Biometals in Alzheimer disease: emerging therapeutic and diagnostic potential of molybdenum and iodine.

The current ageing trend of the world population has, in part, accounted for Alzheimer disease (AD) being a public health issue in recent times. Although some progress has been made in clarifying AD-related pathophysiological mechanisms, effective intervention is still elusive. Biometals are indispensable to normal physiological functions of the human body-for example, neurogenesis and metabolism. However, their association with AD remains highly controversial. Copper (Cu) and zinc (Zn) are biometals that have been investigated at great length in relation to neurodegeneration, whereas less attention has been afforded to other trace biometals, such as molybdenum (Mo), and iodine. Given the above context, we reviewed the limited number of studies that have evidenced various effects following the usage of these two biometals in different investigative models of AD. Revisiting these biometals via thorough investigations, along with their biological mechanisms may present a solid foundation for not only the development of effective interventions, but also as diagnostic agents for AD.

Sox17 protects human brain microvascular endothelial cells from AngII-induced injury by regulating autophagy and apoptosis.

Intracranial aneurysm (IA), is a localized dilation of the intracranial arteries, the rupture of which is catastrophic. Hypertension is major IA risk factor that mediates endothelial cell damage. Sox17 is highly expressed in intracranial vascular endothelial cells, and GWAS studies indicate that its genetic alteration is one of the major genetic risk factors for IA. Vascular endothelial cell injury plays a vital role in the pathogenesis of IA. The genetic ablation of Sox17 plus hypertension induced by AngII can lead to an increased incidence of intracranial aneurysms had tested in the previous animal experiments. In order to study the underlying molecular mechanisms, we established stable Sox17-overexpressing and knockdown cell lines in human brain microvascular endothelial cells (HBMECs) first. Then flow cytometry, western blotting, and immunofluorescence were employed. We found that the knockdown of Sox17 could worsen the apoptosis and autophagy of HBMECs caused by AngII, while overexpression of Sox17 had the opposite effect. Transmission electron microscopy displayed increased autophagosomes after the knockdown of Sox17 in HBMECs. The RNA-sequencing analysis shown that dysregulation of the Sox17 gene was closely associated with the autophagy-related pathways. Our study suggests that Sox17 could protect HBMECs from AngII-induced injury by regulating autophagy and apoptosis.

Upregulations of high mobility group box 1 and TLR4/NF-κB signaling pathway in hippocampus and serum of rats with febrile seizure.

PURPOSE: The aim of this study was to explore the alternations regarding the HMGB1 and TLR4/NF-κB signaling pathway in juvenile rats with febrile seizure (FS). MATERIALS AND METHODS: During the animal modeling of the FS, seizures were triggered every four days by hot water (45 °C), and repeated ten times. After forty days' modeling, rats were divided into different groups according to the degree of seizure (FS (0) - FS (V)). Reverse transcription-polymerase chain reaction (RT-PCR) was used to evaluate the mRNA expressions of the HMGB1, TLR4 and NF-κB in the hippocampus, while Western-blot (WB) and immunofluorescence (IF) were employed to assess protein expressions. The enzyme-linked immunosorbent assay (ELISA) was used for analyzing the protein expressions in peripheral blood. RESULTS: The mRNA levels of the HMGB1, TLR4 and NF-κB in the hippocampus of both FS (V) and FS (IV) groups were significantly higher than WT, while there was no difference between FS (III) and WT. Concerning protein expressions, increased levels of the HMGB1, TLR4, and NF-κB in FS (V) were observed with a good consistency between the WB and IF, while no significant upregulation was shown in FS (IV). The ELISA results showed that the significance of the augmented proteins between the FS (V) and WT were smaller in the serum than the hippocampus. CONCLUSIONS: Our study shows seizure degree-related upregulations of HMGB1 and TLR4/NF-κB signaling pathway both in hippocampus and serum of juvenile rats with FS, suggesting the involvement of TLR/NF-κB pathway in inflammation promoted by HMGB1 during FS.

Husband-wife Relationship, Neonatal Health, Breast Milk Volume and Postpartum Depression: A Prospective Cohort Study.

