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Abstract Background This study aimed to investigate the effects of LINC00240/miR-155/Nrf2 axis on trophoblast function and macrophage polarization in the pathogenesis of preeclampsia. Methods Bindings between LINC00240, miR-155 and Nrf2 were validated by dual luciferase reporter assay or RNA-immunoprecipitation. Cell proliferation, migration, invasion, and pyroptosis were detected by CCK-8, clone formation, wound healing, Transwell system, and flow cytometry, respectively. Macrophage polarization was tested by flow cytometry. The expression levels of LINC00240, miR-155, Nrf2, and oxidative stress and pyroptosis-related markers in in vitro and in vivo preeclampsia models were analyzed by qPCR, western blot, or ELISA assays. Blood pressure, urine protein levels, liver and kidney damages, and trophoblast markers in placenta tissues were further studied in vivo. Results Placenta tissues from preeclampsia patients and animals showed decreased LINC00240 and Nrf2 and increased miR-155 expression levels, and the decreased M2 macrophage polarization. LINC00240 directly bound and inhibited expression of miR-155, which then inhibited oxidative stress-induced pyroptosis, promoting proliferation, migration and invasion abilities of trophoblasts, and M2 macrophage polarization. Inhibition of miR-155 led to increased Nrf2 expression and similar changes as LINC00240 overexpression in trophoblast function and macrophage polarization. Overexpression of LINC00240 in in vivo preeclampsia model decreased blood pressure, urine protein, liver and kidney damages, increased fetal weight and length, and induced trophoblast function and M2 macrophage polarization. Conclusion LINC00240 inhibited symptoms of preeclampsia through regulation on miR-155/Nrf2 axis, which suppressed oxidative stress-induced pyroptosis to improve trophoblast function and M2 macrophage polarization. LINC00240 could be a potential therapeutic target for preeclampsia.

Objective. To study the effect of congenital dyskeratosis 1 (DKC1) on neuroblastoma and its regulation mechanism. Methods. The expression of DKC1 in neuroblastoma was analyzed by TCGA database and molecular assay. NB cells were transfected with siDKC1 to observe the effects of DKC1 on proliferation, cloning, metastasis, and invasion, and apoptosis and apoptosis-related proteins. The tumor-bearing mouse model was constructed, shDKC1 was transfected to observe the tumor growth and tumor tissue changes, and the expression of DKC1 and Ki-67 was detected. Screening and identification of miRNA326-5p targeting DKC1. NB cells were treated with miRNA326-5p mimic or inhibitors to detect the expression of DKC1. NB cells were transfected with miRNA326-5p and DKC1 mimics to detect cell proliferation, apoptosis, and apoptotic protein expression. Results. DKC1 was highly expressed in NB cells and tissues. The activity, proliferation, invasion, and migration of NB cells were significantly decreased by DKC1 gene knockout, while apoptosis was significantly increased. The expression level of B-cell lymphoma-2 in shDKC1 group was significantly lower than that of the control group, while the expression level of BAK, BAX, and caspase-3 was significantly higher than that of the control group. The results of experiments on tumor-bearing mice were consistent with the above results. The results of miRNA assay showed that miRNA326-5p could bind DKC1 mRNA to inhibit the protein expression, thereby inhibiting the proliferation of NB cells, promoting their apoptosis, and regulating the expression of apoptotic proteins. Conclusion. miRNA326-5p targeting DKC1 mRNA regulates apoptosis-related proteins to inhibit neuroblastoma proliferation and promote the apoptotic process.

