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Reperfusion after acute myocardial infarction can cause ischemia/reperfusion (I/R) injury, which not only impedes restoration of the functions of tissues and organs but may also aggravate structural tissue and organ damage and dysfunction, worsening the patient's condition. Thus, the mechanisms that underpin myocardial I/R injury need to be better understood. We aimed to examine the effect of dexmedetomidine on macrophage migration inhibitory factor (MIF) in cardiomyocytes from mice with myocardial I/R injury and to explore the mechanistic role of adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling in this process. Myocardial I/R injury was induced in mice. The expression of serum inflammatory factors, reactive oxygen species (ROS), adenosine triphosphate (ATP), and AMPK pathway-related proteins, as well as myocardial tissue structure and cell apoptosis rate, were compared between mice with I/R injury only; mice with I/R injury treated with dexmedetomidine, ISO-1 (MIF inhibitor), or both; and sham-operated mice. Dexmedetomidine reduced serum interleukin (IL)-6 and tumor necrosis factor-α concentrations and increased IL-10 concentration in mice with I/R injury. Moreover, dexmedetomidine reduced myocardial tissue ROS content and apoptosis rate and increased ATP content and MIF expression. MIF inhibition using ISO-1 reversed the protective effect of dexmedetomidine on myocardial I/R injury and reduced AMPK phosphorylation. Dexmedetomidine reduces the inflammatory response in mice with I/R injury and improves adverse symptoms, and its mechanism of action may be related to the MIF-AMPK pathway.
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Dexmedetomidina , Factores Inhibidores de la Migración de Macrófagos , Daño por Reperfusión Miocárdica , Ratones , Animales , Factores Inhibidores de la Migración de Macrófagos/genética , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/farmacología , Dexmedetomidina/farmacología , Especies Reactivas de Oxígeno , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , ApoptosisRESUMEN
IgA nephropathy (IgAN), an immune-mediated chronic inflammatory kidney disease, is the most common primary glomerular disease in Asia, especially in China and Japan. The pathogenesis of IgAN is complex, and the main cause of IgAN is explained by the 'multiple hit' theory, which states that the deposition of immune complexes in renal mesangial cells induces chronic inflammation that leads to kidney damage. Chronic inflammation is associated with iron metabolism, which also plays an essential role in the pathogenesis, progression, diagnosis and prognosis of IgAN. Overall, this review aimed to explore the application of iron metabolism in IgAN by systematically elaborating the relationship between iron metabolism and chronic inflammation in IgAN to speculate on the possible diagnostic and therapeutic significance of iron metabolism indicators in IgAN.
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Glomerulonefritis por IGA , Insuficiencia Renal Crónica , Humanos , Glomerulonefritis por IGA/patología , Inmunoglobulina A , Riñón/patología , Insuficiencia Renal Crónica/complicaciones , Inflamación , HierroRESUMEN
The positive effect of nostalgia provides an effective way to improve subjective well-being. However, there is little research on the relationship between nostalgia and subjective well-being, especially the mechanism of this link. This study tested the positive effects of nostalgia on emotional well-being (positive affect and negative affect) and cognitive well-being (satisfaction with life) via gratitude. Two experiments were conducted in samples of young adults who were randomized to experimental or control conditions. The analyses involved group comparisons as well as regression-based analyses of mediation. In Experiment 1 (N = 196), we induced nostalgia using a guided autobiographical recall procedure. The nostalgia group had higher positive affect and gratitude, and gratitude partially mediated the association between nostalgia and positive affect. In Experiment 2 (N = 102), we induced nostalgia by showing a nostalgic video from the period when the participants were children. The nostalgia group had higher positive affect and lower negative affect, and gratitude partially mediated these associations. The findings suggest that nostalgia could improve emotional well-being by increasing gratitude, but may not alter cognitive well-being.
