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A simple, rapid, and selective ultra-performance liquid chromatography-tandem mass spectrometry method for determination of l-carnitine (LC) and acetyl-l-carnitine (ALC) in human serum was developed. Acetyl-l-carnitine-d3 (ALC-d3 ) was selected as internal standard (IS). After protein precipitation with acetonitrile-water (1 mL, 2:1, v/v), the analytes and IS were separated on a 2.5-µm XSelect HSS T3 C18 column by gradient elution with methanol-water (containing 0.01% ammonia water) as the mobile phase at a flow rate of 0.2 mL/min. Analytes were detected with multiple reaction monitoring using a positive scan mode with electrospray ionization. Good linearity (R2 > 0.999) was observed in the concentration range for LC and ALC. The inter- and intra-day values of relative error were -10.4% to 10.0% with CVs less than 9.84%. The average recoveries of the two analytes were 91.29%-98.23%. Blood samples containing LC and ALC were stable under various storage conditions. Normal, haemolytic, and hyperlipidaemic serum had no significant effect on the quantification of LC and ALC. This method was successfully applied to study the concentrations of endogenous LC and ALC in the serum of patients with first-episode depression.
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Carnitina/sangre , Cromatografía Líquida de Alta Presión/métodos , Depresión/sangre , Espectrometría de Masas en Tándem/métodos , Acetilcarnitina/sangre , Humanos , Modelos Lineales , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
KISS1 and KISS1R, a novel pair of metastasis suppressors, are likely to be associated with the prognosis of colorectal cancer (CRC). Here, a meta-analysis was performed to study the role of KISS1 and KISS1R in CRC. Heterogeneity, stability and publication bias were all estimated. Six publications describing a total of 559 CRC patients were included in the present study. Low KISS1 expression predicted 70% higher risk of poor prognosis for general patients (HR, 1.71; 95% CI, 1.28-2.29) and 99% higher risk for East Asian patients (HR, 1.99; 95% CI, 1.46-2.72). Limited evidence indicated that decreased KISS1R expression might predict poor outcome (HR, 2.96; 95% CI, 1.51-5.82). Neither heterogeneity nor publication bias was identified. The current analyses suggest that low KISS1 expression predicts poor overall survival among East Asian patients with CRC. Evidence on other races and KISS1R are still insufficient, and additional studies are required to clarify the risk of CRC associated with KISS1R by race.
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Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/metabolismo , Regulación Neoplásica de la Expresión Génica , Kisspeptinas/metabolismo , Humanos , Pronóstico , Receptores de Kisspeptina-1/metabolismoRESUMEN
Introduction: Schizophrenia has a strong genetic basis. It is reported that the matrix metalloproteinase-9 (MMP-9) -1562C/T polymorphism (rs3918242) may be associated with schizophrenia; however, current evidences are conflicting. Methods: A systematic literature search was conducted on PubMed and Web of Science to identify all the available evidences of the association of schizophrenia with rs3918242 polymorphism. Baseline information and genotype distribution were extracted from eligible study for quantitative data synthesis. Odds ratio (OR) and 95% confidence interval (95% CI) were used to estimate the effect size. Quality assessment was performed for each study using Newcastle-Ottawa Scale (NOS). Results: Four eligible studies were included in this study. Data synthesis indicated that rs3918242 polymorphism was not associated with schizophrenia (OR = 1.04, 95% CI = 0.69-1.58), with high heterogeneity (I2 = 75%, p = .007). No publication bias was visually observed according to funnel plot. Sensitivity analysis showed a significant association (OR = 1.29, 95% CI = 1.03-1.63) when a specific study was removed. Conclusions: MMP-9 rs3918242 polymorphism may not be associated with schizophrenia. Given a crucial role of MMP-9 molecule on the pathogenesis of schizophrenia, this result should be verified by more studies with scientifically rigorous design and large population.
