Pigment epithelial growth factor suppresses inflammation by modulating macrophage activation

PURPOSE: To study the contribution of murine retinal pigment epithelial (RPE) cells to the innate immune-privilege status of the subretinal space as determined by the ability of pigment epithelial-derived factor (PEDF) and somatostatin (SOM), produced by RPE, to regulate macrophage-mediated inflammation. METHODS: Serum-free medium was added to RPE eyecups (a healthy monolayer of RPE resting on choroid and sclera) and the supernatants were removed after 24 hours (RPE SN). The RPE SN was assayed for the presence of PEDF and SOM and for its ability to regulate interleukin (IL)-12, IL-10, and nitric oxide (NO) production by resting and activated macrophages. A group of mice received intradermal injection of lipopolysaccharide (LPS) and PEDF in one ear and LPS alone in the other ear. Ear thickness was measured before- and 24 hours after ear injections. RESULTS: Soluble factors present in the RPE SN inhibited IL-12 production and substantially increased IL-10 while having minimal effects on NO production by activated macrophages. The message for PEDF, SOM, and IL-10 was detected in RPE cells, and the protein for these factors was found in the RPE SN. The stimulation of IL-10 and suppression of IL-12 production by RPE-SN-treated macrophages was neutralized by anti-PEDF antibodies. Neutralization of SOM in the RPE SN, suppressed NO production by activated macrophages. Intradermal injection of PEDF substantially inhibited LPS-induced inflammatory response. CONCLUSIONS: PEDF inhibits LPS-driven macrophage activation in vitro and in vivo. By producing PEDF, the RPE contributes to innate immune privilege of the eye.     

Comparison of 5-, 10-, and 15-Point Laparoscopic Ovarian Electrocauterization in Patients With Polycystic Ovarian Disease: a Prospective, Randomized Study

Objective:

We compared 12-month pregnancy and live birth rates in patients with polycystic ovarian disease undergoing 5-, 10-, and 15-point laparoscopic ovarian electrocauterization.

Methods:

This was a prospective, randomized study performed at the Dabirashrafi Fertility and Endoscopy Research Center, Tehran, Iran. The study included 187 patients with polycystic ovarian disease who were randomly assigned to 3 groups. Group I comprised 67 patients whose ovaries received 5-point electrocauterization. Group II comprised 57 patients whose ovaries received 10-point electrocauterization. Group III comprised 63 patients whose ovaries received 15-point electocauterization.Laparoscopic ovarian electrocauterization with a unipolar current was used. The main outcome measures were 12-month pregnancy and live birth rates.

Results:

Patients were homogeneous for age, body mass index, and type and duration of infertility. Twenty pregnancies resulted in Group I, with a pregnancy rate of 29.9% (20/67) and a live birth rate of 20.9% (14/57). Eighteen pregnancies resulted in Group II, with a pregnancy rate of 31.6% (18/57), and a live birth rate of 28.1% (16/57).Thirty-three pregnancies resulted in group III, with a pregnancy rate of 52.4% (33/63), and a live birth rate of 47.6% (30/63). Comparison of Group III with Groups I and II revealed a statistically significant increase in pregnancies (P=0.016) and live birth rates (P=0.004).

Conclusion:

We recommend 15-point electrocauterization of ovaries in patients with polycystic ovarian disease.     

Folic Acid Supplementation Improves Glycemic Control for Diabetes Prevention and Management: A Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials

Background: There is a growing interest in the considerable benefits of dietary supplementations, such as folic acid, on the glycemic profile. We aimed to investigate the effects of folic acid supplementation on glycemic control markers in adults. Methods: Randomized controlled trials examining the effects of folic acid supplementation on glycemic control markers published up to March 2021 were detected by searching online databases, including Scopus, PubMed, Embase, and ISI web of science, using a combination of related keywords. Mean change and standard deviation (SD) of the outcome measures were used to estimate the mean difference between the intervention and control groups at follow-up. Meta-regression and non-linear dose-response analysis were conducted to evaluate the association between pooled effect size and folic acid dosage (mg/day) and duration of the intervention (week). From 1814 detected studies, twenty-four studies reported fasting blood glucose (FBG), fasting insulin, hemoglobin A1C (HbA1C), and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) as an outcome measure. Results: Results revealed significant reductions in FBG (weighted mean difference (WMD): −2.17 mg/dL, 95% CI: −3.69, −0.65, p = 0.005), fasting insulin (WMD: −1.63 pmol/L, 95% CI: −2.53, −0.73, p < 0.001), and HOMA-IR (WMD: −0.40, 95% CI: −0.70, −0.09, p = 0.011) following folic acid supplementation. No significant effect was detected for HbA1C (WMD: −0.27%, 95% CI: −0.73, 0.18, p = 0.246). The dose-response analysis showed that folic acid supplementation significantly changed HOMA-IR (r = −1.30, p-nonlinearity = 0.045) in non-linear fashion. However, meta-regression analysis did not indicate a linear relationship between dose, duration, and absolute changes in FBG, HOMA-IR, and fasting insulin concentrations. Conclusions: Folic acid supplementation significantly reduces some markers of glycemic control in adults. These reductions were small, which may limit clinical applications for adults with type II diabetes. Further research is necessary to confirm our findings.     

Evaluation of combined effect of hyperthermia and ionizing radiation on cytotoxic damages induced by IUdR-loaded PCL-PEG-coated magnetic nanoparticles in spheroid culture of U87MG glioblastoma cell line

Purpose: Glioblastoma multiform (GBM) is the most prevalent and aggressive type of primary brain tumor. None of the current conventional treatment methods has improved treatment considerably. Therefore, in this study the effect of magnetic nanoparticles coated with poly (caprolactone)-poly (ethylene glycol) (PCL-PEG) as a 5-iodo 2′deoxyuridine (IUdR) carrier in the presence of hyperthermia and 6?MV (megavoltage) X-ray radiation, were investigated in a spheroid model of U87MG glioblastoma cell line using colony formation assay.

