Safety of pregnancy in acromegaly patients and maternal and infant outcomes after pregnancy: single-center experience from China and review of the literature.

BACKGROUND: Pregnancy in acromegaly is uncommon and still in debate for fear of tumor progression or potential threat to both mother and fetus's health. Besides, the data for pregnancy complications in uncontrolled acromegaly is limited. Thus, the objective of this study was to summarize pregnancy safety and disease courses after pregnancy in acromegalic patients and review their clinical characteristics based on disease activity in the literature. METHODS: An evaluation of eight acromegalic women from Peking Union Medical College Hospital (PUMCH) with 11 pregnancies was conducted. We also summarized a literature review of 82 disease-active pregnancies and 63 disease-controlled pregnancies with acromegaly. A second analysis was conducted to compare pregnancy courses and outcomes in different disease activities. RESULTS: Before pregnancy, all patients had macroadenomas and underwent pituitary surgery. Pregnancy occurred at a median of 6 years (4-10) after the diagnosis of acromegaly. Assisted reproductive therapy was needed in 42.9% of participants. No cases had a premature birth or congenital malformations. Biochemical control was achieved in 50% of females before pregnancy and 75% at the last follow-up after delivery. Data analysis showed no differences in the prevalence of gestational diabetes mellitus (GDM) or pregnancy-induced hypertension (PIH) between acromegaly-active or acromegaly-controlled groups. The GDM prevalence in patients diagnosed during pregnancy (33.3%) was higher than that in patients diagnosed before pregnancy (4.8%) (p = 0.001). CONCLUSION: Pregnancy without biochemical control in acromegaly and receiving medical treatment during pregnancy are not rare and generally safe for the fetus. There could be a higher prevalence of PIH in acromegalic pregnancies. The treatment of acromegaly and related complications can be managed with regular follow-up after pregnancy.

Interference with long noncoding RNA SNHG3 alleviates cerebral ischemia-reperfusion injury by inhibiting microglial activation.

Neuroinflammation plays a strong part in cerebral ischemia-reperfusion injury, and microglial activation is regarded as a marker for neuroinflammation. Long noncoding RNA small nucleolar RNA host gene 3 (lncRNA SNHG3) is heavily expressed in cerebral ischemia-reperfusion models, but its mechanism is rarely studied. This study aims to explore whether SNHG3 is involved in cerebral ischemia-reperfusion injury by promoting microglial activation and inflammatory factor secretion. Activation of microglia was induced through oxygen-glucose deprivation/reoxygenation (OGD/R) or LPS and the cerebral ischemia-reperfusion injury in mice was induced by transient middle cerebral artery occlusion (tMCAO). Levels of SNHG3, IL-6, and TNF-α were determined by quantitative real-time PCR. Immunofluorescence was used for the detection of Iba-1 expression. Western blot was carried out for the detection of Iba-1 and histone deacetylase 3 (HDAC3) protein levels. An ELISA was performed to detect TNF-α and IL-6 levels. RNA pull-down, RNA immunoprecipitation, and co-Immunoprecipitation assays were conducted to detect the binding between SNHG3 and HDAC3. A H&E staining assay was applied to observe pathologic changes. Microglial activation was observed with immunohistochemistry. Levels of SNHG3, microglial activation marker Iba-1, proinflammatory factors (TNF-α and IL-6) were highly expressed in cell models (treated with OGD/R or LPS) and mouse models (tMCAO). Besides, SNHG3 could bind to HDAC3 and promote its expression. Through further study, we found that SNHG3 could stabilize the protein levels of HDAC3 and inhibit the ubiquitination of HDAC3. Furthermore, interference with SNHG3 down-regulated the levels of HDAC3, Iba-1, TNF-α, and IL-6, whereas the overexpression of HDAC3 reversed the results. The H&E staining assay demonstrated that the condition of vacuoles of different sizes, uneven cytoplasmic staining, and inflammatory infiltration in the brain tissue was improved by interference with SNHG3. The immunohistochemistry result showed that microglial activation marker Iba-1 was increased in the shRNA-SNHG3 group, indicating that interference with SNHG3 inhibited the activation of microglia in the brain. LncRNA SNHG3 aggravated cerebral ischemia-reperfusion injury by promoting the activation of microglia, increasing the levels of HDAC3, and the secretion of inflammatory factors.

miR-139-5p promotes neovascularization in diabetic retinopathy by regulating the phosphatase and tensin homolog.