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Predisposición Genética a la Enfermedad/genética , Metaloproteinasa 9 de la Matriz/genética , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/genética , HumanosRESUMEN
The anorexigenic molecule nesfatin-1 has recently been taken as a potential mood regulator, but the potential mechanisms remain unknown. Results of our previous study have demonstrated that nesfatin-1 could induce anxiety- and depression-like behaviors in rats, accompanied by the hyperactivity of the hypothalamic-pituitary-adrenal axis and the imbalanced mRNA expression of synaptic vesicle proteins. To explore the potential neurobiological mechanism underlying the effect of nesfatin-1 on the synaptic plasticity, the human neuroblastoma SH-SY5Y cells were cultured and treated with different concentrations of nesfatin-1 in the present study. The mRNA and protein expressions of corticotropin-releasing hormone (CRH) were measured via real-time fluorescent quantitative PCR and western blot, respectively. The protein expressions of extracellular signal-regulated kinase 1/2 (ERK1/2), phosphorylated-ERK1/2 (p-ERK1/2), and synapsin I were detected via western blot. The results confirmed that nesfatin-1 (10-9~10-7 mol/L) could up-regulate the expression of CRH. Moreover, nesfatin-1 (10-9~10-7 mol/L) could also increase the protein expressions of p-ERK1/2 and synapsin I, and these effects could be blocked by CP376395, a selective antagonist of CRH type 1 receptor (CRHR1). Furthermore, the increased expression of synapsin I induced by nesfatin-1 could also be reversed by PD98059, a specific inhibitor of the p-ERK. These results indicated that CRHR1 might mediate the effect of nesfatin-1 on the expressions of synapsin I via ERK1/2 signaling pathway.
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Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al ADN/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas del Tejido Nervioso/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Sinapsinas/efectos de los fármacos , Aminopiridinas/farmacología , Línea Celular , Hormona Liberadora de Corticotropina/efectos de los fármacos , Hormona Liberadora de Corticotropina/metabolismo , Flavonoides/farmacología , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Quinasas Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Nucleobindinas , Fosforilación , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Receptores de Hormona Liberadora de Corticotropina/efectos de los fármacos , Sinapsinas/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The major purpose of this study was to investigate the effect of resveratrol (RES) on the spatial learning and memory ability in subclinical hypothyroidism (SCH) rat model and the potential mechanism. A SCH rat model was induced by hemi-thyroid electrocauterization and the activity of hypothalamus-pituitary-thyroid (HPT) axis was detected. The spatial learning and memory ability was tested using Morris water maze (MWM) and Y-maze. The protein expressions of synaptotagmin-1 (syt-1) and brain-derived neurotrophic factor (BDNF) in the hippocampus were measured via western blot. The results showed that SCH rat model was successfully duplicated. The SCH rats showed impaired learning and memory in the behavioral tests. However, these changes were reversed by the treatment of RES (15mg/kg) and levothyroxine (LT4). Moreover, RES treated rats exhibited reduced plasma TSH level and hypothalamic thyrotropin releasing hormone (TRH) mRNA expression, which suggested that the imbalance of HPT axis in the SCH rats could be reversed by RES treatment. Furthermore, RES treatment up-regulated the protein levels of syt-1 and BDNF in hippocampus. These findings indicated an amelioration effect of RES on the spatial learning and memory in the SCH rats, the mechanism of which might be involved with its ability of modifying the hyperactive HPT axis and up-regulating the hippocampal hypo-expression of syt-1 and BDNF.
