Resveratrol alleviates postpartum depression-like behavior by activating autophagy via SIRT1 and inhibiting AKT/mTOR pathway.

BACKGROUND: Postpartum depression (PPD) causes maternal mortality, and has a high disability rate. In recent years, studies have suggested the Sirt1 gene to be involved in the pathogenesis of depression. Resveratrol (RSV), an activator of Sirt1, has been investigated in depressive behavior. However, its effect on PPD remains to be thoroughly elucidated. METHODS: We employed a mice model with bilateral oophorectomy combined with hormone-simulated pregnancy to assess postpartum depression-like behavior. The behavioral tests were performed 2 days after the withdrawal of estradiol benzoate. RSV was administered subcutaneously to the PPD model mice. Several behavioral tests were executed, including the open field test, forced swimming test, and tail suspension test. Western blot analyses and immunofluorescence staining were used to evaluate protein expression levels of SIRT1, autophagy markers, and the AKT/mTOR. RESULTS: Postpartum depressive-like behavior was triggered following the withdrawal of estradiol benzoate after hormone-stimulated-pregnancy. RSV improved postpartum depressive-like behavior of mice via its upregulation of the SIRT1 and autophagy markers, such as Beclin1, ATG5 and LC3B. Also, the downregulation of the p62 protein expression was observed. More importantly, we also detected the inhibition of phosphorylated AKT and mTOR in the hippocampus of postpartum depressive-like mice. CONCLUSION: RSV could alleviate postpartum depression-like behavior in mice by stimulating the SIRT1, induce autophagy and inhibit the AKT/ mTOR signaling pathway.

Thymoquinone has a synergistic effect with PHD inhibitors to ameliorate ischemic brain damage in mice.

BACKGROUND: A blockage in a blood vessel can cause reduced blood flow to the brain, which eventually leads to the death of surrounding tissue. Several studies have attempted to develop an effective intervention to reverse this process and improve the health status of affected individuals. Due to its indirect effect on cellular functions and metabolism, the hypoxia-inducible factor (HIF-1α) protein has been proposed as a promising transcription factor in the treatment of stroke. PURPOSE: The current study aims to explore the relation between HIF-1 α and thymoquinone (TQ) in the attenuation of ischemic brain damage and the possible mechanism of this relation to reduce cell death. METHODS: For this purpose, dimethyloxallyl glycine (DMOG), 8 mg/kg, Acriflavine (ACF), 1.5 mg/kg, and both combined with TQ (5 mg/kg) were assessed. Male C57 mice were used to establish an ischemic stroke model by using endothelin-1 (ET-1) (400 pmole/µl) intra- cranial injection. The ultrastructure alterations of neuronal soma, axons, and mitochondria after stroke and treatment were well addressed. Besides, the expression levels of VEGF, HIF-1α, Nrf2, and HO-1 were evaluated. Meanwhile, apoptosis and autophagy-related proteins were also investigated. RESULTS: Treatment of ischemic stroke by TQ can activate the HIF-1α pathway and its downstream genes such as VEGF, TrkB, and PI3K, which in turn enhance angiogenesis and neurogenesis. Our study revealed that TQ has the same effect as DMOG to activate HIF-1 α and can improve motor dysfunction after ischemic stroke. Further, we demonstrated that both TQ and DMOG effectively attenuate the organelle's damage following ischemic stroke, which was confirmed by the cryogenic transmission electron microscope. The synergistic effect of TQ and DMOG may lead to a chemo-modulation action in the autophagy process after stroke onset and this result is validated by the western blot and rt-qPCR techniques. CONCLUSION: Our finding revealed the potential role of TQ as a HIF-1 α activator to reduce cell death, modulate autophagy and decrease the infarct volume after ischemic stroke onset. The neuroprotective effect of TQ is achieved by decreasing the inflammation and increasing angiogenesis as well as neurogenesis via induction of the HIF-1α-VEGF/Nrf2-HO-1-TrkB-PI3K pathway.

