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In solid tumors, the formidable anti-tumor impact resulting from blocking the "don't eat me" signal, arising from CD47-SIRPα interaction, is constrained, especially compared to its efficacy in hematopoietic malignancies. Activating macrophage anti-tumor activity not only necessitates the inhibition of the "don't eat me" signal, but also the activation of the "eat me" (pre-phagocyte) signal. Intriguingly, the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody (Ab) has been identified to stimulate Fc receptor-mediated active phagocytes in the tumor microenvironment, thereby generating "eat me" signals. This study postulates that concurrently targeting CD47 and CTLA4 could intensify the anti-tumor effects by simultaneously blocking the "don't eat me" signal while triggering the "eat me" signal. The experimental data from this investigation confirm that the combined targeting of CD47 and CTLA4 enhances immunity against solid tumors in LLC cell-transplanted tumor-bearing mice. This effect is achieved by reducing myeloid-derived suppressor cell infiltration while increasing the presence of effector memory CD8+ T cells, NK1.1+ CD8+ T cells, and activated natural killer T cells. Meanwhile, combination therapy also alleviated anemia. Mechanistically, the anti-CD47 Ab is shown to upregulate CTLA4 levels in NSCLC cells by regulating Foxp1. Furthermore, targeting CD47 is demonstrated to promote tumor vascular normalization through the heightened infiltration of CD4+ T cells. These findings suggest that the dual targeting of CD47 and CTLA4 exerts anti-tumor effects by orchestrating the "eat me" and "don't eat me" signals, reshaping the immune microenvironment, and fostering tumor vascular normalization. This combined therapeutic approach emerges as a potent strategy for effectively treating solid tumors.
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AIMS: Tumor-associated macrophages (TAMs) in the immune microenvironment play an important role in the increased drug resistance and recurrence of malignant glioma, but the mechanism remains incompletely inventoried. The focus of this study was to investigate the distinctions of M2-like TAMs in the immune microenvironment between primary and recurrent malignant glioma and its influence in the recurrence. METHODS: We employed single-cell RNA sequencing to construct a single-cell atlas for a total of 23,010 individual cells from 6 patients with primary or recurrent malignant glioma and identified 5 cell types, including TAMs and malignant cells. Immunohistochemical techniques and proteomics analysis were performed to investigate the role of intercellular interaction between malignant cells and TAMs in the recurrence of malignant glioma. RESULTS: Six subgroups of TAMs were annotated and M2-like TAMs were found to increase in recurrent malignant glioma significantly. A pseudotime trajectory and a dynamic gene expression profiling during the recurrence of malignant glioma were reconstructed. Up-regulation of several cancer pathways and intercellular interaction-related genes are associated with the recurrence of malignant glioma. Moreover, the M2-like TAMs can activate the PI3K/Akt/HIF-1α/CA9 pathway in the malignant glioma cells via SPP1-CD44-mediated intercellular interaction. Interestingly, high expression of CA9 can trigger the immunosuppressive response in the malignant glioma, thus promoting the degree of malignancy and drug resistance. CONCLUSION: Our study uncovers the distinction of M2-like TAMs between primary and recurrent glioma, which offers unparalleled insights into the immune microenvironment of primary and recurrent malignant glioma.
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Glioma , Proteómica , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Análisis de Expresión Génica de una Sola Célula , Recurrencia Local de Neoplasia/metabolismo , Macrófagos/patología , Glioma/genética , Línea Celular Tumoral , Microambiente Tumoral/genéticaRESUMEN
Rare-earth nanoparticles have been widely studied for disease diagnosis, in vivo optical imaging, biosensing, and drug delivery. However, the effects of rare-earth nanoparticles on a central nervous system remain unclear. Here, we report that the continuous exposure to rare-earth nanoparticles in mice can cause behavioral alterations including cognitive deficits, anxiety, and depression-like behavior. Using an open-field test and a morris water maze, we showed that long-term exposure to rare-earth nanoparticles may lead to significant depression, anxiety-like behavior, and memory impairment. The histopathological investigation on the neurotoxicological effects of nanoparticles indicated a significant decrease in cell viability after seven days' nanoparticle exposure. Western blotting analysis suggested that the changes of ATP-citrate lyase (ACLY) and O-linked N-acetylglucosamine transferase (OGT, a unique glycosyltransferase enzyme) played important roles in neurobehavioral disorders in mice. These findings provide a pathway to understand the cytotoxicity of rare-earth nanoparticles for medial applications and offer insights into the risk of these nanoparticles in biological systems.