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Enfermedades Asintomáticas , Modelos Animales de Enfermedad , Hipotiroidismo/tratamiento farmacológico , Discapacidades para el Aprendizaje/prevención & control , Trastornos de la Memoria/prevención & control , Nootrópicos/uso terapéutico , Estilbenos/uso terapéutico , Animales , Antioxidantes/uso terapéutico , Conducta Animal/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/agonistas , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Terapia de Reemplazo de Hormonas , Hipotiroidismo/metabolismo , Hipotiroidismo/fisiopatología , Discapacidades para el Aprendizaje/etiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/etiología , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Distribución Aleatoria , Ratas Sprague-Dawley , Resveratrol , Aprendizaje Espacial/efectos de los fármacos , Sinaptotagmina I/agonistas , Sinaptotagmina I/metabolismo , Tiroxina/uso terapéuticoRESUMEN
Inflammation plays an important role in the pathogenesis of depression; however, the underlying mechanisms remain unclear. Apart from the disordered circadian rhythm in animal models and patients with depression, dysfunction of clock genes has been reported to be involved with the progress of inflammation. This study aimed to investigate the role of circadian clock genes, especially brain and muscle ARNT-like 1 (Bmal1), in the linkage between inflammation and depression. Lipopolysaccharide (LPS)-challenged rats and BV2 cells were used in the present study. Four intraperitoneal LPS injections of 0.5 mg/kg were administered once every other day to the rats, and BV2 cells were challenged with LPS for 24 h at the working concentration of 1 mg/L, with or without the suppression of Bmal1 via small interfering RNA. The results showed that LPS could successfully induce depression-like behaviors and an "inflammatory storm" in rats, as indicated by the increased immobility time in the forced swimming test and the decreased saccharin preference index in the saccharin preference test, together with hyperactivity of the hypothalamic-pituitary-adrenal axis, hyperactivation of astrocyte and microglia, and increased peripheral and central abundance of tumor necrosis factor-α, interleukin 6, and C-reactive protein. Moreover, the protein expression levels of brain-derived neurotrophic factor, triggering receptor expressed on myeloid cells 1, Copine6, and Synaptotagmin1 (Syt-1) decreased in the hippocampus and hypothalamus, whereas the expression of triggering receptor expressed on myeloid cells 2 increased. Interestingly, the fluctuation of temperature and serum concentration of melatonin and corticosterone was significantly different between the groups. Furthermore, protein expression levels of the circadian locomotor output cycles kaput, cryptochrome 2, and period 2 was significantly reduced in the hippocampus of LPS-challenged rats, whereas Bmal1 expression was significantly increased in the hippocampus but decreased in the hypothalamus, where it was co-located with neurons, microglia, and astrocytes. Consistently, apart from the reduced cell viability and increased phagocytic ability, LPS-challenged BV2 cells presented a similar trend with the changed protein expression in the hippocampus of the LPS model rats. However, the pathological changes in BV2 cells induced by LPS were reversed after the suppression of Bmal1. These results indicated that LPS could induce depression-like pathological changes, and the underlying mechanism might be partly associated with the imbalanced expression of Bmal1 and its regulated dysfunction of the circadian rhythm.
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Depresión , Lipopolisacáridos , Animales , Ratas , Depresión/inducido químicamente , Hipocampo , Sistema Hipotálamo-Hipofisario/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Músculos/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismoRESUMEN
Oncogene FLT3 internal tandem duplication (FLT3-ITD) mutation accounts for 30 % of acute myeloid leukaemia (AML) cases and induces transformation. Previously, we found that E2F transcription factor 1 (E2F1) was involved in AML cell differentiation. Here, we reported that E2F1 expression was aberrantly upregulated in AML patients, especially in AML patients carrying FLT3-ITD. E2F1 knockdown inhibited cell proliferation and increased cell sensitivity to chemotherapy in cultured FLT3-ITD-positive AML cells. E2F1-depleted FLT3-ITD+ AML cells lost their malignancy as shown by the reduced leukaemia burden and prolonged survival in NOD-PrkdcscidIl2rgem1/Smoc mice receiving xenografts. Additionally, FLT3-ITD-driven transformation of human CD34+ hematopoietic stem and progenitor cells was counteracted by E2F1 knockdown. Mechanistically, FLT3-ITD enhanced the expression and nuclear accumulation of E2F1 in AML cells. Further study using chromatin immunoprecipitation-sequencing and metabolomics analyses revealed that ectopic FLT3-ITD promoted the recruitment of E2F1 on genes encoding key enzymatic regulators of purine metabolism and thus supported AML cell proliferation. Together, this study demonstrates that E2F1-activated purine metabolism is a critical downstream process of FLT3-ITD in AML and a potential target for FLT3-ITD+ AML patients.