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OBJECTIVES: Diabetic kidney disease is one of the most serious complications of diabetes mellitus (DM), and it is a main cause for chronic kidney disease and end-stage kidney disease (ESRD). It is important to find out the factors that cause the progression of renal function. The study aims to explore the relationship between serum uric acid (SUA) trajectory and the progression of renal function in patients with Type 2 diabetes mellitus (T2DM). METHODS: A total of 846 patients with T2DM, who were admitted to the Department of Nephrology and Endocrinology, the Third Xiangya Hospital of Central South University, from January 2009 to December 2021 and met the criteria of baseline estimated glomerular filtration rate (eGFR)≥60 mL/(min·1.73 m2), were selected as the research subjects. The SUA data of multiple measurements were collected and identified as different SUA trajectories by group-based trajectory modeling (GBTM). According to the SUA trajectories, the patients were divided into a low trajectory group (105 cases), a middle trajectory group (396 cases), a middle high trajectory group (278 cases), and a high trajectory group (67 cases). Cox regression analysis was used to examine the effect of SUA trajectory on the progression of renal function in patients with T2DM. Subgroup analysis was performed by sex, age, course of disease, body mass index (BMI) and hemoglobin A1c (HbA1c). RESULTS: The median follow-up was 4.8 years. At the end of follow-up, 158 patients had different degrees of decline in renal function. After adjusting for multiple confounding factors by Cox regression analysis, the risks of eGFR<60 mL/(min·1.73 m2), eGFR reduction rate≥50%, serum creatinine (Scr) doubling and composite endpoint (eGFR reduction rate≥50%, Scr doubling or ESRD) in the high trajectory group were significantly higher than those in the low trajectory group, with HR of 3.84 (95% CI 1.83 to 8.05), 6.90 (95% CI 2.27 to 20.96), 6.29 (95% CI 2.03 to 19.52), and 8.04 (95% CI 2.68 to 24.18), respectively. There was no significant difference in the risk of ESRD among the above 4 groups (all P>0.05). Subgroup analysis showed that: compared with the low trajectory group, the risks of eGFR<60 mL/(min·1.73 m2) in patients with high trajectory in the subgroup of male, female, age<65 years, course of disease<10 years, BMI≥24 kg/m2 and HbA1c≥7% were increased (all P<0.05). The SUA trajectory had no interaction with sex, age, course of disease, BMI and HbA1c (all interactive P>0.05). CONCLUSIONS: The high SUA trajectory increases the risk for progression of renal function in patients with T2DM. Long-term longitudinal changes of SUA should be paid attention to.
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Diabetes Mellitus Tipo 2 , Fallo Renal Crónico , Insuficiencia Renal Crónica , Humanos , Masculino , Femenino , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Estudios de Cohortes , Ácido Úrico , Hemoglobina Glucada , Fallo Renal Crónico/complicaciones , Tasa de Filtración Glomerular , Riñón/fisiología , Factores de RiesgoRESUMEN
BACKGROUND: Reperfusion of ischemic tissue has adverse impact on the myocardium. Dexmedetomidine (Dex) is a α2-adrenergic receptor (α2-AR) agonist with sedative and analgesic effects. Macrophage migration inhibition factor (MIF) is a pressure-regulating cytokine and is responsible for inflammatory and immune diseases. This study aims to reveal the consequences of Dex on myocardial ischemia-reperfusion injury (IRI) in young mice. METHODS: Fifty mice were raised and examined. At the end of the experiment, all mice were euthanized. The anterior descending department of the left coronary artery in mice was under ischemia for 60 min, then the ligation line was released and reperfused for 120 min to establish the IRI model. Mice were randomly divided into Sham, control, treatment using 4,5-dihydro-3-(4-hydroxyphenyl)-5-isoxazoleacetic acid (ISO-1), Dex treatment, and Dex combined ISO-1 treatment groups. Interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) and ATP levels were recorded. The expressions of MIF, P-adenosine monophosphate-activated kinase α (AMPKα), glucose transporter (GLUT)4, Bax and Bcl-2 were detected by Western Blot (WB). Hematoxylin and Eosin (H&E) staining was used to study cell morphology. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. Echocardiography was carried out at the end of reperfusion, and the infarct size was calculated by Electron microscopy. RESULTS: I/R + Dex group showed significantly increased IL-6 and TNF-α levels and reduced myocardial cell necrosis and apoptosis. H&E staining showed alleviated myocardial disorder, myocardial cell swelling, myocardial fiber fracture, and inflammatory cell infiltration in I/R + Dex group. Myocardial cell necrosis and apoptosis were significantly reduced in I/R + Dex group. ATP level in myocardial tissue of mice in I/R group was substantially decreased, while that in Dex group was increased. WB results showed that MIF, P-AMPK α, GLUT4 and Bcl-2 levels were increased and Bax levels were decreased in I/R + Dex group. CONCLUSION: Dex may exert myocardial protection in young mice through MIF/AMPK/GLUT4 axis.
