risk stratification is important for proper management. We aimed to evaluate the role of contrast-enhanced multidetector computed tomography (MDCT) for risk stratification in patients with acute UGI bleeding in the emergency room (ER). METHODS: This retrospective study included patients with UGI bleeding in the ER. Glasgow-Blatchford risk score-computed tomography (GBS-CT) was assessed using a combination of GBS and the MDCT scan scoring system. RESULTS: Of the 297 patients with UGI bleeding, 124 (41.8%) underwent abdominal MDCT. Among them, 90.3% were classified as high-risk by GBS, and five patients died (4.0%). Rebleeding occurred in nine patients (7.3%). The high-risk GBS-CT group had significantly higher in-hospital mortality (10.5% in high-risk vs. 1.4% in moderate risk vs. 0% in low-risk, p = 0.049), transfusion amount (p < 0.001), and endoscopic hemostasis (p < 0.001) compared to the moderate- and low-risk groups. CONCLUSION: Adding MDCT scans to the existing validated prognosis model when predicting the risk of UGI bleeding in patients in the ER plays a significant role in determining in-hospital mortality, transfusions, and the need for endoscopic hemostasis.


Asunto(s)
Servicio de Urgencia en Hospital , Hemorragia Gastrointestinal , Humanos , Estudios Retrospectivos , Medición de Riesgo/métodos , Índice de Severidad de la Enfermedad , Hemorragia Gastrointestinal/diagnóstico por imagen , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/terapia , Enfermedad Aguda , Factores de Riesgo , Pronóstico , Tomografía Computarizada por Rayos X , Tomografía , Curva ROC
9.
Cell Death Dis ; 13(9): 760, 2022 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-36055997

RESUMEN

Selective removal of senescent cells, or senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even for reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced the death of primary human dermal fibroblasts undergoing RS. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without inducing cytotoxicity. Interestingly, the mechanism by which nintedanib activated caspase-9 in the intrinsic apoptotic pathway differed from that of ABT263 apoptosis induction; specifically, nintedanib did not decrease the levels of Bcl-2 family proteins in senescent cells. Moreover, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused the drug-induced death of senescent cells. STAT3 knockdown in senescent cells induced caspase activation. Moreover, nintedanib reduced the number of senescence-associated ß-galactosidase-positive senescent cells in parallel with a reduction in STAT3 phosphorylation and ameliorated collagen deposition in a mouse model of bleomycin-induced lung fibrosis. Consistently, nintedanib exhibited a senolytic effect through bleomycin-induced senescence of human pulmonary fibroblasts. Overall, we found that nintedanib can be used as a new senolytic agent and that inhibiting STAT3 may be an approach for inducing the selective death of senescent cells. Our findings pave the way for expanding the senolytic toolkit for use in various aging statuses and age-related diseases.


Asunto(s)
Indoles , Senoterapéuticos , Animales , Bleomicina/farmacología , Senescencia Celular , Fibroblastos/metabolismo , Humanos , Indoles/metabolismo , Indoles/farmacología , Ratones , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo
10.
Commun Biol ; 5(1): 702, 2022 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-35835838

RESUMEN

The multifaceted nature of senescent cell cycle arrest necessitates the targeting of multiple factors arresting or promoting the cell cycle. We report that co-inhibition of ATM and ROCK by KU-60019 and Y-27632, respectively, synergistically increases the proliferation of human diploid fibroblasts undergoing replicative senescence through activation of the transcription factors E2F1 and FOXM1. Time-course transcriptome analysis identified FOXM1 and E2F1 as crucial factors promoting proliferation. Co-inhibition of the kinases ATM and ROCK first promotes the G2/M transition via FOXM1 activation, leading to accumulation of cells undergoing the G1/S transition via E2F1 activation. The combination of both inhibitors increased this effect more significantly than either inhibitor alone, suggesting synergism. Our results demonstrate a FOXM1- and E2F1-mediated molecular pathway enhancing cell cycle progression in cells with proliferative potential under replicative senescence conditions, and treatment with the inhibitors can be tested for senomorphic effect in vivo.