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Leucemia Mieloide Aguda , Humanos , Ratones , Animales , Ratones Endogámicos NOD , Leucemia Mieloide Aguda/metabolismo , Células Cultivadas , Antígenos CD34 , Purinas , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Mutación , Factor de Transcripción E2F1/genéticaRESUMEN
Purpose: To investigate the changes of plasma 25(OH)D levels in type 2 diabetes mellitus (T2DM) patients and explore its role in the dysfunction of glucose and lipid metabolism and cognition. Methods: One hundred and thirty-two T2DM patients were enrolled and the demographic and clinical data were collected. The plasma concentration of 25(OH)D was detected and the patients were divided into two groups including a Vitamin D insufficient (VDI) group and a normal VD group according to the clinical diagnostic criterial of VDI with the plasma 25(OH)D level less than 29 ng/mL. The glycolipid metabolic and routine blood biochemical indices were detected, the plasma concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), soluble myeloid soluble trigger receptor 1 (sTREM1) were measured. The cognitive function was assessed using the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A). The depressive symptomatology was assessed using the Center for Epidemiological Survey Depression Scale (CES-D). Sleep quality was assessed using the Pittsburgh sleep quality index (PSQI). Results: There were 70 T2DM patients with VDI (70/132, 53.03%) in this study. The plasma concentrations of glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial blood glucose (PBG), IL-6, and sTREM1 were remarkably increased in T2DM patients with VDI as compared with that with the normal VD, accompanied with an elevated BRIEF-A scores. There was no significant difference between groups with regard to the indices of blood lipid, liver function, and scores in CES-D and PSQI. Moreover, results of Pearson correlation test showed that the plasma 25(OH)D levels were negatively correlated with HbA1c, FPG, PBG, CRP, IL-6, sTREM1, CES-D sum scores, and PSQI sum scores, but positively correlated with the plasma levels of Serum creatinine (Scr). Furthermore, result of Receiver Operating Characteristic (ROC) curve analysis showed a predictive role of VDI levels in discriminating T2DM patients with higher cognitive impairments, with the sensitivity and specificity being 62.12% and 62.12%, respectively. Conclusion: VDI is harmful for T2DM patients with a significant relation with the hyperglycosemia and cognitive dysfunction.
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Disfunción Cognitiva , Diabetes Mellitus Tipo 2 , Adulto , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Hemoglobina Glucada , Interleucina-6/metabolismo , Glucemia/análisis , Disfunción Cognitiva/complicaciones , Metabolismo de los Lípidos , GlucolípidosRESUMEN
Protracted alcohol withdrawal symptoms (PAWS), characterized by the presence of substance-specific signs and symptoms (including anxiety, irritability, mood instability, insomnia, and cravings), make alcohol abstinence difficult and increase the risk of relapse in recovering alcoholics. The goal of this study was to evaluate the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on PAWS and plasma brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and leptin levels in patients with alcohol dependency. A total of 114 patients with alcohol dependence were randomly divided into two groups: the treatment group and the control group. The patients in the treatment group were treated with taVNS of the bilateral auricular concha using an ear vagus nerve stimulator. The Pennsylvania Alcohol Craving Scale was used to evaluate the extent of craving for alcohol. The Self-Rating Anxiety Scale and Self-Rating Depression Scale (SDS) were used to evaluate the extent of anxiety and depression symptoms, respectively. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. Enzyme-linked immunosorbent assay was used to measure plasma BDNF, IL-6, TNF-α, and leptin levels. The results showed that the SDS and PSQI scores were significantly lower in the treatment group than in the control group. Moreover, compared with the control group, the average BDNF levels in the treatment group were significantly increased. These results suggest that taVNS could improve the depression symptoms and sleep quality in alcohol-dependent patients after withdrawal, which might be related to the upregulation of plasma BDNF levels.
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Epidemiological data suggest that the incidence of rheumatoid arthritis (RA) increases in postmenopausal women, which may be related to estrogen deficiency. Tissue acidosis is a common symptom of RA. Acid-sensitive ion channel 1a (ASIC1a), a member of the extracellular H+-activated cation channel family, could be activated by changes in extracellular pH and plays a crucial role in the pathogenesis of RA. As the only cellular component in cartilage tissue, chondrocytes play an extremely important role in maintaining cartilage tissue homeostasis. The aim of this study was to investigate whether estrogen could protect acid-stimulated chondrocytes by regulating the expression of ASIC1a and explore the possible mechanism. The results showed that estrogen could protect against acid-induced chondrocyte injury by reducing ASIC1a protein expression. Moreover, lysosome inhibitor chloroquine (CQ) and autophagy inhibitor 3-methyladeniine (3-MA) could reverse the reduction of ASIC1a protein caused by estrogen, indicating that autophagy-lysosome pathway contributes to estrogen-induced degradation of ASIC1a protein. Furthermore, the down-regulation of ASIC1a expression by estrogen was attenuated by MPP, a specific inhibitor of estrogen-related receptor-alpha (Esrra), indicating that Esrra is involved in the process of estrogen regulating the expression of ASIC1a. Additionally, adenosine 5'-monophosphate (AMP)-activated protein kinase/unc-51-like kinase 1 (AMPK-ULK1) signaling pathway was activated by estrogen treatment, which was abrogated by Esrra-silencing, and AMPK-specific inhibitor Compound C pretreatment could reduce estrogen-induced downregulation of ASIC1a protein. Taken together, these results indicate that estrogen could promote autophagy-lysosome pathway-dependent ASIC1a protein degradation and protect against acidosis-induced cytotoxicity, the mechanisms of which might relate to Esrra-AMPK-ULK1 signaling pathway.
