Pathological personality traits of maladaptive daydreamers measured by the Personality Inventory for DSM-5 in a psychiatric sample.

This study aimed to estimate the frequency of maladaptive daydreaming and to explore the pathological personality traits of probable maladaptive daydreamers. Our sample consisted of 239 psychiatric patients. After screening, 42 persons were probable maladaptive, while 197 participants prove to be normal daydreamers. Two pathological domains and three facets measured by the Personality Inventory for DSM-5 showed a moderate significant correlation with the Maladaptive Daydreaming Scale. The score of nearly every domain and facet was slightly higher among probable maladaptive daydreamers. To quantify the difference between the groups, effect sizes were calculated: Significant difference was found on the domain level in Antagonism, while on the facet level in Hostility, Grandiosity, Attention Seeking, Unusual Beliefs and Experiences, Cognitive and Perceptual Dysregulation. The group of probable maladaptive daydreamers was further examined to identify potential subgroups. Cluster analysis revealed heterogeneity in the severeness and patterns of pathological personality domains. Cluster 1 showed higher mean scores on the PID domains and on the MDS compared to Cluster 2. Clusters 1 and 2 broke further down into two subclusters: Cluster 1a and Cluster 1b differed in their mean scores on the domains of Antagonism and Detachment; the mean scores of Cluster 2a were uniformly low on each domain, while the mean values of Cluster 2b were scattered in a mixed way on the domains. Our results suggest that maladaptive daydreaming might manifest with differently pathological personality profiles in the background. This aspect might worth considering in planning treatment.

[Personalized treatment options for spinal muscular atrophy]. / A spinalis izomatrophia személyre szabott terápiás lehetoségei.

Spinal muscular atrophy (SMA) is an autosomal recessive disease leading to progressive muscle weakness and atrophy, in severe cases also affecting the bulbar and respiratory muscles.The clinical spectrum of the disease is extremely variable, in the most severe cases resulting in perinatal death, while at the least severe end of the spectrum causing some motor deficits in old age without the loss of ambulation. Spinal muscular atrophy care has changed dramatically in recent years due to the availability of new therapeutic options. 
The FDA approved nusinersen in 2016, this was followed by the approval of onasemnogene abeparvovec in 2019 and risdiplam in 2020. The EMA approved all three therapies a year later. Two of the threapies work at the pre-mRNA level, one at the DNA level. The clinical studies leading to the approval of the three drugs included patients of different ages and clinical conditions, and utilised partly different motor and functional scales. Therefore, direct comparison of these clinical studies is not possible. However, an increasing amount of real-world data contribute to the better understanding of the efficacy of the different therapies for patients of different ages and clinical conditions, in a real-world setting. Thus, the question may arise “Which is the best SMA therapy?”. This is an impossible question to answer. Indeed the question “Which therapy is the most suitable for a certain patient at a certain time?” is much more realistic. Here, we provide a brief overview of the objectively measurable results of the three therapies to date and an outlook into future therapeutic avenues. 

Childhood traumatization and dissociative experiences among maladaptive and normal daydreamers in a Hungarian sample.

The aim of the study was to identify some potential etiological segments of maladaptive daydreaming, especially the relationships between maladaptive daydreaming, childhood traumatization, and dissociative propensity. The questionnaire package included the Hungarian version of the Maladaptive Daydreaming Scale, the Traumatic Antecedents Questionnaire, as well as the Dissociation Questionnaire. 717 participants were recruited online, 106 of whom were problematic daydreamers. The results revealed that certain types of childhood trauma occurred significantly more frequently in the group of maladaptive daydreamers. Furthermore, maladaptive daydreamers possessed a significantly higher level of dissociative propensity compared to normal daydreamers. The estimated SEM models showed that dissociative experiences - more precisely Identity confusion and fragmentation and Lack of control - mediated the relationship between certain childhood traumatic experiences and maladaptive daydreaming. The results suggest that we should consider childhood traumatization and increased dissociative propensity as potentially significant factors in the etiology of maladaptive daydreaming.

Phase 1 and preclinical profiling of ESM-HDAC391, a myeloid-targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia.

