Invited review Role of melatonin in Alzheimer-like neurodegeneration

Abstract Alzheimer disease (AD), an age-related neurodegenerative disorder with progressive loss of memory and deterioration of comprehensive cognition, is characterized by extracellular senile plaques of aggregated β-amyloid (Aβ), and intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein. Recent studies showed that melatonin, an indoleamine secreted by the pineal gland, may play an important role in aging and AD as an antioxidant and neuroprotector. Melatonin decreases during aging and patients with AD have a more profound reduction in this hormone. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning, and slows down the progression of cognitive impairment in Alzheimer's patients. Melatonin efficiently protects neuronal cells from Aβ-mediated toxicity via antioxidant and anti-amyloid properties: it not only inhibits Aβ generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Aβ. Our recent studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting cholinergic neurons and in anti-inflammation. Here, the neuroprotective effects of melatonin and the underlying mechanisms by which it exerts its effects are reviewed. The capacity of melatonin to prevent or ameliorate tau and Aβ pathology further enhances its potential in the prevention or treatment of AD

Tetra­kis(μ-anthracene-9-carboxyl­ato)bis­[(anthracene-9-carboxyl­ato)(2,2′-bipyrid­yl)lanthanum(III)]

The title complex, [La2(C15H9O2)6(C10H8N2)2], has a centrosymmetric binuclear cage structure in which two LaIII atoms are both nine-coordinated and bridged by four anthracene-9-carboxyl­ate ligands, with an La⋯La separation of 4.0880 (4) Å. The remaining coordination sites are occupied by two N atoms of a 2,2′-bipyridine (bipy) and two O atoms of an anthracene-9-carboxyl­ate ligand. The six anthracene-9-carboxyl­ate groups coordinate each LaIII atom in three different ways. Adjacent discrete dinuclear units are arranged into a one-dimensional chain along the [111] direction by inter­molecular π–π stacking inter­actions, with a centroid–centroid separation of 3.704 (7) Å

A Meta-Analysis of Survival Outcomes Following Reoperation in Recurrent Glioblastoma: Time to Consider the Timing of Reoperation

Background: Glioblastoma multiforme (GBM) inevitably recurs, but no standard regimen has been established for recurrent patients. Reoperation at recurrence alleviates mass effects, and the survival benefit has been reported in many studies. However, in most studies, the effect of reoperation timing on survival benefit was ignored. The aim of this meta-analysis was to investigate whether reoperation provided similar survival benefits in recurrent GBM patients when it was analyzed as a fixed or time-dependent covariate.Methods: A systematic literature search of PubMed, EMBASE, and Cochrane databases was performed to identify original articles that evaluated the associations between reoperation and prognosis in recurrent GBM patients.Results: Twenty-one articles involving 8,630 patients were included. When reoperation was considered as a fixed covariate, it was associated with better overall survival (OS) and post-progression survival (PPS) (OS: HR = 0.66, 95% CI 0.61-0.71, p < 0.001, I2 = 0%; PPS: HR = 0.70, 95% CI 0.57–0.88, p < 0.01, I2 = 70.2%). However, such a survival benefit was not observed when reoperation was considered as a time-dependent covariate (OS: HR = 2.19, 95% CI 1.47–3.27, p < 0.001; PPS: HR = 0.95, 95% CI 0.82–1.10, p = 0.51, I2 = 0%). The estimate bias caused by ignoring the time-dependent nature of reoperation was further demonstrated by the re-analysis of survival data in three included studies.Conclusions: The timing of reoperation may have an impact on the survival outcome in recurrent GBM patients, and survival benefits of reoperation in recurrent GBM may be overestimated when analyzed as fixed covariates. Proper analysis methodology should be used in future work to confirm the clinical benefits of reoperation

Recent Advances in Small Peptides of Marine Origin in Cancer Therapy

Cancer is one of the leading causes of death in the world, and antineoplastic drug research continues to be a major field in medicine development. The marine milieu has thousands of biological species that are a valuable source of novel functional proteins and peptides, which have been used in the treatment of many diseases, including cancer. In contrast with proteins and polypeptides, small peptides (with a molecular weight of less than 1000 Da) have overwhelming advantages, such as preferential and fast absorption, which can decrease the burden on human gastrointestinal function. Besides, these peptides are only connected by a few peptide bonds, and their small molecular weight makes it easy to modify and synthesize them. Specifically, small peptides can deliver nutrients and drugs to cells and tissues in the body. These characteristics make them stand out in relation to targeted drug therapy. Nowadays, the anticancer mechanisms of the small marine peptides are still largely not well understood; however, several marine peptides have been applied in preclinical treatment. This paper highlights the anticancer linear and cyclic small peptides in marine resources and presents a review of peptides and the derivatives and their mechanisms

Uterine artery embolization with and without local methotrexate infusion for the treatment of cesarean scar pregnancy