Levels of inter-alpha-trypsin inhibitor heavy chain H4 urinary polypeptide in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) can cause a variety of adverse maternal and fetal complications. The purpose of this study was to screen and identify the urinary polypeptides related to the severity of GDM and to analyze the correlation between urinary peptide levels and neonatal metabolic indices. A total of 31 normal pregnant women (N group) and 74 patients with GDM (GDM group) were randomly selected between February 2018 and August 2019. Patients with GDM were divided into two groups according to their fasting plasma glucose (FPG) levels. The urine samples were enriched using weak cation-exchange magnetic beads (MB-WCX), and eight different urine polypeptides were screened and analyzed. The peptide spectra were obtained using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). The urinary peptide signatures of the two groups were compared using the BioExplorer software. The difference analysis of the eight urinary polypeptides between the normal pregnant (N) group and GDM group showed that two polypeptides with mass-to- charge ratios (m/z) of 2175.7 and 2318.8, respectively, were significantly different between the two groups (P < 0.01). The m/z 2175.7 polypeptide was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS), and the corresponding name of the molecule was inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4). The changes in ITIH4 levels correlated with those in the neonatal metabolic indices. By establishing the Fisher discriminant function equation for the GDM group, the difference in sample distribution and mean value of the two groups could be observed directly.Abbreviations: GDM: gestational diabetes mellitus; FPG: fasting plasma glucose; MB-WCX: weak cation exchange magnetic beads; MALDI-TOF MS: matrix-assisted laser desorption ionization time-of-flight mass spectrometry; m/z: mass charge ratio; LC-MS: liquid chromatography-tandem mass spectrometry; glycosylated hemoglobin (HbA1c); PPG: postprandial plasma glucose; ITIH4: inter-alpha-trypsin inhibitor heavy chain H4; IR: insulin resistance; NFPG: neonatal fasting plasma glucose; NH: neonatal height; NW: neonatal weight; BMI: body mass index; RPL: recurrent pregnancy loss; OGTT: oral glucose tolerance test; ADA: American Diabetes Association; LIS: Laboratory Information System.

Therapeutic impact of thymoquninone to alleviate ischemic brain injury via Nrf2/HO-1 pathway.

Introduction: Reactive oxygen species (ROS)-mediated inflammation plays a crucial role in ischemic brain injury. Therefore, the activation of the nuclear erythroid 2 related protein and heme-oxygenase-1 (Nrf2/HO-1) pathway by thymoquinone (TQ) could ameliorate ischemic brain damage.Areas covered: The photo-thrombotic method was employed to assess the impact of TQ in attenuating ischemic brain damage in C57BL/6 J mice and thy1-YFP-16 transgenic mice. In vitro study of TQ efficiency to attenuate the oxygen-glucose deprivation/reoxygenation (OGD/R) induced cell death by fluorescence-activated cell sorting (FACs) analysis was also analyzed. The protein expression levels of Nrf2/HO-1, inflammatory, and apoptotic were evaluated by immunofluorescence and western blot techniques. Besides, mRNA expression level of inducible nitric oxide synthase (iNOS), proto-oncogene (c-MYC), proto-oncogene (c-FOS), 5-hydroxytryptamine receptors (5-HT), and autophagy-related 5 (Atg5) were evaluated by RT-qPCR. The dendritic spine density of YFP slices was determined by confocal microscope.Results: Our in vivo and in vitro results indicated that TQ significantly mitigates brain damage and motor dysfunction after ischemic stroke. These observations coincided with curtailed cell death, inflammation, oxidative stress, apoptosis, and autophagy. Most importantly, Nrf2/HO-1 signaling pathway activation by TQ was vital in the modulation of the above processes. Lastly, we found TQ to have minimal toxicity in liver tissue.Conclusion: Our study gives credence to TQ as a promising intervention therapy for cerebral ischemia that decreases inflammation, oxidative stress, and neuronal cell death via the Nrf2/HO-1 pathway, along with modulation of apoptotic and autophagic processes.

Hypoxia Inducible Factor-1α Attenuates Ischemic Brain Damage by Modulating Inflammatory Response and Glial Activity.