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Condrocitos , Canales Iónicos Sensibles al Ácido , Acidosis , Animales , Cartílago Articular , Humanos , Proteolisis , RatasRESUMEN
BACKGROUND: Psoriasis is a chronic autoinflammatory skin disease, and its aetiology remains incompletely understood. Recently, gut microbial dysbiosis is found to be tightly associated with psoriasis. OBJECTIVE: We sought to reveal the causal role of gut microbiota dysbiosis in psoriasis pathogenesis and investigate the protective effect of healthy commensal bacteria against imiquimod -induced psoriasis-like skin response. METHODS: By using fecal microbial transplantation (FMT), 16S rRNA gene-based taxonomic profiling and Lactobacillus supplement, we have assessed the effect of FMT from healthy individuals on psoriasis-like skin inflammation and associated immune disorders in imiquimod-induced psoriasis mice. RESULTS: Here, by using psoriasis mice humanized with the stools from healthy donors and psoriasis patients, the imiquimod-induced psoriasis in mice with psoriasis patient stool was found to be significantly aggravated as compared to the mice with healthy donor stools. Further analysis showed fecal microbiota of healthy individuals protected against Treg/Th17 imbalance in psoriasis. Moreover, we found the gut and skin microbiome in mice receipted with gut microbiota of healthy individuals (HD) differed from those of mice receipted with gut microbiota of psoriasis patients (PSD). 16S rRNA sequencing revealed that Lactobacillus reuteri was greatly enriched in fecal and cutaneous microbiome of HD mice as compared to PSD mice. Intriguingly, supplement with Lactobacillus reuteri was sufficient to increase the expression of anti-inflammatory gene IL-10, reduce Th17 cells counts and confer resistance to imiquimod-induced inflammation on the mice with gut microbiota dysbiosis. CONCLUSION: Our results suggested that the gut microbiota dysbiosis is the potential causal factor for psoriasis and the gut microbiota may serve as promising therapy target for psoriasis patients.
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The goal of this study was to determine whether the plasma leptin, nesfatin-1, cortisol, brain-derived neurotrophic factor (BDNF), and inflammatory cytokines could be used as potential biomarkers for the degree of craving in the alcohol-dependent patients after 1 month of abstinence. A total of 83 patients with alcohol use disorder (AUD) and 61 healthy subjects were assessed. Patients with AUD were selected from Department of Material Dependence, Anhui Mental Health Center, and subjects in the control group were selected from healthy volunteers. The Alcohol Urge questionnaire Scale (AUQ) was used to evaluate the extent of craving for alcohol, and the Michigan Alcoholism Screening Test (MAST), the Fagerstrom Test for Nicotine Dependence (FTND), the Self-Rating Anxiety Scale (SAS), and the Self-Rating Depression Scale (SDS) were also assessed in patients with AUD. Enzyme-Linked Immunosorbent Assay (ELISA) was used for the measurement of plasma leptin, nesfatin-1, cortisol, BDNF, Interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) levels. Compare with healthy controls, the average leptin, leptin/BMI, IL-6, CRP, and TNF-α levels in patients with AUD were significantly increased, while the BDNF levels were significantly decreased. Moreover, the partial correlational analysis showed that the AUQ scores of the alcohol-dependent patients were positively correlated with the plasma leptin levels (r = 0.613, P < 0.001), rather than nesfatin-1 (r = 0.066, P = 0.569) after controlling for age as covariate. Furthermore, plasma nesfatin-1 levels were found to be correlated with the SDS scores (r = 0.366, P = 0.001) in the AUD group. In addition, plasma leptin levels were positively associated with the plasma IL-6 (r = 0.257, P = 0.033), CRP (r = 0.305, P = 0.011), and TNF-α (r = 0.311, P = 0.009) levels, and negatively associated with the BDNF levels (r = -0.245, P = 0.042) in patients with AUD. These results suggest that plasma leptin, but not nesfatin-1, might be a potential biomarker for the degree of craving in alcohol-dependent patients after 1 month of abstinence, the mechanism of which might be related to the dysfunction of the inflammatory cytokines and BDNF levels.