Background: Rare cases of concurrent primary aldosteronism (PA) and renal artery stenosis (RAS) have been reported. Methods: In this retrospective case–control study, we selected a cohort of 10 PA with RAS patients and a control group of 20 PA without RAS patients from January 1, 2006, to January 1, 2016. Results: All patients presented with refractory hypertension, and a nonstatistically significant trend toward lower mean serum potassium was seen in the PA with RAS group (p =.07). PA with RAS patients had lower mean orthostatic aldosterone-to-renin ratios (38.4 ± 41.4 ng dL−1/ng mL−1 h−1 vs. 87.4.4 ± 38.4 ng dL−1/ng mL−1 h−1, respectively; p

Abstract Background Disorders of the metabolism and absorption of vitamin B12 can lead to decrease in activity of methionine synthetase and methylmalonate coenzyme A mutase (MMUT), which results in increased levels of methylmalonic acid and homocysteine in blood and urine. Often, combined methylmalonic acidemia (MMA) and homocysteinemia is misdiagnosed due to a lack of specific symptoms. The clinical manifestations are diverse, but proteinuria as the initial presentation is rare. Case presentation Two cases of MMA with homocysteinemia in children are reported. Proteinuria were a primary presenting symptom, followed by anemia and neurologic symptoms (frequent convulsions and unstable walking, respectively). Screening of amino acids and acyl carnitine in serum showed that the propionyl carnitine:acetylcarnitine ratio increased. Profiling of urinary organic acids by gas chromatography–mass spectrometry revealed high levels of methylmalonic acid. Homocysteine content in blood was increased. Comprehensive genetic analyses of peripheral blood-derived DNA demonstrated heterozygous variants of methylmalonic aciduria type C and homocystinuria (MMACHC) and amnionless (AMN) genes in our two patients, respectively. After active treatment, the clinical manifestations in Case 1 were relieved and urinary protein ceased to be observed; Case 2 had persistent proteinuria and was lost to follow-up. Conclusions Analyses of the organic acids in blood and urine suggested MMA combined with homocysteinemia. In such diseases, reports of renal damage are uncommon and proteinuria as the initial presentation is rare. Molecular analysis indicated two different genetic causes. Although the pathologic mechanisms were related to vitamin B12, the severity and prognosis of renal lesions were different. Therefore, gene detection provides new insights into inherited metabolic diseases.

Background/Aims: Liddle syndrome (LS) is a rare autosomal dominant disease caused by mutations in genes coding for epithelial sodium channel (ENaC) subunits. The aim of this study was to identify the mutation responsible for the LS in an extended Chinese family. Methods: DNA samples from the proband with early-onset, treatment-resistant hypertension, and hypokalemia and 19 additional relatives were all sequenced for mutations in exon 13 of the β-ENaC and γ-ENaC genes, using amplification by polymerase chain reaction and direct DNA sequencing. Results: Genetic testing of exon 13 of SCNN1B revealed duplication of guanine into a string of 3 guanines located at codon 602. This frameshift mutation is predicted to generate a premature stop codon at position 607, resulting in truncated β-ENaC lacking the remaining 34 amino acids, including the crucial PY motif. Among a total of 9 participants with the identical mutation, different phenotypes were identified. Tailored treatment with amiloride was safe and effective in alleviating disease symptoms in LS. No mutation of SCNN1G was identified in any of the examined participants. Conclusions: We report here a family affected by LS harboring a frameshift mutation (c.1806dupG) with a premature stop codon deleting the PY motif of β-ENaC. Our study demonstrates that the earlier LS patients are diagnosed by genetic testing and treated with tailored medication, the greater the likelihood of preventing or minimizing complications in the vasculature and target organs.

Background: Liddle syndrome is an autosomal dominant form of monogenic hypertension. Phenotypic variability makes it difficult to identify patients with Liddle syndrome, resulting in misdiagnosis and severe complications at early age. Objectives: To identify mutation in SCNN1B and SCNN1G genes in an adolescent with suspicious Liddle syndrome and his family members and to explore the screening target subjects of Liddle syndrome. Methods: Genetic analysis of the C-terminus of SCNN1B and SCNN1G genes was conducted in an adolescent, with treatment-resistant hypertension and hypokalemia, who was suspected of having Liddle syndrome, and his family members. A Medline research of the reported cases with Liddle syndrome was also performed. Results: A recurrent SCNN1B mutation, c.1853C>A (p.P618H), was detected in the 19-year-old male patient, and family screening identified five additional members who were heterozygous for the mutation. The diagnosis of Liddle syndrome was made in all affected individuals. Despite the phenotypic variability, a systematic review of 54 reported index cases revealed the early-onset hypertension, aged no more than 30 years, as a common feature. Conclusions: Genetic screening for Liddle syndrome should be considered in hypertensive subjects with early penetrance, maybe no more than 30 years, after exclusion of common secondary causes of hypertension.