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Dexmedetomidina , Factores Inhibidores de la Migración de Macrófagos , Daño por Reperfusión Miocárdica , Proteínas Quinasas Activadas por AMP , Adenosina Trifosfato , Agonistas de Receptores Adrenérgicos alfa 2 , Animales , Dexmedetomidina/farmacología , Interleucina-6 , Ratones , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Necrosis , Proteínas Proto-Oncogénicas c-bcl-2 , Factor de Necrosis Tumoral alfa , Proteína X Asociada a bcl-2RESUMEN
OBJECTIVES: Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand activated transcription factors and belongs to bile acid receptor. Studies have shown that the expression of FXR in renal tissue can reduce renal injury via regulation of glucose and lipid metabolism, inhibition of inflammatory response, reduction of oxidative stress and renal fibrosis. However, it is unclear whether FXR is involved in autophagy in renal diseases. This study aims to investigate the role of FXR in cisplatin-induced acute renal injury and whether its mechanism is related to autophagy regulation. METHODS: Twelve male WT or FXR-KO mice at 12 weeks were randomly divided into a WT group, a WT+cisplatin group, a FXR-KO group, and a FXR-KO+cisplatin group, with 6 mice in each group. The WT+cisplatin group and the FXR-KO+cisplatin group were intraperitoneally injected with cisplatin (20 mg/kg), and the WT group and the FXR-KO group were intraperitoneally injected with equal volume of cisplatin solvent. Seventy-two hours later, the mice were killed and blood and renal tissue samples were collected. The levels of SCr and BUN were detected by immunoturbidimetry. After the staining, the pathological changes of renal tissue were observed under optical microscope. The protein levels of LC3 and p62 were detected by Western blotting and immunohistochemistry. The clearance of damaged mitochondria and the accumulation of lysosomal substrate were observed under electron microscope. The apoptosis of renal tubular epithelial cells was detected by TUNEL. RESULTS: Compared with the WT group or the FXR-KO group, both SCr and BUN levels in the WT+cisplatin group or the FXR-KO+cisplatin group were significantly increased (P<0.01 or P<0.001), and SCr and BUN levels in the FXR-KO+cisplatin group were significantly higher than those in the WT+cisplatin group (both P<0.05). Under the light microscope, there were no obvious pathological changes in the renal tissue of mice in the WT group and the FXR-KO group. Both the WT+cisplatin group and the FXR-KO+cisplatin group had vacuolar or granular degeneration of renal tubular epithelial cells, flat cells, lumen expansion, brush edge falling off, and even exposed basement membrane and tubular formation. The scores of renal tubular injury in the WT+cisplatin group and the FXR-KO+cisplatin group were significantly higher than those in the WT group and the FXR-KO group, respectively (both P<0.001), and the score in the FXR-KO+cisplatin group was significantly higher than that in the WT+cisplatin group (P<0.05). Under the transmission electron microscope, the mitochondria of mouse tubular epithelial cell in the WT+cisplatin group and the FXR-KO+cisplatin group was swollen, round, vacuolated, cristae broken or disappeared; the lysosome was uneven and high-density clumps, and the change was more obvious in the FXR-KO+cisplatin group. Western blotting showed that the ratio of LC3-II to LC3-I was decreased and the expression of p62 was increased in the WT+cisplatin group compared with the WT group and the FXR-KO+cisplatin group compared with FXR-KO group (P<0.05 or P<0.01); compared with the FXR-KO group, the ratio of LC3-II to LC3-I was decreased and the expression of p62 was increased significantly in the FXR-KO+cisplatin group (both P<0.05). Immunohistochemistry results showed that the expression of total LC3 and p62 in renal cortex of the WT+cisplatin group and the FXR-KO+cisplatin group was increased significantly, especially in the FXR-KO+cisplatin group. TUNEL results showed that the mice in the WT group and the FXR-KO group had negative staining or only a few apoptotic tubular epithelial cells, and the number of apoptotic cells in the WT+cisplatin group and the FXR-KO+cisplatin group were increased. The apoptosis rates of renal tubular epithelial cells in the WT+cisplatin group and the FXR-KO+cisplatin group were significantly higher than those in the WT group and the FXR-KO group, respectively (both P<0.001), and the apoptosis rate in the FXR-KO+cisplatin group was significantly higher than that in the WT+cisplatin group (P<0.05). CONCLUSIONS: Knockout of FXR gene aggravates cisplatin induced acute renal injury, and its mechanism may be related to inhibiting autophagy and promoting apoptosis.
