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Myocardial infarction (MI) and depression are leading causes of mortality and morbidity globally, and these conditions are increasing recognized as being fundamentally interconnected. The recently recognized gut-heart-brain axis offers insights into depression following MI, but effective treatments for this comorbidity remain lacking. To address this medical need, we employed an animal model of MI to investigate the potential repurposing of sotagliflozin (SOTA), an approved sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor for diabetes, for managing depression following MI and identifying potential SOTA-associated microbial mechanisms. SOTA treatment improved cardiac dysfunction and alleviated depression-like behaviors induced by MI, accompanied by alterations in gut microbiota composition, such as changes in the Prevotellaceae NK3B31 group, Alloprevotella, and Prevotellaceae UCG-001. Moreover, fecal microbiota transplantation (FMT) using fecal samples from SOTA-treated MI mice demonstrated that gut microbiota contributed to the beneficial effects of SOTA on cardiac dysfunction and depression-like behaviors in MI mice. Intriguingly, FMT-based intervention and concordance analysis of gut microbiota before and after FMT suggested that Prevotellaceae NK3B31 group, Alloprevotella, and Prevotellaceae UCG-001 were associated with the beneficial effects of SOTA. Furthermore, functional prediction of gut microbiota and correlation analysis support the significance of these dynamic microbial communities. In conclusion, these findings suggest that SOTA could serve as a potential drug to ameliorate cardiac dysfunction and depressive symptoms in MI patients via through the gut-heart-brain axis.
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Depresión , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Infarto del Miocardio , Animales , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/complicaciones , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Depresión/tratamiento farmacológico , Masculino , Eje Cerebro-Intestino/efectos de los fármacos , Eje Cerebro-Intestino/fisiología , Glicósidos/farmacología , Trasplante de Microbiota Fecal/métodos , Modelos Animales de EnfermedadRESUMEN
PURPOSE: This pilot study was prospectively designed to evaluate and compare the diagnostic value of PET/CT using a PSMA-specific tracer [68Ga]Ga-P16-093 and a glucose metabolism probe 2-[18F]FDG in clear cell renal cell carcinoma (ccRCC) patients. METHODS: Forty-two pathologically confirmed ccRCC patients were included. Within 1 week, each patient underwent [68Ga]Ga-P16-093 and 2-[18F]FDG PET/CT. In addition to visual analysis of tumor number, the standardized uptake value (SUV) was measured for semiquantitative comparison and correlation analysis. RESULTS: For primary ccRCC patients, [68Ga]Ga-P16-093 PET/CT demonstrated a significantly higher detection rate (19/22 vs. 13/22, P = 0.031) and higher tumor uptake (15.7 ± 9.0 vs. 5.1 ± 3.4, P < 0.001) than 2-[18F]FDG PET/CT. In addition, the SUVmax of the primary tumor on [68Ga]Ga-P16-093 and 2-[18F]FDG PET/CT was significantly correlated with pT stage (for [68Ga]Ga-P16-093, r = 0.550, P = 0.008; for 2-[18F]FDG, r = 0.514, P = 0.014) and WHO/ISUP grade (for [68Ga]Ga-P16-093, r = 0.566, P = 0.006; for 2-[18F]FDG, r = 0.492, P = 0.020), respectively. For metastatic ccRCC patients, [68Ga]Ga-P16-093 PET/CT also demonstrated a better detection rate (21/22 vs. 14/22, P = 0.008) and higher tumor uptake (11.0 ± 6.4 vs. 4.4 ± 2.7, P < 0.001) than 2-[18F]FDG PET/CT. The SUVmax on [68Ga]Ga-P16-093 PET/CT had a significant association with PSMA expression in primary ccRCC (r = 0.776, P < 0.001) and metastatic ccRCC (r = 0.626, P = 0.029). CONCLUSIONS: [68Ga]Ga-P16-093 PET/CT demonstrates significantly better tumor detectability than 2-[18F]FDG PET/CT for ccRCC patients. TRIAL REGISTRATION: 68Ga-P16-093 and 18F-FDG PET/CT Imaging in the Same Group of Clear Cell Renal Cell Carcinoma Patients (NCT05432947, Registered 27 June 2021, retrospectively registered) URL OF REGISTRY: https://clinicaltrials.gov/ct2/show/NCT05432947 .