Platelet-derived growth factor receptor alpha (PDGFRα) is a marker of oligodendrocyte precursor cells in the central nervous system. NG2 is also considered a marker of oligodendrocyte precursor cells. However, whether there are differences in the distribution and morphology of oligodendrocyte precursor cells labeled by NG2 or PDGFRα in the developing neonatal rat brain remains unclear. In this study, by immunohistochemical staining, NG2 positive (NG2+) cells were ubiquitous in the molecular layer, external pyramidal layer, internal pyramidal layer, and polymorphic layer of the cerebral cortex, and corpus callosum, external capsule, piriform cortex, and medial septal nucleus. NG2+ cells were stellate or fusiform in shape with long processes that were progressively decreased and shortened over the course of brain development. The distribution and morphology of PDGFRα positive (PDGFRα+) cells were coincident with NG2+ cells. The colocalization of NG2 and PDGFRα in the cell bodies and processes of some cells was confirmed by double immunofluorescence labeling. Moreover, cells double-labeled for NG2 and PDGFRα were predominantly in the early postnatal stage of development. The numbers of NG2+/PDGFRα+ cells and PDGFRα+ cells decreased, but the number of NG2+ cells increased from postnatal days 3 to 14 in the developing brain. In addition, amoeboid microglial cells of the corpus callosum, newborn brain macrophages in the normal developing brain, did not express NG2 or PDGFRα, but NG2 expression was detected in amoeboid microglia after hypoxia. The present results suggest that NG2 and PDGFRα are specific markers of oligodendrocyte precursor cells at different stages during early development. Additionally, the NG2 protein is involved in inflammatory and pathological processes of amoeboid microglial cells.

Background: Takayasu arteritis (TA) is a rare inflammatory arteriopathy of unknown etiology. The aim of this study was to investigate the genetic susceptibility to TA in a Chinese population. Methods: Four single nucleotide polymorphisms (SNPs) those locate in the IL12B region (rs56167332), the MLX region (rs665268), the FCGR2A/FCGR3A locus (rs10919543), and the HLA-B/MICA locus (rs12524487), associated with TA in different population, were genotyped in 123 Chinese TA patients and 147 healthy controls from January 2013 to August 2014. A Chi-square test was used to test for genotype/allele frequencies variants. Results: Among the four SNPs, rs10919543 was found to be significantly associated with TA in the studied population. The GG genotype of rs10919543 at the FCGR2A/FCGR3A locus is a high risk factor (odds ratio [OR] = 6.532, 95% confidence interval [CI] = 2.402 − 17.763, P < 0.001) for TA. Among TA patients, the level of eosinophil granulocytes (Eos) in the peripheral blood was observed to be higher in the GG group of rs10919543 (n = 23, Eos = 0.11 [0.08, 0.17] ×109/L) than the GA + AA group (n = 100, Eos = 0.08 [0.05, 0.13] ×109/L, P = 0.028). No correlation between the genotypes of the other three SNPs and TA patients was observed. Conclusions: Our findings revealed unique genetic pattern in Chinese TA patients that may be partly responsible for the higher risk of TA in this population. FCGR2A/FCGR3A-related immune disorder might contribute to the etiology of TA.