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Ansiedad/inducido químicamente , Trastornos de la Memoria/inducido químicamente , Nanopartículas del Metal/química , Metales de Tierras Raras/toxicidad , ATP Citrato (pro-S)-Liasa/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Caspasa 3/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos ICRRESUMEN
Background. Qishen granules (QSG) are a frequently prescribed formula with cardioprotective properties prescribed to HF for many years. RNA-seq profiling revealed that regulation on cardiac mitochondrial energy metabolism is the main therapeutic effect. However, the underlying mechanism is still unknown. In this study, we explored the effects of QSG on regulating mitochondrial energy metabolism and oxidative stress through the PGC-1α/NRF1/TFAM signaling pathway. RNA-seq technology revealed that QSG significantly changed the differential gene expression of mitochondrial dysfunction in myocardial ischemic tissue. The mechanism was verified through the left anterior descending artery- (LAD-) induced HF rat model and oxygen glucose deprivation/recovery- (OGD/R-) established H9C2 induction model both in vivo and in vitro. Echocardiography and HE staining showed that QSG could effectively improve the cardiac function of rats with myocardial infarction in functionality and structure. Furthermore, transcriptomics revealed QSG could significantly regulate mitochondrial dysfunction-related proteins at the transcriptome level. The results of electron microscopy and immunofluorescence proved that the mitochondrial morphology, mitochondrial membrane structural integrity, and myocardial oxidative stress damage can be effectively improved after QSG treatment. Mechanism studies showed that QSG increased the expression level of mitochondrial biogenesis factor PGC-1α/NRF1/TFAM protein and regulated the balance of mitochondrial fusion/fission protein expression. QSG could regulate mitochondrial dysfunction in ischemia heart tissue to protect cardiac function and structure in HF rats. The likely mechanism is the adjustment of PGC-1α/NRF1/TFAM pathway to alleviate oxidative stress in myocardial cells. Therefore, PGC-1α may be a potential therapeutic target for improving mitochondrial dysfunction in HF.
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PURPOSE: We aimed to evaluate whether the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune inflammation index (SII) were associated with primary open-angle glaucoma (POAG). MATERIALS AND METHODS: This retrospective case-control study included 240 patients with POAG and 300 age- and sex-matched control subjects. Complete ophthalmological examination and blood count measurements were performed for all subjects. RESULTS: The values of NLR, PLR, and SII in the POAG group were significantly increased compared with the control group (p < 0.001; p = 0.012; p < 0.001). However, the LMR value was lower in the POAG patients than in the control group (p < 0.001). When we divided the subjects into different age and gender subgroups, the NLR and SII values in the POAG patients were always higher than those in the control group. In the comparison of laboratory parameters in POAG subjects stratified according to severity, we also found that NLR and SII increased with the severity. The receiver operating characteristic (ROC) analysis revealed that the areas under the ROC curve of NLR, PLR, LMR, and SII to predict patients with POAG were found to be 0.627, 0.569, 0.382, and 0.986, respectively. The best cutoff point of NLR was 1.998 with a sensitivity of 59.8% and a specificity of 63.0%, and the SII was 947.365 with a sensitivity of 95.4% and a specificity of 95.7%. Multivariable logistic regression analysis showed that NLR was positively associated with mean deviation; moreover, NLR and SII were independent indicators correlated with POAG (OR 1.502; 95% CI 1.227-1.839; p < 0.001; OR 1.02; 95% CI 1.009-1.021; p < 0.001). CONCLUSION: We speculated that elevated NLR and SII might serve as readily available inflammatory predictors in POAG patients.
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Plaquetas/inmunología , Glaucoma de Ángulo Abierto/sangre , Inflamación/sangre , Linfocitos/inmunología , Monocitos/inmunología , Neutrófilos/inmunología , Adulto , Anciano , Recuento de Células Sanguíneas , Estudios de Casos y Controles , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Estudios RetrospectivosRESUMEN
BACKGROUND: Several ocular factors have been identified for primary angle-closure glaucoma (PACG), such as a small cornea, elevated intraocular pressure (IOP), shallow anterior chamber, and short axial length (AL). However, the relationship between the severity of PACG and various ocular parameters [IOP, anterior chamber depth, AL, central corneal thickness] is not fully understood. METHODS: A 7-year cross-sectional study. A total of 2254 eyes of 1312 PACG patients (females = 856 [1479 eyes] and males = 456 [775 eyes]) were included. A detailed eye examination was performed. The participants were categorized into gender subgroups followed by subdivision into three different severity groups according to their mean deviation (MD) of the visual fields results as follows: mild (MD ≤ 6 dB), moderate (MD 6-12 dB), and severe (MD > 12 dB) PACG. The associations of ocular biometry with severity of PACG were analyzed using paired Student's t test, multivariate linear regression, and logistic regression analysis. RESULTS: There was a significant positive correlation between the MD and AL in the female subgroup (B = 0.663, p = 0.001, 95%CI = 1.070 to 1.255) but not in the male subgroup. Increased AL levels (mild [OR = 1], moderate [OR = 1.047, p = 0.062, 95%CI = 0.947 to 2.462], and severe [OR = 1.274, p < 0.001, 95%CI = 1.114 to 1.457]) were only associated with the severity of PACG in females. Paired Student's t tests showed that the long AL female eyes have a higher MD value than in the short AL female eyes (mean difference = 3.09, t = 6.846, p < 0.001) in the same subjects, but not in the male subgroup (p = 0.648). CONCLUSIONS: The AL was positively and significantly related to the severity of PACG in female but not male subjects. This finding refers to the PACG pathogenesis and suggests the use of AL assessment in glaucoma monitoring, diagnosis, and progression. This may contribute to further development of personalized strategies in preventive medicine.
