Problem
Preeclampsia (PE) and intrauterine growth restriction (IUGR) are leading causes of perinatal complications, affecting 8%–10% of all pregnancies. Inflammasomes are suspected to be one of the ...mechanisms that lead to the process of term and preterm labors. This study evaluated the inflammasome‐dependent inflammation processes in placental tissue of women with PE and IUGR.
Methods of Study
In this prospective cohort study, 14 women with PE, 15 with placental‐related IUGR and 19 with normal pregnancy (NP) were recruited during admission for delivery. Maternal blood was obtained prior to delivery and neonatal cord blood and placental tissue were obtained after delivery.
Results
NLRP7 and PYCARD protein expression were higher in placental PE and IUGR samples versus NP samples. Immunostaining revealed that NLRP7 and PYCARD were upregulated in PE and IUGR placental syncytiotrophoblast, stroma and endothelial cells. PYCARD serum levels were significantly higher in women with PE and IUGR. No significant changes were observed in neonatal cord blood.
Conclusions
NLRP7 and PYCARD are key inflammatory proteins that are significantly elevated in PE and IUGR. Better understanding their significance may enable them to become markers of prediction or progression of PE and IUGR.
Peritoneal dialysis (PD) causes structural and functional changes in the peritoneal membrane, which are attributed to local inflammatory process. This study assessed the presence of galectin‐3 ...(Gal‐3), a known inflammatory modulator, in dialysate effluent and correlated its levels with markers of inflammatory process. Gal‐3 levels in serum and dialysate effluent were measured in prevalent PD patients on morning visits (n = 27) or during peritoneal equilibration tests (PET, n = 16), it association with clinical and laboratory parameters, including dialysate/plasma creatinine (D/P creatinine) and interleukin‐6 (IL‐6) levels was analysed. Gal‐3 levels in dialysate effluent correlated with D/P creatinine (0.663, p = 0.005) and dialysate effluent IL‐6 levels (0.674, p = 0.002), but not with serum Gal‐3 levels or dialysis vintage. Patients who were high transporters had higher Gal‐3 levels in dialysate effluent, as compared to lower transporters. In multivariate regression analysis, dialysate IL‐6 level was the strongest predictor of dialysate Gal‐3 levels. This study found Gal‐3 in dialysate effluent correlated with D/P creatinine and dialysate IL‐6 levels. These findings may imply that Gal‐3 has a role in the intraperitoneal inflammatory process. However, this needs to be investigated further.
SUMMARY AT A GLANCE
Galectin‐3 (Gal‐3) is an important inflammatory modulator. This study showed that dialysate Gal‐3 levels correlated with peritoneal transport parameters, suggesting that Gal‐3 may play a role in the regulation of peritoneal transport.
Background
Emerging evidence demonstrates the involvement of Janus tyrosine kinase/signal transducer and transcription activator (JAK/STAT) proteins in the pathophysiology of diabetic kidney disease ...(DKD). The JAK/STAT pathway is involved in the inflammatory response and endothelial cell dysfunction observed in DKD. The glucagon‐like peptide‐1 (GLP‐1) analog liraglutide is an effective treatment for type 2 diabetes because it improves the inflammatory changes observed in experimental models of DKD. This study used db/db mice and endothelial cells (ECs) to determine the effect of diabetic environment on the JAK/STAT pathway and to assess the potential effect of liraglutide (200 μg/kg) in both models.
Methods
Diabetic db/db mice (12 weeks old) were treated with liraglutide for 14 weeks. The kidneys were then perfused with saline and removed for mRNA, protein, and immunohistochemical analyses. Endothelial cells were stimulated advanced glycation end products (AGEs) (200 μg/μL) glucose (200 mg/dL) and liraglutide (100 nM) for 24 hours. Total RNA and protein were extracted and analyzed for expression of JAK/STAT signaling.
Results
Phosphorylated (p‐) STAT3 was significantly upregulated in db/db mice compared with non‐diabetic mice. Liraglutide significantly downregulated p‐STAT3 protein expression in db/db mice. In db/db mice, p‐STAT3 was primarily expressed in the glomeruli, whereas p‐JAK2 was also expressed in kidney tubules. In ECs, liraglutide treatment prevented increased expression of p‐STAT3 and p‐JAK2. Liraglutide inhibited the target gene suppressor of cytokine signaling 3 (SOCS3) and sirtuin 1 (SIRT1) in db/db mice and in cultured EC.
Conclusions
This study suggests that the GLP‐1 analog liraglutide inhibits the JAK/STAT pathway, which participates in intracellular processes in experimental models of diabetes.