Background Anemia is a common comorbidity of patients with Takayasu arteritis (TA). This study evaluated the prevalence, clinical characteristics, and treatment in Chinese TA patients with anemia. Methods This retrospective study included 533 consecutive patients hospitalized for TA from January 2009 to April 2018. Anemia was diagnosed on the basis of hemoglobin level, according to World Health Organization criteria. Results A total of 194 patients (36.4%) were diagnosed with anemia. Most had mild anemia (177, 91.2%). Female patients were predominant (92.8% of anemic patients). Normocytic anemia (62.9%) was the most common pattern. Anemic patients were more likely than non-anemic patients to have dizziness (29.4% vs. 21.2%), low body mass index (22.0 ± 3.6 vs. 22.9 ± 3.4 kg/m²), and active disease stage (64.9% vs. 50.1%); pulmonary involvement (12.4% vs. 26.8%), pulmonary hypertension (12.9% vs. 20.1%) and pulmonary hypertensive-target drugs (2.8% vs. 11.6%) were less common among anemic than non-anemic patients (all P < 0.05). Larger left ventricular end-diastolic diameter and lower left ventricular ejection fraction were observed in anemic patients. Over a median follow-up of four months, the increase of hemoglobin in anemic patients was associated with the use of iron supplementation. Conclusions Anemia is a very common concurrent condition in TA, especially in young, female patients. Patients with anemia are more likely to be in the active disease stage. Iron supplementation helps increase hemoglobin. [ABSTRACT FROM AUTHOR]

Background Tuberculosis (TB) infection has been reported to have a possible relationship with the occurrence and clinical course of Takayasu arteritis (TA). We aimed to describe the characteristics of TB in a large population of TA patients. Methods We included a total of 1105 patients with TA, who were hospitalized between January 1992 and December 2017. Comparisons of clinical features were made according to the presence of TB. Results Among the 1105 patients, 109 (9.9%) had TB, including 53 patients (48.6%) diagnosed with TB before the onset of TA, 23 (21.1%) with a concurrent diagnosis of TB and TA, and 24 patients (22.0%) who developed TB after TA. Pulmonary TB was the most frequently identified (97 patients, 89.0%). Patients with TB had more frequent involvement of the pulmonary artery and experienced more chest discomfort and constitutional symptoms but had less interventional treatment. Demographic characteristics, comorbid diseases, and use of steroids were similar between patients with and without TB. Conclusions The proportion of Chinese TA patients with TB was not low, and about half of the patients had TB before TA. Pulmonary TB was the most common. Pulmonary artery involvement and pulmonary hypertension was more frequent in TA patients with TB. [ABSTRACT FROM AUTHOR]

Airway remodeling in asthma contributes to airway hyperreactivity, loss of lung function and persistent symptoms. Current therapies do not adequately treat the structural airway changes associated with asthma. Statin drugs have improved respiratory health and their therapeutic potential in asthma has been tested in clinical trials. However, the mechanism of action of statins in this context has remained elusive. The present study hypothesized that atorvastatin treatment of ovalbumin-exposed mice attenuates early features of airway remodeling via a mevalonate-dependent mechanism. BALB/c mice were sensitized with ovalbumin and atorvastatin was delivered via oral gavage prior to each ovalbumin exposure. Reverse transcription-semi-quantitative polymerase chain reaction (RT-semi-qPCR), ELISA and western blot analysis were used to assess the expression of a number of relevant genes, including tissue transglutaminase (tTG), triggering receptor expressed on myeloid cells (TREM)-1, nuclear factor erythroid 2-related factor (Nrf) 2, hypoxia-inducible factor (HIF)-1α, transforming growth factor (TGF)-β1, matrix metalloproteinase (MMP)-9 and tissue inhibitors of metalloproteinases (TIMP)-1 in lung tissue. α-Smooth muscle actin (α-SMA) activity was measured by immunohistochemistry. Airway hyperresponsiveness, lung collagen deposition, airway wall area, airway smooth muscle thickness and lung pathology were also assessed. Atorvastatin treatment led to downregulation of tTG and TREM-1 expression in lung tissue after ovalbumin sensitization, blocked the activity of MMP-9, vascular endothelial growth factor, nuclear factor-κB p65, α-SMA, HIF-α and TGF-β1 and up-regulated Nrf2 expression. Furthermore, the number of lymphocytes and eosinophils in the atorvastatin group was significantly lower than that in the control group. In addition, airway hyperresponsiveness, lung collagen deposition, airway wall area, airway smooth muscle thickness and pathological changes in the lung were significantly decreased in the atorvastatin group, and tumor necrosis factor-α, interleukin (IL)-8, IL-13 and IL-17 in serum were significantly decreased. Histological results demonstrated the attenuating effect of atorvastatin on ovalbumin-induced airway remodeling in asthma. In conclusion, the present study indicated that atorvastatin significantly alleviated ovalbumin-induced airway remodeling in asthma by downregulating tTG and TREM-1 expression. The marked protective effects of atorvastatin suggest its therapeutic potential in ovalbumin-induced airway remodeling in asthma treatment. [ABSTRACT FROM AUTHOR]