Materials and methods: First, the human glioblastoma cell line U87MG was cultured as a spheroid using the liquid overlay technique. Spheroids on day 10 with 100?mm diameters were treated with 1 µM IUdR or nanoparticles as IUdR carriers for one volume doubling time (VDT) of spheroids (67?h) and hyperthermia at 43?°C for 1?h, and then irradiated with 2?Gy of 6?MV X-ray in different groups. Finally, the effect of treatment on colony-forming ability was obtained by colony formation and alkaline assay.

Results: Our results revealed that hyperthermia in combination with radiation could significantly reduce the colony number of glioblastoma spheroid cells treated with IUdR or nanoparticles as IUdR carriers. However, the extent of reduction in colony number following treatment with IUdR-loaded nanoparticles in combination with hyperthermia and then X-ray radiation was significantly more than free IUdR.

Conclusion: According to this study, PCL-PEG-coated magnetic nanoparticles are effective delivery vehicles for IUdR into cells. Moreover, they can act as a radiosensitizer and thermosensitizer in the treatment of the glioblastoma cell line.     

Effects of URB597 as an inhibitor of fatty acid amide hydrolase on modulation of nociception in a rat model of cholestasis

Cholestasis is associated with increased activity of the endogenous opioid system that results in analgesia. Endocannabinoid system can reduce pain sensitivity. The use of inhibitors of endocannabinoid metabolism is a novel means of pharmacologically increasing endocannabinoid levels. Considering the interaction that has been shown between the endogenous opioid and endocannabinoid systems in nociception processing, we studied the effects of URB597, a selective inhibitor of FAAH (fatty acid amide hydrolase), on modulation of nociception in a model of elevated endogenous opioid tone, cholestasis. Cholestasis was induced by ligation of the main bile duct using two ligatures and then transection of the duct at the midpoint between them. Seven days after surgery, tail-flick latencies were measured at 60 min after drug administration. A significant increase (P<0.001) in nociception threshold was observed in cholestatic rats compared to unoperated and sham groups. Administration of URB597 (0.3 mg/kg, i.p.) in cholestatic animals significantly (P<0.001) increased tail-flick latency compared to the vehicle treated cholestatic group. URB597 injection to unoperated and sham groups caused a significant (P<0.05, P<0.05) increase in tail-flick latency compared to their respective vehicle treated groups. The antinociceptive effect of URB597 was blocked by coadministration of a cannabinoid CB(1) receptor antagonist, AM251 (1 mg/kg, i.p.) but not by a cannabinoid CB(2) receptor antagonist, SR144528 (1 mg/kg, i.p.) with URB597. These data showed that URB597 as a FAAH inhibitor potentiates antinociception induced by cholestasis in tail-flick test and that the inhibitory effects of URB597 in this model are mediated by cannabinoid CB(1) and not CB(2) receptors.     

The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis

The widespread distribution of Toll-like receptors (TLRs) and their ligands raises the question whether they contribute to the production of inflammatory and tissue destructive molecules in rheumatoid arthritis (RA). We examined the expression and function of TLR2 and TLR4 and their downstream signaling adaptors MyD88 and Mal/TIRAP in synovial membrane cultures from RA tissue. Both TLR2 and TLR4 were detected by flow cytometry, and stimulation with TLR2 and TLR4 ligands augmented the spontaneous production of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, indicating that TLR2 and TLR4 are functional in these cultures. In addition, overexpression of dominant-negative forms of MyD88 and Mal/TIRAP significantly down-regulated the spontaneous production of cytokines tumor necrosis factor-alpha, IL-6, and vascular endothelial growth factor, and enzymes MMP-1, MMP-2, MMP-3, and MMP-13 in RA synovial membrane cell cultures. Because TLR2 and TLR4 require both MyD88 and Mal/TIRAP for signaling, this study suggests that TLR function may regulate the expression of these factors in the RA synovium. Conditioned media from synovial membrane cell cultures stimulated human macrophages in a MyD88- and Mal-dependent manner, suggesting the release of a TLR ligand(s) from these cells. Thus, TLRs not only protect against infection but may also promote the inflammatory and destructive process in RA.     

Prevalence of virulence determinants and antibiotic resistance patterns of Enterococcus faecalis strains in patients with community-acquired urinary tract infections in Iran

The aim of this study was to characterize virulence factors and antibiotic resistance patterns in E. faecalis strains obtained from community-acquired urinary tract infections. A total of 70 E. faecalis isolates from Labbafinejad Hospital in Tehran were collected. Antibiotic resistance and virulence determinants were examined by phenotypic and molecular methods.

Among 70 E. faecalis isolates, efba (97.1%), ace (95.7%), and gelE (94.3%) were the most prevalent virulence genes. The most common antibiotic resistance pattern was tetracycline (88.6%) and minocycline (87.1%). Multi-drug resistant phenotype was detected among 10% of them.

Our results showed capability of E. faecalis strains for infection of the urinary tract in community. Involvement of virulence determinants in the pathogenesis of community acquired E. faecalis strains was proposed due to their high prevalence rates. Food producing animals were proposed as their environmental reservoirs, due to dominance of tetracycline resistance phenotype among them.     

Brown adipose tissue and alzheimer’s disease

Metabolic Brain Disease - Alzheimer’s disease (AD), the most common type of senile dementia, is a chronic neurodegenerative disease characterized by cognitive dysfunction and behavioral...