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Lesión Renal Aguda , Cisplatino , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Animales , Apoptosis/fisiología , Cisplatino/efectos adversos , Femenino , Humanos , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
High expression of suppressors of cytokine signalling (SOCS) has been detected during various viral infections. As a negative feedback regulator, SOCS participates in the regulation of multiple signalling pathways. In this study, to study the related mechanism between SOCS and BDV and to explore the effect of SOCS on IFN pathways in nerve cells, downregulated of SOCS1/3 in oligodendroglial (OL) cells and OL cells persistently infected with BDV (OL/BDV) were constructed with RNA interference technology. An interferon inducer (poly I:C, PIC) and an IFN-α/ß R1 antibody were used as stimulation in the SOCS1/3 low-expression cell models, qRT-PCR was used to detect type I IFN and BDV nucleic acid expression, Western blot was used to detect the expression of BDV P40 protein. After BDV acute infection with OL cells which with downregulated SOCS expression, the virus accounting was not detected, and the viral protein expression was lower than that of OL/BDV cells; the OL/BDV cells with downregulated SOCS expression had lower virus nucleic acid and protein expression than OL/BDV cells. Stimulated by IFN-α/ß R1 antibody, the expression of type I interferon in OL/BDV cells decreased, and the content of BDV nucleic acid and protein increased, which was higher than that of OL/BDV cells. From the results, it was concluded that downregulating SOCS1/3 can inhibit the formation of acute BDV infection and virus replication in persistent BDV infection by promoting the expression of IFN-α/ß and that SOCS can be used as a new target for antiviral therapy.
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Enfermedad de Borna/genética , Enfermedad de Borna/virología , Virus de la Enfermedad de Borna/fisiología , Regulación de la Expresión Génica , Proteínas Supresoras de la Señalización de Citocinas/genética , Biomarcadores , Enfermedad de Borna/metabolismo , Línea Celular , Células Cultivadas , Interacciones Huésped-Patógeno , Humanos , Interferón-alfa/genética , Interferón beta/genética , ARN Mensajero/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Replicación ViralRESUMEN
MiRNAs play essential roles in processes of physiological status and disease conditions including in renal diseases, while extracellular vesicles (EVs) serve as important mediators for cell-cell communication. In body fluid or extracellular spaces, miRNAs are packaged into EVs and transferred to targeted cells to perform their bioeffects under particular conditions. In the present review, we aim to summarize and update the known and verified EV-carrying miRNAs (EV-miRNAs) and their general roles in kidney diseases. In addition to performing a systemic analysis, we try to provide some clues and perspectives for the future study of EV-miRNAs in renal diseases.
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Vesículas Extracelulares/metabolismo , Enfermedades Renales/metabolismo , Riñón/metabolismo , MicroARNs/metabolismo , Animales , Biomarcadores/metabolismo , Vesículas Extracelulares/genética , Vesículas Extracelulares/patología , Vesículas Extracelulares/trasplante , Regulación de la Expresión Génica , Humanos , Riñón/patología , Enfermedades Renales/genética , Enfermedades Renales/patología , Enfermedades Renales/terapia , MicroARNs/genética , PronósticoRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a kind of malignancies to impact human health. It has been reported that aberrant toll-like receptor (TLR) signaling may contribute to the development and progression of HCC, especially TLR4. MiR-122, which extensively involved in hepatitis virus infection and the apoptosis of hepatoma cells, might be decreased in HCC patients livers. The hypothesis of this study was whether miR-122 plays a role in inflammatory pathways through regulating TLR4 expression in hepatoma cells. METHODS: The expression of miR-122 in the tissues of HCC patients compared to controls in TCGA datasets was analyzed. The relationship between miR-122 and TLR4 was detected in HCC cell lines by increasing/decreasing miR-122 expression. The target of miR-122 on TLR4 was confirmed by luciferase reporter assays. The proliferation of HCC cells and production of proinflammatory cytokines were measured with miR-122 upregulation and inhibition. RESULTS: We found that the expression of miR-122 was decreased in HCC tissues and showed the diagnostic capacity for HCC in TCGA datasets. MiR-122 and TLR4 expression have negative correlation in normal liver cells and HCC cells. Upregulation of miR-122 significantly inhibited TLR4 expression in hepatoma cells, including in hepatoma cells with the induction of LPS, while knocking down miR-122 increased TLR4 expression. By screening potential miR-122 targets among TLR4, we found that there was a putative miR-122 target in TLR4 3'UTR. Mutations in the nt1603-nt1609 region of TLR4 3'UTR abandoned the impact of miR-122 on TLR4 expression. Over-expression/down-expression of miR-122 could influence the proliferation and the expression of natural immune factors. CONCLUSIONS: MiR-122 might target TLR4 and regulate host innate immunity in hepatoma cells, which revealed a new molecular mechanism of miR-122 on the regulation of innate immunity.
