Anticancer and Antitumor Potential of Fucoidan and Fucoxanthin, Two Main Metabolites Isolated from Brown Algae

Seaweed is one of the largest producers of biomass in marine environment and is a rich arsenal of active metabolites and functional ingredients with valuable beneficial health effects. Being a staple part of Asian cuisine, investigations on the crude extracts of Phaeophyceae or brown algae revealed marked antitumor activity, eliciting a variety of research to determine the active ingredients involved in this potential. The sulfated polysaccharide of fucoidan and carotenoid of fucoxanthin were found to be the most important active metabolites of brown algae as potential chemotherapeutic or chemopreventive agents. This review strives to provide detailed account of all current knowledge on the anticancer and antitumor activity of fucoidan and fucoxanthin as the two major metabolites isolated from brown algae

The role of decidual mesenchymal stem/stromal cells and their secreted extracellular vesicles in ageing of the human placenta

© 2018 Dr. Ramin KhanabdaliAgeing is an inevitable process associated with age-related diseases. Unhealthy ageing is a major risk factor for many chronic diseases including cardiovascular and neurodegenerative diseases. The human placenta, despite being a short-lived and transient organ, does not escape the effects of ageing and aberrant placental ageing is a feature of important placental pathologies including preeclampsia (PE) and fetal growth restriction (FGR). Recent evidence shows placental tissues undergo significant molecular age-related changes in a short period, between early-term (ET) (37 0/7– 38 6/7 weeks gestation) to late/post-term (L/PT) (41 0/7 weeks gestation and beyond), after the due date of the pregnancy has been reached. Moreover, there is a dramatic increase in the risk of unexplained antepartum stillbirths in pregnancies that progress into the L/PT period, which may be linked to increased ageing of placenta. The role of ageing and the underlying mechanisms that regulate aberrant placental ageing during this period remain unclear. The maternal-fetal interface develops between the chorionic placenta to the maternal uterine wall and is vital for the maintenance of a healthy pregnancy. The decidua is the maternal tissue between the placenta and the muscular uterine wall. Age-related tissue and cellular changes are evident throughout the decidua and placenta. The decidua basalis tissue, which is the focus of this study, and underlying myometrium are continually exposed to damaging reactive oxygen species (ROS) and inflammatory molecules secreted primarily by the placenta. The decidua basalis must withstand harsh physical conditions associated with changes in blood flow into the intervillous space during uncomplicated pregnancy. However, the extent of decidual ageing in uncomplicated pregnancies that reach term, and how decidual ageing affects the placenta, are not well understood. Stem cell exhaustion and dysfunction are major contributors to the decline in tissue and organ functionality associated with ageing. The placenta and decidua are rich sources of stem cells, particularly mesenchymal stem/stromal cells (MSCs) which are highly active and involved in placental development and growth. However, the role of stem cells and their association with ageing of the chorionic placenta and maternal decidua basalis, especially in the short period between ET and L/PT, has not been investigated. The work of this thesis focuses on maternal decidua basalis derived MSCs (DMSCs). The first aim of this study was to compare ageing/senescence functions of ET DMSCs (ET- DMSCs) from (37-39 gestational weeks) with L/PT DMSCs (L/PT-DMSCs) (41-42 gestational weeks). The second aim was to screen for differentially expressed known and novel small RNAs between ET-DMSCs and L/PT-DMSCs. The third aim was to analyse and characterise ET-DMSCs and L/PT-DMSCs secreted extracellular vesicles (EVs). EVs are nanosized particles secreted by MSCs, and they potentially regulate health and the ageing processes. The final aim of this work was to treat ET-DMSCs, L/PT-DMSCs and PE-DMSCs with a low dose of aspirin, which is an anti-aging and anti-inflammatory drug. ET, L/PT, and PE-affected placentae were collected with informed consent. DMSCs were successfully isolated from decidua basalis of ET, L/PT, and PE placentae using an enzymatic digestion method and then characterised for their stem/stromal cell properties. The phenotypic characterization of DMSCs met the minimum criteria of MSCs. L/PT-DMSCs, when compared to ET-DMSCs, showed significantly lower cell proliferation and a significant higher level of cell apoptosis. Using a quantitative Aldefluor assay, ET-DMSCs showed a significantly higher resistance to oxidative stress compared with L/PT-DMSCs. There was a significant decrease in antioxidant capacity of L/PT-DMSCs compared with ET-DMSCs. Western blot analysis revealed increased expression of the stress-mediated p38MAPK protein in L/PT- DMSCs. These data provide the first evidence of advanced ageing and loss of important stem cell functions in L/PT-DMSCs. Sequencing of small RNAs and validation by qRT-PCR demonstrated miR-516-5p, which is a member of the chromosome 19 miRNA cluster (C19MC), was present at significantly lower levels in L/PT-DMSCs. This miRNA was also contained in EVs isolated from ET- and L/PT-DMSCs and the difference in levels of this miRNA in whole ET- and L/PT-DMSCs was also maintained in their respective EVs. This demonstrated that EV miRNAs are origin-dependent and their differences in levels reflected those in the ET- and L/PT-DMSCs that they were secreted from. EVs from both groups were further analysed using a novel method resonance enhanced atomic force microscopy and infrared spectroscopy (AFM-IR) which revealed a distinct fingerprint of biomolecules between these two groups. There were substantial differences in peak intensity of EVs contents between ET- and L/PT-DMSCs, particularly those associated with lipid and protein content. The combination of conventional assays and AFM-IR provide the first evidence of advanced age-related, and other changes, in EVs from L/PT decidua MSCs. Finally, low dose aspirin treatment improved PE-DMSCs functionality by a novel mechanism via increasing cell adhesion. Aspirin treatment also increased antioxidant capacity and decreased inflammatory markers in PE-DMSCs. Aspirin had no similar effect on ET- and L/PT-DMSCs