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Uric acid (UA) is a major antioxidant molecule in the human blood, and it has been linked with cell longevity. However, it is unclear whether serum UA levels are associated with red blood cell (RBC) indexes. This cross-sectional study included 10,759 Chinese subjects, recruited from the Shanghai Xuhui Central Hospital from January 2014 to December 2017. The participants were categorized into gender groups and then further divided into three different subgroups according to their UA reference range as follows: low (male (UA < 0.202 mmol/l), female (UA < 0.143 mmol/l)), normal (male (0.417 mmol/l > UA ≥ 0.202 mmol/l), female (0.339 mmol/l > UA ≥ 0.143 mmol/l)), and high (male (UA ≥ 0.417 mmol/l), female (UA ≥ 0.339 mmol/l)). The associations of UA levels with RBC parameters were analyzed using 1-way ANOVA, Pearson correlations, and multivariate linear regression. The levels of mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, RBCs, and hemoglobin were lowest in the low UA group, followed by the normal UA group and high UA group (p < 0.001). Pearson analysis showed that there was a statistically significant correlation between UA levels with mean corpuscular hemoglobin, mean corpuscular hemoglobin concentrations, mean corpuscular volumes, RBC counts, and hemoglobin (p < 0.05). Multiple linear regression analysis suggested that there were statistically significant positive correlations between UA levels and RBC counts (B = 0.245, p < 0.001, 95% CI = 0.003 to 0.092), as well as UA levels and hemoglobin concentrations (B = 0.138, p < 0.001, 95% CI = 0.002 to 0.082). Furthermore, similar results were observed in both the male and female subgroups. The serum UA levels may be independently associated with RBC parameters, regardless of sex, and UA may protect RBCs owing to its antioxidant effect.
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Antioxidantes/metabolismo , Eritrocitos/metabolismo , Caracteres Sexuales , Ácido Úrico/sangre , Adulto , Anciano , Estudios Transversales , Recuento de Eritrocitos , Eritrocitos/citología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: To systematically evaluate the associations between oxidative stress status and different types of glaucoma. DESIGN: Systematic review and meta-analysis. METHODS: We searched PubMed, EMBASE, and the Web of Science for randomized controlled trials written in the English language between January 1, 1990, and November 30, 2016. A random effects model was used to estimate oxidative stress status along with weighted mean differences and 95% confidence intervals (CIs). A funnel plot analysis and Egger's test were performed to assess potential publication bias. MAIN OUTCOME MEASURES: Oxidative stress status was abnormal and different in patients with OAG (open-angle glaucoma) and EXG (exfoliation glaucoma). RESULTS: Blood TAS (total antioxidant status) was lower in the OAG group than in the control group, with a mean difference of 0.580 mmol/L (p < 0.0001, 95% CI = -0.668 to -0.492). The aqueous humor SOD (superoxide dismutase), GPX (glutathione peroxidase), and CAT (catalase) levels were higher in the OAG group than in the control group, with mean differences of 17.989 U/mL (p < 0.0001, 95% CI = 14.579-21.298), 12.441 U/mL (p < 0.0001, 95% CI = 10.423-14.459), and 1.229 fmol/mL (p=0.042, 95% CI = 0.043-2.414), respectively. Blood TAS was lower in the EXG group than in the control group, with a mean difference of 0.262 mmol/L (p < 0.0001, 95% CI = -0.393 to -0.132). However, there were no differences in blood TOS and aqueous humor TOS between the EXG group and the control group. CONCLUSIONS: This meta-analysis indicates that OAG patients had a lower TAS in the blood and higher levels of SOD, GPX, and CAT in the aqueous humor, while EXG patients only had a decreased TAS in the blood.