摘要
背景
越来越多的证据表明Janus酪氨酸激酶/信号转导与转录激活因子(Janus tyrosine kinase/signal transducer and transcription activator，JAK/STAT)蛋白参与了糖尿病肾病(diabetic kidney disease，DKD)的病理生理学过程。在DKD中观察到的炎症反应以及内皮细胞功能障碍与JAK/STAT通路有关。胰高血糖素样肽‐1(glucagon‐like peptide‐1，GLP‐1)类似物利拉鲁肽是一种有效的2型糖尿病治疗药物，因为在DKD实验模型中观察到它可以改善炎症反应。这项研究利用db/db小鼠与内皮细胞(endothelial cells，ECs)来测定糖尿病环境对JAK/STAT通路的影响，并且在这两个模型中评估了利拉鲁肽(200 μg/kg)的潜在影响。
方法
糖尿病db/db小鼠(12周龄)使用利拉鲁肽治疗14周。然后在肾脏中灌入生理盐水，取出后进行mRNA、蛋白质以及免疫组化分析。使用晚期糖基化终产物(200 μg/μL)、葡萄糖(200 mg/dl)与利拉鲁肽(100 nM)刺激内皮细胞24小时。提取出全部的RNA与蛋白质并且分析了JAK/STAT信号的表达。
结果
与非糖尿病小鼠相比较，在db/db小鼠中磷酸化STAT(p‐ STAT3)显著上调了。在db/db小鼠中利拉鲁肽可以显著下调p‐STAT3蛋白的表达。在db/db小鼠中，p‐STAT3主要在肾小球中表达，而p‐JAK2在肾小管中也有表达。在ECs中，使用利拉鲁肽治疗后可以防止p‐STAT3与p‐JAK2表达增加。在db/db小鼠以及培养的EC中，利拉鲁肽可以抑制细胞因子信号3(suppressor of cytokine signaling，SOCS3)以及sirtuin 1(SIRT1)的靶基因抑制因子。
结论
这项研究表明，GLP‐1类似物利拉鲁肽可以抑制JAK/STAT通路，这个通路与糖尿病实验模型的细胞内进程有关。
Highlights
Diabetic conditions elevated expression of signal transducer and activator of transcription (STAT) 3 and Janus tyrosine kinase (JAK) 2.
Diabetic conditions elevated expression of suppressor of cytokine signaling 3 and sirtuin 1 (SIRT1).
The glucagon‐like peptide‐1 (GLP‐1) analog, liraglutide, is an inhibited STAT3/JAK2 expression, possibly through SIRT1 signaling.
Preeclampsia (PE) and intrauterine growth restriction (IUGR) are leading causes of perinatal complications, affecting 8-10% of all pregnancies. Inflammasomes are suspected to be one of the mechanisms ...that lead to the process of term and preterm labors. This study evaluated the inflammasome-dependent inflammation processes in placental tissue of women with PE and IUGR.
In this prospective cohort study, 14 women with PE, 15 with placental-related IUGR and 19 with normal pregnancy (NP) were recruited during admission for delivery. Maternal blood was obtained prior to delivery and neonatal cord blood and placental tissue were obtained after delivery.
NLRP7 and PYCARD protein expression were higher in placental PE and IUGR samples vs. NP samples. Immunostaining revealed that NLRP7 and PYCARD were upregulated in PE and IUGR placental syncytiotrophoblast, stroma and endothelial cells. PYCARD serum levels were significantly higher in women with PE and IUGR. No significant changes were observed in neonatal cord blood.
NLRP7 and PYCARD are key inflammatory proteins that are significantly elevated in PE and IUGR. Better understanding their significance may enable them to become markers of prediction or progression of PE and IUGR. This article is protected by copyright. All rights reserved.
Brain atrophy (BA) is often found in neuroimaging of hemodialysis patients, representing parenchymal cerebral damage. Likely contributing factors to BA are age, chronic hypertension, diabetes ...mellitus and other cardiovascular risk factors of atherosclerosis that are also common among hemodialysis patients. BA may also occur due to focal ischemia and hypoperfusion during hemodialysis. However, data on optimal blood pressure (BP) in these patients are limited. The goal of this study was to determine whether the prevalence and severity of BA would be higher among hemodialysis patients with lower BP. A blinded neuroradiologist graded BA of all hemodialysis patients who underwent brain non‐contrast computerized tomography (CT) from 2015 to 2017 in our institution. Age‐ and sex‐matched patients with normal kidney function who underwent brain CT during the same period and technique served as the control group. A total of 280 patients were included in this retrospective study, with average BP of 140/70 mmHg among hemodialysis patients and 142/75 mmHg in the control group. BA was more common in dialysis patients and its severity increased with age and traditional cardiovascular risk factors. We observed a significant negative correlation between diastolic BP (DBP) at dialysis initiation and BA. Average DBP decreased with increasing severity of BA. These findings were observed in both hemodialysis and non‐CKD patients. BA was associated with lower DBP, which may induce cerebral hypoperfusion and ischemia. This finding should discourage over‐treatment of hypertension among hemodialysis patients.
Patients with end stage kidney disease undergoing maintenance hemodialysis (MHD) are prone to malnutrition and infections.
The objective of this study was to evaluate the effect of polymorphonuclear ...(PMN) cell dysfunction on clinical outcomes of MHD patients, in association with nutritional status.
This prospective study investigated 39 MHD patients by evaluating the oxidative activity of their PMN cells using Phorbol 12-Myristate-13-Acetate (PMA) stimulation. Blood samples were taken from each participant at dialysis initiation. Demographics, laboratory data, and clinical outcomes during a 24-month follow-up period were obtained from electronic medical records.