Postpartum depression (PPD) is a major public health problem that has negative effects on mothers, infants, and society. This study was aimed at investigating the prevalence of PPD and elucidating the delivery factors implicated in PPD so as take more targeted measures for reducing the potential risk factors. A prospective cohort study was conducted. Following the criterion, 151 pregnant women were included in the study. The Edinburgh Postpartum Depression Scale (EPDS) and the general questionnaire were filled out 2-3 days after delivery. At weeks 2 and 6 postpartum, the EPDS was reassessed either online or via telephone. Also, electronic medical records based on relevant information during the delivery period were collected. Statistical significance was defined as p < 0.05. A high rate of PPD (31.13%) was reported. Univariate correlation analysis showed statistically significant differences in the husband-wife relationship (χ2 = 18.497, p < 0.001), neonatal health (χ2 = 14.710, p < 0.001), and breast milk volume (χ2 = 5.712, p = 0.017) between PPD and normal control groups. Adjusting for other covariates, multivariate logistic regression analysis showed that satisfactory conjugal relation could reduce the risk of PPD (OR, 0.053; p = 0.022); Neonatal health problems significantly increase the risk of PPD (OR, 6.497; p = 0.001); Adequate breast milk could alleviate the risk of PPD (OR, 0.351; P = 0.045). Data analysis suggests that marital discord and unhealthy new-born are independent risk factors; nevertheless, sufficient breast milk is a protective factor against PPD. Healthcare workers such as hospital and community doctors and social workers should pay attention to PPD. Furthermore, perinatal emotional support, health education, and EPDS assessment need to be incorporated into maternity care. Screening and personalized psychological counselling should be carried out for high-risk pregnant women with PPD.

Defects of parvalbumin-positive interneurons in the ventral dentate gyrus region are implicated depression-like behavior in mice.

Depression is an increasingly common but extremely serve mood disorder that remains poorly understood and inadequately treated. Fast-spiking parvalbumin-positive interneurons (PVIs), a subpopulation of GABAergic interneurons (GABA, g-aminobutyric acid), exhibit a widespread distribution throughout the hippocampus, and has been reported to play an important role in a variety of mental disorders. However, the relationship between depression and hippocampal PVIs remains unclear. Here in this present study, a series of experiments were conducted to clarify the potential relationship. Here, chronic unpredicted mild stress (CUMS) and Lipopolysaccharide (LPS) injection were introduced to induce depression-like behavior in mice, and led to a clear decline in PVIs numbers in the ventral hippocampal (vHPC), particularly in the ventral dentate gyrus (vDG) subfield. After a selectively removal of the PVIs in PV-ires-Cre::Ai14 mice, we confirmed that ablation of PVIs from the vDG induced depression-like behavior. Furthermore, we found that the removal of vDG-PVIs induced depression likely to be accounted for upregulation of neuroinflammation. These findings facilitate us better understand the role of hippocampal PVIs in depression.

Exploratory Investigation of Intestinal Structure and Function after Stroke in Mice.

Stroke is the second leading cause of death worldwide. Patients who have a stroke are susceptible to many gastrointestinal (GI) complications, such as dysphagia, GI bleeding, and fecal incontinence. However, there are few studies focusing on the GI tract after stroke. The current study is to investigate the changes of intestinal structure and function in mice after ischemic stroke. Ischemic stroke was made as a disease model in mice, in which brain and ileal tissues were collected for experiments on the 1st and 7th day after stroke. Intestinal motility of mice was inhibited, and intestinal permeability was increased after stroke. Hematoxylin-eosin (HE) staining showed the accumulation of leucocytes in the intestinal mucosa. Myeloperoxidase (MPO) activity and inflammatory proteins (nuclear factor kappa-B (NF-κB), inducible nitric oxide synthase (iNOS)) in the small intestine were significantly increased in mice after stroke. The expression of tight junction (TJ) proteins (zonula occludens-1 (ZO-1), occludin, and claudin-1) was downregulated, and transmission electron microscopy (TEM) showed broken TJ of the intestinal mucosa after stroke. Glial fibrillary acidic protein (GFAP) and the apoptosis-associated proteins (tumor necrosis factor (TNF-α), caspase-3, and cleaved caspase-3) were notably upregulated as well. Ischemic stroke led to negative changes on intestinal structure and function. Inflammatory mediators and TNF-α-induced death receptor signaling pathways may be involved and disrupt the small intestinal barrier function. These results suggest that stroke patients should pay attention to GI protection.