Characterization and differentiation potential of rat bone marrow Mesenchymal stem cells into cardiac-like cells / Ramin Khanabdali

Heart diseases are the leading cause of death worldwide. Despite the development of a broad array of treatment options, current therapies only delay progression of the disease and failed to prevent myocardial scar formation and replace the lost cardiomyocytes (cardiac muscle cells). Over the past decade the use of adult stem cells, particularly bone marrow derived mesenchymal stem cells, to safely facilitate recovery of cardiac function after myocardial infarction has received a lot of interest. Mesenchymal stem cells (MSCs), which are adherent stromal cells of a non-hematopoietic origin, have great differentiation potential and under appropriate in vitro culture conditions can trans-differentiate into cardiomyocyte cells. This study investigated the characterization of rat bone marrow derived-mesenchymal stem cells (BM-MSCs) and in vitro differentiation potential of them into cardiomyocyte-like cells by two DNA-demethylating agents, 5-azacytidine and zebularine. MSCs were isolated from Sprague Dawley’s bone marrow and cultured in complete Dulbecco’s Modified Eagle Medium (DMEM). Morphological characteristics of MSCs were analyzed by phase contrast microscopy. Selected surface antigens CD44, CD117, known MSCs markers, and CD34, a hematopoietic marker (negative marker), were analyzed by immunocytochemistry. In addition, CD45, known hematopoietic marker (negative marker) and CD44 were analyzed by flow cytometry for the MSC cell population count. Passage 1 (P1) cultured MSCs were then treated in separate culture flasks for 24 hours with a 3μM optimized concentration of 5-azacytidine and zebularine. After 20 days, treated cells were analyzed for the expression of rat cardiac specific genes; namely, alpha-myosin heavy chain (CAMHC), cardiac troponin-T (cTnT), and cardiac transcription factor (GATA-4) by reverse transcriptase polymerase chain reaction (RT-PCR). The endogenous housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal standard gene for normalization of mRNA. The isolation of MSCs from rat bone marrow was successfully completed. Isolated MSCs exhibited spindle-shaped morphology with adherence ability to the surface of flasks and proliferated in the culture medium. Immunocytochemistry results showed that cell surface antigen expression was observed to be positive for CD44 and CD117. However, MSCs were negative for CD34 (hematopoietic marker); hence, confirming the absence of hematopoietic cells. Furthermore, CD44 was found to be >85% positive, while CD45 was more than 60% negative in MSCs after flow cytometry cell population analysis. Upon induction with 5-azacytidine and zebularine, the morphology of the MSCs changed and the cells showed extended cytoplasmic processes with ball-like appearance. After 20 days, they were connected with adjoining cells forming myotube-like structures. The mRNAs of CAMHC, cTnT and GATA-4 were detected in both treated and untreated cells. However, RT-PCR analysis for the expression of cardiac specific genes showed that treated MSC cells expressed cTnT, CAMHC and GATA-4 significantly higher compared to untreated cells. While there were no significant differences between 5-azacytdine and zebularine treated cells, zebularine could be a good replacement for 5-azacytidine as it is more stable and less toxic to biological system. These results showed that bone marrow mesenchymal stem cells (BM-MSCs) could differentiate in vitro towards a cardiomyogenic lineage

Ageing in human parturition: impetus of the gestation clock in the decidua

Despite sharing many common features, the relationship between ageing and parturition remains poorly understood. The decidua is a specialized lining of endometrial tissue, which develops in preparation for pregnancy. The structure and location of the decidua support its role as the physical scaffold for the growing embryo and placenta, and thus, it is vital to sustain pregnancy. Approaching term, the physical support properties of the decidua are naturally weakened to permit parturition. In this review, we hypothesize that the natural weakening of decidual tissue at parturition is promoted by the ageing process. Studies of the ageing-related functional and molecular changes in the decidua at parturition are reviewed and classified using hallmarks of ageing as the framework. The potential roles of decidual mesenchymal stem/stromal cell (DMSC) ageing in labor are also discussed because, although stem cell exhaustion is also a hallmark of ageing, its role in labor is not completely understood. In addition, the potential roles of extracellular vesicles secreted by DMSCs in labor, and their parturition-related miRNAs, are reviewed to gain further insight into this research area. In summary, the literature supports the notion that the decidua ages as the pregnancy progresses, and this may facilitate parturition, suggesting that ageing is the probable impetus of the gestational clocks in the decidua. This conceptual framework was developed to provide a better understanding of the natural ageing process of the decidua during parturition as well as to encourage future studies of the importance of healthy ageing for optimal pregnancy outcomes