AIMS: To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase-sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase-1 (CES1). METHODS: This first-in-human study comprised single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1elo mouse strain. RESULTS: ESM-HDAC391 showed transient systemic exposure (plasma half-life of 21-30 min) but selective retention of processed acid for at least 12 hours, resulting in robust targeted mechanistic engagement (increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production). ESM-HDAC391 was well tolerated and clinical toxicities common to non-targeted HDACi were not observed. ESM-HDAC391 treatment was accompanied by the novel finding of a dose-dependent monocyte depletion that was transient and reversible and which plateaued at 0.06 × 109 monocytes/L after repeat dosing with 20 or 40 mg. Characterisation of monocyte depletion in transgenic mice (CES1/Es1elo ) suggested that colony stimulating factor 1 receptor loss on circulating cells contributed to ESM-HDAC-mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi-mediated change in myeloid fate through modulation of colony stimulating factor 1 receptor and downstream effects on cell differentiation. CONCLUSION: These findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM-HDACi treatment, with implications for potential benefit of these molecules in myeloid-driven diseases.

[The importance of patient reported outcome measures in Pompe disease]. / A betegek által riportált kimeneti mutatók jelentosége Pompe-kórban.

BACKGROUND AND PURPOSE: In recent decades it has become increasingly important to involve patients in their diagnostic and treatment process to improve treatment outcomes and optimize compliance. By their involvement, patients can become active participants in therapeutic developments and their observations can be utilized in determining the unmet needs and priorities in clinical research. This is especially true in rare diseases such as Pompe disease. Pompe disease is a genetically determined lysosomal storage disease featuring severe limb-girdle and axial muscle weakness accompanied with respiratory insufficiency, in which enzyme replacement therapy (ERT) now has been available for 15 years. METHODS: In our present study, patient reported outcome measures (PROMs) for individuals affected with Pompe disease were developed which included questionnaires assessing general quality of life (EuroQoL, EQ-5D, SF36), daily activities and motor performance (Fatigue Severity Score, R-PAct-Scale, Rotterdam and Bartel disability scale). Data were collected for three subsequent years. The PROM questionnaires were a good complement to the physician-recorded condition assessment, and on certain aspects only PROMs provided information (e.g. fatigue in excess of patients' objective muscle weakness; deteriorating social activities despite stagnant physical abilities; significant individual differences in certain domains). The psychological effects of disease burden were also reflected in PROMs. RESULTS: In addition to medical examination and certain endpoints monitored by physicians, patient perspectives need to be taken into account when assessing the effectiveness of new, innovative treatments. With involvement of patients, information can be obtained that might remain uncovered during regular medical visits, although it is essential in determining the directions and priorities of clinical research. CONCLUSION: For all orphan medicines we emphasize to include patients in a compulsory manner to obtain general and disease-specific multidimensional outcome measures and use them as a quality indicator to monitor treatment effectiveness.

[Consensus statement of the Hungarian Clinical Neurogenic Society about the therapy of adult SMA patients]. / A Magyar Klinikai Neurogenetikai Társaság konszenzusajánlása a felnottkori spinalis izomatrophia (SMA) kezeléséhez.

BACKGROUND AND PURPOSE: Background - Spinal muscular atrophy (SMA) is an autosomal recessive, progressive neuromuscular disorder resulting in a loss of lower motoneurons. Recently, new disease-modifying treatments (two drugs for splicing modification of SMN2 and one for SMN1 gene replacement) have become available. Purpose - The new drugs change the progression of SMA with neonatal and childhood onset. Increasing amount of data are available about the effects of these drugs in adult patients with SMA. In this article, we summarize the available data of new SMA therapies in adult patients. METHODS: Methods - Members of the Executive Committee of the Hungarian Clinical Neurogenetic Society surveyed the literature for palliative treatments, randomized controlled trials, and retrospective and prospective studies using disease modifying therapies in adult patients with SMA. Patients - We evaluated the outcomes of studies focused on treatments of adult patients mainly with SMA II and III. RESULTS: In this paper, we present our consensus statement in nine points covering palliative care, technical, medical and safety considerations, patient selection, and long-term monitoring of adult patients with SMA. CONCLUSION: This consensus statement aims to support the most efficient management of adult patients with SMA, and provides information about treatment efficacy and safety to be considered during personalized therapy. It also highlights open questions needed to be answered in future. Using this recommendation in clinical practice can result in optimization of therapy.