Triptolide improves spinal cord injury by promoting autophagy and inhibiting apoptosis.

We investigated the effect of triptolide (TP) on spinal cord injury (SCI), and its underlying mechanism. Following the establishment of the SCI model using YFP H-line transgenic mice, TP was intraperitoneally injected at a dose of 0.2 mg/kg once daily for 7 days. Behavioral tests, Nissl staining, and hematoxylin-eosin staining were employed to assess motor function recovery and neuronal cell death. Western blot and immunofluorescence staining were used to assess autophagy-associated proteins (LC3B, p62, Beclin-1) and the apoptosis-associated proteins (Bcl-2, caspase-3, Bax). The TP-treated group showed improved motor functions, and reduced neuronal cell death. Also, significant upregulation of Bcl-2 and LC3B expressions, with the downregulation of p62, Bax and caspase-3 expressions were found in the TP-treated group. Additionally, phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1 and ERK2) was decreased in the TP-treated group. TP mediates its protective effect in SCI by promoting the autophagic pathway while inhibiting the MAPK/ERK1/2 signaling pathway. These results demonstrate the therapeutic potential of TP in SCI.

Application of gene chip technology in the diagnostic and drug resistance detection of Helicobacter pylori in children.

BACKGROUND AND AIMS: Helicobacter pylori (HP) culture for diagnosing HP infection is time-consuming and technologically complex. This study evaluated the clinical significance of gastric mucosal gene chip technology in the rapid diagnosis of HP infection and detection of drug resistance in children. METHODS: Patients (between the age of 2.5 and 16.0 years old) manifesting gastrointestinal symptoms were enrolled in this study. HP culture of gastric mucosa and drug sensitivity test were performed. A gene chip of gastric mucosa was used to detect the presence of HP infection, some single nucleotide polymorphisms in HP drug resistance genes, or associated gene mutation. DNA sequencing was investigated and compared with the gene chip test results. RESULTS: Out of 267 cases, HP culture was positive in 169 cases and negative in 98 cases. HP detection by the gene chip method was positive in 208 cases and negative in 59 cases. The sensitivity, specificity, and accuracy of the gene chip technology for diagnosing HP infection were 96.1, 85.0, and 93.6%, respectively. HP resistance gene locus using the gene chip showed the main mutation locus of clarithromycin to be 2143A/G, levofloxacin at locus GyrA 91 and GyrA 87, and amoxicillin at PBP1 556ser. Concordance rates between gene chip and DNA sequencing for VacA-S/M, 16S rRNA, 23S rRNA, and GyrA were greater than 95%, and that of PBP1 was greater than 82%. CONCLUSION: Gastric mucosal gene chip technology can be used for rapid diagnosis and drug resistance detection of HP infection in children.

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.

Inhibited CSF1R Alleviates Ischemia Injury via Inhibition of Microglia M1 Polarization and NLRP3 Pathway.

Ischemia cerebral stroke is one of the common neurological diseases with severe inflammatory response and neuron death. The inhibition of colony-stimulating factor 1 receptor (CSF1R) which especially expressed in microglia/macrophage exerted neuroprotection in stroke. However, the underlying neuroinflammatory regulation effects of CSF1R in ischemia stroke are not clear. In this study, cerebral ischemia stroke mice model was established. The C57/B6J mice were administered with Ki20227, a CSF1R inhibitor, by gavage for 7 consecutive days (0.002 mg/kg/day) before modeling. The Rota-Rod test and neurobehavioral score test were investigated to assess neurobehavioral functions. The area of infarction was assessed by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The mRNA expressions of M1/M2 microglia markers were evaluated by real-time PCR. Immunofluorescence and Western blot were utilized to detect the changes of Iba1 and NLRP3 pathway proteins. Results showed that neurobehavioral function improvement was demonstrated by an increased stay time on the Rota-Rod test and a decreased neurobehavioral score in the Ki20227 treatment group. The area of infarction reduced in Ki20227 group when compared to the stroke group. Moreover, the mRNA expression of M1 microglia markers (TNF-α and iNOS) decreased while M2 microglia markers (IL-10 and Arg-1) increased. Meanwhile, compared to the stroke and stroke+PBS group, Ki20227 administration downregulated the expression of NLRP3, active caspase 1, and NF-κB protein in the ischemia penumbra of Ki20227 treatment group mice. In short, the CSF1R inhibitor, Ki20227, played vital neuroprotective roles in ischemia cerebral stroke mice, and the mechanisms may be via inhibiting microglia M1 polarization and NLRP3 inflammasome pathway activation. Our study provides a potential new target for the treatment of ischemic stroke injury.