AbstractObjectiveTo compare the clinical value of uterine artery embolization (UAE) with local methotrexate (MTX) infusion to embolization without MTX in the treatment of cesarean scar pregnancies (CSPs).Materials and methodsFrom January 2009 to December 2013, 50 patients with CSP treated with UAE receiving or not receiving local MTX infusion prior to curettage were analyzed retrospectively. Twenty-two patients were offered UAE with local MTX infusion prior to curettage (UAE + MTX group), whereas 28 patients received UAE alone prior to curettage (UAE group). Clinical data and the outcomes were analyzed, followed by a brief review of the published literature summarizing what is known about UAE with and without MTX for the treatment of CSP.ResultsUAE was successful in 42 of 50 cases (84%), with complications occurring in only five patients. There were no significant differences in the success rate, complication rate, recovery time, or hospitalization costs between the UAE + MTX group and the UAE group. However, blood loss in the UAE + MTX group was significantly higher than in the UAE group.ConclusionUAE with or without local MTX infusion might be an effective treatment for CSP. Compared with UAE alone, UAE with local MTX infusion did not dramatically improve the therapeutic effect of UAE. A larger and more comprehensive random control study is warranted to better evaluate the therapeutic effects of UAE in the treatment of CSP

YKL-40 in high-grade glioma: Prognostic value of protein versus mRNA expression

Background: YKL-40 has been reported to be associated with the prognosis of glioma patients. However, expression of YKL-40 was detected at protein or mRNA level in different studies. This may result in conclusion bias. This study is to investigate the prognostic value of increased YKL-40 protein versus mRNA expression in glioma patients. Methods: A comprehensive systematic search and review were performed using PubMed, EMBASE, and NKI databases to identify literature (published before May 1, 2018) that evaluated the association between YKL-40 and survival in glioma patients. Results: Thirteen relevant studies, involving 2139 patients, were included in this study. Elevated YKL-40 expression was associated with worse overall survival (OS) in glioma patients (hazard ratio [HR] = 1.44, 95% confidence interval [CI]: 1.27–1.63, P < 0.001), especially in high-grade glioma (anaplastic glioma: HR = 1.37, 95% CI: 1.09–1.74, P = 0.008; glioblastoma multiform: HR = 1.52, 95% CI: 1.33–1.73, P < 0.001). The increased YKL-40 protein level in serum (detected by ELISA) or in tumor tissues (detected by immunohistochemistry) was associated with worse OS (ELISA: HR = 1.43, 95% CI: 1.29–1.59, P < 0.001; immunohistochemistry: HR = 1.52, 95% CI: 1.20–1.93, P = 0.001). However, the association between elevated YKL-40 mRNA level (detected by real-time PCR) with worse OS was not significant (HR = 1.44, 95% CI: 0.73–2.83, P = 0.29, I2 = 68.3%). In addition when status of IDH1 mutation or/and O6-methylguanine-DNA methyltransferase promoter was incorporated as multivariate, increased expression level of YKL-40 was not associated with poorer survival (HR = 1.39, 95% CI: 0.99–1.93, P = 0.055). Conclusion: YKL-40 protein level, rather than mRNA level, may be a valuable biomarker to assess the prognosis in glioma patients

Effects of endogenous beta-amyloid overproduction on tau phosphorylation in cell culture

Alzheimer's disease is characterized by beta-amyloid (A beta) overproduction and tau hyperphosphorylation. Recent studies have shown that synthetic A beta promotes tau phosphorylation in vitro. However, whether endogenously overproduced A beta promotes tau phosphorylation and the underlying mechanisms remain unknown. Here, we used mouse neuroblastoma N2a stably expressing wild-type amyloid precursor protein (APPwt) or the Swedish mutant APP (APPswe) to determine the alterations of phosphorylated tau and the related protein kinases. We found that phosphorylation of tau at paired helical filament (PHF)-1, pSer396 and pThr231 epitopes was significantly increased in cells transfected with APPwt and APPswe, which produced higher levels of A beta than cells transfected with vector or amyloid precursor-like protein 1. The activity of glycogen synthase kinase-3 (GSK-3) was up-regulated with a concomitant reduction in the inhibitory phosphorylation of GSK-3 at its N-terminal Ser9 residue. In contrast, the activity of cyclin-dependent kinase-5 (CDK-5) and protein kinase C (PKC) was down-regulated. Inhibition of GSK-3 by LiCl, but not inhibition of CDK-5 by roscovitine, arrested A beta secretion and tau phosphorylation. Inhibition of PKC by GF-109203X activated GSK-3, whereas activation of PKC by phorbol-12,13-dibutyrate inhibited GSK-3. These results suggest that endogenously overproduced A beta induces increased tau phosphorylation through activation of GSK-3, and that inactivation of PKC is at least one of the mechanisms involved in GSK-3 activation