Huperzine A ameliorates cognitive dysfunction and neuroinflammation in kainic acid-induced epileptic rats by antioxidant activity and NLRP3/caspase-1 pathway inhibition.

Temporal lobe epilepsy (TLE) is one of the most prevalent types of epilepsy in human. Huperzine A (Hup-A) has been reported to possess antioxidative and anti-inflammatory properties; however, its role in TLE induced by kainic acid has not been determined. The current study investigated the protective effects of Hup-A (0.1 mg/kg) in kainic acid-induced model of TLE in the rat. In the current study, it was found that Hup-A significantly prevented the seizure intensity and learning and memory deterioration which was assessed by Morris water maze (MWM) and novel object recognition task (NOR). Additionally, Hup-A inhibited oxidative stress, inflammation, and acetylcholinesterase activity (AChE). In addition, catalase and superoxide dismutase (SOD) activities increased after Hup-A treatment, while malondialdehyde (MDA) and nitrite levels significantly reduced. Regarding inflammation, this drug decreased kainic acid-induced NLRP3 expression in microglial cells and caspase-1 activity in hippocampal tissue, possibly through diminishing oxidative stress. Taken together, our data showed that Hup-A could be a potential protective substance to ameliorate seizure severity and some memory deficits related to epilepsy via attenuating neuroinflammation and protection of neurons.

Wnt5A regulates the expression of ROR2 tyrosine kinase receptor in ovarian cancer cells.

Wnt5A and receptor tyrosine kinase-like orphan receptor 2 (ROR2) proteins both regulate developmental processes, cell movement, and cell polarity. The purpose of this study was to evaluate a possible regulatory role of Wnt5A on ROR2 expression in human ovarian cancer cell lines. Moreover, the expression of Wnt5A and ROR2 mRNA and protein levels were assessed in human epithelial serous ovarian cancer (HSOC) specimens. ROR2 was strongly decreased in cells treated with siRNA against Wnt5A compared with scramble-treated or lipofectamine-treated cells (P < 0.001). There was 34% decreased cell invasion (P < 0.01) in Wnt5A knock-down cells compared with lipofectamine-treated and scramble-treated cells; however, cell invasion remained unchanged upon addition of anti-ROR2 antibody to the culture media of these cells. In contrast, addition of anti-ROR2 antibody to the culture media for lipofectamine-treated and scramble-treated cells led to 32% decreased cell invasion (P < 0.01). Normal ovarian specimens were negative, and variable immunostaining was observed in HSOC for Wnt5A and ROR2 immunostaining. Furthermore, there was a positive correlation between Wnt5A and ROR2 expression in high-grade SOC samples at the mRNA level (P < 0.05; r = 0.38). This is the first report to show the regulatory role of Wnt5A on ROR2 expression in ovarian cancer.

Wnt5A exerts immunomodulatory activity in the human ovarian cancer cell line SKOV-3.

The purpose of this study was three fold: (1) to reveal the implications of Wnt5A for cytokine and chemokine production by human ovarian cancer cell line SKOV-3 cells, (2) to determine the influence of Wnt5A on chemotactic SKOV-3 cell migration, and (3) to assess the effect of inflammatory mediators on Wnt5A expression levels and to describe its underlying molecular mechanisms. A cytokine array was performed using a conditioned medium harvested from SKOV-3 cells transfected with specific siRNAs against Wnt5A or with scrambled siRNA and a transfection reagent alone as negative controls for 48 h. Chemotactic cell migration was performed using transwells. Inflammation-induced Wnt5A expression was determined by treating cells with recombinant human (rh) IL-1ß, IFNß, or TNFα alone or in combination with STAT3 and NF-κB inhibitors for different time durations. The cytokine array showed the suppression of GCSF, GM-CSF, IL-1α, IL-2, IL-13, and MCP-3 production, whereas cell RANTES and IL-7 showed increased levels in Wnt5A knock-down cells compared with those in controls. Chemotactic migration decreased significantly when the conditioned medium from Wnt5A knock-down cells was applied to the upper chamber of the transwell. Compared with the control, there were 30-fold and five-fold increases in Wnt5A mRNA levels in cells treated, with rhIL-1ß and rhIFNß, respectively after 8 h (P < 0.001). Compared with the control, TNF-α had a 1.8-fold increased levels of Wnt5A mRNA after 4 h (P < 0.01). Both NF-κB and STAT3 inhibitors decreased inflammation-induced Wnt5A expression. This study revealed a previously unrecognized immunomodulatory role of endogenous Wnt5A in ovarian cancer cells, which could further influence chemotactic cell migration.