Asunto(s)
Senescencia Celular , Factor de Transcripción E2F1 , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular , Factor de Transcripción E2F1/genética , Factor de Transcripción E2F1/metabolismo , Factor de Transcripción E2F1/farmacología , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Proteína Forkhead Box M1/farmacología , Humanos
11.
J Ginseng Res ; 46(1): 138-146, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35058730

RESUMEN

BACKGROUND: Red Ginseng has been used for many years to treat diseases. Ginsenoside Rg3 has documented therapeutic effects, including anticancer and anti-inflammatory activities. However, the anticancer effect of Rg3-enriched red ginseng extract (Rg3-RGE) and its underlying mechanisms have not been fully explored. We investigated whether Rg3-RGE plays an anti-tumor role in lung cancer cells. METHODS: To examine the effect of Rg3-RGE on lung cancer cells, we performed cell viability assays, flow cytometry, western blotting analysis, and immunofluorescence to monitor specific markers. RESULTS: Rg3-RGE significantly inhibited cell proliferation and induced mitochondria-dependent apoptosis. Furthermore, Rg3-RGE also increased expression of mitophagy-related proteins such as PINK1 and Parkin. In addition, treatment with Rg3-RGE and mitophagy inhibitors stimulated cell death by inducing mitochondria dysfunction. CONCLUSIONS: Rg3-RGE could be used as a therapeutic agent against lung cancer.

12.
J Neurol ; 269(6): 2999-3005, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34783885

RESUMEN

OBJECTIVE: Acute ischemic stroke in the territory of anterior cerebral artery (ACA) is uncommon. Therefore, large population studies evaluating ACA infarction are scarce. We sought to evaluate epidemiological and etiological characteristics of ACA infarction compared to other territorial infarctions. METHODS: We analyzed a prospectively collected stroke registry of all acute ischemic stroke patients for 19 years at two tertiary hospitals. We included patients with acute ischemic stroke caused by large vessel stenosis or occlusion including ACA, middle cerebral artery (MCA), posterior cerebral artery (PCA), and vertebrobasilar artery (VBA). RESULTS: A total of 4171 patients were enrolled. Patients with ACA infarction (N = 288) were significantly older with more females than those with MCA, PCA, or VBA infarction. There were more patients with history of prior ischemic stroke in the ACA infarction group than in other groups. The etiology of the ACA infarction was similar to those of the MCA, PCA and also the total population (66.7-71.8% of LAA and 17.9-20.9% of CE). When patients had prior ischemic stroke history, ACA infarction was more likely to be caused by LAA than MCA or PCA infarction (OR = 6.2, 95% CI 2.0-19.2, p = 0.002 and OR = 4.0, 95% CI 1.1-14.6, p = 0.038, respectively). CONCLUSIONS: Patients with ACA infarction had significantly more prior ischemic stroke than those with MCA, PCA, or VBA infarction. The etiology of ACA infarction in patients with prior ischemic stroke showed significantly more LAA than that of MCA or PCA infarction.


Asunto(s)
Infarto de la Arteria Cerebral Anterior , Infarto de la Arteria Cerebral Posterior , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Arteria Cerebral Anterior/diagnóstico por imagen , Femenino , Humanos , Infarto de la Arteria Cerebral Anterior/diagnóstico por imagen , Infarto de la Arteria Cerebral Anterior/epidemiología , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Posterior/complicaciones , Infarto de la Arteria Cerebral Posterior/diagnóstico por imagen , Infarto de la Arteria Cerebral Posterior/epidemiología , Accidente Cerebrovascular/complicaciones
13.
J Ultrasound Med ; 41(2): 439-446, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33885173

RESUMEN

OBJECTIVES: Transcranial Doppler ultrasound (TCD) is noninvasive and highly sensitive and specific for the diagnosis of patent foramen ovale (PFO). We evaluated the diagnostic implications of the TCD with a saline agitation test as a routine work-up for ischemic stroke patients. METHODS: A TCD bubble study was performed in all consecutive ischemic stroke patients as a routine work-up. We evaluated the prevalence of microembolic signals (MES) for each stroke etiology and the optimal number of MES for predicting the PFO-attributable stroke. RESULTS: Subjects (N = 499) with acute ischemic stroke were enrolled. A significant fraction of patients had MES during both normal respiration (5.7-44.4%) and the Valsalva maneuver (19.5-55.6%) across all stroke etiology categories. The optimal MES threshold for the diagnosis of PFO-attributable stroke confirmed by transesophageal echocardiography was 46 MES during the Valsalva maneuver (96% sensitivity and 95% specificity). Applying ≥46 MES during the Valsalva maneuver as a threshold effectively increased the ability to differentially diagnose PFO-attributable stroke from other etiologies. The number of MES during the Valsalva maneuver was negatively correlated with increasing age (r = -.108; P = .016). CONCLUSIONS: A significant fraction of patients had right to left shunt across all Trial of ORG 10172 in Acute Stroke Treatment etiologies. A threshold number of MES facilitated the differential diagnosis of PFO-attributable stroke from other etiologies, and the optimal threshold was 46 MES during the Valsalva maneuver.