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Carcinoma Hepatocelular , Inmunidad Innata/genética , Neoplasias Hepáticas , MicroARNs/genética , Receptor Toll-Like 4/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Proliferación Celular/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Transducción de Señal , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
The biological effects mediated by vitamin D and vitamin D receptor (VDR) are involved in the regulation of multiple pathophysiologic processes, including calcium phosphorus metabolism, immune regulation, anti-inflammation, anti-infection and cancer prevention, etc. Autophagy is a eukaryotic cell lysosome-mediated catabolic pathway, which is classified into 3 different types: macroautophagy, microautophagy, and chaperone-mediated autophagy. Since autophagy is vital to maintain energy and metabolism in cells, autophagy dysfunction is closely associated with various pathological processes such as inflammation, infection and tumor. Studies have shown that vitamin D/VDR can affect the different stages of autophagy and regulate inflammation in autophagy. Moreover, vitamin D/VDR and autophagy play an important role in autoimmune disease, diabetes, cardiovascular disease, cancer and other inflammatory diseases.
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Autofagia , Enfermedades Autoinmunes , Humanos , Inflamación , Receptores de Calcitriol , Vitamina DRESUMEN
BACKGROUND: Ganoderma lucidum polysaccharides (GLPS) have been used as traditional Chinese medicine for their properties of cancer prevention and immunomodulation. However, it is unclear whether GLPS has therapeutic effect on anti-hepatocellular carcinoma (HCC) in vivo. In this study, the effect of GLPS and their impact on the balance of regulatory T cell (Treg) and effector T cell (Teff) was measured in a model of hepatoma-bearing mice. METHODS: The effect of GLPS and their impact on the balance of regulatory T cell (Treg) and effector T cell (Teff) were measured in a model of hepatoma-bearing mice. Real-time PCR detected the levels of MicroRNAs (miRNAs) and mRNA. The effects of Tregs on Teff proliferation were determined via suppression assay. The mircroRNA-125b (miR-125b) inhibitor was used to down-regulate miR-125b expression. RESULTS: GLPS significantly suppressed tumor growth in hepatoma-bearing mice associated with an increase of the ratio of Teffs to Tregs. Moreover, GLPS eliminate Treg suppression of Teff proliferation with an increase in IL-2 secretion. Addition of GLPS to treat T cells inhibited Notch1 and FoxP3 expression through increase of miR-125b expression. In hepatoma-bearing mice, miR-125b inhibitor obviously abolished the effect of GLPS on tumor growth. CONCLUSIONS: This finding provides the novel evidence for GLPS on inhibition of HCC through miR-125b inhibiting Tregs accumulation and function.
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Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Regulación hacia Abajo/efectos de los fármacos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , MicroARNs/metabolismo , Polisacáridos/farmacología , Linfocitos T Reguladores/inmunología , Animales , Carcinoma Hepatocelular/genética , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Células Jurkat , Neoplasias Hepáticas/genética , Masculino , Ratones Endogámicos BALB C , MicroARNs/genética , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
BACKGROUND: This was controversial whether vitamin E-coated dialyzer therapy was beneficial for the complications associated with hemodialysis. Therefore, we performed this systematic review to evaluate the effects of vitamin E-coated dialyzer. METHODS: Related trials were searched from multiple electronic databases. We conducted meta-analysis to assess changes in the predefined outcomes using RevMan 5.3 software. RESULTS: Meta-analysis showed vitamin E-coated dialyzer therapy could decrease erythropoietin (EPO) resistance index (SMD, -0.24; 95% CI, -0.47 to -0.01; p = 0.04). However, pooled-analysis showed vitamin E-coated dialyzer therapy could not decrease weekly EPO dose (SMD, -0.11; 95% CI, -0.32 to 0.09; p = 0.28) and intima-media thickness (IMT) of the carotid artery (MD, -0.09; 95% CI, -0.2 to 0.01; p = 0.09), and vitamin E-coated dialyzer therapy did not improve the serum hemoglobin (MD, -0.03; 95% CI, -0.18 to 0.13; p = 0.74), albumin levels (SMD, -0.64; 95% CI, -1.62 to 0.34; p = 0.2), in addition, there was no significant difference in serum cholesterol (SMD, -0.07; 95% CI, -0.45 to 0.31; p = 0.71), triglycerides (MD, -2.77; 95% CI, -32.42 to 26.87; p = 0.85), high density lipoprotein (HDL) (SMD, 0.24; 95% CI, -0.14 to 0.62; p = 0.22) and low density lipoprotein (LDL) (SMD, 0.00; 95% CI, -0.38 to 0.37; p = 0.98) levels. CONCLUSIONS: Vitamin E-coated dialyzer may reduce the EPO resistance, but there is no conclusive evidence that vitamin E-coated dialyzer can improve the renal anemia, malnutrition, dyslipidemia and atherosclerosis status in hemodialysis (HD) patients. However, high-quality trials with hard clinical endpoints are required to fully elucidate the clinical value of vitamin E-coated dialyzer therapy.