WNT5A-ROR2 is induced by inflammatory mediators and is involved in the migration of human ovarian cancer cell line SKOV-3.

BACKGROUND: Wnt5A, which is a member of the non-transforming Wnt protein family, is implicated in inflammatory processes. It is also highly expressed by ovarian cancer cells. ROR2, which is a member of the Ror-family of receptor tyrosine kinases, acts as a receptor or co-receptor for Wnt5A. The Wnt5A-ROR2 signaling pathway plays essential roles in the migration and invasion of several types of tumor cell and influences their cell polarity. We investigated the modulation of Wnt5A-ROR2 by inflammatory mediators and its involvement in the migration of the human ovarian cancer cell line SKOV-3. METHODS: SKOV-3 cells were treated with LPS (lipopolysaccharide), LTA (lipoteichoic acid) and recombinant human IL-6 alone or in combination with STAT3 inhibitor (S1155S31-201) or NF-kB inhibitor (BAY11-7082) for 4, 8, 12, 24 and 48 h. The Wnt5A and ROR2 expression levels were determined at the gene and protein levels. Cells were transfected with specific siRNA against Wnt5A in the absence or presence of human anti-ROR2 antibody and cell migration was assessed using transwells. RESULTS: There was a strong downregulation of Wnt5A expression in the presence of STAT3 or NF-kB inhibitors. Cell stimulation with LTA or IL-6 for 8 h led to significantly increased levels of Wnt5A (5- and 3-fold higher, respectively). LPS, LTA or IL-6 treatment significantly increased ROR2 expression (2-fold after 48 h). LPS- or LTA-induced Wnt5A or ROR2 expression was abrogated in the presence of STAT3 inhibitor (p < 0.001). IL-6-induced Wnt5A expression was abrogated by both STAT3 and NF-kB inhibitors (p < 0.001). Although not significant, IL-6-induced ROR2 expression showed a modest decrease when STAT3 inhibitor was used. Moreover, cell migration was decreased by 80 % in siRNA Wnt5A-transfected cells in the presence of anti-human ROR2 antibody (p < 0.001). CONCLUSIONS: This study revealed for the first time that inflammatory mediators modulate Wnt5A and ROR2 through NF-kB and STAT3 transcription factors and this may play a role in ovarian cancer cell migration. The results described here provide new insight into the role of the Wnt5A-ROR2 complex in ovarian cancer progression in relation to inflammation.

Celecoxib adjunctive therapy for acute bipolar mania: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Recent research has focused on the inflammatory cascade as a key culprit in the etiology of bipolar disorder. We hypothesized that celecoxib, via its anti-inflammatory properties, may have a therapeutic role in mood disorder. METHODS: Forty-six inpatients with the diagnosis of acute bipolar mania without psychotic features participated in a parallel, randomized, double-blind, placebo-controlled trial, and underwent six weeks of treatment with either celecoxib (400 mg daily) or placebo as an adjunctive treatment to sodium valproate. Patients were evaluated using the Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS). The primary outcome measure with respect to efficacy was the mean decrease in YMRS score from baseline to the study endpoint, which was compared between the two groups. RESULTS: A significant difference was observed in the change in YMRS scores on Day 42 compared to baseline in the two groups (p < 0.001). The changes at the endpoint compared to baseline were -29.78 ± 21.78 (mean ± standard deviation) and -21.78 ± 7.16 for the celecoxib and placebo groups, respectively. A significantly higher remission rate was observed in the celecoxib group (87.0%) than the placebo group (43.5%) at Week 6 (p = 0.005). General linear model repeated measures demonstrated a significant effect for the time × treatment interaction on the YMRS scores [F(2.27,99.98) = 6.67, p = 0.001]. CONCLUSIONS: Celecoxib is an effective adjuvant therapy in the treatment of manic episodes (without psychotic features) of bipolar mood disorder. The mood-stabilizing role of the drug might be mediated via its action on the inflammatory cascade.

The relation between occupational exposure to lead and blood pressure among employed normotensive men.