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Abstinencia de Alcohol/estadística & datos numéricos , Alcoholismo/fisiopatología , Biomarcadores/sangre , Ansia/fisiología , Leptina/sangre , Nucleobindinas/sangre , Adolescente , Adulto , Anciano , Alcoholismo/sangre , Factor Neurotrófico Derivado del Encéfalo/sangre , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Acidsensing ion channel 1a (ASIC1a), member of the degenerin/epithelial sodium channel protein superfamily, serves a critical role in various physiological and pathological processes. The aim of the present study was to examine the role of ASIC1a in the autophagy of rat articular chondrocytes. Autophagy was induced by acidic stimulation in rat articular chondrocytes and the extent of autophagy was evaluated via the expression levels of microtubuleassociated protein 1 light chain 3II, Beclin1 and uncoordinated51 like kinase1. Suppression of ASIC1a was achieved using small interfering RNA technology and/or inhibitor psalmotoxin1. The expression levels of autophagy markers were measured by western blot analysis and reverse transcriptionquantitative polymerase chain reaction methods. Intracellular calcium ([Ca2+]i) was analyzed using a Ca2+imaging method. Additionally, protein expression levels of the Ca2+/calmodulindependent protein kinase kinase ß (CaMKKß)/5'monophosphateactivated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway were measured by western blot analysis. The results showed that autophagy was increased in a pH and timedependent manner with exposure to an acidic environment. In addition, silencing ASIC1a significantly decreased the expression levels of autophagy makers, accompanied by abrogation of the acidinduced [Ca2+]i increase. Furthermore, silencing of ASIC1a downregulated the levels of CaMKKß/ßactin and phosphorylated (p) AMPK/AMPK, and upregulated the levels of pmTOR/mTOR. These results indicated that ASIC1a is a potent regulator of autophagy in chondrocytes, which may be associated with decreased Ca2+ influx and the CaMKKß/AMPK/mTOR pathway.
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Canales Iónicos Sensibles al Ácido/metabolismo , Autofagia , Señalización del Calcio , Condrocitos/citología , Condrocitos/metabolismo , Ácidos , Adenilato Quinasa/metabolismo , Animales , Autofagia/efectos de los fármacos , Biomarcadores/metabolismo , Quelantes del Calcio/farmacología , Señalización del Calcio/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Condrocitos/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Concentración de Iones de Hidrógeno , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Masculino , Modelos Biológicos , Péptidos/toxicidad , Ratas Sprague-Dawley , Venenos de Araña/toxicidad , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Depression is a debilitating mental illness that affects up to 120 million people worldwide; it is currently determined based on subjective diagnostic schemes that are limited by high uncertainty. Hence, there is an urgent need to identify effective and reliable biomarkers to increase diagnostic accuracy. MicroRNAs (miRNAs) constitute a recently discovered class of non-coding RNAs that play a key role in the regulation of gene expression by modulating translation, messenger RNA (mRNA) degradation, or stability of mRNA targets. Dysregulated expression of miRNAs is being investigated as a clinical biomarker for a variety of diseases, including depression. Accumulating evidence has shown that miRNAs participate in many aspects of neural plasticity, neurogenesis, and the stress response. This is supported by more direct studies based on human postmortem brain tissue that strongly indicate that miRNAs not only play a key role in the pathogenesis of major depressive disorder, but also present potential for the development of therapeutic targets. miRNAs in the peripheral and central nervous system are being considered as potential biomarkers in the diagnosis of depression and in monitoring the therapeutic response to antidepressants, owing to their stability, tissue-specificity, and disease-specific expression. In this review, we focus on various miRNAs in tissues and fluids that could be employed as diagnostic and therapeutic biomarkers in patients with depression.