Hypoxia-inducible factor 1 can sufficiently control the progress of neurological symptoms after ischemic stroke owing to their actions associated with its downstream genes. In this study, we evaluated the role of HIF-1α in attenuating brain damage after endothelin-1 injection. Focal cerebral ischemia in mice were induced by endothelin-1 microinjection. Hypoxia-inducible factor 1 activator, dimethyloxalylglycine (DMOG), and HIF-1α inhibitor, acriflavine (ACF), were used to evaluate the hypoxia-inducible factor 1 activity during cerebral ischemia. The expression levels of HIF-1α, glial fibrillary acidic protein (GFAP), interleukin-10 (IL-10), inducible nitric oxide synthase (iNOS), phosphorylated I-kappa-B-alpha/total I-kappa-B-alpha (p-IκBα/IκBα) and nuclear factor kappa B (NF-kB) were assessed. Besides, mRNA levels of IL-10, tumor necrosis factor- alpha (TNF-α), and NF-kB were also analyzed. Results showed a noticeable increase in hypoxia-inducible factor 1 and IL-10 levels in the DMOG group with a decline in iNOS, TNF-α, and NF-kB levels, implying the anti-inflammatory role of hypoxia-inducible factor 1 activator following stroke. These findings were further corroborated by GFAP immunostaining that showed astrocytic activation to be inhibited 12 days post-ischemia, as well as histological and TEM analyses that demonstrated hypoxia-inducible factor 1 induction to alleviate neuronal soma damage and cell death. Based on our study, HIF-1α could be a potential therapeutic target for ischemic stroke.

Establishment of clinical diagnostic models using glucose, lipid, and urinary polypeptides in gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) has many adverse outcomes that seriously threaten the short-term and long-term health of mothers and infants. This study comprehensively analyzed the clinical diagnostic value of GDM-related clinical indexes and urine polypeptide research results, and established comprehensive index diagnostic models. METHODS: In this study, diagnostic values from the clinical indexes of serum triglyceride (TRIG), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c), and 7 GDM-related urinary polypeptides were analyzed retrospectively. The multiple logistic regression equation, multilayer perceptron neural network model, radial basis function, and discriminant analysis function models of GDM-related indexes were established using machine language. RESULTS: The results showed that HbA1c had the highest diagnostic value for GDM, with an area under the curve (AUC) of 0.769. When the cut-off value was 4.95, the diagnostic sensitivity and specificity were 70.5% and 70.0%, respectively. Among the seven GDM-related urinary polypeptides, human hemopexin (HEMO) had the highest diagnostic value, with an AUC of 0.690. When the cut-off value was 368.5, the sensitivity and specificity were 79.5% and 43.3%, respectively. The AUC of the multilayer perceptron neural network model was 0.942, followed by binary logistic regression (0.938), radial basis function model (0.909), and the discriminant analysis function model (0.908). CONCLUSION: The establishment of a GDM diagnostic model combining blood glucose, blood lipid, and urine polypeptide indexes can lay a foundation for exploring machine language and artificial intelligence in diagnostic systems.

Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence.

ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. Recent studies have shown that ARID1A deficiency induces global changes in the epigenetic landscape of enhancers and promoters. These broad and complex effects make it challenging to identify the driving mechanisms of ARID1A deficiency in promoting cancer progression. Here, we identified the anti-senescence effect of Arid1a deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in a mouse model. In a human cell line model, we found that ARID1A deficiency upregulates the expression of aldehyde dehydrogenase 1 family member A1 (ALDH1A1), which plays an essential role in attenuating the senescence induced by oncogenic KRAS through scavenging reactive oxygen species. As a subunit of the SWI/SNF chromatin remodeling complex, our ATAC sequencing data showed that ARID1A deficiency increases the accessibility of the enhancer region of ALDH1A1. This study provides the first evidence that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence through the upregulation of ALDH1A1 expression.

MicroRNAs in urine as diagnostic biomarkers for multiple myeloma.