The responses ofVallisneria natansto different water depths were analyzed in potted plants cultivated in a pond. The aim of the present study was to outline the effects of turbid water (i.e. low light) on the morphological parameters and photosynthetic efficiency ofV. natans. After 60 days,V. natansplants of morphological characteristics (blade length, width, area, and growth rate) at a depth of 140–170 cm showed a significant decrease with increasing water depth and each parameter was negatively correlated with water depth (p< 0.01); the growth rate was remarkably inhibited with increasing water depth. The portion of light energy absorbed for electron transfer through the antenna pigments gradually decreased at a water depth of 120–170 cm and the concentration of electrons involved in CO2fixation andqPdecreased. However,qNexhibited an opposite trend in the leaves (p< 0.01). The utilized light intensity decreased with the increasing depth. Thus, both the morphology and physiology ofV. natansare significantly affected by water depth. Moreover, the development of PS II and growth characteristics provided a basis for theoretical comparative analysis of light-dependent fluorescence signals observed in different samples under various conditions. [ABSTRACT FROM PUBLISHER]

Background: Puerarin, extracted from Radix puerariae, was reported to ameliorate airway inflammation, lung injury and lung fibrosis induced by paraquat (PQ) in mice. However, effects of Radix puerariae extracts (RPEs) on lung fibrosis or signalling pathways in PQ-induced lung injury have not been well studied. Therefore, the goals of our study were to investigate whether Radix puerariae extracts are antifibrotic in a paraquat (PQ) induced lung fibrosis model in mice and to propose possible mechanisms of action of the RPE effects. Methods: We used a long-term exposure model of PQ-induced lung fibrosis in mice to evaluate effects of antioxidant-containing RPE. We examined effects of miR-21 on follistatin-like 1 (Fstl 1) pathways and oxidative stress in the lung. Gene expression levels of miR-21, Fstl 1, transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), collagen-1 and collagen III were measured by real-time PCR. Protein expression levels of Fstl 1(FSTL1), heme oxygenase-1 (HO-1), nuclear factor erythroid 2p45-related factor-2 (Nrf2), Smad2/3, p38MAPK, nuclear factor-κB 65 (NF-κB65), and matrix metalloproteinase-9 were detected by western blotting. FSTL1 andalpha-smooth muscle actin (ct-SMA) in lung tissue were detected by immunohistochemistry. Malondialdehyde, superoxide dismutase (SOD), reduced (GSH) and oxidised (GSSH) glutathione and reactive oxygen species levels, hydroxyproline and total lung collagen were also determined. Results: Long-term challenge with PQ enhanced miRNA-21 (miR-21), Fstl 1 pathways, oxidative stress and development of fibrotic features in the lungs. RPE reduced features of lung fibrosis by blocking Fstl 1 pathways and oxidative stress through decreased miR-21 expression. This was accompanied by suppression of CTGF, TGF-β1, vascular endothelial growth factor, collagen I, and collagen III. In addition, PQ-induced activation of NF-κB, Nrf2 and ct-SMA were enhanced by puerarin. We also found that puerarin increased HO-1, SOD and GSH levels. Conclusions: These findings demonstrated that RPEs blocked PQ-induced Fstl 1 pathways and oxidative stress by inhibiting miR-21 expression, leading to attenuation of PQ-induced lung fibrosis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the