Asunto(s)
Isquemia Encefálica , Foramen Oval Permeable , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Isquemia Encefálica/complicaciones , Isquemia Encefálica/diagnóstico por imagen , Ecocardiografía Transesofágica , Foramen Oval Permeable/complicaciones , Foramen Oval Permeable/diagnóstico por imagen , Humanos , Prevalencia , Sensibilidad y Especificidad , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/epidemiología , Ultrasonografía Doppler Transcraneal , Maniobra de Valsalva
14.
Exp Mol Med ; 53(6): 1092-1108, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34188179

RESUMEN

Senescent cells exhibit a reduced response to intrinsic and extrinsic stimuli. This diminished reaction may be explained by the disrupted transmission of nuclear signals. However, this hypothesis requires more evidence before it can be accepted as a mechanism of cellular senescence. A proteomic analysis of the cytoplasmic and nuclear fractions obtained from young and senescent cells revealed disruption of nucleocytoplasmic trafficking (NCT) as an essential feature of replicative senescence (RS) at the global level. Blocking NCT either chemically or genetically induced the acquisition of an RS-like senescence phenotype, named nuclear barrier-induced senescence (NBIS). A transcriptome analysis revealed that, among various types of cellular senescence, NBIS exhibited a gene expression pattern most similar to that of RS. Core proteomic and transcriptomic patterns common to both RS and NBIS included upregulation of the endocytosis-lysosome network and downregulation of NCT in senescent cells, patterns also observed in an aging yeast model. These results imply coordinated aging-dependent reduction in the transmission of extrinsic signals to the nucleus and in the nucleus-to-cytoplasm supply of proteins/RNAs. We further showed that the aging-associated decrease in Sp1 transcription factor expression was critical for the downregulation of NCT. Our results suggest that NBIS is a modality of cellular senescence that may represent the nature of physiological aging in eukaryotes.


Asunto(s)
Senescencia Celular , Proteómica , Núcleo Celular/metabolismo , Senescencia Celular/genética , Regulación hacia Abajo
15.
Aging (Albany NY) ; 12(9): 8221-8240, 2020 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-32379705

RESUMEN

The selective removal of senescent cells by senolytics is suggested as a potential approach to reverse aging and extend lifespan. Using high-throughput screening with replicative senescence of human diploid fibroblasts (HDFs), we identified a novel senolytic drug R406 that showed selective toxicity in senescent cells. Using flow cytometry and caspase expression analysis, we confirmed that R406 caused apoptotic cell death along with morphological changes in senescent cells. Interestingly, R406 altered the cell survival-related molecular processes including the inhibition of phosphorylation of the focal adhesion kinase (FAK) and p38 mitogen-activated protein kinase (MAPK) in senescent cells. This pattern was not observed in other known senolytic agent ABT263. Correspondingly, apoptotic cell death in senescent cells was induced by simultaneously blocking the FAK and p38 pathways. Taken together, we suggest that R406 acts as a senolytic drug by inducing apoptosis and reducing cell attachment capacity.


Asunto(s)
Compuestos de Anilina/farmacología , Senescencia Celular/fisiología , Sulfonamidas/farmacología , Quinasa Syk/antagonistas & inhibidores , Apoptosis , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Fosforilación
16.
Int J Mol Sci ; 22(1)2020 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-33396907

RESUMEN

Near the bone remodeling compartments (BRC), extracellular calcium concentration (Ca2+o) is locally elevated and bone marrow stromal cells (BMSCs) close to the BRC can be exposed to high calcium concentration. The calcium-sensing receptor (CaSR) is known to play a key role in maintaining extracellular calcium homeostasis by sensing fluctuations in the levels of extracellular calcium (Ca2+o). When human BMSCs (hBMSCs) were exposed to various calcium concentrations (1.8, 3, 5, 10, 30 mM), moderate-high extracellular calcium concentrations (3-5 mM) stimulated proliferation, while a high calcium concentration (30 mM) inhibited the proliferation. Exposure to various calcium concentrations did not induce significant differences in the apoptotic cell fraction. Evaluation of multi-lineage differentiation potential showed no significant difference among various calcium concentration groups, except for the high calcium concentration (30 mM) treated group, which resulted in increased calcification after in vitro osteogenic differentiation. Treatment of NPS2143, a CaSR inhibitor, abolished the stimulatory effect on hBMSCs proliferation and migration indicating that CaSR is involved. These results suggest that the calcium concentration gradient near the BRC may play an important role in bone remodeling by acting as an osteoblast-osteoclast coupling mechanism through CaSR.