[Pompe disease treated with enzyme replacement therapy in pregnancy]. / Tapasztalataink Pompe-betegségben terhesség alatt alkalmazott enzimpótló kezeléssel és az irodalom áttekintése.

Pompe disease is a rare lysosomal storage disease inherited in a recessive manner resulting muscular dystrophy. Due to the lack of the enzyme alpha glucosidase, glycogen accumulates in the cells. In the infantile form of Pompe disease hypotonia and severe cardio-respiratory failure are common leading to death within 2 years if left untreated, while the late-onset form is characterized with limb-girdle and axial muscle weakness accompanied with respiratory dysfunction. Pompe disease has been treated with regular intake of the missing enzyme since 2006, which significantly improved the survival and severity of symptoms in patients of both subtypes. The enzyme replacement therapy (ERT) is safe and well tolerated. However, limited data are available on its use in pregnancy. Our goal is to share our experience and review the literature on the safety of enzyme replacement therapy for Pompe disease during pregnancy and post partum.

[Investigation of sleep and fatigue in patients with cancer]. / Az alvás és a kimerültség vizsgálata daganatos betegek körében.

INTRODUCTION: The diagnosis of cancer elicits greater distress than any other diagnosis. The prevalence of psychological difficulties is high in cancer, and resources of the medical staff are limited. The development of efficient screening measures is therefore of utmost importance. Sleep is vital to all psychological functioning and poor sleep is a known problem in cancer. AIM: The main goal of the present study was testing of visual analogue scales assessing sleep quality and fatigue. METHOD: Sleep quality and fatigue were assessed with visual analogue scales. The Sleep Condition Indicator, the Athens Insomnia Scale and the Cancer Fatigue Scale were also included. Psychological distress was assessed with the Generalized Anxiety Disorder Scale, the Beck Depression Inventory and the Brief Difficulties in Emotion Regulation Scale. Pain and well-being was measured with the Faces of Pain Scale and the WHO Well-being Scale, respectively. A total of 71 patients with cancer were enrolled in this study. RESULTS: Insomnia and fatigue - measuring them with visual and several-item scales - showed high correlation with the measures of distress (anxiety, depression, emotion regulation difficulties) and pain. Distress and pain showed significant negative correlation with well-being. CONCLUSIONS: It has been affirmed that sleep quality is crucial in the changes of distress, pain and general well-being in cancer patients. It affirms that the visual analogue scales assessing sleep quality and fatigue - besides sleep quality and fatigue - are acceptable screening tools of distress and decreased well-being. Their use in clinical practice is recommended for screening in cancer patients and providing indications for onco-psychological treatment. Orv Hetil. 2018; 159(42): 1720-1726.

Direct mapping of melanoma cell - endothelial cell interactions.

The most life-threatening aspect of cancer is metastasis; cancer patient mortality is mainly due to metastasis. Among all metastases, presence of brain metastasis is one with the poorest prognosis; the median survival time can be counted in months. Therefore, prevention or decreasing their incidence would be highly desired both by patients and physicians. Metastatic cells invading the brain must breach the cerebral vasculature, primarily the blood-brain barrier. The key step in this process is the establishment of firm adhesion between the cancer cell and the cerebral endothelial layer. Using the atomic force microscope, a high-resolution force spectrograph, our aim was to explore the connections among the cell morphology, cellular mechanics, and biological function in the process of transendothelial migration of metastatic cancer cells. By immobilization of a melanoma cell to an atomic force microscope's cantilever, intercellular adhesion was directly measured at quasi-physiological conditions. Hereby, we present our latest results by using this melanoma-decorated probe. Binding characteristics to a confluent layer of brain endothelial cells was directly measured by means of single-cell force spectroscopy. Adhesion dynamics and strength were characterized, and we present data about spatial distribution of elasticity and detachment strength. These results highlight the importance of cellular mechanics in brain metastasis formation and emphasize the enormous potential toward exploration of intercellular dynamic-related processes.

Characteristics and Development of Nonsuicidal Super Self-Injury among Borderline Inpatients.