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PURPOSE: It has been hypothesised that uric acid (UA) has a protective effect against oxidative damage in the central nervous system. Therefore, we investigated serum UA concentrations in patients with primary open-angle glaucoma (POAG) and explored the relationship between serum UA concentration and glaucoma severity. METHODS: This prospective, cross-sectional, case-control study was conducted in 163 POAG patients and 103 normal controls. Clinical and demographic information was obtained from the medical data platform of the Eye & ENT Hospital of Fudan University, Shanghai, China. The POAG patients were categorised into mild [median deviation (MD) ≤ 6.00 dB], moderate (MD > 6 Db-≥12 dB) and severe (MD > 12 dB) subgroups, based on their visual field MD results. RESULTS: The level of serum UA in the POAG group (0.321 ± 0.084 mmol/l) was approximately 12.77% lower (p < 0.001) than that of the control group (0.362 ± 0.053 mmol/l). The UA/creatinine (Cr) ratio was approximately 14.99% lower (p < 0.001) in patients with POAG (4.47 ± 1.15), compared with the control group (5.14 ± 1.05). The mean level of UA was lowest in the severe POAG group, followed by the moderate POAG group, and the mild POAG group (p < 0.001). A similar trend was observed when UA levels were compared between the POAG and control groups in males. Multivariate regression analyses showed a significant negative correlation between UA and vertical cup-disc ratio (B = -0.320, p = 0.034), and UA and MD (B = -0.441, p = 0.031) in males. CONCLUSION: Primary open-angle glaucoma patients have lower UA levels; however, a negative association between UA levels and disease severity was evident in male patients.
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Glaucoma de Ángulo Abierto/sangre , Presión Intraocular/fisiología , Ácido Úrico/sangre , Campos Visuales/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Casos y Controles , China/epidemiología , Estudios Transversales , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Glaucoma de Ángulo Abierto/diagnóstico , Glaucoma de Ángulo Abierto/epidemiología , Humanos , Incidencia , Masculino , Microscopía Acústica , Persona de Mediana Edad , Disco Óptico/patología , Pronóstico , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Adulto JovenRESUMEN
Coronary artery disease (CAD) is one of the leading causes of deaths worldwide. Energy metabolism disorders, including a reduction in fatty acids oxidation and upregulation of glycolysis pathway, are involved in the process of CAD. Therapeutic angiogenesis has become a promising treatment for CAD. Traditional Chinese medicines, such as Danqi Pill (DQP), have been proven to be effective in treating CAD in China for many years. However, the pro-angiogenic effects of DQP based on fatty acids oxidation are still unknown and the mechanism is worthy of investigation. In this study, left anterior descending (LAD) coronary artery was ligated to induce the CAD models in vivo, and cardiac functions were examined using echocardiography. Human umbilical vein endothelial cells (HUVEC) were subjected to H2O2-induced oxidative stress in vitro. The effects of DQP on CAD rat models and in vitro HUVEC were detected. Our results showed that DQP had cardio-protective effects in rat model. The intensity of capillaries in the marginal area of infarction of the rat heart was increased remarkably in DQP group, and the expression of PPARα and VEGF-2 were increased. The key enzymes involved in the transportation and intake of fatty acids, including CPT1A and CD36, both increased. In H2O2-induced endothelial cells injury models, DQP also showed protective roles and promoted capillary-like tube formation. DQP up-regulated key enzymes in fatty acids oxidation in H2O2-treated HUVEC. In addition, inhibition of CPT1A compromised the pro-angiogenic effects of DQP. In conclusion, fatty acids oxidation axis PPARα-CD36-CPT1A was involved in the pro-angiogenic roles of DQP against CAD. Cardiac CPT1A may serve as a target in therapeutic angiogenesis in clinics.