Phagocytic activity was described in percentiles of mean fluorescence intensity (MFI) of PMA levels. There were no differences in comorbidities between patients with low or high MFI-PMA percentiles. Patients in the lowest (25th) MFI-PMA percentile (N = 10) had poorer nutritional status and more frequent severe infections compared to the other 29 patients (4.3 ± 3.4 events versus 2 ± 2.2 events, p = 0.017). Furthermore, they had more frequent hospitalizations (>3) due to infections (70% versus 41%, p = 0.073) and their mortality rate was higher (80% versus 31%, p = 0.007). The odds ratio for all-cause mortality was 8.85. In multivariate analysis, the MFI-PMA percentile and ischemic heart disease were the strongest predictors of all-cause mortality (p = 0.02 and p = 0.005, respectively).
Low MFI-PMA levels were associated with poor nutritional status and adverse clinical outcomes and might serve as a prognostic biomarker, predicting severe infections and mortality among malnourished MHD patients.
To evaluate changes in the inflammatory response of thioredoxin (TXN), thioredoxin interacting protein (TXNIP), transducer and activator of transcription 3, NFƙB-p50 and STAT3 at the level of ...maternal serum, placenta, and umbilical cord blood of women with gestational diabetes mellitus type 2 (GDMA2) compared to normal pregnancies (NP). Thirty pregnant women (20 with GDMA2 and 10 NP) were recruited during admission for delivery. Blood samples were obtained from the parturients and umbilical cords, as well as placental tissue for mRNA and protein extraction. TXNIP mRNA expression was significantly increased in maternal serum of women with GDMA2 compared to NP women. TXNIP mRNA was significantly decreased in GDMA2 placentas and cord blood compared to NP. TXN/TXNIP mRNA ratio showed significantly high absolute values in placental and cord blood (2.39 and 1.66) respectively, compared to maternal ratio (1.084) (P < 0.001). TXN/TXNIP placenta protein ratio showed similar values between GDMA2 and NP (0.98 and 0.86; P = 0.7). STAT3 and its target protein SOCS3, as well as NFƙB-p50 mRNA expression were significantly increased in placentas of GDMA2. NFƙB-p50 mRNA expression was significantly decreased in cord blood compared to both maternal and placental mRNA expression. Pro-inflammatory changes are expressed by low mRNA TXN/TXNIP ratio in maternal blood of GDMA2 patients, but not in placental and umbilical cord blood samples. This, as well as the feedback role of SOCS3 in STAT3 pathway and NFƙB-p50 expression, may indicate that the placenta has a role in protecting the fetus from damage due to inflammatory response, which is common in diabetes.
Introduction
Arterial calcification is an integral component of active atherosclerosis and is an independent risk factor for cardiovascular disease. Atherosclerosis is a systemic, life‐threating ...disease that may occur at different sites and in various clinical presentations. Intracranial and valvular calcifications are common among dialysis patients and have been associated with poor cardiovascular outcomes. The aim of this study was to assess the clinical impact of valvular and intracranial arterial calcifications on mortality among chronic hemodialysis patients.
Methods
A blinded neuroradiologist graded intracranial calcifications (ICC) of all hemodialysis patients who underwent brain computerized tomography (CT) from 2015 to 2017 in our institution. Valvular calcifications were assessed by echocardiography. Only hemodialysis patients with available echocardiography and brain CT were included.
Findings
This study included 119 patients (mean age 70.6 ± 12.6 years, 57.1% men, and mean dialysis vintage 25.8 ± 42.6 months). Among the cohort, 19 (16%) had no cardiac or brain calcifications and 65 (54.6%) had both valvular and intracranial calcifications. Considering the patients with no calcification as the reference group yielded adjusted odds ratios for all‐cause mortality of 3.68 (95%CI 1.55–8.75) among patients with any brain calcifications, p = 0.002. While valvular calcifications alone did not increase the 1‐year mortality rate, ICC was the most important predictor of all‐cause 1‐year mortality in the study cohort.
Discussion
We found an independent association between ICC and the risk of death among hemodialysis patients. Assessing ICC may contribute to the risk stratification of hemodialysis patients. These calcifications are no less important than valvular calcifications.
Infection is one of the leading causes of mortality in dialysis patients, second only to cardiovascular disease. This retrospective study assessed the efficacy and clinical outcomes of influenza ...vaccination among hemodialysis (HD) patients. In the 2014–2015 season, 104 of 164 (63.6%) HD patients were vaccinated for influenza by the outpatient community health system facilities. Significantly more patients, 159 of 170 (93.8%), were vaccinated in 2015–2016 by the hospital dialysis unit staff during an inpatient HD session (P <0.001). A trend toward fewer complications from influenza infection was observed in vaccinated patients. Among HD patients with diabetes (who comprised 56% of the study population), the incidence of influenza was 17% among nonvaccinated patients vs. 6.3% among those who were vaccinated (P =0.026). The inpatient vaccination policy resulted in a greater rate of vaccination. HD patients with diabetes benefit from influenza vaccination, with a significantly lower incidence of influenza infection.
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