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.

Localization of estrogen receptor ERα, ERß and GPR30 on myenteric neurons of the gastrointestinal tract and their role in motility.

Estrogen is well known to have a modulatory role on gastrointestinal tract, particularly through its interaction with nuclear estrogen receptors (ERs), alpha and beta (ERα/ß). Recent functional studies also indicate that estrogen can activate a G-protein coupled estrogen receptor, GPR30, or GPER1. The present study was designed to identify either the presence or absence of nuclear ERs and GPR30 in the myenteric plexus of the stomach, duodenum, jejunum, ileum and colon of female and male mice. Immunofluorescence staining revealed a high expression of GPR30 in the cytoplasm but not within the nucleus of enteric neurons in female and male mice. ERß localization was similar to GPR30, where it was expressed in cytoplasm of enteric neurons, but was absent from nuclei, opening up the possibility that ERß and GPR30 might work together to manifest estrogenic effects. Comparatively, ERα was mainly located in the nuclei of enteric neurons. ERα, ERß and GPR30 were also expressed in the cytoplasm of glial cells in the stomach and small intestine, but levels were lower in the colon. The expression nuclear:cytoplasm ratio of ERα was higher in male than female mice, which might relate to sex-dependent translocation of ERα from cytoplasm to nucleus in response to known plasma levels of estrogen. A functional study using isolated ileal segments showed that ERα, ERß and GPR30 are involved in the neuronal-mediated contractions in female tissues, but only ERα was involved in male tissues. This may indicate although expression level was similar between males and females, the downstream mechanisms of ERß and GPR30 could be different between sexes. The present study provides a rationale for the action of estrogen to modulate gastrointestinal function in health and disease in different sexes.

Stimulation of Anxiety-Like Behavior via ERK Pathway by Competitive Serotonin Receptors 2A and 1A in Post-Traumatic Stress Disordered Mice.

BACKGROUND/AIMS: Serotonin 5HT2A and 5HT1A receptors (5HT2AR, 5HT1AR) have the closest connection to anxiety-like behavior in post-traumatic stress disorder (PTSD). However, the underlying mechanism remains unclear. In this study, we explored the connection between 5HT2A and 5HT1A receptors and anxiety-like behavior. METHODS: In the PTSD animal model, mice were exposed to conditioned fear stress coupled with single-prolonged stress (CF+SPS). Post stress infliction and behavioral tests, of which include open field, freezing behavior and elevated plus maze tests were carried out to examine establishment of the proposed model. Both Western blot analysis and immunofluorescence labeling were used to evaluate protein expressions of 5HT2AR, 5HT1AR, ERK1, ERK2 and c-Myc in the hippocampi of the mice and RT Q-PCR was employed for evaluation of the relative mRNA expressions. RESULTS: Based on the model established utilizing the CF+SPS procedure, we found 5HT2AR to play a positive role on anxiety-like behavior by inhibiting the expression of 5HT1AR. In addition, the ERK-c-Myc pathway elicited the effect of 5HT2AR and 5HT1AR on anxiety-like behavior in PTSD, 5-HT enhanced the anxiety-like behavior through both 5HT2AR and 5HT1AR. CONCLUSION: These findings suggest competive interaction between 5HT2AR and 5HT1AR actively affects anxiety-like behavior in the hippocampi of PTSD mice via the ERK pathway.

Improved Neural Regeneration with Olfactory Ensheathing Cell Inoculated PLGA Scaffolds in Spinal Cord Injury Adult Rats.