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BACKGROUND Serum biomarkers are associated with eye diseases, which results in the need for cryopreservation of serum samples. However, the effect on serum biomarker levels of repeatedly freezing and thawing remains poorly understood. The aim of this study was to evaluate the effects of repeated freeze-thaw on the serum levels of the protein, complement C3c (C3c), the micromolecule, uric acid (UA), and the enzyme, angiotensin-converting enzyme (ACE). MATERIAL AND METHODS Serum samples were obtained from 50 patients who attended an ophthalmic outpatient department. Following baseline measurements, the serum samples from each subject were divided into aliquots and stored at -80°C for further analysis, following between one to six freeze-thaw cycles. The serum levels of C3c, UA, and ACE were measured immediately after the stored serum samples were thawed. RESULTS The serum level of C3c was significantly changed after the first freeze-thaw cycle (p<0.05), and a significant alteration in serum ACE levels occurred after the third freeze-thaw cycle (p<0.05). The serum UA level remained unchanged after all freeze-thaw cycles. Repeated freeze-thaw cycles significantly increased the serum levels of C3c and decreased the serum levels of ACE. The serum levels of C3c, UA, and ACE, respectively were significantly correlated (p<0.001), while the correlation coefficient for C3c and UA were improved when compared with ACE. CONCLUSIONS Repeated freeze-thaw can have variable effects on the serum levels of biomarkers, C3c, UA and ACE, which supports the need for quality control of cryopreserved serum for biomarker evaluation.
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Biomarcadores/sangre , Criopreservación/métodos , Congelación/efectos adversos , Adulto , Biomarcadores/química , Complemento C3c/análisis , Oftalmopatías/sangre , Femenino , Humanos , Masculino , Peptidil-Dipeptidasa A/análisis , Peptidil-Dipeptidasa A/sangre , Temperatura , Ácido Úrico/análisis , Ácido Úrico/sangreRESUMEN
OBJECTIVE: To evaluate the association between coagulation function and patients with primary angle closure glaucoma (PACG). DESIGN: A retrospective, hospital-based, case-control study. SETTING: Shanghai, China. PARTICIPANTS: A total of 1778 subjects were recruited from the Eye & ENT Hospital of Fudan University from January 2010 to December 2015, including patients with PACG (male=296; female=569) and control subjects (male=290; female=623). OUTCOME MEASURES: Sociodemographic data and clinical data were collected. The one-way analysis of variance test was used to compare the levels of laboratory parameters among the mild, moderate and severe PACG groups. Multivariate logistic regression analyses were performed to identify the independent risk factors for PACG. The nomogram was constructed based on the logistic regression model using the R project for statistical computing (R V.3.3.2). RESULTS: The activated partial thromboplastin time (APTT) of the PACG group was approximately 4% shorter (p<0.001) than that of the control group. The prothrombin time (PT) was approximately 2.40% shorter (p<0.001) in patients with PACG compared with the control group. The thrombin time was also approximately 2.14% shorter (p<0.001) in patients with PACG compared with the control group. The level of D-dimer was significantly higher (p=0.042) in patients with PACG. Moreover, the mean platelet volume (MPV) of the PACG group was significantly higher (p=0.013) than that of the control group. A similar trend was observed when coagulation parameters were compared between the PACG and control groups with respect to gender and/or age. Multiple logistic regression analyses revealed that APTT (OR=1.032, 95% CI 1.000 to 1.026), PT (OR=1.249, 95% CI 1.071 to 1.457) and MPV (OR=1.185, 95% CI 1.081 to 1.299) were independently associated with PACG. CONCLUSION: Patients with PACG had a shorter coagulation time. Our results suggest that coagulation function is significantly associated with patients with PACG and may play an important role in the onset and development of PACG.
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Trastornos de la Coagulación Sanguínea , Glaucoma de Ángulo Cerrado , Trastornos de la Coagulación Sanguínea/complicaciones , Estudios de Casos y Controles , Femenino , Glaucoma de Ángulo Cerrado/complicaciones , Glaucoma de Ángulo Cerrado/terapia , Humanos , Masculino , Estudios RetrospectivosRESUMEN
OBJECTIVE: Inflammatory mechanisms may have a role in the pathogenesis of primary angle closure glaucoma (PACG). The objective of this study was to investigate the diagnostic value of white blood cell (WBC), neutrophil, neutrophil to lymphocyte ratio (NLR), and lymphocyte to monocyte ratio (LMR) in patients with PACG and its association with glaucoma severity. METHOD: The study was retrospectively assessed in 771 consecutive PACG patients and 770 control subjects, laboratory parameters and clinical parameters were obtained from a medical data platform. Patients were divided into three groups with different severity based on perimetry, i.e. mild (mean deviation (MD) ≤6.00 dB), moderate (12 dB≥ MD>6 dB) and severe (MD>12 dB). We developed a nomogram to specifically identify individual patient's risk. RESULTS: The mean levels of neutrophil, NLR and WBC was higher in PACG than control group, and lowest in the mild PACG group, followed by moderate PACG and severe PACG (p<0.05). The AUROC value of NLR and LMR was found to be 0.719, 0.699, respectively. Multiple linear regressions showed that there was a significant correlation between WBC and MD (B=0.151, p<0.001), neutrophil and MD (B=0.143, p=0.003), NLR and MD (B=0.144, p=0.001), LMR and MD (B=-0.100, p=0.034). Logistic regression analyses revealed that WBC (OR=1.208, 95%CI=1.179-1.238), neutrophil (OR=1.598, 95%CI=1.541-1.656), NLR (OR=2.313, 95%CI=2.200-2.431), and LMR (OR=0.682, 95%CI=0.666-0.699) were associated with PACG. CONCLUSION: Our study suggested that WBC, neutrophil, NLR, and LMR was related with PACG, and NLR and LMR may be useful as biomarkers.