INTRODUCTION: Multiple myeloma (MM) is a hematological malignancy. It is of great clinical significance to screen microRNAs (miRNAs) in urine as noninvasive diagnostic biomarkers for MM. METHODS: Urinary miRNAs in MM were performed by Agilent Bioanalyzer 2100 and verified by quantitative real-time PCR (qRT-PCR). Receiver operator characteristic (ROC) was used to evaluate the diagnostic value of abnormal miRNAs for MM. Progression-free survival (PFS) of MM was calculated by Kaplan-Meier. RESULTS: In microarray analysis, twelve down-regulated miRNAs dysregulated in MM. The expression levels of miR-134-5p, miR-6500-5p, miR-548q, and miR-548y were validated. These miRNAs were significantly lower in MM (P < .05), but there was no significant difference between newly diagnosed, relapse, and remission group of MM (P> .05). ROC curve analysis showed that the sensitivity of miR-134-5p, miR-6500-5p, miR-548q, and miR-548y to MM was 91.7%, 100%, 100%, and 91.7%, and the specificity was 66.7%, 75.0%, 75.0%, and 100%, respectively. The four miRNAs were negatively correlated with the total urinary light chain (r = -0.427 P = .030, r = -0.461 P = .018, r = -0.469 P = .016, r = -0.493 P = .011). In addition, miR-134-5p, miR-6500-5p, and miR-548q were positively correlated with serum ALB (r = 0.518 P = .006, r = 0.400 P = .039,r = 0.492 P = .009). The expression level of miRNAs had no significant influence on PFS in MM patients (P> .05). CONCLUSION: The results show that miR-134-5p, miR-6500-5p, miR-548q, and miR-548y are potential noninvasive diagnostic biomarkers for MM.

Combinational Pretreatment of Colony-Stimulating Factor 1 Receptor Inhibitor and Triptolide Upregulates BDNF-Akt and Autophagic Pathways to Improve Cerebral Ischemia.

Ki20227, a selective inhibitor of colony-stimulating factor 1 receptor (CSF1R), has been suggested to regulate microglia inflammatory function and neuronal synaptic plasticity. Triptolide (TP) pretreatment has neuroprotective effects through its anti-inflammatory and antiapoptotic features in ischemic stroke mice. However, the underlying mechanism and pathway are presently unclear. We thus investigated the association between neuroprotective effects of combined TP and Ki20227 and BDNF-Akt and autophagy pathways. Ki20227 was administrated for 7 days, and TP was administered once 24 hours prior to building the ischemic stroke model in C57BL/6 mice. Behavioral tests, Golgi staining, immunofluorescence, and western blot analyses were employed to examine neuroprotective effects of TP and Ki20227. TP and Ki20227 pretreatments improved the neurobehavioral function in stroke mice. Synaptic protein expressions and density of dendritic spine density were upregulated in Ki20227 and TP pretreated stroke mice. Further, optimized integration of TP and Ki20227 pretreatments upregulated the NeuN expression and downregulated Iba1 expression after stroke. In addition, both TP and Ki20227 pretreatments significantly upregulated BDNF, p-Akt/Akt, and Erk1/2 protein expressions and autophagy related proteins (LC3II/I, Atg5, and p62), indicating the activation of BDNF and autophagic pathways. Optimized integration of TP and Ki20227 can improve cerebral ischemia by inhibiting CSF1R signal and trigger autophagy and BDNF-Akt signaling pathways to increase dendritic spine density and synaptic protein expressions, which in turn enhances neurobehavioral function.

Expression of AKT and p-AKT protein in lung adenocarcinoma and its correlation with PD-L1 protein and prognosis.

BACKGROUND: The PI3K/AKT/mTOR signaling pathway were significantly associated with EGFR mutation in lung adenocarcinoma (LUAD), but its correlation with PD-L1 protein and prognosis are not clear. The aim of this study was to evaluate the expression of AKT and phosphorylated AKT (p-AKT) in LUAD and its correlation with programmed death ligand-1 (PD-L1); and to analyze the factors affecting LUAD prognosis. METHODS: The expression of AKT, p-AKT, and PD-L1 was examined using immunohistochemistry in LUAD tissues from 110 patients who underwent surgical treatment. RESULTS: AKT protein expression was examined in 64.5% (71/110) of the LUAD samples, and p-AKT protein expression was examined in 44.5% (49/110) of the LUAD samples. The positive rate of PD-L1 at TC1/2/3 was 38.2% (42/110). AKT and p-AKT expression was significantly associated with epidermal growth factor receptor (EGFR) mutation (P=0.016, P=0.014 respectively). Pearson's correlation analysis indicated a negative correlation of p-AKT with PD-L1 protein (P=0.022). Out of the 62 patients with EGFR mutation, the expression of PD-L1 was negatively correlated with that of p-AKT protein (P=0.032). The expressions of AKT and p-AKT were not associated with prognosis. Multivariate analysis showed that tumor-node-metastasis (TNM) stage (P=0.013) and differentiation (P=0.046) were independent prognostic factors for overall survival. CONCLUSIONS: PI3K/AKT/mTOR in the downstream pathway of EGFR may negatively regulate the expression of PD-L1, which may partly explain why patients with EGFR mutation respond poorly to PD-1/PD-L1 inhibitors.