renal-protective effect of lercanidipine in patients undergoing renal artery intervention. Methods: A prospective, single-center, cohort study was conducted and patients, 30–75 years of age, with atherosclerotic renal artery stenosis were consecutively enrolled between September 2011 and October 2012. Lercanidipine (10–20 mg/day) was regularly taken after the intervention. Follow up visits were performed at 3 and 6 months after the intervention. Serum creatinine, clinical blood pressure, 24 hour ambulatory blood pressure, pulse wave velocity, and 24 hour urine protein were assessed. Adverse events were recorded. Results: In total, 55 patients (mean age 63.5 ± 8.9 years) were enrolled and 52 completed the study. Renal function, estimated glomerular filtration rate (eGFR) and 24 hour urine protein at 3 months after the intervention were not statistically different compared with the baseline. At 6 months after the intervention eGFR significantly increased versus baseline (78 ± 23 ml/min/1.73 m2 vs 71 ± 21 ml/min/1.73 m2, p = 0.021); 24 hour urine protein decreased significantly (0.02 g [IQR, 0.01–0.1] vs 0.03 g [IQR, 0.01–0.28], p = 0.042). Blood pressure control improved at 3 months and 6 months after the intervention. The need for antihypertensive drugs decreased; clinical systolic blood pressure, diastolic blood pressure and 24 hour average systolic blood pressure and diastolic blood pressure decreased. The pulse wave velocity decreased after 3 and 6 months. At the end of follow-up, none of the following adverse events occurred: death, dialysis, myocardial infarction or stroke. Mild lower extremity edema occurred in only one patient. No other side effects occurred. Conclusions: This study showed that lercanidipine can improve renal function in patients undergoing renal artery intervention. [ABSTRACT FROM AUTHOR]

AbstractAim:The genetic background of orthostatic blood pressure dysregulation remains poorly understood. Since the renin-angiotensin system plays an important role in blood pressure regulation and response to position change, we hypothesized that angiotensin-converting enzyme (ACE) and ACE2 genetic polymorphisms might contribute, at least partially, to orthostatic blood pressure dysregulation in hypertensive patients.Methods:Two tag single nucleotide polymorphisms (SNPs) of ACE2 and ACE I/D were genotyped in 3630 untreated hypertensive patients and 826 normotensive subjects. Orthostatic hypertension was defined as an increase in systolic blood pressure of 20 mmHg or more and orthostatic hypotension as a drop in blood pressure of 20/10 mmHg or more within three minutes of assumption of upright posture.Results:Female and male patients had similar rates of orthostatic hypertension (16.5% vs 15.3%) and hypotension (22.5% vs 23.8%). No significant differences were detected in the minor allele frequency of ACE2 rs2106809, rs2285666, or ACE I/D in either female or male patients with orthostatic hypertension (15.1%, 22.7%, 19.6%, respectively), hypotension (13.8%, 25%, 16.5%), or normal orthostatic blood pressure response (14.4%, 21.9%, 15.8%) in additive, dominant or recessive models after adjustment for confounders (all P>0.05). The orthostatic changes in systolic and diastolic blood pressure were also comparable among patients carrying different genotypes. Similar results were observed in normotensive subjects.Conclusion:These data provide no support for the involvement of ACE or ACE2 in the genetic predisposition to orthostatic hypotension or hypertension. [ABSTRACT FROM AUTHOR]