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Fluorodesoxiglucosa F18/metabolismo , Carcinoma de Células Renales/diagnóstico por imagen , Radioisótopos de Galio , Proyectos Piloto , Neoplasias Renales/diagnóstico por imagenRESUMEN
The self-assembly of the high-nuclearity Ln-exclusive nanoclusters is challenging but of significance due to its aesthetically pleasing architectures and far-reaching latent applications in magnetic cooling technologies. Herein, two novel high-nuclearity lanthanide nanoclusters were successfully synthesized under solvothermal conditions, formulated as {[Gd18(IN)20(HCOO)8(µ6-O)(µ3-OH)24(H2O)4]·4H2O}n and {[Eu18(IN)16(HCOO)8(CH3COO)4(µ6-O)(µ3-OH)24(H2O)4]·5H2O}n (abbreviated as Gd18 and Eu18, HIN = isonicotinic acid). Both of them possess novel and exquisite windmill-shaped cationic cores in the family of high-nuclearity Ln-exclusive nanoclusters. Remarkably, the adjacent second building units are interconnected into a three-dimensional (3D) metal-organic framework by IN- ligands. As expected, the abundant existence of GdIII ions endows Gd18 with a favorable magnetic entropy change at 2.0 K for ΔH = 7.0 T (-ΔSmmax = 40.0 J kg-1 K-1), and Eu18 displays the typical luminescence of EuIII ions.
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BACKGROUND: The X-linked inhibitor of apoptosis (XIAP) protein is encoded by the XIAP gene and is critical for multiple cell responses and plays a role in preventing cell death. XIAP mutations are associated with several diseases, primarily including hemophagocytic lymphohistiocytosis and inflammatory bowel disease (IBD). We report the clinical features and results associated with hemizygous mutation of the XIAP gene in a young male with Crohn's disease complicated with acute heart failure.This 16-year-old patient ultimately died of heart failure. CASE PRESENTATION: A young male of 16 years of age was initially diagnosed with Crohn's disease based on evidences from endoscopic and histological findings. Although supportive care, anti-infective drugs and biologics were administered consecutively for 11 months, his clinical manifestations and laboratory indices (patient's condition) did not improved. Additionally, the patient exhibited a poor nutritional status and sustained weight loss. Subsequently, acute heart failure led to the exacerbation of the patient's condition. He was diagnosed with wet beriberi according to thiamine deficiency, but the standard medical therapy for heart failure and thiamine supplementation did not reverse the adverse outcomes. Comprehensive genetic analysis of peripheral blood-derived DNA revealed a novel hemizygous mutation of the XIAP gene (c.1259_1262 delACAG), which was inherited from his mother. CONCLUSION: A novel XIAP mutation (c.1259_1262 delACAG) was identified in this study. It may be one of the potential pathogenic factors in Crohn's disease and plays an important role in the progression of heart failure. Additionally, thiamine deficiency triggers a vicious cycle.
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Enfermedad de Crohn , Insuficiencia Cardíaca , Deficiencia de Tiamina , Masculino , Humanos , Adolescente , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/genética , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/genética , Pérdida de Peso , Apoptosis , Proteína Inhibidora de la Apoptosis Ligada a X/genéticaRESUMEN
PURPOSE: This study was prospectively designed to evaluate the early dynamic organ distribution and tumor detection capability of [68 Ga]Ga-P16-093, which was compared with [68 Ga]Ga-PSMA-617 in the same group of recurrent prostate cancer patients. METHODS: Twenty patients with recurrent prostate cancer were enrolled. In 2 consecutive days, each patient underwent a 60-min dynamic PET/CT scan after intravenous administration of 148-185 MBq (4-5 mCi) [68 Ga]Ga-P16-093 and [68 Ga]Ga-PSMA-617, respectively. Following a low-dose CT scan, serial dynamic PET scans were performed from head to proximal thigh at 9 time points (30 s/bed at 4, 7, 10, 13, and 16 min; 1 min/bed at 20, 30, and 45 min; and 2 min/bed at 60 min). Standardized uptake values were measured for semi-quantitative comparison. RESULTS: [68 Ga]Ga-P16-093 PET/CT revealed a significantly higher tumor uptake at 4 min (SUVmax 7.88 ± 5.26 vs. 6.01 ± 3.88, P < 0.001), less blood pool retention at 4 min (SUVmean 5.12 ± 1.16 vs. 6.14 ± 0.98, P < 0.001), and lower bladder accumulation at 60 min (SUVmean 31.33 ± 27.47 vs. 48.74 ± 34.01, P = 0.042) than [68 Ga]Ga-PSMA-617 scan. Significantly higher [68 Ga]Ga-P16-093 uptakes were also observed in the parotid gland, liver, spleen, and kidney. Besides, [68 Ga]Ga-P16-093 exhibited a better detectability of tumor than [68 Ga]Ga-PSMA-617 (366 vs. 321, P = 0.009). CONCLUSIONS: [68 Ga]Ga-P16-093 showed advantages over [68 Ga]Ga-PSMA-617 with higher tumor uptakes, tumor-to-blood pool ratio and detection capability, less blood pool, and bladder accumulation in recurrent prostate cancer patients. TRIAL REGISTRATION: [68 Ga]Ga-P16-093 and [68 Ga]Ga-PSMA-617 PET/CT Imaging in the Same Group of Prostate Cancer Patients (NCT04796467, Registered 12 March 2021, retrospectively registered) URL of registry: https://clinicaltrials.gov/ct2/show/NCT04796467.