Pathological retinal neovascularization is a driver of the progression of diabetic retinopathy (DR). The present study sought to identify the microRNAs (miRNAs) that are differentially expressed during the progression of DR as well as to explore the specific regulatory mechanism of those miRNAs in retinal neovascularization. Using a microarray data set and a diabetic mouse model, it was determined that miR-139-5p was significantly upregulated during the progression of DR. The in vitro investigation revealed an elevation in the miR-139-5p level in both the high glucose (HG)-treated mouse retinal microvascular endothelial cells (mRMECs) and the HG-treated human RMECs (hRMECs). The miR-139-5p overexpression elevated cell migration, facilitated tube formation, and increased vascular endothelial growth factor (VEGF) protein level in the hRMECs. While the angiogenic effect of miR-139-5p overexpression was halted by an anti-VEGF antibody. Meanwhile, the miR-139-5p knockdown eliminated the VEGF-induced cell migration and tube formation in the hRMECs. The phosphatase and tensin homolog (PTEN) was the target gene of the miR-139-5p. PTEN overexpression removed the angiogenic effect of miR-139-5p overexpression, which led to reduced cell migration and tube formation. In the diabetic mice, the miR-139-5p antagomir effectively decreased the acellular capillaries and suppressed the formation of aberrant blood vessels in the retinal tissues. Taken together, miR-139-5p promotes retinal neovascularization by repressing PTEN expression.

MicroRNA-409-5p promotes retinal neovascularization in diabetic retinopathy.

BACKGROUND: Retinal neovascularization, which is characterized by the increased proliferation, migration, and tube formation of retinal microvascular endothelial cells (RMECs), contributes to the progression of diabetic retinopathy (DR). MiR-409-5p has been reported to be upregulated in peripheral blood of DR patients and in vascular endothelial growth factor (VEGF)-induced RMECs. However, the role of miR-409-5p in retinal neovascularization of DR remains unelucidated. METHOD: The expression of miR-409-5p was measured in retinal tissues of streptozocin-induced and db/db diabetic mice, in high glucose-induced mouse RMECs (mRMECs), and in vitreous fluid of proliferative DR patients. Antagomir of miR-409-5p was intravitreally injected into diabetic mice. Proliferation, migration, and tube formation were detected using cell counting kit-8 assay, transwell assay, and microscope observation, respectively. Luciferase reporter assay was used to detect the direct interaction between miR-409-5p and peroxisome proliferator-activated receptor-α (PPARα). RESULT: MiR-409-5p was upregulated in retinal tissues of diabetic mice, in high glucose-induced mRMECs, and in vitreous fluid of proliferative DR patients. The knockdown of miR-409-5p attenuated retinal neovascularization in vivo. The overexpression of miR-409-5p promotes the proliferation, migration, and tube formation, and increased VEGF expression and secretion, while the knockdown of miR-409-5p suppressed the VEGF-induced retinal neovascularization in vitro. PPARα is a downstream target of miR-409-5p, and PPARα overexpression negated the promotion of miR-409-5p overexpression on the proliferation, migration, and tube formation of mRMECs. CONCLUSION: Our findings demonstrated that miR-409-5p acted as a neovasculogenic factor in DR, and anti-miR-409-5p therapy may provide a novel strategy in treating DR.

Changes of the Expression and Activity of Phosphodiesterase V in the Basilar Artery Before and After Cerebral Vasospasm in a Rabbit Model.