BACKGROUND: Nonsuicidal self-injury (NSSI) is a key feature of borderline personality disorder (BPD), which is strongly associated with childhood traumatization. To the best of our knowledge, there has been a lack of studies investigating extensively the characteristics of borderline patients who engage in extremely high numbers of NSSI, and their features of NSSI, trauma history and psychopathology. The aim of this study is to identify groups of borderline inpatients on the basis of the lifetime number of NSSI, and to explore the characteristics of these groups regarding the onset, reasons and methods of NSSI, history of childhood traumatization, and severity of psychopathology. SUBJECTS AND METHODS: 80 psychiatric inpatients with BPD were included in the study, of whom 63 had a history of NSSI and 17 had not. The frequency and characteristics of NSSI were assessed by the Ottawa Self-Injury Inventory and the childhood traumatization were assessed by the Traumatic Antecedents Questionnaire and the Early Trauma Inventory. RESULTS: In this study among self-injuring borderline inpatients a super self-injuring group was identified, who engaged in extremely high numbers of NSSI (75.0±28.4 acts/lifetime). Compared to moderate self-injurers, super self-injurers began harming themselves at a younger age (p=0.008), used more severe forms of NSSI, and all of them reported an anti-dissociation function of NSSI. Adverse childhood experiences were more prevalent in the super self-injuring group. The strongest predictors of the lifetime number of NSSI were early sexual abuse (p<0.001), intrafamilial physical abuse (p<0.001), a higher cumulative trauma score (p=0.030) and a greater number of BPD criteria (p<0.001). CONCLUSIONS: Our results suggest that the frequency of NSSI in borderline inpatients can be seen as an indicator of clinically-relevant anamnestic data, namely, of the severity, complexity and onset of childhood traumatization, and of the severity of current borderline psychopathology.

[The etiology of obsessive-compulsive disorder from the aspects of attachment theory, with special regard to perceived parental treatment, attachment patterns and emotion regulation difficulties].

BACKGROUND AND AIMS: The focus of our study was the etiology of obsessive-compulsive disorder from attachment aspects. Our aim was to examine the representations of perceived parental treatment, attachment patterns and the level of emotion regulation of people who suffer from obsessive-compulsive disorder. METHOD: 223 people participated in our study. The clinical group consisted of 92 persons with obsessive-compulsive symptoms, while the control group involved 131 people without OC symptoms. In the study we used the Young Parenting Inventory, the Relationship Questionnaire, and the Difficulties in Emotion Regulation Scale. Besides we compiled a questionnaire based on the DSM-5 and a demographic questionnaire. Respondents could fill the questionnaires online. RESULTS: The clinical group is characterized by significantly higher toxic frustration of each five basic emotional needs than the control group. Specifically, in the case of people with OC smptoms the toxic parental treatments for Defectiveness/ Shame, Dependence/Incompetence, Enmeshment/Undeveloped self, Entitlement/Grandiosity, Approval-seeking/ Recognition-seeking, Negativity/Pessimism, Emotional inhibition, Unrelenting standards/Hypercriticalness and Punitiveness were significantly more frequent than in the control group. The OC group is also characterized by significantly lower rate of secure attachment style, while dismissive attachment style proved to be the most frequent attachment style among them. The OC group also struggle with significantly higher level of emotion regulation difficulties.

Differences in the molecular structure of the blood-brain barrier in the cerebral cortex and white matter: an in silico, in vitro, and ex vivo study.

The blood-brain barrier (BBB) is the main interface controlling molecular and cellular traffic between the central nervous system (CNS) and the periphery. It consists of cerebral endothelial cells (CECs) interconnected by continuous tight junctions, and closely associated pericytes and astrocytes. Different parts of the CNS have diverse functions and structures and may be subject of different pathologies, in which the BBB is actively involved. It is largely unknown, however, what are the cellular and molecular differences of the BBB in different regions of the brain. Using in silico, in vitro, and ex vivo techniques we compared the expression of BBB-associated genes and proteins (i.e., markers of CECs, brain pericytes, and astrocytes) in the cortical grey matter and white matter. In silico human database analysis (obtained from recalculated data of the Allen Brain Atlas), qPCR, Western blot, and immunofluorescence studies on porcine and mouse brain tissue indicated an increased expression of glial fibrillary acidic protein in astrocytes in the white matter compared with the grey matter. We have also found increased expression of genes of the junctional complex of CECs (occludin, claudin-5, and α-catenin) in the white matter compared with the cerebral cortex. Accordingly, occludin, claudin-5, and α-catenin proteins showed increased expression in CECs of the white matter compared with endothelial cells of the cortical grey matter. In parallel, barrier properties of white matter CECs were superior as well. These differences might be important in the pathogenesis of diseases differently affecting distinct regions of the brain.