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Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Dipéptidos , Ácido Edético , Radioisótopos de Galio , Compuestos Heterocíclicos con 1 Anillo , Humanos , Masculino , Recurrencia Local de Neoplasia , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones , Antígeno Prostático Específico , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patologíaRESUMEN
ABSTRACT: Tolterodine is a first-line antimuscarinic drug used to treat overactive bladder. Adverse cardiac effects including tachycardia and palpitations have been observed, presumably because of its inhibition of the human ether-à-go-go-related gene (hERG) K + channel. However, the molecular mechanism of hERG channel inhibition by tolterodine is largely unclear. In this study, we performed molecular docking to identify potential binding sites of tolterodine in hERG channel, and two-microelectrode voltage-clamp to record the currents of hERG and its mutants expressed in Xenopus oocytes. The results of computational modeling demonstrated that phenylalanine at position 656 (F656) and tyrosine at position 652 (Y652) on the S6 helix of hERG channel are the most favorable binding residues of tolterodine, which was validated by electrophysiological recordings on Y652A and F656A hERG mutants. The Y652A and F656A mutations decreased inhibitory potency of tolterodine 345-fold and 126-fold, respectively. The Y652A mutation significantly altered the voltage dependence of channel inhibition by tolterodine. For both the wild-type and the mutant channels, tolterodine reduced the currents in a time-dependent manner, and the blockade occurred with the channel activated. Tolterodine did not interfere with hERG channel deactivation, whereas channel inactivation greatly impaired its blocking effect. The inhibition of hERG channel by tolterodine is independent of its action on muscarinic acetylcholine receptors. In conclusion, tolterodine is an open-state blocker of hERG K + channel with nanomolar potency. Y652 and F656, 2 aromatic residues on the inner S6 helix, are responsible for the high-affinity binding of tolterodine to hERG channel.
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Canales de Potasio Éter-A-Go-Go , Bloqueadores de los Canales de Potasio , Humanos , Canales de Potasio Éter-A-Go-Go/genética , Canales de Potasio Éter-A-Go-Go/química , Bloqueadores de los Canales de Potasio/farmacología , Tartrato de Tolterodina/farmacología , Simulación del Acoplamiento Molecular , Mutación , Éteres , Relación Dosis-Respuesta a DrogaRESUMEN
Aim - To explore the role and possible mechanism of KNTC1 gene in the development of bladder cancer. Methods - The expression level of KNTC1 in bladder cancer tissues and adjacent tissues was detected by immuno-histochemistry. Mann-Whitney U, Spearman, and Kaplan-Meier analyses were used to analyze the correlation between KNTC1 expression level and various characteristics of bladder cancer cases. KNTC1 was knocked down by RNA interference to detect the proliferation, apoptosis, cell cycle, migration, and in vivo tumorigenesis of bladder cancer cells. Human apoptosis antibody array and Western blot were used to detect the expression level changes of related proteins after KNTC1 knockdown to explore the possible mechanism. Results - KNTC1 was highly expressed in bladder cancer tissues and was related to the pathological grade and overall survival rate of bladder cancer. Knockdown of KNTC1 can inhibit the proliferation, migration, and in vivo tumorigenesis of bladder cancer cells and promote apoptosis. KNTC1 knockdown changes the levels of many proteins in bladder cancer cells, including Caspase 3, Fas, p-Akt, CDK6, PIK3CA, and MAPK9. Conclusion - KNTC1 plays a crucial role in the development of bladder cancer, and our findings provide evidence for its use as a therapeutic target.