Asunto(s)
Remodelación Ósea , Calcificación Fisiológica , Calcio/metabolismo , Células Madre Mesenquimatosas/citología , Osteoblastos/citología , Osteoclastos/citología , Receptores Sensibles al Calcio/metabolismo , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Humanos , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo
17.
Genes (Basel) ; 10(10)2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31618982

RESUMEN

One of the 100 worst invasive exotic species, Solenopsis invicta (red imported fire ant), has the possibility to induce an allergic reaction that may eventually cause death from its aggressive stinging. In 2017, S. invicta was found at a container yard in Gamman Port, Busan, South Korea for the first time. It may result in an infestation of fire ants in the Korean environment. After this incident, sensitive quarantine procedures are required to detect possible contamination of fire ants in imported containers. However, currently, fire ant identification relies on phenotypic characteristics. This requires highly trained experts for identification and there are not enough to cover all imported containers. Here, we develop a key molecular marker to distinguish S. invicta from others using the whole genome sequence (WGS) of collected S. invicta from Gamman Port and NCBI-deposited WGS data of S.invicta and S. geminata. The consolidated genotypes of Solenopsis genus successfully indicate the distinguishable gene. The gel-based experimental validation confirmed expected classification and the developed cleaved amplified polymorphic sequences (CAPS) marker also gave a consistent result. Using the CAPS marker derived from our consolidated genotypes, the samples collected from containers in several ports can be easily tested by PCR in a few hours. The quick and easy test would increase not only the labor efficiency but also the environmental safety from fire ants.


Asunto(s)
Hormigas/clasificación , Hormigas/genética , Animales , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Especies Introducidas , Polimorfismo Genético/genética , República de Corea , Especificidad de la Especie , Secuenciación Completa del Genoma/métodos
18.
Front Aging Neurosci ; 10: 269, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30319390

RESUMEN

Recent studies have shown that Liuwei Dihuang pills (LWPs) can positively affect learning, memory and neurogenesis. However, the underlying molecular mechanisms are not understood. In the present study, we developed ALWPs, a mixture of Antler and LWPs, and investigated whether ALWPs can affect neuroinflammatory responses. We found that ALWPs (500 mg/ml) inhibited lipopolysaccharide (LPS)-induced proinflammatory cytokine IL-1ß mRNA levels in BV2 microglial cells but not primary astrocytes. ALWPs significantly reduced LPS-induced cell-surface levels of TLR4 to alter neuroinflammation. An examination of the molecular mechanisms by which ALWPs regulate the LPS-induced proinflammatory response revealed that ALWPs significantly downregulated LPS-induced levels of FAK phosphorylation, suggesting that ALWPs modulate FAK signaling to alter LPS-induced IL-1ß levels. In addition, treatment with ALWPs followed by LPS resulted in decreased levels of the transcription factor NF-κB in the nucleus compared with LPS alone. Moreover, ALWPs significantly suppressed LPS-induced BV2 microglial cell migration. To examine whether ALWPs modulate learning and memory in vivo, wild-type C57BL/6J mice were orally administered ALWPs (200 mg/kg) or PBS daily for 3 days, intraperitoneally injected (i.p.) with LPS (250 µg/kg) or PBS, and assessed in Y maze and NOR tests. We observed that oral administration of ALWPs to LPS-injected wild-type C57BL/6J mice significantly rescued short- and long-term memory. More importantly, oral administration of ALWPs to LPS-injected wild-type C57BL/6J mice significantly reduced microglial activation in the hippocampus and cortex. Taken together, our results suggest that ALWPs can suppress neuroinflammation-associated cognitive deficits and that ALWPs have potential as a drug for neuroinflammation/neurodegeneration-related diseases, including Alzheimer's disease (AD).