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Background: The goal of this study was to identify the physiological factors related to the blood concentration of lithium in Chinese Han patients with bipolar disorder (BD). Materials and methods: A total of 186 Chinese Han patients with BD were assessed. Patients were recruited from the Anhui Mental Health Center. The concentrations of serum lithium were measured by a Dimension RxL Max biochemistry analyzer. Physiological factors, including body weight, body mass index (BMI), and routine laboratory parameters, were collected. Relationships between the serum lithium concentration and relevant clinical data were analyzed by Pearson correlation tests, and the independent relationships were determined by multivariate linear regression analysis. Results: Pearson correlation analysis showed that serum lithium concentrations were positively correlated with creatinine concentrations (r=0.147, P=0.046), Mg2+ concentrations (r=0.151, P=0.04), and the percentage of neutrophils (r=0.178, P=0.015) and negatively correlated with high-density lipoprotein (HDL) concentrations (r=-0.142, P=0.05), apolipoprotein A1 concentrations (r=-0.169, P=0.02), and Na+ concentrations (r=-0.148, P=0.046) in 186 patients with BD. Furthermore, multivariate linear regression analysis showed that serum lithium concentrations were negatively associated with Na+ concentrations and positively associated with the percentage of neutrophils. Conclusion: These results suggest that physiological factors, including creatinine, HDL, apolipoprotein A1, Na+, and Mg2+ concentrations and percentage of neutrophils, might be related to serum lithium concentrations and provide a basis for parameter selection of lithium population pharmacokinetics in Chinese Han patients with BD.
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Resveratrol (RES) is a polyphenolic compound, and our previous results have demonstrated its neuroprotective effect in a series of animal models. The aim of this study was to investigate its potential effect on a nonalcoholic fatty liver disease (NAFLD) rat model. The parameters of liver function and glucose and lipid metabolism were measured. Behavior performance was observed via the open field test (OFT), the sucrose preference test (SPT), the elevated plus maze (EPM), the forced swimming test (FST), and the Morris water maze (MWM). The protein expression levels of Copine 6, p-catenin, catenin, p-glycogen synthase kinase-3beta (GSK3ß), GSK3ß, and cyclin D1 in the hippocampus and prefrontal cortex (PFC) were detected using Western blotting. The results showed that RES could reverse nesfatin-1-related impairment of liver function and glucolipid metabolism, as indicated by the decreased plasma concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), glucose, insulin, and nesfatin-1; increase the plasma level of high-density lipoprotein cholesterol (HDL-C); and reduce hepatocyte steatosis in NAFLD rats. Although there was no significant difference among groups with regard to performance in the OFT, EPM, and FST tasks, RES-treated NAFLD rats showed an increased sucrose preference index in the SPT and improved learning and memory ability in the MWM task. Furthermore, the imbalanced protein expression levels of Copine 6, p-catenin, and p-GSK3ß in the hippocampus and PFC of NAFLD rats were also restored to normal by treatment with RES. These results suggested that four consecutive weeks of RES treatment not only ameliorated glucolipid metabolic impairment and liver dysfunction in the NAFLD rat model but also mitigated the attendant behavioral and cognitive impairments. In addition to the mediating role of nesfatin-1, the mechanism underlying the therapeutic effect of RES on NAFLD might be associated with its ability to regulate the imbalanced expression level of Copine 6 and the Wnt signaling pathway in the hippocampus and PFC.
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BACKGROUND: Previous studies have revealed a conflicting relationship of xeroderma pigmentosum group G (XPG) gene polymorphism with gastric cancer (GC) risk. To our knowledge, this is the first meta-analysis to investigate the association between rs751402 mutation located on the XPG promoter region and GC risk. METHODS: We undertook a meta-analysis by identifying relevant articles from the PubMed, Web of Science and China National Knowledge Infrastructure (CNKI) databases on February 28, 2017. By pooling 9 eligible studies, 3,539 GC cases and 3,948 controls were included. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated using the fixed-effects or random-effects model depending on the existence of heterogeneity across studies. The population attributable risk (PAR%) was estimated to better understand the public health risk. RESULTS: All included studies had been conducted in China. Significant associations were found between the XPG rs751402 polymorphism and the risk of GC (TT vs. CC: OR = 1.43, 95% CI, 1.11-1.84; CT vs. CC: OR = 1.15, 95% CI, 1.04-1.26; dominant model: OR = 1.17, 95% CI, 1.07-1.29; recessive model: OR = 1.30, 95% CI, 1.05-1.62; T vs. C: OR = 1.18, 95% CI, 1.06-1.32). The estimated PAR% was about 4.9%-8.8%. Funnel plots did not reveal any potential publication bias. The sensitivity analyses showed that the results were relatively robust. CONCLUSIONS: This meta-analysis indicates that the XPG rs751402 polymorphism may be a risk factor for GC in the Chinese population.