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Carcinogénesis/genética , Carcinogénesis/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Animales , Apoptosis , Carcinogénesis/patología , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patología , Ciclo Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Técnicas de Silenciamiento del Gen/métodos , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Interferencia de ARN , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
To examine the effect of chronic intermittent hypobaric hypoxia (CIHH) on heart rate variability (HRV), male adult Sprague Dawley rats were exposed to hypoxia (oxygen 11.1%) in a hypobaric chamber for 42 days, 6 hours each day, simulating an altitude of 5000 m. The body weight and blood pressure of rats were recorded once a week, electrocardiograms were analyzed continuously using biotelemetry, before, during and after CIHH treatment each day, and HRV was evaluated using spectrum analysis. No significant difference of body weight and blood pressure was found between CIHH and control rats. After 4 weeks of CIHH treatment, total power (TP) and very low-frequency component (VLF) were lower in CIHH rats than in control rats under hypobaric hypoxia condition. During CIHH treatment, low frequency (LF) was higher in 1 week and lower in 5-6 weeks in CIHH rats than control rats under hypobaric hypoxia, but not normoxic conditions. The high-frequency component (HF) was not changed during CIHH treatment, so LF/HF increased initially, and then recovered under the hypobaric hypoxia condition following 3 weeks of CIHH treatment. In addition, the HR was increased in CIHH rats after 4 weeks of CIHH treatment compared with control rats. Furthermore, HRV was altered significantly in control rats, but not in CIHH rats exposed to acute normobaric hypoxia. These data suggest that CIHH treatment modulates cardiac autonomic activity adaptively and inhibits the acute normobaric hypoxia-induced changes in HRV.
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Frecuencia Cardíaca/fisiología , Hipoxia/fisiopatología , Altitud , Animales , Presión Sanguínea/fisiología , Peso Corporal/fisiología , Electrocardiografía/métodos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The surged systemic vascular inflammation after acute myocardial infarction (AMI) aggravates the atherosclerotic endothelial injury. To explore roles of miR-499 released from cardiomyocytes during AMI in endothelial injury. Using qPCR and ELISA, we discovered that patients with AMI had significantly increased plasma miR-499, which was directly correlated with serum thrombomodulin, a marker for endothelial injury. Plasma of AMI patients, when incubated with human umbilical vein endothelial cells (HUVECs), significantly increased the expression of endothelial injury markers, which could be abrogated by antagomiR-499. In vitro, neonatal rat cardiomyocytes subjected to hypoxia/reoxygenation (HX/R) released miR-499 that could be internalized into rat pulmonary microvascular endothelial cells (RPMECs), worsening the high glucose-induced injury. In silico analysis demonstrated that CHRNA7 encoding α7-nAchR is a target of miR-499, which was validated in cell lines expressing endogenous α7-nAchR. In high glucose-induced RPMECs injury model, miR-499 aggravated, whereas forced CHRNA7 expression ameliorated the injury. Moreover, the perfusate from Langendorff perfused rat heart subjected to HX/R contained higher level of miR-499 that significantly impaired the Bradykinin-mediated endothelium-dependent relaxation in both conduit and resistance arteries, which could be partially abrogated by antagomiR-499. Finally, the correlation between plasma miR-499 and endothelial injury was further confirmed in another cohort of AMI patients. We conclude that miR-499 released from injured cardiomyocytes contributes to the endothelial injury by targeting α7-nAchR. This study implies that miR-499 may serve as a potential target for the treatment of the surged vascular inflammation post-AMI.