BACKGROUND: Lead is a pollutant with numerous adverse effects on health. Since it can affect blood pressure, peripheral blood vessels, and the heart, the present study aimed to evaluate the relation between occupational exposure to lead and blood pressure. MATERIALS AND METHODS: This cross-sectional study included male individuals working in battery firms in Isfahan. A questionnaire covering demographic characteristics and the history of different diseases and occupational exposure to lead was completed. Each participant's blood pressure was also measured and recorded. After obtaining blood samples and determining lead levels, mean and frequency analyses were performed. In addition, Pearson's correlation test and linear regression were used to assess the relation between blood lead levels (BLLs) and systolic and diastolic blood pressure. All analyses were performed in SPSS.19. RESULTS: The mean age of the 182 studied workers was 42.85 ± 13.65 years. They had worked in battery firms for a mean period of 23.67 ± 14.72 years. Moreover, the mean value of BLLs among the participants was 7.92 ± 3.44 µg/dL. Correlation between BLL and systolic and diastolic blood pressure was not significant. The effects of lead on systolic and diastolic blood pressure after stepwise regression were B = -0.327 [confidence interval (CI) 95%: -0.877 to 0.223] and B = -0.094 (CI 95%: -0.495 to 0.307), respectively. CONCLUSION: This study revealed that BLLs in battery firm workers to be normal. Additionally, BLLs were not significantly related with either systolic or diastolic blood pressure which might have been the result of normal BLLs.

Relations between steroids and AMH: impact of basal and intrafollicular steroids to AMH ratios on oocyte yield and maturation rate in women with or without polycystic ovary undergoing in vitro fertilization.

OBJECTIVE: This study sought to determine the relationships between serum or intrafollicular ovarian steroids and anti-mullerian hormone (AMH) and to predict impact of steroids to AMH ratios on oocyte quantity and metaphase II (MII) oocyte rate in normo-ovulatory (control) and polycystic ovary syndrome (PCOS) patients. DESIGN: Prospective study. SETTING: University hospital and research center. PATIENTS: Thirty-two patients with PCOS and 37 controls undergoing IVF-ET. METHODS: Serum (day 3) and follicular fluid (FF) from more than one follicle ≥ 17 mm on the day of oocyte retrieval were collected from each patients. MAIN OUTCOME MEASURES: Serum or follicular fluid steroids, AMH, retrieved oocytes number and maturation rate. RESULTS: In control group, intrafollicular AMH levels were positively related to P4 and T levels (p = .002, p = .011, respectively). Multiple linear regression analysis showed serum basal AMH and T levels as independent positive predictors while T/AMH ratio and intrafollicular AMH were negative predictors for both retrieved and MII oocyte number. The presence of PCOS and intrafollicular P4/AMH ratio revealed as important negative factors influencing oocyte maturation rate. CONCLUSIONS: Serum basal T, AMH as well as their ratio and intrafollicular P4/AMH ratio may be used as predictors for retrieved oocyte number and their nuclear maturation rate, respectively.

Intrathecal administration of the extracellular vesicles derived from human Wharton's jelly stem cells inhibit inflammation and attenuate the activity of inflammasome complexes after spinal cord injury in rats.

Activation of inflammasome complexes during spinal cord injury (SCI) lead to conversion of pro-inflammatory cytokines, interleukin-1beta (IL-1ß) and interleukin-18 (IL-18) to their active form to initiates the neuroinflammation. Mesenchymal stem cells (MSCs) showed anti-inflammatory properties through their extracellular vehicles (EVs). We investigated immunomodulatory potential of human Wharton's jelly mesenchymal stem cells derived extracellular vesicles (hWJ-MSC-EVs) on inflammasome activity one week after SCI in rats. The gene expression and protein level of IL-1ß, IL-18, tumor necrosis factor alpha (TNF-α) and caspase1, were assessed by QPCR and western blotting. Immunohistochemistry (IHC) was done to measure the glial fibrillary acidic protein (GFAP) and Nestin expression. Cell death, histological evaluation and hind limb locomotion was studied by TUNEL assay, Nissl staining and Basso, Beattie, Bresnaham (BBB), respectively. Our finding represented that intrathecally administrated of hWJ-MSC-EVs significantly attenuated expression of the examined factors in both mRNA (P < 0.05 and P ≤ 0.01) and protein levels (P < 0.05 and P ≤ 0.01), decreased GFAP and increased Nestin expression (P < 0.05), reduced cell death and revealed the higher number of typical neurons in ventral horn of spinal cord. Consequently, progress in locomotion. We came to the conclusion that hWJ-MSC-EVs has the potential to control the inflammasome activity after SCI in rats. Moreover, EVs stimulated the neural progenitor cells and modulate the astrocyte activity.

Determinants of uncontrolled hypertension in an Iranian population.