BACKGROUND/AIMS: Every year, around the world, between 250000 and 500000 people suffer from spinal cord injury (SCI). This study investigated the potential for poly (lactic-co-glycolic acid) (PLGA) complex inoculated with olfactory ensheathing cells (OECs) to treat spinal cord injury in a rat model. METHODS: OECs were identified by immunofluorescence based on the nerve growth factor receptor (NGFR) p75. The Basso, Beattie, and Bresnahan (BBB) score, together with an inclined plane (IP) test were used to detect functional recovery. Nissl staining along with the luxol fast blue (LFB) staining were independently employed to illustrate morphological alterations. More so, immunofluorescence labeling of the glial fibrillary acidic protein (GFAP) and the microtubule-associated protein-2 (MAP-2), representing astrocytes and neurons respectively, were investigated at time points of weeks 2 and 8 post-operation. RESULTS: The findings showed enhanced locomotor recovery, axon myelination and better protected neurons post SCI when compared with either PLGA or untreated groups (P < 0.05). CONCLUSION: PLGA complexes inoculated with OECs improve locomotor functional recovery in transected spinal cord injured rat models, which is most likely due to the fact it is conducive to a relatively benevolent microenvironment, has nerve protective effects, as well as the ability to enhance remyelination, via a promotion of cell differentiation and inhibition of astrocyte formation.

The post-therapeutic effect of rapamycin in mild traumatic brain-injured rats ensuing in the upregulation of autophagy and mitophagy.

Mild traumatic brain injury (mTBI), common in juveniles, has been reported to be caused by sports-related concussion. Many young children may suffer from post-concussion syndrome. mTBI, in early stages of life, could play a part in neuron apoptosis and degeneration, cognitive and motor coordination impairment, as well as dementia. Our study was aimed at further investigating the post-therapeutic efficacy of rapamycin in the recuperation of mTBI while at the same time investigating the metamorphosis in both autophagy and mitophagy in mTBI. We created a weight-drop rat mTBI model with the administration of rapamycin at 4 h after every mTBI. Behavioral tests of beam walking and open field task indicated the expected improvement of cognitive and motor coordination functions. Both Western blot and immunofluorescence examinations revealed increased Beclin-1 and PINK1 in the treated rats as well as reduction of caspase-3 and cytochrome C (Cyt C). More so, the TUNEL staining evidenced curtailment of apoptotic cells following treatment with rapamycin. The upregulation of Beclin-1 and PINK1 and the downregulation of caspase-3 and Cyt C extrapolate that rapamycin plays neuroprotective as well as anti-apoptotic role via interposition of both autophagy and mitophagy.

Lucky gene 5-HTTLPR and postpartum depression: A systematic review.

BACKGROUND: Postpartum depression (PPD) should be given more attention for its increasing incidences, severe complications and complex pathogenesis. Previous studies of PPD have mainly been focused on the social contributions to its etiology such as age, marriage and economic status, whilst less attention has been given to inner biological factors. Currently, emerging researches have endeavored to explore 5-HTT related pathogenesis of PPD. OBJECTIVE: This report was aimed at proffering updates on some research advancements in the field of PPD through the reviewing published papers concerning postpartum depression, with prime focus on the role of 5-HTT. SEARCH STRATEGY: This review report dug into articles containing both PPD and 5-HTTLPR. Web of Science, Pubmed and CNKI (National Knowledge Infrastructure) were employed for searching relevant publications. SELECTION CRITERIA: There was a strong association between 5-HTTLPR polymorphism and the pathogenesis of PPD, with established evidence showing that L allele (Long allele) in 5-HTTLPR was associated with reduced susceptibility to PPD. LIMITATIONS: All things considered, sufficient clinical experiments are needed to ascertain the feasibility of our theoretical statements. In addition, relevant articles are comparatively scarce presently.

[Tripotolide ameliorates inflammation and apoptosis induced by focal cerebral ischemia/reperfusion in rats].