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Endotelio/metabolismo , MicroARNs/genética , Infarto del Miocardio/genética , Receptor Nicotínico de Acetilcolina alfa 7/genética , Animales , Apoptosis/genética , Biomarcadores/sangre , Hipoxia de la Célula/genética , Células Endoteliales/metabolismo , Células Endoteliales/patología , Endotelio/lesiones , Endotelio/patología , Femenino , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Masculino , Infarto del Miocardio/sangre , Infarto del Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , RatasRESUMEN
PURPOSE: This translational study is designed to assess the safety, dosimetry and therapeutic response to a single, low-dose of 177Lu-EB-PSMA-617 in comparison to 177Lu-PSMA-617 in patients with mCRPC. METHODS: Following institutional review board approval and informed consent, nine patients with mCRPC were recruited. Four patients accepted intravenous injection of 0.80-1.1 GBq (21.5-30 mCi) of 177Lu-EB-PSMA-617, then underwent serial whole-body planar and SPECT/CT imaging at 2, 24, 72, 120 and 168 h. The other five patients accepted intravenous injection of 1.30-1.42 GBq (35-38.4 mCi) 177Lu-PSMA-617, then underwent the same imaging procedures at 0.5, 2, 24, 48, and 72 h. All patients were evaluated by 68Ga-PSMA-617 PET/CT before and one month after the treatment. Dosimetry evaluation was compared in both patient groups. RESULTS: When the bone metastasis tumors with comparable baseline SUVmax in the range of 10.0-15.0 were selected from the two groups for comparison, the accumulated radioactivity of 177Lu-EB-PSMA-617 was about 3.02-fold higher than that of 177Lu-PSMA-617. Imaging dose of 177Lu-EB-PSMA-617 treatment showed significant decrease of 68Ga-PSMA-617 uptake within a month, which was not observed in patients imaged with 177Lu-PSMA-617 (SUV change: -32.43 ± 0.14% vs. 0.21 ± 0.37%; P = 0.002). 177Lu-EB-PSMA-617 also had higher absorbed doses in the red bone marrow and kidneys than 177Lu-PSMA-617 (0.0547 ± 0.0062 vs. 0.0084 ± 0.0057 mSv/MBq for red bone marrow, P < 0.01; 2.39 ± 0.69 vs. 0.39 ± 0.06 mSv/MBq for kidneys, P < 0.01). CONCLUSION: This first-in-human study demonstrated that 177Lu-EB-PSMA-617 had higher accumulation in mCRPC and that low imaging dose appears to be effective in treating tumors with high 68Ga-PSMA-617 uptakes. Elevated uptakes of 177Lu-EB-PSMA-617 in kidneys and red bone marrow were well tolerated at the administered low dose. Further investigations with increased dose and frequency of administration are warranted.
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Dipéptidos/farmacocinética , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Radiofármacos/farmacocinética , Anciano , Anciano de 80 o más Años , Dipéptidos/efectos adversos , Dipéptidos/uso terapéutico , Azul de Evans , Compuestos Heterocíclicos con 1 Anillo/efectos adversos , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Humanos , Lutecio , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/patología , Radiofármacos/efectos adversos , Radiofármacos/uso terapéutico , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
The purpose of this study was to investigate the renal protective effect of celastrol on diabetic rats. Furthermore, the mechanism of its action was discussed whether it was related to MAPK/NF-κB signaling pathway. There were a total of 36 rats. Six rats were randomly chosen as the control group. The remaining 30 rats were given 1% streptozotocin intraperitoneal injection (50 mg/kg) and were randomly divided into five groups: the model control group, the low-dose celastrol group, the high-dose celastrol group, the Tripterygium wilfordii polyglycosides group, and the MAPK/NF-κB inhibitor group. After 4 weeks of continuous administration, 24-hr urine volume, urinary protein, blood urea nitrogen, and serum creatinine content were observed, and hematoxylin-eosin (HE) staining of the kidney and liver were evaluated. p38MAPK was designated by immunohistochemical method, and NF-κB p65 in renal tissue was detected by western blotting. Our results showed that celastrol could not only reduce contents of creatinine and urea nitrogen in blood but also reduce excretion of urinary protein in diabetic rats, improve renal pathological injury, and down-regulate the expression of p38MAPK and NF-κB p65. In conclusion, celastrol could protect kidney of diabetic rats by regulating the signal pathway of MAPK/NF-κB, inhibiting inflammation and delaying renal injury.
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Diabetes Mellitus Experimental , Nefropatías Diabéticas , Riñón , FN-kappa B , Tripterygium , Triterpenos , Animales , Masculino , Ratas , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Riñón/efectos de los fármacos , Riñón/patología , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Triterpenos Pentacíclicos , Ratas Sprague-Dawley , Factor de Transcripción ReIA/metabolismo , Tripterygium/química , Triterpenos/farmacología , Triterpenos/uso terapéuticoRESUMEN
BACKGROUND This study investigated the effect and the possible mechanism of trimetazidine in atherosclerosis. MATERIAL AND METHODS We established an atherosclerotic rat model by high-fat diet and vitamin D injection. Rats were separated into 3 different groups: control, atherosclerosis, and trimetazidine (n=10). The aortic artery was isolated and its morphological features were examined by hematoxylin and eosin (HE) staining. Serum low-density lipoprotein cholesterol (LDL-c), total cholesterol (TC), and triglycerides (TG) were analyzed using an automatic biochemical analyzer. Human aortic smooth muscle cells (HASMCs) were cultured and divided into 5 groups: no treatment, H2O2 treatment only, trimetazidine preincubation before H2O2 treatment, oxidized low-density lipoprotein (oxLDL) treatment only, and trimetazidine preincubation before oxLDL treatment. HASMCs proliferation was tested using the Cell Counting Kit-8. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels, superoxide dismutase (SOD) activity of the aortic artery, and HASMCs were measured using commercially available kits. RESULTS HE staining assay showed that trimetazidine suppressed the progression of atherosclerosis and reduced foam cell formation in the aortic artery without affecting serum lipid levels. HASMCs proliferation assay revealed that trimetazidine alleviated the inhibitory effect of H2O2 on HASMCs proliferation and inhibited oxLDL-induced proliferation of HASMCs. Moreover, trimetazidine ameliorated ROS up-regulation elicited by H2O2 or oxLDL in HASMCs. Additionally, trimetazidine restored SOD activity and reduced MDA content of HASMCs. CONCLUSIONS Trimetazidine suppressed the progression of atherosclerosis by enhancing energy value, decreasing ROS level of aortic artery, modulating HASMCs proliferation, and reducing oxidative stress in HASMCs.