Urinary Peptides Associated Closely with Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is a common disease of pregnant women, which has a higher incidence in recent years. The purpose of this study is to explore urinary biomarkers that could predict and monitor gestational diabetes mellitus (GDM). Urine samples from 30 normal pregnant women and 78 GDM patients were collected and purified by weak cationic exchange magnetic beads (MB-WCX), then analyzed by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS). The urinary peptide signatures of the two groups were compared by BioExplorer software. The potential ability of the differently expressed peptides to distinguish GDM patients from normal pregnant women was evaluated by receiver operating characteristic (ROC) analysis. At last, the differently expressed peptides were identified by liquid chromatography tandem mass spectrometry (LC-MS). There were four differently expressed peptides (m/z 1000.5, 1117.5, 1142.9, and 2022.9) between two groups, which were identified as fragments of urinary albumin, α2-macroglobulin, human hemopexin, and α1-microglobulin, respectively. The diagnostic efficacy of m/z 1142.9 was better than the other peptides. The area under the curve (AUC) of the m/z 1142.9 was 0.690 (95% CI: 0.583-0.796). The discovery of urinary polypeptides provides the possibility for the early prediction of GDM and the monitoring of glucose metabolism in GDM patients by a noninvasive method.

Screening and analysis of small molecular peptides in urine of gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a common clinical disease with complicated clinical process and harmful effects on pregnant women and fetus. The purpose of this study is to use the convenient urine samples in combination with glucose levels to detect or predict GDM. In this study, urine samples of non-pregnant women, normal pregnant women and GDM patients were collected. The peptides in urine were enriched by weak cationic exchange magnetic beads (MB-WCX) and analyzed by matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). 46 polypeptide peaks with statistical difference (P < 0.01) were screened out by using Bioexplorer analysis software. The level of molecules with mass-to-charge ratio of 1079.2, 1290.6 and 1500.7 was higher in the GDM group than the other two groups. Through the analysis of differential molecules by liquid chromatography tandem mass spectrometry (LC-MS), the above molecules were identified as coagulation factor IX, TBC1 family member 5 isoform a [Homo sapiens] (TBC1D5a) and immunoglobulin kappa constant. The discovery of polypeptides provides the research basis for further primary screening and assistant diagnosis of GDM through urine samples.

Recent advances of induced pluripotent stem cells application in neurodegenerative diseases.

Stem cell is defined by its ability to self-renewal and generates differentiated functional cell types, which are derived from the embryo and various sources of postnatal animal. These cells can be divided according to their potential development into totipotent, unipotent, multipotent andpluripotent. Pluripotent is considered as the most important type due to its advantageous capability to create different cell types of the body in a similar behavior as embryonic stem cell. Induced pluripotent stem cells (iPSCs) are adult cells that maintain the characteristics of embryonic stem cells because it can be genetically reprogrammed to an embryonic stem cell-like state via express genes and transcription factors. Such cells provide an efficient pathway to explorehuman diseases and their corresponding therapy, particularly, neurodevelopmental disorders. Consequently, iPSCs can be investigated to check the specific mutations of neurodegenerative disease due to their unique ability to differentiate into neural cell types and/or neural organoids. The current review addresses the different neurodegenerative diseases model by using iPSCs approach such as Alzheimer's diseases (AD), Parkinson diseases (PD),multiplesclerosis(MS) and psychiatric disorders. We also highlight the importance of autophagy in neurodegenerative diseases.

Progesterone and fluoxetine treatments of postpartum depressive-like behavior in rat model.