Objective: To investigate the effects of triptolide on inflammation and apoptosis induced by focal cerebral ischemia/reperfusion in rats. Methods: The rat model of focal cerebral ischemia/reperfusion injury was established according to Longa's method. A total of 80 SD rats were randomly divided into 5 groups:normal control, sham group, DMSO group, middle cerebral artery occlusion (MCAO) group, and MCAO with tripolide treatment group. TTC staining was used to examine the site and volume of cerebral infarction, and Longa score was employed for neurological disorders measurement. Number of astrocytes was measured by fluorescence staining, and neuronal apoptosis was determined by TUNEL staining. The expressions of inducible nitric oxide synthase(iNOS), cyclooxygenase 2(COX-2) and NF-κB proteins were detected by immunohistochemistry, and the expression of iNOS, COX-2 mRNA was detected by real-time PCR. Results: Compared with DMSO group and MCAO group, brain edema was improved (80.03±0.46)% (P<0.05), infarct volume was reduced (8.3±1.4)% (P<0.01), Longa score was decreased (1.38±0.20, P<0.05) in triptolide treatment group. Meanwhile triptolide also dramatically reduced the number of GFAP-positive astrocytes (P<0.05), alleviated protein expression of COX-2 (91.67±1.31), iNOS (95.24±5.07) and NF-κB (75.03±2.06) triggered by MCAO (all P<0.05), and induced a down-regulation of cell apoptosis as showed by TUNEL assay (64.15±3.52, P<0.05). Conclusion: Triptolide can reduce the cerebral infarction volume, attenuate brain edema and ameliorate the neurological deficits induced by cerebral ischemia-reperfusion injury rats, indicating that it might be used as a potential anti-inflammatory agent.

Autophagy upregulation and apoptosis downregulation in DAHP and triptolide treated cerebral ischemia.

It has previously been demonstrated that ischemic stroke activates autophagy pathways; however, the mechanism remains unclear. The aim of this study is to further investigate the role that autophagy plays in cerebral ischemia. 2, 4-diamino-6-hydroxy-pyrimidine (DAHP), for its nitric oxide synthase (NOS) inhibiting neuroprotective effect, and triptolide (TP), for its anti-inflammatory property, were selected to administer pre middle cerebral artery occlusion (MCAO). The drugs were administered 12 hours prior to MCAO. Both magnetic resonance imaging (MRI) and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining showed that the drugs reduce the area of infarction. Immunoblotting analysis revealed increases in Beclin-1 and myeloid cell leukelia-1(Mcl-1) in treated rats. This could be a contributing factor to the reduction in autophagy induced damage. Immunochemistry and western blot showed that mTOR expression in treated rats was marginally different 24 h after injury, and this could also be significant in the mechanism. Furthermore, terminal deoxynucleotidyl transferase- (TdT-) mediated dUTP nick end labeling (TUNEL) staining proved that the drugs are effective in reducing apoptosis. The upregulation of Beclin-1 and Mcl-1 and downregulation of Bcl-2, caspase-3, and the Bcl-2/Beclin-1 ratio infer that the neuroprotective effect of DAHP and TP act via the mediation of autophagy and apoptosis pathways.

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.

Systematic hypothesis for post-stroke depression caused inflammation and neurotransmission and resultant on possible treatments.

Post-stroke depression (PSD) is a prevalent complex psychiatric disorder that causes delay to functional recovery from rehabilitation and also increases cognitive impairment. The etiology of PSD remains controversial and appears to be physical and psycho-social in origin, alone or in combination. The causes of PSD as well as the mechanisms conferring beneficial antidepressant effects in the context of ischemic brain injury are still unknown. In addition, appropriate treatment strategies for therapy to prevent stroke-induced depression-like behavior remain to be developed. This paper, therefore, proposes two hypotheses for post-stroke depression: The inflammatory hypothesis, which is the increased production of proinflammatory cytokines resulting from brain ischemia in cerebral areas causing the pathogenesis of post-stroke depression and the glutamate hypothesis, where the excess glucocorticoids released from stress-induced over-activation of hypothalamus-pituitary-adrenal (HPA) lead to dysfunction of glutamatergic transmission. Neurotrophins, especially brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) both play various roles in the central nervous system (CNS), attenuate apoptosis in cultured neurons, stimulate neurogenesis and increase survival and protect neuronal tissues from cell death induced by ischemia or depression. We also touch upon recent treatment strategies including inhibition of pro-inflammatory cytokines, SSRI, neurotrophins and cell-based therapies. In the present review, we provide an overview of recent evidence concerning the mechanisms of post-stroke depression and propose four prospective treatment strategies so as to provide references for clinical evidence-based medications.