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Aterosclerosis/tratamiento farmacológico , Trimetazidina/farmacología , Animales , Aorta/citología , Línea Celular , Proliferación Celular/efectos de los fármacos , China , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Humanos , Lipoproteínas LDL , Masculino , Malondialdehído/metabolismo , Miocitos del Músculo Liso/citología , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno , Superóxido Dismutasa/metabolismo , Triglicéridos/sangreRESUMEN
AIMS: To investigate the effects of ketamine on human hyperpolarization-activated cyclic nucleotide-gated (hHCN) 1, 2, 4 channel currents expressed in Xenopus oocytes and spontaneous action potentials (APs) of rabbit sinoatrial node (SAN). METHODS: The 2-electrode voltage clamp and standard microelectrode techniques were respectively applied to record hHCN channels currents expressed in Xenopus oocytes and APs of SAN separated from rabbit heart. RESULTS: Ketamine (1-625 µmol/L) blocked hHCN1, 2, and 4 currents with IC50 of 67.0, 89.1, and 84.0 µmol/L, respectively, in a concentration-dependent manner. The currents were rapidly blocked by ketamine and partially recovered after washout. The steady-state activation curves of hHCN1, 2, and 4 currents demonstrated a concentration-dependent shift to the left and the rates of activation were significantly decelerated. But ketamine blocked hHCN channels in a voltage-independence and non-use-dependent manner, and did not modify the voltage dependence of activation and reversal potentials. Furthermore, ketamine suppressed phase-4 spontaneous depolarization rate in isolated rabbit SAN and decreased the beat rates in a concentration-dependent manner. CONCLUSION: Ketamine could inhibit hHCN channels expressed in Xenopus oocytes in a concentration-dependent manner as a close-state blocker and decrease beat rates of isolated rabbit SAN. This study may provide novel insights into other unexplained actions of ketamine.
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Potenciales de Acción/efectos de los fármacos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/antagonistas & inhibidores , Ketamina/farmacología , Nodo Sinoatrial/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Humanos , Oocitos , Conejos , Nodo Sinoatrial/metabolismo , Transfección , Xenopus laevisRESUMEN
Acehytisine, a multi-ion channel blocker, can markedly inhibit INa, ICa, IKur, If at various concentrations and effectively terminate and prevent atrial fibrillation (AF) in patients and animal models, but the molecular mechanism underlying its blockage remains elusive. In this study, we investigated the effects of acehytisine on action potentials and sodium channels of atrial and ventricular myocytes isolated from rabbit, using whole-cell recording system. We found that acehytisine exerted stronger blocking effects on sodium channels in atria than in ventricles, especially at depolarization (IC50: 48.48 ± 7.75 µmol/L in atria vs. 560.17 ± 63.98 µmol/L in ventricles). It also significantly shifted steady state inactivation curves toward negative potentials in atrial myocytes, without affecting the recovery kinetics from inactivation of sodium channels in the same cells. In addition, acehytisine inhibited INa in a use-dependent manner and regulated slow inactivation kinetics by different gating configurations. These findings indicate that acehytisine selectively blocks atrial sodium channels and possesses affinity to sodium channel in certain states, which provides additional evidence for the anti-AF of acehytisine.