PEGylation of Reduced Graphene Oxide Induces Toxicity in Cells of the Blood-Brain Barrier: An in Vitro and in Vivo Study.

Polyethylene glycol (PEG) coating has been frequently used to improve the pharmacokinetic behavior of nanoparticles. Studies that contribute to better unravel the effects of PEGylation on the toxicity of nanoparticle formulation are therefore highly relevant. In the present study, reduced graphene oxide (rGO) was functionalized with PEG, and its effects on key components of the blood-brain barrier, such as astrocytes and endothelial cells, were analyzed in culture and in an in vivo rat model. The in vitro studies demonstrated concentration-dependent toxicity. The highest concentration (100 µg/mL) of non-PEGylated rGO had a lower toxic influence on cell viability in primary cultures of astrocytes and rat brain endothelial cells, while PEGylated rGO induced deleterious effects and cell death. We assessed hippocampal BBB integrity in vivo by evaluating astrocyte activation and the expression of the endothelial tight and adherens junctions proteins. From 1 h to 7 days post-rGO-PEG systemic injection, a notable and progressive down-regulation of protein markers of astrocytes (GFAP, connexin-43), the endothelial tight (occludin), and adherens (ß-catenin) junctions and basal lamina (laminin) were observed. The formation of intracellular reactive oxygen species demonstrated by increases in the enzymatic antioxidant system in the PEGylated rGO samples was indicative of oxidative stress-mediated damage. Under the experimental conditions and design of the present study the PEGylation of rGO did not improve interaction with components of the blood-brain barrier. In contrast, the attachment of PEG to rGO induced deleterious effects in comparison with the effects caused by non-PEGylated rGO.

Investigation of the Antiproliferative Properties of Natural Sesquiterpenes from Artemisia asiatica and Onopordum acanthium on HL-60 Cells in Vitro.

Plants and plant extracts play a crucial role in the research into novel antineoplastic agents. Four sesquiterpene lactones, artecanin (1), 3ß-chloro-4α,10α-dihydroxy-1α,2α-epoxy-5α,7αH-guaia-11(13)-en-12,6α-olide (2), iso-seco-tanapartholide 3-O-methyl ether (3) and 4ß,15-dihydro-3-dehydrozaluzanin C (4), were isolated from two traditionally used Asteraceae species (Onopordum acanthium and Artemisia asiatica). When tested for antiproliferative action on HL-60 leukemia cells, these compounds exhibited reasonable IC50 values in the range 3.6-13.5 µM. Treatment with the tested compounds resulted in a cell cycle disturbance characterized by increases in the G1 and G2/M populations, while there was a decrease in the S phase. Additionally, 1-3 elicited increases in the hypodiploid (subG1) population. The compounds elicited concentration-dependent chromatin condensation and disruption of the membrane integrity, as revealed by Hoechst 33258-propidium staining. Treatment for 24 h resulted in significant increases in activity of caspases-3 and -9, indicating that the tested sesquiterpenes induced the mitochondrial pathway of apoptosis. The proapoptotic properties of the sesquiterpene lactones were additionally demonstrated withannexin V staining. Compounds 1 and 2 increased the Bax/Bcl-2 expression and decreased the expressions of CDK1 and cyclin B2, as determined at the mRNA level by means of RT-PCR. These experimental results indicate that sesquiterpene lactones may be regarded as potential starting structures for the development of novel anticancer agents.

[Investigation of CNTF, COMT, DDR1, DISC1, DRD2, DRD3, and DTNBP1 candidate genes in schizophrenia: Results from the Hungarian SCHIZOBANK Consortium]. / CNTF, COMT, DDR1, DISC1, DRD2, DRD3 és DTNBP1 kandidáns gének vizsgálata szkizofréniában: eredmények a Magyar SCHIZOBANK Konzorcium vizsgálatából.