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Anemia , Dislipidemias , Fallo Renal Crónico/terapia , Membranas Artificiales , Estado Nutricional/efectos de los fármacos , Diálisis Renal , Vitamina E/farmacología , Anemia/diagnóstico , Anemia/etiología , Antioxidantes/farmacología , Materiales Biocompatibles Revestidos/farmacología , Dislipidemias/diagnóstico , Dislipidemias/etiología , Humanos , Evaluación de Resultado en la Atención de Salud , Ensayos Clínicos Controlados Aleatorios como Asunto , Diálisis Renal/efectos adversos , Diálisis Renal/instrumentación , Diálisis Renal/métodosRESUMEN
OBJECTIVE: To evaluate the prognosis of cervical intraepithelial neoplasia grade 1 (CIN1) at different follow-up time points in Chinese women and the relationship with high-risk human papillomavirus (HR-HPV) infection. METHODS: Biopsy-confirmed CIN1 women were followed up from cervical cancer screening cohorts established during 1999 to 2008 in Xiangyuan county, Yangcheng county, Qinxian county and Wuxiang county, Shanxi Province.In each follow-up visit, participants were examined by visual inspection with acetic acid, liquid-based cytology and HR-HPV DNA testing. Those with any positive results received colposcope and biopsies. The cumulative incidence rates of CIN grade 2 or worse (CIN2+) and CIN grade 3 or worse (CIN3+), regression rates and persistent rates were calculated using pathological findings as a gold standard. The risks of progression related with HR-HPV were evaluated stratified by baseline and follow-up HR-HPV status. RESULTS: A total of 228, 224, 261 and 105 CIN1 women received the 1-year, 2-year, 6-year and 11-year follow-up exams, respectively. The cumulative incidence rate of CIN2+ among baseline HR-HPV positive women was 4.8% (6/126), 10.7% (16/150), 16.9% (29/172) and 35% (19/55) in the above follow-up visits, respectively, and their risk of progression was 2.7(95%CI:0.3-22.0), 2.9 (95%CI:0.7-12.1), 12.0 (95%CI:1.7-86.2) and 30.6 (95%CI:1.9-493.5) times higher than baseline HR-HPV negative women. Moreover, the cumulative incidence of CIN2+ among women with positive HR-HPV both at baseline and follow-up visit was 11% (6/55), 14% (6/42), 17% (10/60) and 50% (13/26) in the above follow-up visits, respectively.No new CIN2+ cases were found among those with negative HR-HPV both at baseline and follow-up visits. CONCLUSION: Given that CIN1 progression is related to HR-HPV infection, different follow-up intervals and strategies for CIN1 should be taken according to HR-HPV infection status.
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Progresión de la Enfermedad , Infecciones por Papillomavirus , Pronóstico , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Anciano , Biopsia , Femenino , Humanos , Estudios ProspectivosRESUMEN
Tumor-associated platelets can bind to tumor cells and protect circulating tumor cells from NK-mediated immune surveillance. Tumor-associated platelets secrete cytokines to induce the epithelial-mesenchymal transition (EMT) in tumor cells, which promotes tumor metastasis. Combining chemotherapeutic agents with antiplatelet drugs can reduce the occurrence of metastasis, but the systemic application of chemotherapeutic agents and antiplatelet drugs is prone to causing serious side effects. Therefore, delivering drugs to the tumor microthrombus site for long-lasting inhibition is a problem that needs to be addressed. Here, we show that small molecule peptide nanoparticles containing the Cys-Arg-Glu-Lys-Ala (CREKA) peptide can deliver the platelet inhibitor dipyridamole (DIP) and the chemotherapeutic drug paclitaxel (PTX) to tumor tissues, thereby inhibiting tumor-associated platelet function while killing tumor cells. The drug-loaded nanoparticles PD/Pep1 inhibited platelet-tumor cell interactions, were effectively taken up by tumor cells, and underwent morphological transformation induced by alkaline phosphatase (ALP) to prolong the retention time of the drugs. After intravenous injection, PD/Pep1 can target tumors and inhibit tumor metastasis. Thus, this small molecule peptide nanoformulation provides a simple strategy for efficient drug delivery and shows promise as a novel cancer therapy platform.