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Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Bloqueadores de los Canales de Sodio/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/metabolismo , Atrios Cardíacos/citología , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Técnicas de Placa-Clamp , ConejosRESUMEN
AIM: The augmentation of late sodium current (INa.L) not only causes intracellular Na+ accumulation, which results in intracellular Ca2+ overload via the reverse mode of the Na+/Ca2+ exchange current (reverse-INCX), but also prolongs APD and induces early afterdepolarizations (EAD), which can lead to arrhythmia and cardiac dysfunction. Thus, the inhibition of INa.L is considered to be a potential way for therapeutic intervention in ischemia and heart failure. In this study we investigated the effects of tolterodine (Tol), a competitive muscarinic receptor antagonist, on normal and veratridine (Ver)-augmented INa.L, reverse-INCX and APD in isolated rabbit ventricular myocytes, which might contribute to its cardioprotective activity. METHODS: Rabbit ventricular myocytes were prepared. The INa.L and reverse-INCX were recorded in voltage clamp mode, whereas action potentials and Ver-induced early afterdepolarizations (EADs) were recorded in current clamp mode. Drugs were applied via superfusion. RESULTS: Tol (3-120 nmol/L) concentration-dependently inhibited the normal and Ver-augmented INa.L with IC50 values of 32.08 nmol/L and 42.47 nmol/L, respectively. Atropine (100 µmol/L) did not affect the inhibitory effects of Tol (30 nmol/L) on Ver-augmented INa.L. In contrast, much high concentrations of Tol was needed to inhibit the transient sodium current (INa.T) with an IC50 value of 183.03 µmol/L. In addition, Tol (30 nmol/L) significantly shifted the inactivation curve of INa.T toward a more depolarizing membrane potential without affecting its activation characteristics. Moreover, Tol (30 nmol/L) significantly decreased Ver-augmented reverse-INCX. Tol (30 nmol/L) increased the action potential duration (APD) by 16% under the basal conditions. Ver (20 µmol/L) considerably extended the APD and evoked EADs in 18/24 cells (75%). In the presence of Ver, Tol (30 nmol/L) markedly decreased the APD and eliminated EADs (0/24 cells). CONCLUSION: Tol inhibits normal and Ver-augmented INaL and decreases Ver-augmented reverse-INCX. In addition, Tol reverses the prolongation of the APD and eliminates the EADs induced by Ver, thus prevents Ver-induced arrhythmia.
Asunto(s)
Antiarrítmicos/farmacología , Antagonistas Muscarínicos/farmacología , Miocitos Cardíacos/efectos de los fármacos , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/fisiología , Intercambiador de Sodio-Calcio/metabolismo , Tartrato de Tolterodina/farmacología , Veratridina/farmacología , Potenciales de Acción , Animales , Femenino , Ventrículos Cardíacos/citología , Técnicas In Vitro , Masculino , Miocitos Cardíacos/fisiología , Técnicas de Placa-Clamp , ConejosRESUMEN
BACKGROUND: The incidence of atrial fibrillation (AF) in rheumatic heart diseases (RHD) is very high and increases with age. Occurrence and maintenance of AF are very complicated process accompanied by many different mechanisms. Ion-channel remodeling, including the voltage-gated potassium channel Kv1.5, plays an important role in the pathophysiology of AF. However, the changes of Kv1.5 channel expression in Han Chinese patients with RHD and AF remain poorly understood. The aim of the present study was to investigate whether the Kv1.5 channels of the right atria may be altered with RHD, age, and sex to contribute to AF. MATERIAL/METHODS: Right atrial appendages were obtained from 20 patients with normal cardiac functions who had undergone surgery, and 26 patients with AF. Subjects were picked from 4 groups: adult and aged patients in normal sinus rhythm (SR) and AF. Patients were divided into non-RHD and RHD groups or men and women groups in normal SR and AF, respectively. The expression of Kv1.5 protein and messenger RNA (mRNA) were measured using Western blotting and polymerase chain reaction (PCR) method, respectively. RESULTS: Compared with the SR group, the expression of Kv1.5 protein decreased significantly in the AF group. However, neither Kv1.5 protein nor KCNA5 mRNA had significant differences in adult and aged groups, non-RHD and RHD group, and men and women group of AF. CONCLUSIONS: The expression of Kv1.5 channel protein changes with AF but not with age, RHD, and sex in AF.