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Uric acid (UA) is a major antioxidant molecule and has been hypothesized to have a protective effect on the central nervous system against oxidative damage. We prospectively investigated the serum concentration of UA in primary angle closure glaucoma (PACG), and explored the association between serum concentration of UA and the severity of PACG. Using a retrospective case-control study design, 886 PACG subjects and 994 control subjects who attended the Eye & ENT Hospital of Fudan University, were eligible for this study. Glaucoma severity was classified as mild (MD ≤ 6.00 dB), moderate (12 dB ≥ MD > 6 dB) and severe (MD > 12 dB) based on the MD (mean deviation). The levels of UA were significantly lower (p = 0.025) in PACG (0.286 ± 0.082 mmol/l) compared with control (0.295 ± 0.085 mmol/l). The mean serum UA levels were lowest in the severe group (0.281 ± 0.074 mmol/l) followed by moderate (0.282 ± 0.080 mmol/l) and mild (0.297 ± 0.090 mmol/l) with significant differences among the three groups (p = 0.032). In multivariate regression analysis, there was a significant negative correlation between UA level and vertical cup-disc ratio (B = -0.165, p = 0.035). Significantly lower serum UA concentration in PACG and its negative association with disease severity presented it as an important candidate in reaction to oxidative stress in glaucoma pathogenesis.
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Glaucoma de Ángulo Cerrado/sangre , Glaucoma de Ángulo Cerrado/diagnóstico , Ácido Úrico/sangre , Anciano , Biomarcadores , Estudios de Casos y Controles , Creatinina/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Danqi pill (DQP) is one of the most widely prescribed formulas and has been shown to have remarkable protective effect on coronary heart disease (CHD). However, its regulatory effects on lipid metabolism disorders haven't been comprehensively studied so far. We aimed to explore the effects of DQP on Peroxisome Proliferator activated receptors α (PPARα), lipid uptake-transportation-metabolism pathway and arachidonic acid (AA)-mediated inflammation pathway in rats with CHD. METHODS: 80 Sprague-Dawley (SD) Rats were randomly divided into sham group, model group, positive control group and DQP group. Rat model of CHD was induced by ligation of left ventricle anterior descending artery and fed with high fat diet in all but the sham group. Rats in sham group only underwent thoracotomy. After surgery, rats in the positive control and DQP group received daily treatments of pravastatin and DQP respectively. At 28 days after surgery, rats were sacrificed and plasma lipids were evaluated by plasma biochemical detection. Western blot and PCR were applied to evaluate the expressions of PPARα, proteins involved in lipid metabolism and AA pathways. RESULTS: Twenty eight days after surgery, dyslipidemia developed in CHD model rats, as illustrated by elevated plasma lipid levels. Expressions of apolipoprotein A-I (ApoA-I), cluster of differentiation 36 (CD36) and fatty acid binding protein (FABP) in the heart tissues of model group were down-regulated compared with those in sham group. Expressions of carnitine palmitoyl transferase I (CPT-1A) and lipoproteinlipase (LPL) were also reduced significantly. In addition, levels of phospholipase A2 (PLA2) and cyclooxygenase 2 (COX-2) were up-regulated. Expressions of Nuclear factor-κB (NF- κB) and signal transducer and activator of transcription 3 (STAT3) also increased. Furthermore, Expression of PPARα decreased in the model group. DQP significantly up-regulated expressions of ApoA-I and FABP, as well as the expressions of CPT-1A and CD36. In addition, DQP down-regulated expressions of PLA2, COX-2 and NF-κB in inflammation pathway. Levels of STAT3 and LPL were not affected by DQP treatment. In particular, DQP up-regulated PPARα level significantly. CONCLUSIONS: DQP could effectively regulate lipid uptake-transportation-metabolism process in CHD model rats, and the effect is achieved mainly by activating ApoA-I-CD36-CPT-1A molecules. Interestingly, DQP can up-regulate expression of PPARα significantly. The anti-inflammatory effect of DQP is partly exerted by inhibiting expressions of PLA2-COX2 -NF-κB pathway.