Asunto(s)
Proteínas de Unión al ADN/genética , Endonucleasas/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas Nucleares/genética , Neoplasias Gástricas/genética , Factores de Transcripción/genética , China/epidemiología , Genotipo , Humanos , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/patologíaRESUMEN
In traditional Chinese medicine practice, crude herbs are often subjected to traditional processing (Paozhi in Chinese) for a special medicinal purpose. Bran-frying is one of processing methods for Paeoniae Radix Alba (PRA). Previous studies found that paeoniflorin and paeoniflorin sulfonate, a principle bioactive compound and its sulfur-fumigation induced characteristic sulfur-containing derivative, could be used together with sulfur dioxide residue as chemical markers for the quality control of sulfur-fumigated PRA crude material. In this paper, the feasibility of these three markers used for the quality control of bran-fried sulfur-fumigated PRA was further investigated. First, homemade samples of sulfur-fumigated PRA with different sulfur-fumigation duration (0.5-6â¯h) were bran-fried, and stored for 12 months. Second, the contents of sulfur dioxide residue, paeoniflorin and paeoniflorin sulfonate were dynamically quantified respectively. Third, the variation of the marker contents and their correlation during bran-frying and storage was evaluated. A validation was conducted using commercial bran-fried PRA samples. The results showed that bran-frying caused an averaged reduction of 20% in the content of sulfur dioxide residue, and during the first two months of storage the content of sulfur dioxide residue was decreased by up to 27%, then the content was tending towards stability for the subsequent ten months of storage (RSDâ¯=â¯3.92%). Meanwhile, paeoniflorin and paeoniflorin sulfonate were relatively stable, the contents of which were not affected by bran-frying processing and 12 months of storage. The correlations between the contents of sulfur dioxide residue and paeoniflorin/paeoniflorin sulfonate were obviously influenced by storage duration. Since sulfur dioxide residue is a safety marker, while paeoniflorin and paeoniflorin sulfonate can reflect the inner quality and the impact extent of sulfur-fumigation on the quality of bran-fried PRA respectively, these three chemicals might be used together as markers for the quality control, and consequently to ensure the safety and efficacy of bran-fried PRA.
Asunto(s)
Medicamentos Herbarios Chinos/normas , Fumigación/métodos , Medicina Tradicional China/normas , Paeonia/química , Raíces de Plantas/química , Control de Calidad , Química Farmacéutica/métodos , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicina Tradicional China/métodos , Azufre/farmacologíaRESUMEN
OBJECTIVES: The aim of the present study was to evaluate the plasma nesfatin-1, corticosterone, and inflammatory cytokine (IL-6, CRP, and TNF-α) concentrations cross-sectionally in patients with major depressive disorder. METHODS: Subjects in the patient group were randomly selected from the Anhui Mental Health Center, and subjects in the control group were selected from healthy volunteers. Healthy control subjects were matched in terms of weight and body mass index. The Hamilton Depression Rating Scale (HAM-D) was used to evaluate both groups. ELISAs were used for the measurement of plasma nesfatin-1, corticosterone, IL-6, CRP, and TNF-α levels. RESULTS: The HAM-D scores and average nesfatin-1, corticosterone, IL-6, and CRP levels were significantly higher in patients with major depressive disorder than those in the control group. Positive correlation was found between nesfatin-1 and corticosterone (râ¯=â¯0.305, Pâ¯=â¯0.007), IL-6 (râ¯=â¯0.333, Pâ¯=â¯0.003), and CRP (râ¯=â¯0.244, Pâ¯=â¯0.034) concentrations. CONCLUSIONS: Increased plasma nesfatin-1 levels may be associated with corticosterone, IL-6, and CRP levels in patients with major depressive disorder.