BACKGROUND: Uncontrolled hypertension, a major concern among hypertensive patients, may be caused by various factors such as inadequate knowledge and inappropriate attitude, unhealthy lifestyle, and ineffective treatment. The present study tried to cast light on factors leading to uncontrolled hypertension. METHODS: In this cross-sectional study, all hypertensive participants of the third phase of the Isfahan Healthy Heart Program were contacted and invited to take part in the study. A questionnaire including knowledge of and attitude toward hypertension and its control and treatment methods, and practice about lifestyle and pharmacological treatment was completed for all patients who consented to participate. The participants' anthropometric indices and blood pressure were then measured. Chi-square and Student's t-tests were used to compare the groups with controlled and uncontrolled blood pressure. The effect of each factor on uncontrolled blood pressure was assessed by employing stepwise logistic regression. RESULTS: Of 114 participants, 43 (37.12%) and 71 (62.28%) individuals had controlled and uncontrolled blood pressure, respectively. Stepwise logistic regression revealed body mass index > 25 kg/m2 to have the greatest effects on uncontrolled blood pressure [Odds ratio (OR) = 13.091, Confidence interval of 95% (95% CI): 1.437-116.352, P = 0.021). In addition, male gender increased the risk for uncontrolled blood pressure (OR = 8.475, CI95%: 1.276-56.313, P = 0.027), while inappropriate attitude decreased the mentioned risk (OR = 0.047, CI95%: 0.007-0.318, P = 0.002). CONCLUSION: According to our findings, obesity is the most important cause of uncontrolled blood pressure. Therefore, weight has to be closely monitored and controlled in hypertensive patients.

Effects of occupational exposure to lead on left ventricular echocardio graphic variables.

BACKGROUND: Lead contamination can affect many body organs including the heart. This study assessed a number of echocardiographic indices to clarify the effects of lead on cardiac function among battery factory workers who are in constant exposure to lead. METHODS: In a cross-sectional study, 142 male battery factory workers who had been exposed to lead for at least 1 year were evaluated. The subjects aged 25-55 years old and were excluded if they had hypertension, diabetes, or cardiovascular diseases. Demographic characteristics, professional profile, lead exposure, history of respiratory diseases, drugs intake, and lifestyle information of the participants were collected. Height, weight and blood pressure measurements were then performed. Blood tests were also ordered to determine blood lead levels. The subjects finally underwent M-mode and Doppler echocardiography. Linear regression analysis was used to establish the effects of lead on the target indices. All statistical analyses were conducted in SPSS18. RESULTS: The mean age and mean duration of lead exposure of the subjects were 41.78 ± 13.58 and 23.54 ± 14.44 years, respectively. The mean blood lead level was 7.59 ± 2.75 µg/dl. Left ventricular hypertrophy was detected in 12% of the participants. Blood lead levels were not significantly related with echocardiographic indices in the crude model or after adjustments for age alone or for age and other risk factors. CONCLUSION: Blood lead levels of our participants were below standard values. In addition, no significant relation was found between left ventricular function indices and blood lead levels. The absence of such relations could have been caused by the exclusion of individuals with hypertension or cardiovascular diseases. Structural modifications in battery factories following legislations in Iran might have been responsible for low blood lead levels among the subjects.

Comparing serum basal and follicular fluid levels of anti-Müllerian hormone as a predictor of in vitro fertilization outcomes in patients with and without polycystic ovary syndrome.

BACKGROUND AND OBJECTIVES: The prediction of in vitro fertilization (IVF) outcomes by anti-Müllerian hormone (AMH) measurement is getting increasing attention from clinicians. This study compares the relationship between serum or intrafollicular AMH levels and IVF outcomes in women with and without polycystic ovary syndrome (PCOS). METHODS: This prospective study was carried out in two university-based fertility clinics. Serum samples were collected on cycle day 3 and follicular fluid (FF) was collected on the day of oocyte retrieval from 26 women with PCOS and 42 normo-ovulatory controls. AMH levels were measured in the samples using immunoenzymatic assay. The relationship between serum or FF AMH levels and IVF outcomes, including number of oocytes retrieved, oocyte maturation rate, fertilization rate, implantation rate, high quality grade embryo rate, and biochemical and clinical pregnancy rates were further assessed. RESULTS: Median serum basal AMH and FF AMH levels were significantly higher in the PCOS group as compared to controls, the values being 14.2 ng/mL vs. 3.2 ng/mL (P<.001) and 8.2 ng/g protein vs. 4.7 ng/g protein (P<.01), respectively. In both groups, serum basal AMH levels showed a positive correlation with number of oocytes retrieved (r=0.323; P=.037 in control vs. r=0.529; P=.005 in PCOS). In the control group, there was a positive relationship between serum basal AMH levels and percentage of matured oocytes (r = 0.331; P=.032) and implantation rate (r=0.305; P=.05). CONCLUSION: Serum basal, and not intrafollicular, AMH levels may be a good predictive factor for quantitative and qualitative IVF outcomes in normo-ovulatory, but not in PCOS patients.