Schizophrenia is a chronic, debilitating psychiatric disorder characterized by heterogeneous clinical symptoms. Although the pathogenesis of this disorder is poorly understood, several lines of evidence support the role of both common and rare genetic variants in the etiology of schizophrenia. Common variants, single nucleotide polymorphisms can be investigated by candidate gene association studies or genome-wide association studies, while rare variants, single nucleotide variants are assessable by means of candidate gene resequencing or whole-exome and genome sequencing using next generation sequencing. In this study we investigated polymorphisms of 7 candidate genes in a Hungarian schizophrenia cohort. Candidate genes were chosen on the basis of previous results and biological plausibility. 390 patients were recruited in 5 centers in the framework of the Hungarian SCHIZOBANK Consortium, the schizophrenia sample was contrasted to 1069 healthy control individuals. In this sample SNPs of DDR1 and DRD2 genes demonstrated significant association with schizophrenia. The role of DDR1 and DRD2 genes in the etiology of schizophrenia warrant further investigation, based on their genomic localization and biological functions.

A molecular understanding of D-homoestrone-induced G2/M cell cycle arrest in HeLa human cervical carcinoma cells.

2-Methoxyestradiol (ME), one of the most widely investigated A-ring-modified metabolites of estrone, exerts significant anticancer activity on numerous cancer cell lines. Its pharmacological actions, including cell cycle arrest, microtubule disruption and pro-apoptotic activity, have already been described in detail. The currently tested D-ring-modified analogue of estrone, D-homoestrone, selectively inhibits cervical cancer cell proliferation and induces a G2/M phase cell cycle blockade, resulting in the development of apoptosis. The question arose of whether the difference in the chemical structures of these analogues can influence the mechanism of anticancer action. The aim of the present study was therefore to elucidate the molecular contributors of intracellular processes induced by D-homoestrone in HeLa cells. Apoptosis triggered by D-homoestrone develops through activation of the intrinsic pathway, as demonstrated by determination of the activities of caspase-8 and -9. It was revealed that D-homoestrone-treated HeLa cells are not able to enter mitosis because the cyclin-dependent kinase 1-cyclin B complex loses its activity, resulting in the decreased inactivation of stathmin and a concomitant disturbance of microtubule formation. However, unlike 2-ME, D-homoestrone does not exert a direct effect on tubulin polymerization. These results led to the conclusion that the D-homoestrone-triggered intracellular processes resulting in a cell cycle arrest and apoptosis in HeLa cells differ from those in the case of 2-ME. This may be regarded as an alternative mechanism of action among steroidal anticancer compounds.

Regulation of NOD-like receptors and inflammasome activation in cerebral endothelial cells.

Cerebral endothelial cells (CECs) forming the blood-brain barrier are at the interface of the immune and the central nervous systems and thus may play an important role in the functional integration of the two systems. Here, we investigated how CECs recognize and respond to pathogen- and damage-associated molecular patterns to regulate the functions of the neurovascular unit. First we detected the expression of several NOD-like receptors (NLRs) - including NOD1, NOD2, NLRC4, NLRC5, NLRP1, NLRP3, NLRP5, NLRP9, NLRP10, NLRP12, NLRA, and NLRX - in human brain endothelial cells. Inflammatory cytokines, such as interferon-γ, tumor necrosis factor-α, and IL-1ß had stimulatory effects on the transcription of many of these receptors. Expression of key inflammasome components (NOD2, NLRP3, and caspase 1) along with caspase-cleaved interleukins IL-1ß and IL-33 could be induced by priming with lipopolysaccharide and activation with muramyl dipeptide. In addition, combined treatment with lipopolysaccharide and muramyl dipeptide resulted in IL-1ß secretion in a caspase- and ERK1/2 kinase-dependent manner. Our findings demonstrate that NLRs and inflammasomes can be activated in cerebral endothelial cells, which may confer a yet unexplored role to the blood-brain barrier in neuroimmune and neuroinflammatory processes.

Evaluation of lignans from Heliopsis helianthoides var. scabra for their potential antimetastatic effects in the brain.