Circular RNAs: Isolation, characterization and their potential role in diseases

Circular RNA (circRNA) generated by alternative splicing represents a special class of non-coding RNA molecule. CircRNAs are abundant in the eukaryotic cell cytoplasm and have a characteristic organization, timing of action and disease specificity. In contrast to linear RNA, circRNAs are resistant to RNA exonuclease. Consequently, circRNA escapes normal RNA turnover and this improves circRNA stability. CircRNAs can be degraded by microRNA (miRNA) and this results in linearization of the circRNA, which can then act as competitor to endogenous RNA. Through interactions with disease-related miRNA, circRNA can play an important regulatory role in specific diseases. Furthermore, circRNAs have significant potential to become new clinical diagnostic markers

The Emerging Role of HMGB1 in Neuropathic Pain: A Potential Therapeutic Target for Neuroinflammation

Neuropathic pain (NPP) is intolerable, persistent, and specific type of long-term pain. It is considered to be a direct consequence of pathological changes affecting the somatosensory system and can be debilitating for affected patients. Despite recent progress and growing interest in understanding the pathogenesis of the disease, NPP still presents a major diagnostic and therapeutic challenge. High mobility group box 1 (HMGB1) mediates inflammatory and immune reactions in nervous system and emerging evidence reveals that HMGB1 plays an essential role in neuroinflammation through receptors such as Toll-like receptors (TLR), receptor for advanced glycation end products (RAGE), C-X-X motif chemokines receptor 4 (CXCR4), and N-methyl-D-aspartate (NMDA) receptor. In this review, we present evidence from studies that address the role of HMGB1 in NPP. First, we review studies aimed at determining the role of HMGB1 in NPP and discuss the possible mechanisms underlying HMGB1-mediated NPP progression where receptors for HMGB1 are involved. Then we review studies that address HMGB1 as a potential therapeutic target for NPP

An Update on Inflamm-Aging: Mechanisms, Prevention, and Treatment

Inflamm-aging is a challenging and promising new branch of aging-related research fields that includes areas such as immunosenescence. Increasing evidence indicates that inflamm-aging is intensively associated with many aging diseases, such as Alzheimer’s disease, atherosclerosis, heart disease, type II diabetes, and cancer. Mounting studies have focused on the role of inflamm-aging in disease progression and many advances have been made in the last decade. However, the underlying mechanisms by which inflamm-aging affects pathological changes and disease development are still unclear. Here, we review studies of inflamm-aging that explore the concept, pathological features, mechanisms, intervention, and the therapeutic strategies of inflamm-aging in disease progression

Functional changes in decidual mesenchymal stem/stromal cells are associated with spontaneous onset of labour

Ageing and parturition share common pathways, but their relationship remains poorly understood. Decidual cells undergo ageing as parturition approaches term, and these age-related changes may trigger labour. Mesenchymal stem/stromal cells (MSCs) are the predominant stem cell type in the decidua. Stem cell exhaustion is a hallmark of ageing, and thus ageing of decidual MSCs (DMSCs) may contribute to the functional changes in decidual tissue required for term spontaneous labour. Here, we determine whether DMSCs from patients undergoing spontaneous onset of labour (SOL-DMSCs) show evidence of ageing-related functional changes compared with those from patients not in labour (NIL-DMSCs), undergoing Caesarean section. Placentae were collected from term (37-40 weeks of gestation), SOL (n = 18) and NIL (n = 17) healthy patients. DMSCs were isolated from the decidua basalis that remained attached to the placenta after delivery. DMSCs displayed stem cell-like properties and were of maternal origin. Important cell properties and lipid profiles were assessed and compared between SOL- and NIL-DMSCs. SOL-DMSCs showed reduced proliferation and increased lipid peroxidation, migration, necrosis, mitochondrial apoptosis, IL-6 production and p38 MAPK levels compared with NIL-DMSCs (P < 0.05). SOL- and NIL-DMSCs also showed significant differences in lipid profiles in various phospholipids (phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine), sphingolipids (ceramide, sphingomyelin), triglycerides and acyl carnitine (P < 0.05). Overall, SOL-DMSCs had altered lipid profiles compared with NIL-DMSCs. In conclusion, SOL-DMSCs showed evidence of ageing-related reduced functionality, accumulation of cellular damage and changes in lipid profiles compared with NIL-DMSCs. These changes may be associated with term spontaneous labour