Asunto(s)
Pueblo Asiatico/genética , Fibrilación Atrial/genética , Fibrilación Atrial/metabolismo , Canal de Potasio Kv1.5/genética , Canal de Potasio Kv1.5/metabolismo , Adolescente , Adulto , Factores de Edad , Fibrilación Atrial/etiología , Estudios de Casos y Controles , Femenino , Atrios Cardíacos/metabolismo , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Cardiopatía Reumática/complicaciones , Cardiopatía Reumática/genética , Cardiopatía Reumática/metabolismo , Factores Sexuales , Adulto JovenRESUMEN
The essence of endogenous turbidity in Chinese medicine (CM) is different from cream, fat, phlegm, retention, damp, toxicity, and stasis. Along with the development of modern scientific technologies and biology, researches on the essence of endogenous turbidity should keep pace with the time. Its material bases should be defined and new connotation endowed at the microscopic level. The essence of turbidity lies in abnormal functions of zang-fu organs. Sugar, fat, protein, and other nutrient substances cannot be properly decomposed, but into semi-finished products or intermediate metabolites. They are inactive and cannot participate in normal material syntheses and decomposition. They cannot be transformed to energy metabolism, but also cannot be synthesized as executive functioning of active proteins. If they cannot be degraded by autophagy-lysosome or ubiquitin-prosome into glucose, fatty acids, amino acids, and other basic nutrients to be used again, they will accumulate inside the human body and become endogenous turbidity. Therefore, endogenous turbidity is different from final metabolites such as urea, carbon dioxide, etc., which can transform vital qi. How to improve the function of zang-fu organs, enhance its degradation by autophagy-lysosome or ubiquitin-prosome is of great significance in normal operating of zang-fu organs and preventing the emergence and progress of related diseases.
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Medicina Tradicional China , Autofagia , Humanos , Complejo de la Endopetidasa ProteasomalRESUMEN
Licorice has a marked detoxifying effect that can treat drug poisoning and/or relieve adverse effects. However, the exact mechanism of this action is not entirely elucidated, but is believed to be related to the modulation of drug disposition when interacting with other drugs. Additionally, Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a significant role in mediating phase II xenobiotic metabolizing enzymes (XMEs) and phase III transporters. In the present study, we showed that licorice induced the mRNA expression of phase II XMEs UDP-glucuronosyltransferases 1A1 (UGT1A1), glutamate cysteine ligase (GCL), glutathione-s-transferase (GST) and phase III transporters multidrug resistance protein 2 (MRP2), as well as a rapid increase in Nrf2 nuclear accumulation. These findings suggests that licorice may intervene in the Nrf2 signal pathway to induce UGT1A1, GCLC, GST and MRP2, which provide a novel mechanism for the use of licorice to treat drug poisoning and/or relieve adverse effects.
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Proteínas Portadoras/metabolismo , Enzimas/metabolismo , Glycyrrhiza , Extractos Vegetales/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Línea Celular , Humanos , Oxigenasas de Función Mixta/metabolismo , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
Ischemic heart disease (IHD) is a common clinical cardiovascular disease with high morbidity and mortality. Sodium glucose cotransporter protein inhibitor (SGLTi) is a novel hypoglycemic drug. To date, both clinical trials and animal experiments have shown that SGLTi play a protective role in IHD, including myocardial infarction (MI) and ischemia/reperfusion (I/R). The protective effects may be involved in mechanisms of energy metabolic conversion, anti-inflammation, anti-fibrosis, ionic homeostasis improvement, immune cell development, angiogenesis and functional regulation, gut microbiota regulation, and epicardial lipids. Thus, this review summarizes the above mechanisms and aims to provide theoretical evidence for therapeutic strategies for IHD.
RESUMEN
BACKGROUND: Several lines of evidence point to an interaction between genetic predisposition and environmental factors in the onset of major depressive disorder (MDD). This study is aimed to investigate the pathogenesis of MDD by identifying key biomarkers, associated immune infiltration using bioinformatic analysis and human postmortem sample. METHODS: The Gene Expression Omnibus (GEO) database of GSE98793 was adopted to identify hub genes linked to endoplasmic reticulum (ER) stress-related genes (ERGs) in MDD. Another GEO database of GSE76826 was employed to validate the novel target associated with ERGs and immune infiltration in MDD. Moreover, human postmortem sample from MDD patients was utilized to confirm the differential expression analysis of hub genes. RESULTS: We discovered 12 ER stress-related differentially expressed genes (ERDEGs). A LASSO Cox regression analysis helped construct a diagnostic model for these ERDEGs, incorporating immune infiltration analysis revealed that three hub genes (ERLIN1, SEC61B, and USP13) show the significant and consistent expression differences between the two groups. Western blot analysis of postmortem brain samples indicated notably higher expression levels of ERLIN1 and SEC61B in the MDD group, with USP13 also tending to increase compared to control group. LIMITATIONS: The utilization of the MDD gene chip in this analysis was sourced from the GEO database, which possesses a restricted number of pertinent gene chip samples. CONCLUSIONS: These findings indicate that ERDEGs especially including ERLIN1, SEC61B, and USP13 associated the infiltration of immune cells may be potential diagnostic indicators for MDD.