Research studies have indicated that alterations in plasma progesterone levels might be associated with the hippocampal synaptic plasticity of postpartum depressive-like behavior. Herein, we assess both progesterone and fluoxetine effects in adult female Sprague-Dawley rats with postpartum depressive-like behavior. Depressive-like behavior of postpartum rats was established using chronic ultra-mild stress (CUMS) method for 1 week from gestation day 15. Postpartum rats that showed depressive-like behavior were treated with either progesterone (subcutaneously, 0.5 mg/kg) from gestation day 17 to gestation day 22 or fluoxetine (by gavage, 10 mg/kg/day) for 4 weeks after birth. Open field and sucrose preference tests were conducted at the start, week 2 and week 4 postpartum. Golgi staining, immunofluorescence and Western blot analyses of rats' hippocampi were conducted on week 4 postpartum. Results showed CUMS increases depressive-like behavior, however, treatment with progesterone and fluoxetine improves this behavior. Both progesterone and fluoxetine treatments increase the numbers of dendritic spines pyramidal neurons in the CA3 region of the hippocampus as well as protein expression levels of microtubule-associated protein 2 (MAP-2) and synaptophysin (SYP). CUMS-induced decrement of MAP-2 and SYP protein expressions can be prevented by treatment with progesterone in advanced pregnant stage and fluoxetine in the postpartum period.

SIRT1 Protects Against Apoptosis by Promoting Autophagy in the Oxygen Glucose Deprivation/Reperfusion-Induced Injury.

Silent information regulator 1 (SIRT1) contributes to cellular regulation. Previous studies have reported SIRT1 to be abnormally expressed in the ischemic penumbra of cerebral ischemia/reperfusion (I/R) injury rat model. We investigated the effect of SIRT1 on oxygen and glucose deprivation/reperfusion (OGD/R) cell injury. Over-expressed or silenced SIRT1 pheochromocytoma 12 (PC12) cells were exposed to an in-vitro OGD/R injury. Western blot, TUNEL staining and immunofluorescence analyses were performed to assess apoptosis and autophagy. We found autophagy and apoptosis to be up-regulated and down-regulated, respectively, following the over-expression of SIRT1 in the OGD/R-induced PC12 cells. We also found the silencing of SIRT1 to culminate in the down-regulation and up-regulation of autophagy and apoptosis, respectively. On the basis of our results, we surmise that SIRT1 can promote autophagy and inhibit apoptosis in-vitro, and thus exhibit potential neuroprotection against OGD/R-induced injury. This could facilitate in the development of therapeutic approaches for cerebral I/R injury.

Ovarian hormones ameliorate memory impairment, cholinergic deficit, neuronal apoptosis and astrogliosis in a rat model of Alzheimer's disease.

Ovarian hormones, including progesterone (P4) and 17 ß-estradiol (E2), have been shown to affect memory functions; however, the underlying mechanism whereby ovarian hormone replacement therapy may decrease the risk of Alzheimer's disease (AD) is currently unclear. The present study aimed to investigate the effects of P4 and E2 on spatial and learning memory in an ovariectomized rat model of AD. ß-amyloid (Aß) or saline were stereotaxically injected into the hippocampus of the rats and, after 1 day, ovariectomy or sham operations were performed. Subsequently, the rats were treated with P4 alone, E2 alone, or a combination of P4 and E2. Treatment with E2 and/or P4 was shown to improve the learning and memory functions of the rats, as demonstrated by the Morris water maze test. In addition, treatment with E2 and P4 was associated with increased expression levels of choline acetyltransferase and 5-hydroxytryptamine receptor 2A (5-HT2A), and decreased expression levels of the glial fibrillary acidic protein in the hippocampus of the rats. Furthermore, E2 and P4 treatment significantly attenuated neuronal cell apoptosis, as demonstrated by terminal deoxynucleotidyl transferase dUTP nick end labeling assays; thus suggesting that the ovarian hormones were able to protect against Aß-induced neuronal cell toxicity. The results of the present study suggested that the neuroprotective effects of P4 and E2 were associated with amelioration of the cholinergic deficit, suppression of apoptotic signals and astrogliosis, and upregulation of 5-HT2A expression levels. Therefore, hormone replacement therapy may be considered an effective strategy for the treatment of patients with cognitive disorders and neurodegenerative diseases.

Anti-Inflammatory and Neuroprotective Effects of Triptolide via the NF-κB Signaling Pathway in a Rat MCAO Model.