19.
J Neuroinflammation ; 15(1): 271, 2018 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-30231870

RESUMEN

BACKGROUND: The FDA-approved small-molecule drug ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib inhibits Bruton's tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. However, the potential regulation of neuroinflammatory responses in the brain by ibrutinib has not been comprehensively examined. METHODS: BV2 microglial cells were treated with ibrutinib (1 µM) or vehicle (1% DMSO), followed by lipopolysaccharide (LPS; 1 µg/ml) or PBS. RT-PCR, immunocytochemistry, and subcellular fractionation were performed to examine the effects of ibrutinib on neuroinflammatory responses. In addition, wild-type mice were sequentially injected with ibrutinib (10 mg/kg, i.p.) or vehicle (10% DMSO, i.p.), followed by LPS (10 mg/kg, i.p.) or PBS, and microglial and astrocyte activations were assessed using immunohistochemistry. RESULTS: Ibrutinib significantly reduced LPS-induced increases in proinflammatory cytokine levels in BV2 microglial and primary microglial cells but not in primary astrocytes. Ibrutinib regulated TLR4 signaling to alter LPS-induced proinflammatory cytokine levels. In addition, ibrutinib significantly decreased LPS-induced increases in p-AKT and p-STAT3 levels, suggesting that ibrutinib attenuates LPS-induced neuroinflammatory responses by inhibiting AKT/STAT3 signaling pathways. Interestingly, ibrutinib also reduced LPS-induced BV2 microglial cell migration by inhibiting AKT signaling. Moreover, ibrutinib-injected wild-type mice exhibited significantly reduced microglial/astrocyte activation and COX-2 and IL-1ß proinflammatory cytokine levels. CONCLUSIONS: Our data provide insights on the mechanisms of a potential therapeutic strategy for neuroinflammation-related diseases.


Asunto(s)
Antiinflamatorios/uso terapéutico , Citocinas/metabolismo , Inflamación/tratamiento farmacológico , Microglía/efectos de los fármacos , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adenina/análogos & derivados , Animales , Animales Recién Nacidos , Línea Celular Transformada , Células Cultivadas , Medio de Cultivo Libre de Suero/farmacología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Citocinas/genética , Modelos Animales de Enfermedad , Compuestos Heterocíclicos con 3 Anillos/farmacología , Inflamación/inducido químicamente , Lipopolisacáridos/efectos adversos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/citología , Piperidinas , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/química , Pirimidinas/química , Ratas , Transducción de Señal/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos
20.
J Cell Biochem ; 119(2): 2036-2047, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28833404

RESUMEN

Numerous anti-cancer agents inhibit cell cycle progression via a p53-dependent mechanism; however, other genes such as the proto-oncogene c-Myc are promising targets for anticancer therapy. In the present study, we provide evidence that ascochlorin, an isoprenoid antibiotic, is a non-toxic anti-cancer agent that induces G1 cell cycle arrest and p21WAF1/CIP1 expression by downregulating of c-Myc protein expression. Ascochlorin promoted the G1 arrest, upregulated p53 and p21WAF1/CIP1 , and downregulated c-Myc in HCT116 cells. In p53-deficient cells, ascochlorin enhanced the expression of G1 arrest-related genes except p53. Small interfering RNA (siRNA) mediated c-Myc silencing indicated that the transcriptional repression of c-Myc was related to ascochlorin-mediated modulation of p21WAF1/CIP1 expression. Ascochlorin suppressed the stabilization of the c-Myc protein by inhibiting ERK and P70S6K/4EBP1 phosphorylation, whereas it had no effect on c-Myc degradation mediated by PI3K/Akt/GSK3ß. The ERK inhibitor PD98059 and siRNA-mediated ERK silencing induced G1 arrest and p21WAF1/CIP1 expression by downregulating c-Myc in p53-deficient cells. These results indicated that ascochlorin-induced G1 arrest is associated with the repression of ERK phosphorylation and c-Myc expression. Thus, we reveal a role for ascochlorin in inhibiting tumor growth via G1 arrest, and identify a novel regulatory mechanism for ERK/c-Myc.


Asunto(s)
Alquenos/farmacología , Antibióticos Antineoplásicos/farmacología , Neoplasias Colorrectales/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Fenoles/farmacología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Puntos de Control del Ciclo Celular , Neoplasias Colorrectales/tratamiento farmacológico , Regulación hacia Abajo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Humanos , Fosforilación/efectos de los fármacos , Proto-Oncogenes Mas
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