OBJECTIVE: To examine changes of expression and activity of phosphodiesterase V (PDE V) in the basilar artery following cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) in a rabbit model. METHODS: A rabbit model of CVS after SAH was constructed by double blood injection into the cisterna magna. Subjects were divided into 3 groups: blank control group, normal saline group, and SAH group. Transcranial Doppler and selective vertebrobasilar digital subtraction angiography were performed to identify changes of CVS. Changes of PDE V expression and activity were examined. RESULTS: Mean basilar arterial blood flow rate measured by transcranial Doppler was significantly increased in the SAH group compared with the blank control group and normal saline group. Mean basilar artery diameter measured by digital subtraction angiography in the SAH group was narrower than in the other 2 groups. Compared with the other 2 groups, the expression of PDE V in the SAH group was significantly upregulated, and the activity was significantly enhanced. CONCLUSIONS: The rabbit model of SAH-induced CVS was successfully constructed through double blood injection method. Increased basilar artery blood flow, narrowing of the basilar artery, increased PDE V expression, and enhanced PDE V activity in the basilar artery were detected in the CVS rabbits, suggesting that PDE V has the potential to be used as a target for CVS therapy.

WITHDRAWN: To evaluate the Changes of the expression and activity of Phosphodiesterase V in the Basilar Artery Before and After Cerebral Vasospasm in Rabbits model.

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Correlation between PPAR-α methylation level in peripheral blood and inflammatory factors of NAFLD patients with DM.

The correlation between the methylation levels of peroxisome proliferator-activated receptor-α (PPAR-α) in the peripheral blood and the inflammatory factors associated with non-alcoholic fatty liver disease (NAFLD) patients with diabetes mellitus (DM) was investigated. Thirty-two samples of normal liver tissues (group N) and 35 samples of liver tissues from NAFLD patients with DM (group M) were used for the present study. The levels of alanine transaminase (ALT) and aspartate transaminase (AST) were measured using commercially available kits. The accumulation of lipid droplets and glycogen in the two groups was determined through Oil Red O staining and Sudan III staining. mRNA expression of tumor necrosis factor-α (TNF-α), interleukin-lß (IL-1ß) and IL-6 in liver tissues of groups N and M were detected using reverse transcription-polymerase chain reaction (RT-PCR). In addition, western blotting was used to detect the protein expression of PPAR-α in liver tissues of both groups. The Statistical Product and Service Solutions (SPSS) 17.0 statistical software was used to analyze the expression difference of PPAR-α in liver tissues in the groups. The high levels of ALT and AST indicated severe liver injury in group M. Oil Red O staining and Sudan III staining showed a large number of lipid droplets and glycogen accumulation in the liver of group M patients. RT-PCR showed that the expression of inflammatory factors was extremely high and that the inflammatory injury was severe in the liver of group M patients. Western blotting showed that the expression of PPAR-α in group N was significantly higher than that in group M. ANOVA results showed that the expression of PPAR-α in liver tissues of groups N and M patients were statistically significantly different (P<0.01). Therefore, the abnormal expression of PPAR-α is closely associated with the occurrence and development of NAFLD complicated with DM, and that the abnormal expression of PPAR-α is closely related to inflammatory factors. Results from the present study suggest PPAR-α has important value in the study on NAFLD complicated with DM. The expression of PPAR-α can be used as a new basis for the diagnosis and treatment of NAFLD complicated with DM.

Correlation between PPAR-α methylation level in peripheral blood and atherosclerosis of NAFLD patients with DM.

We investigated the correlation between the methylation levels of peroxisome proliferator-activated receptor-α (PPAR-α) in the peripheral blood and atherosclerosis in patients with nonalcoholic fatty liver disease (NAFLD) with diabetes mellitus (DM). A total of 50 normal subjects (group N) and 50 NAFLD patients with DM (group M) were selected at Qilu Hospital of Shandong University. The levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in groups N and M were detected. The mRNA and protein expressions of PPAR-α in groups N and M were detected using reverse transcription polymerase chain reaction (PCR) and immunofluorescence. The differences in expression of PPAR-α in group N and M and the correlation between PPAR-α methylation level and atherosclerosis were analyzed using SPSS17.0 statistical software. TC, TG, HDL and LDL in groups N and M were significantly different (P<0.01). Hematoxylin and eosin staining showed that the histopathological damage was severe in group M. PCR and immunofluorescence showed that PPAR-α was significantly higher in N than in group M (P<0.01). The abnormal expression of PPAR-α is closely related to atherosclerosis, indicating that the correlation between PPAR-α methylation levels in peripheral blood and atherosclerosis of NAFLD patients with DM can provide a new direction of diagnosis and treatment.