Two new arylbenzofuran-type neolignans, 1"-dehydroegonol 3"-methyl ether (1) and egonol 3"-methyl ether (2), and four known lignan derivatives, namely, helioxanthin (3), (7E)-7,8-dehydroheliobuphthalmin (4), heliobuphthalmin (5), and 7-acetoxyhinokinin (6), were isolated from a chloroform-soluble partition of the methanol extract of the fresh roots of Heliopsis helianthoides var. scabra. These six compounds were evaluated in vitro in terms of their ability to inhibit the various steps involved in brain tumor metastasis formation. Compounds 3 and 4 inhibited the migration of both melanoma and brain endothelial cells, and 3 also reduced the adhesion of melanoma cells to the brain endothelium. Furthermore, 3 and 4 additionally enhanced the barrier function of the blood-brain barrier and the expression of the tight junction protein ZO-1 at the junctions of the endothelial cells. These findings suggest that 3 and 4 may have the potential to interfere with different steps of brain metastasis formation and to enhance the barrier function of cerebral endothelial cells.

Antiproliferative activity of Artemisia asiatica extract and its constituents on human tumor cell lines.

The extract of Artemisia asiatica herb with antiproliferative activity against four human tumor cell lines (A2780, A431, HeLa, and MCF7) was analyzed by the MTT assay, and bioassay-directed fractionation was carried out in order to identify the compounds responsible for the cytotoxic activity. Guaianolide (1-4), seco-guianolide (5), germacranolide (6) and eudesmanolide sesquiterpenes (7), monoterpenes (8, 9), including the new compound artemisia alcohol glucoside (8), and flavonoids (10-16) were isolated as a result of a multistep chromatographic procedure (CC, CPC, PLC, and gel filtration). The compounds were identified by means of UV, MS, and NMR spectroscopy, including (1)H-and (13)C-NMR, (1)H-(1)H COSY, NOESY, HSQC, and HMBC experiments. The isolated compounds 1-16 were evaluated for their tumor cell growth-inhibitory activities on a panel of four adherent cancer cell lines, and different types of secondary metabolites were found to be responsible for the cytotoxic effects of the extract. Especially cirsilineol (13), 3ß-chloro-4α,10α-dihydroxy-1α,2α-epoxy-5α,7αH-guai-11(13)-en-12,6α-olide (3), and iso-seco-tanapartholide 3-O-methyl ester (5) exerted marked cytotoxic effects against the investigated cell lines, while jaceosidin (12), 6-methoxytricin (15), artecanin (2), and 5,7,4',5'-tetrahydroxy-6,3'-dimethoxyflavone (14) were moderately active. All the sesquiterpenes and monoterpenes are reported here for the first time from this species, and in the case of artecanin (2), 3α-chloro-4ß,10α-dihydroxy-1ß,2ß-epoxy-5α,7αH-guai-11(13)-en-12,6α-olide (4), ridentin (6), and ridentin B (7), previously unreported NMR spectroscopic data were determined.

CB2 receptor activation inhibits melanoma cell transmigration through the blood-brain barrier.

During parenchymal brain metastasis formation tumor cells need to migrate through cerebral endothelial cells, which form the morphological basis of the blood-brain barrier (BBB). The mechanisms of extravasation of tumor cells are highly uncharacterized, but in some aspects recapitulate the diapedesis of leukocytes. Extravasation of leukocytes through the BBB is decreased by the activation of type 2 cannabinoid receptors (CB2); therefore, in the present study we sought to investigate the role of CB2 receptors in the interaction of melanoma cells with the brain endothelium. First, we identified the presence of CB1, CB2(A), GPR18 (transcriptional variant 1) and GPR55 receptors in brain endothelial cells, while melanoma cells expressed CB1, CB2(A), GPR18 (transcriptional variants 1 and 2), GPR55 and GPR119. We observed that activation of CB2 receptors with JWH-133 reduced the adhesion of melanoma cells to the layer of brain endothelial cells. JWH-133 decreased the transendothelial migration rate of melanoma cells as well. Our results suggest that changes induced in endothelial cells are critical in the mediation of the effect of CB2 agonists. Our data identify CB2 as a potential target in reducing the number of brain metastastes originating from melanoma.