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Ácido Araquidónico/metabolismo , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Trastornos del Metabolismo de los Lípidos/tratamiento farmacológico , PPAR alfa/metabolismo , Animales , Enfermedad de la Arteria Coronaria/metabolismo , Corazón/efectos de los fármacos , Trastornos del Metabolismo de los Lípidos/metabolismo , Lípidos/sangre , Lipoproteínas/sangre , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To explain the essence of pungent-hot herb property express according to in vivo and in vitro studies on its effect on calmodulin on the base of the observation of the adjustment in hypothalamic-pituitary-gonad axis functions of Aconiti Lateralis Radix Praeparata, Curculiginis Rhizoma, Cinnamomi Cortex and bitter-cold herb Phellodendri Chinensis Cortex in rats under the state of yang deficiency. METHOD: The yang-deficient model was duplicated by intramuscularly injecting hydrocortisone sodium succinate powder injection. After the intervention with Aconiti Lateralis Radix Praeparata, Curculiginis Rhizoma, Cinnamomi Cortex and bitter-cold herb Phellodendri Chinensis Cortex for seven days, TSH, T3, T4, 17-OHCS, COR, T, E2 of hypothalamus-pituitary-target gland axis and other relevant indexes were detected. The calmodulin expression in livers and L02 cells cultured in vitro was detected by using Western blot. RESULT: Pungent-hot herbs Aconiti Lateralis Radix Praeparata, Curculiginis Rhizoma, Cinnamomi Cortex can significantly correct indicators of hypothalamic-pituitary-gonad axis and calmodulin, whereas the bitter-cold herb Phellodendri Chinensis Cortex showed no obvious effect. CONCLUSION: The pungent-hot herb property expression may be closely related to calmodulin.
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Calmodulina/metabolismo , Medicamentos Herbarios Chinos/administración & dosificación , Gónadas/efectos de los fármacos , Hígado/efectos de los fármacos , Deficiencia Yang/tratamiento farmacológico , Animales , Medicamentos Herbarios Chinos/química , Gónadas/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Deficiencia Yang/metabolismoRESUMEN
BACKGROUND: Chinese herbal formulae are composed of complex components and produce comprehensive pharmacological effects. Unlike chemical drugs that have only one clear single target, the components of Chinese herbal formulae have multiple channels and targets. How to discover the pharmacological targets of Chinese herbal formulae and their underlying molecular mechanism are still under investigation. METHODS: DanQi pill (DQP), which is one of the widely prescribed traditional Chinese medicines, is applied as an example drug. In this study, we used the drug target prediction model (DrugCIPHER-CS) to examine the underlying molecular mechanism of DQP, followed by experimental validation. RESULTS: A novel therapeutic effect pattern of DQP was identified. After determining the compounds in DQP, we used DrugCIPHER-CS to predict their potential targets. These potential targets were significantly enriched in well-known cardiovascular disease-related pathways. For example, the biological processes of neuroactive ligand-receptor interaction, calcium-signaling pathway, and aminoacyl-tRNA biosynthesis were involved. A new and significant pathway, arachidonic acid (AA) metabolism, was also identified in this study. This predicted pathway alteration was validated with an animal model of heart failure (HF). Results show that DQP had effect both on thromboxane B2 (TXB2) and Prostaglandin I2 (PGI2) in different patterns. It can down-regulate the TXB2 and up-regulate the PGI2 in diverse way. Remarkably, it also had effect on cyclooxygenase (COX)-1 and COX2 by suppressing their levels, which may be the critical and novel mechanism of cardiacprotective efficacy for DQP. Furthermore, leukotrienes B4 (LTB4) receptor, another key molecule of AA metabolism which finally mediated gastrotoxic leukotrienes, was also reduced by DQP. CONCLUSIONS: The combination of drug target prediction and experimental validation provides new insights into the complicated mechanism of DQP.