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Nanopartículas , Células Neoplásicas Circulantes , Humanos , Paclitaxel , Inhibidores de Agregación Plaquetaria/farmacología , Dipiridamol/farmacología , Péptidos/farmacología , Péptidos/química , Nanopartículas/química , Línea Celular TumoralRESUMEN
PURPOSE: To investigate the regulatory effect and mechanism of Vitamin D receptor (VDR) on mitochondrial function in renal tubular epithelial cell under diabetic status. METHODS: The diabetic rats induced by streptozotocin (STZ) and HK-2 cells under high glocose(HG)/transforming growth factor beta (TGF-ß) stimulation were used in this study. Calcitriol was administered for 24 weeks. Renal tubulointerstitial injury and some parameters of mitochondrial function including mitophagy, mitochondrial fission, mitochondrial ROS, mitochondrial membrane potential (MMP), mitochondrial ATP, Complex V activity and mitochondria-associated ER membranes (MAMs) integrity were examined. Additionally, paricalcitol, 3-MA (an autophagy inhibitor), VDR over-expression plasmid, VDR siRNA and Mfn2 siRNA were applied in vitro. RESULTS: The expression of VDR, Pink1, Parkin, Fundc1, LC3II, Atg5, Mfn2, Mfn1 in renal tubular cell of diabetic rats were decreased significantly. Calcitriol treatment reduced the levels of urinary albumin, serum creatinine and attenuated renal tubulointerstitial fibrosis in STZ induced diabetic rats. In addition, VDR agonist relieved mitophagy dysfunction, MAMs integrity, and inhibited mitochondrial fission, mitochondrial ROS. Co-immunoprecipitation analysis demonstrated that VDR interacted directly with Mfn2. Mitochondrial function including mitophagy, mitochondrial membrane potential (MMP), mitochondrial Ca2+, mitochondrial ATP and Complex V activity were decreased dramatically in HK-2 cells under HG/TGF-ß ambience. In vitro pretreatment of HK-2 cells with autophagy inhibitor 3-MA, VDR siRNA or Mfn2 siRNA negated the activating effects of paricalcitol on mitochondrial function. Pricalcitol and VDR over-expression plasmid activated Mfn2 and then partially restored the MAMs integrity. Additionally, VDR restored mitophagy was partially associated with MAMs integrity through Fundc1. CONCLUSION: Activated VDR could contribute to restore mitophagy through Mfn2-MAMs-Fundc1 pathway in renal tubular cell. VDR could recover mitochondrial ATP, complex V activity and MAMs integrity, inhibit mitochondrial fission and mitochondrial ROS. It indicating that VDR agonists ameliorate renal tubulointerstitial fibrosis in diabetic rats partially via regulation of mitochondrial function.
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Diabetes Mellitus Experimental , Nefropatías Diabéticas , Receptores de Calcitriol , Animales , Ratas , Adenosina Trifosfato/metabolismo , Calcitriol/farmacología , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Células Epiteliales/metabolismo , Fibrosis , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , ARN Interferente Pequeño/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Defective mitophagy in renal tubular epithelial cells is one of the main drivers of renal fibrosis in diabetic kidney disease. Our gene sequencing data showed the expression of PINK1 and BNIP3, two key molecules of mitophagy, was decreased in renal tissues of VDR-knockout mice. Herein, streptozotocin (STZ) was used to induce renal interstitial fibrosis in mice. VDR deficiency exacerbated STZ-induced renal impairment and defective mitophagy. Paricalcitol (pari, a VDR agonist) and the tubular epithelial cell-specific overexpression of VDR restored the expression of PINK1 and BNIP3 in the renal cortex and attenuated STZ-induced kidney fibrosis and mitochondrial dysfunction. In HK-2 cells under high glucose conditions, an increased level of α-SMA, COL1, and FN and a decreased expression of PINK1 and BNIP3 with severe mitochondrial damage were observed, and these alterations could be largely reversed by pari treatment. ChIP-qPCR and luciferase reporter assays showed VDR could positively regulate the transcription of Pink1 and Bnip3 genes. These findings reveal that VDR could restore mitophagy defects and attenuate STZ-induced fibrosis in diabetic mice through regulation of PINK1 and BNIP3.
Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Ergocalciferoles , Proteínas de la Membrana , Ratones Noqueados , Mitofagia , Proteínas Quinasas , Receptores de Calcitriol , Estreptozocina , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genética , Ratones , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genética , Mitofagia/genética , Mitofagia/efectos de los fármacos , Proteínas Quinasas/metabolismo , Proteínas Quinasas/genética , Humanos , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/genética , Masculino , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Fibrosis , Túbulos Renales/metabolismo , Túbulos Renales/patología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Ratones Endogámicos C57BL , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacosRESUMEN
Aims: This study investigated the regulatory effect of Mitofusin2 (Mfn2) on mitochondria-associated endoplasmic reticulum membrane (MAM) integrity and cellular injury in cisplatin-induced acute kidney injury (CP-AKI). Results: CP-AKI mice exhibited decreased expression of Mfn2, increased expression of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), abnormal mitochondrial morphology, and reduced MAMs integrity, accompanied by the activation of mitochondrial reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress (inositol-requiring enzyme 1 [IRE1] and PERK pathways). In in vitro studies, CP-induced mitochondrial ROS, ER-stress activation, and increased apoptosis were accompanied by the downregulation of Mfn2 and MAMs integrity reduction in Boston University mouse proximal tubular cells (BUMPT) and human proximal tubular epithelial cells (HK-2). Pretreatment of BUMPT cells with the Mfn2 plasmid partially restored the integrity of MAMs, negatively controlled IRE1 and PERK pathways, and inhibited cell apoptosis. In contrast, ER-stress and MAMs integrity violations were increased after Mfn2 small-interfering RNA (siRNA) treatment in HK-2 cells under CP treatment. Coimmunoprecipitation analysis demonstrated that Mfn2 interacted with PERK and IRE1. Furthermore, the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), acadesine (AICAR), had a similar effect to Mfn2 plasmid in the regulation of ER stress and MAMs. Conversely, the ER-stress inhibitor, 4-phenylbutyric acid (4-PBA), had no effect on the expression of Mfn2 and MAMs integrity. Innovation and Conclusion: This is the first study to explore the association between MAMs, ER stress, and Mfn2 in CP-AKI. Downregulation of Mfn2 expression abolished the MAMs integrity, and induced ER stress, mitochondrial ROS, and tubular cell apoptosis. This suggests that the Mfn2-MAMs pathway is a potential therapeutic target in CP-AKI. Antioxid. Redox Signal. 40, 16-39. The Ethical Registration number of animal experiment in this study was CSU-2022-01-0095.
Asunto(s)
Lesión Renal Aguda , Cisplatino , Ratones , Humanos , Animales , Especies Reactivas de Oxígeno/metabolismo , Cisplatino/efectos adversos , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Estrés del Retículo Endoplásmico , Mitocondrias/metabolismo , Retículo Endoplásmico/metabolismo , Apoptosis , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismoRESUMEN
Resveratrol (RSV), a polyphenol, is known to play an important role in inhibiting proliferation and inducing apoptosis of glioma cells. The aim of this study was to explore the mechanism of RSV on U251 cells apoptosis. RSV showed a dose-dependent decrease in U251 cell viability. It could reduce IκB phosphorylation, nuclear P65 protein levels and NF-κB transcriptional activity, which suggested that signaling pathway are involved in RSV-induced apoptosis. In addition, RSV could inhibit miR-21 expression and down-regulation of miR-21 expression could suppress NF-κB activity. Interestingly, over-expression of miR-21 can reverse the effect of RSV on NF-κB activity and apoptosis in U251 cells. These results suggest that RSV can effectively induce apoptosis of U251 cells and modulation of miR-21 possibly contributes to this antitumor action.
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MicroARNs/metabolismo , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Estilbenos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , MicroARNs/genética , FN-kappa B/genética , Resveratrol , Transducción de Señal/genéticaRESUMEN
BACKGROUND AND AIM: Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity, hyperlipidemia, and type 2 diabetes mellitus. Several studies have found that fat mass and the obesity-associated (FTO) gene is linked to obesity. The aim of this work is to investigate the expression and function of FTO in liver with lipid metabolism diseases. METHODS: We investigated the basal FTO expression in an NAFLD rat model and compared it with control subjects. The function of FTO in lipid metabolism was further studied in L02 cells through overexpression experiments. RESULTS: A significant increase in FTO mRNA and protein levels was found in the NAFLD group. In addition, the FTO levels were positively associated with malondialdehyde and superoxide dismutase concentrations. FTO overexpression in L02 cells enhanced lipogenesis and oxidative stress. CONCLUSIONS: This study demonstrates that increased FTO levels in the liver are involved in oxidative stress and lipid deposition, which characterize NAFLD.
Asunto(s)
Grasas de la Dieta/farmacología , Hígado Graso/genética , Lipogénesis/genética , Estrés Oxidativo/genética , Proteínas/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Animales , Peso Corporal , Dieta Alta en Grasa , Hígado Graso/sangre , Hígado Graso/patología , Hígado/metabolismo , Hígado/patología , Masculino , Tamaño de los Órganos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
A study conducted by Stamps (2011) examines the effect of boundary height on perceived enclosure based on an experiment asking participants to scale a set of images. The experiment and results are quite instructive. However, some parts of this experimental design should be reconsidered by future researchers because the provided images may not support accurate perceptual recognition in a full 360-degree view and some irrelevant factors should be excluded to the extent possible in realistic designs, conditions, and stimuli.