Stroke is the leading cause of neurological disability in humans. Middle cerebral artery occlusion (MCAO) followed by reperfusion is widely accepted to mimic stroke in basic medical research. Triptolide is one of the major active components of the traditional Chinese herb Tripterygium wilfordii Hook F, and has been reported to have potent anti-inflammatory and immunosuppressive properties. Since its preclinical effects on stroke were still unclear, we decided to study the effects of Triptolide on focal cerebral ischemia/reperfusion injury in this study. The results showed that Triptolide treatment significantly attenuates brain infarction volume, water content, neurological deficits, and neuronal cell death rate, which were increased in the MCAO model rats. Immunohistochemistry was used to analyze the expression of glial fibrillary acidic protein (GFAP), Cyclooxygenase-2 (COX-2), inducible nitric oxide (iNOS), and NF-κB in the ischemic brains. The administration of Triptolide showed down-regulation of the iNOS, COX-2, GFAP, and NF-κB expression in MCAO rats. It also increased the expression of bcl-2, and suppressed levels of bax and caspase-3 compared with the MCAO group. Our findings revealed that Triptolide exerts its neuroprotective effects against inflammation with the involvement of inhibition of NF-κB activation.

Association between single nucleotide polymorphisms of sterol regulatory element binding protein-2 and liver X receptor α gene and risk of polycystic ovary syndrome in a Chinese Han population.

To investigate associations of single nucleotide polymorphisms (SNPs) rs2228314 of sterol regulatory element-binding protein-2 (SREBP-2) or rs11039155 of liver X receptor α (LXRα) with susceptibility to polycystic ovary syndrome (PCOS) in a Chinese Han population. SREBP-2 rs2228314 and LXRα rs11039155 polymorphisms were genotyped in patients with PCOS and age- and sex-matched PCOS-free controls from a Chinese Han population. A total of 605 patients with PCOS and 615 controls were recruited in this study. We found that GC and CC genotypes of rs2228314, and variant C, were associated with a significantly increased risk of PCOS. In addition, GA and AA genotypes of rs11039155, as well as variant A, were also associated with a significantly increased risk of PCOS. Our results showed that SREBP-2 rs2228314 G to C change and variant C genotype as well as LXRα rs11039155 G to A change and variant A may contribute to PCOS in Chinese Han population.

Mifepristone: a potential clinical agent based on its anti-progesterone and anti-glucocorticoid properties.

Nowadays, unwanted pregnancy is a major globe tragedy for millions of women, associated with significant direct and indirect costs, no matter for individuals or society. The progesterone receptor antagonist steroid, mifepristone has been widely and effectively using throughout the world for medical abortion, but to a lesser extent for emergency contraception. In this review, we hope to explore the role of mifepristone as a contraceptive, particularly for emergency contraception. Studies of mifepristone have also been expanding to the fields of endometriosis and uterine fibroids. Furthermore, this initially considered reproductive medicine has been investigated in some psychotic diseases and various disorders of hypercortisolism, because of its glucocorticoid receptor antagonism. Mifepristone was approved suitable for patients with hyperglycemia secondary to Cushing's syndrome by the United States Food and Drug Administration (FDA) in 2012. The aim of this article is to review published reports on the anti-progesterone and anti-glucocorticoid properties of mifepristone as a clinical agent. There is a new insight into systematically describing and evaluating the potential efficiency of mifepristone administrated in the field of endocrine and neuroendocrine, not only in obstetrics and gynecology.

Dose-dependent anti-inflammatory and neuroprotective effects of an ανß3 integrin-binding peptide.

Previous studies have shown that prevention of leukocyte infiltration by targeting integrins involved in transendothelial migration may suppress the clinical and pathological features of neuroinflammatory disease. This study was designed to investigate the effects of C16, an ανß3 integrin-binding peptide, in an acute experimental allergic encephalomyelitis (EAE) rat model. Multiple histological and immunohistochemical staining, electron microscopy observation, ELISA assay, Western blot, and magnetic resonance imaging (MRI) were employed to assess the degree of inflammation, axonal loss, neuronal apoptosis, white matter demyelination, and extent of gliosis in the brain and spinal cord of differently treated EAE models. The results showed that C16 treatment could inhibit extensive leukocyte and macrophage accumulation and infiltration and reduce cytokine tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) expression levels. A significantly lower clinical score at the peak time of disease was also demonstrated in the C16 treated group. Moreover, astrogliosis, demyelination, neuronal death, and axonal loss were all alleviated in C16 treated EAE animals, which may be attributed to the improvement of microenvironment. The data suggests that C16 peptide may act as a protective agent by attenuating inflammatory progression and thus affecting the expression of some proinflammatory cytokines during neuroinflammatory disease.