Asunto(s)
Cardiotónicos/farmacología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Medicamentos Herbarios Chinos/farmacología , Insuficiencia Cardíaca , Leucotrieno B4/metabolismo , Animales , Cardiotónicos/uso terapéutico , Medicamentos Herbarios Chinos/uso terapéutico , Epoprostenol/metabolismo , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/prevención & control , Masculino , Medicina Tradicional China , Panax notoginseng , Fitoterapia , Ratas Sprague-Dawley , Receptores de Leucotrieno B4/metabolismo , Salvia miltiorrhiza , Tromboxano B2/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Fuzi-Lizhong pill (FLZ) is a traditional Chinese medicine for treating patients with Spleen Yang deficient syndrome. Ghrelin, a peptide with 28 amino acid residues, plays multiple roles in thermogenesis. This study aims to explore FLZ regulating ghrelin to compensate hypothermia in rats with hypothyroid and indigestion. MATERIALS AND METHODS: In litter-matched rats, hypothermia was developed with both thyroidectomy at d1 and interscapular brown adipose (IBA) removal at d42, indigestion was induced with both high fat diet and fasting-feeding cycle from d56; the littermates with hypothermia and indigestion were administrated with FLZ from d70. Adaptive thermogenesis, thyroid hormones, metabolites, ghrelin dynamics were measured at d98. RESULTS: The results showed that plasma ghrelin levels were inversely correlated with the gastric ghrelin levels and adaptive thermogenesis in rats undergone both thyroidectomy and IBA removal. Fatty diet and FLZ enhanced the increase of plasma ghrelin of hypothyroid rats. These were supported by the changes of plasma thyroid related hormones, plasma metabolites, gastric ghrelin mRNA and protein, and the effects of fatty diet or FLZ. CONCLUSIONS: Our results suggest that more ghrelin release compensate chronic hypothermia in rats with both hypothyroidism and indigestion. It could explain the mechanisms of FLZ in relieving chronic hypothermia.
Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Ghrelina/sangre , Hipotermia/tratamiento farmacológico , Hipotiroidismo/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/administración & dosificación , Femenino , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Ghrelina/metabolismo , Hipotermia/etiología , Hipotermia/metabolismo , Hipotiroidismo/complicaciones , Hipotiroidismo/metabolismo , Masculino , Ratas , Ratas Wistar , Termogénesis/efectos de los fármacos , Hormonas Tiroideas/sangreRESUMEN
We aim to investigate the therapeutic effects of QSYQ, a drug of heart failure (HF) in clinical practice in China, on a rat heart failure (HF) model. 3 groups were divided: HF model group (LAD ligation), QSYQ group (LAD ligation and treated with QSYQ), and sham-operated group. After 4 weeks, rats were sacrificed for cardiac injury measurements. Rats with HF showed obvious histological changes including necrosis and inflammation foci, elevated ventricular remodeling markers levels(matrix metalloproteinases-2, MMP-2), deregulated ejection fraction (EF) value, increased formation of oxidative stress (Malondialdehyde, MDA), and up-regulated levels of apoptotic cells (caspase-3, p53 and tunnel) in myocardial tissue. Treatment of QSYQ improved cardiac remodeling through counter-acting those events. The improvement of QSYQ was accompanied with a restoration of NADPH oxidase 4 (NOX4) and NADPH oxidase 2 (NOX2) pathways in different patterns. Administration of QSYQ could attenuate LAD-induced HF, and AngII-NOX2-ROS-MMPs pathway seemed to be the critical potential targets for QSYQ to reduce the remodeling. Moreover, NOX4 was another key targets to inhibit the p53 and Caspase3, thus to reduce the hypertrophy and apoptosis, and eventually provide a synergetic cardiac protective effect.
RESUMEN
OBJECTIVE: To establish a method for the determination of theacrine in rat plasma after ig. administration of theacrine. METHOD: Blood sample was taken timely from the eyes canthus of rats. Plasma was isolated and the protein was precipitated by ethyl acetate. Then the plasma concentration of theacrine was determined with RP-HPLC. Caffeine was used as the internal standard. The chromatographic conditions were as follows: Phenomenex Luna C18 (4.6 mm x 250 mm, 5 microm) at 25 degrees C, a mixture of methanol-water (25: 75) as the mobile phase, at the flow rate of 1.0 mL x min(-1) and the detection wavelength of 290 nm. RESULT: The linear range of theacrine was 0.5-100 mg x L(-1) (R2 = 0.998 9). The lower limit of quantification was 0.5 mg x L(-1). The intra-day RSD was 1.49% 4.40% and inter-day RSD was 0.80% -10.27%. The average extraction recoveries of theacrine were 90.3% -95.8% at concentrations of 0.5, 5.0, 50 mg x L(-1). The main pharmacokinetic parameters after ig. administration of theacrine at concentration of 30 mg x kg(-1) were as follow: C(max) (35.45 +/- 30 2.68) mg x L(-1), t(max) (0.51 +/- 0.13) h, t1/2 (3.13 +/- 1.37) h, AUC(0-infinity) (2.65.39 +/- 94.71) mg x L(-1) x h. CONCLUSION: The method has been confirmed to be simple, stable, reproducible and with high specificity, and can be used for the pharmacokinetic study of theacrine in rats.