Chronic intrahippocampal interleukin-1β overexpression in adolescence impairs hippocampal neurogenesis but not neurogenesis-associated cognition

Both neuroinflammation and adult hippocampal neurogenesis (AHN) are implicated in many neurodegenerative disorders as well as in neuropsychiatric disorders, which often become symptomatic during adolescence. A better knowledge of the impact that chronic neuroinflammation has on the hippocampus during the adolescent period could lead to the discovery of new therapeutics for some of these disorders. The hippocampus is particularly vulnerable to altered concentrations of the pro-inflammatory cytokine interleukin-1β (IL-1β), with elevated levels implicated in the aetiology of neurodegenerative disorders such as Alzheimer’s and Parkinson’s, and stress-related disorders such as depression. The effect of acutely and chronically elevated concentrations of hippocampal IL-1β have been shown to reduce AHN in adult rodents. However, the effect of exposure to chronic overexpression of hippocampal IL-1β during adolescence, a time of increased vulnerability, hasn’t been fully interrogated. Thus, in this study we utilized a lentiviral approach to induce chronic overexpression of IL-1β in the dorsal hippocampus of adolescent male Sprague Dawley rats for 5 weeks, during which time its impact on cognition and hippocampal neurogenesis were examined. A reduction in hippocampal neurogenesis was observed along with a reduced level of neurite branching on hippocampal neurons. However, there was no effect of IL-1β overexpression on performance in pattern separation, novel object recognition or spontaneous alternation in the Y maze. Our study has highlighted that chronic IL-1β overexpression in the hippocampus during the adolescent period exerts a negative impact on neurogenesis independent of cognitive performance, and suggests a degree of resilience of the adolescent hippocampus to inflammatory insult

Rhodacyanine Derivative Selectively Targets Cancer Cells and Overcomes Tamoxifen Resistance

MKT-077, a rhodacyanine dye, was shown to produce cancer specific cell death. However, complications prevented the use of this compound beyond clinical trials. Here we describe YM-1, a derivative of MKT-077. We found that YM-1 was more cytotoxic and localized differently than MKT-077. YM-1 demonstrated this cytotoxicity across multiple cancer cell lines. This toxicity was limited to cancer cell lines; immortalized cell models were unaffected. Brief applications of YM-1 were found to be non-toxic. Brief treatment with YM-1 restored tamoxifen sensitivity to a refractory tamoxifen-resistant MCF7 cell model. This effect is potentially due to altered estrogen receptor alpha phosphorylation, an outcome precipitated by selective reductions in Akt levels (Akt/PKB). Thus, modifications to the rhodocyanine scaffold could potentially be made to improve efficacy and pharmacokinetic properties. Moreover, the impact on tamoxifen sensitivity could be a new utility for this compound family

Relationships of Cetacea (Artiodactyla) Among Mammals: Increased Taxon Sampling Alters Interpretations of Key Fossils and Character Evolution

BACKGROUND: Integration of diverse data (molecules, fossils) provides the most robust test of the phylogeny of cetaceans. Positioning key fossils is critical for reconstructing the character change from life on land to life in the water. METHODOLOGY/PRINCIPAL FINDINGS: We reexamine relationships of critical extinct taxa that impact our understanding of the origin of Cetacea. We do this in the context of the largest total evidence analysis of morphological and molecular information for Artiodactyla (661 phenotypic characters and 46,587 molecular characters, coded for 33 extant and 48 extinct taxa). We score morphological data for Carnivoramorpha, Creodonta, Lipotyphla, and the raoellid artiodactylan Indohyus and concentrate on determining which fossils are positioned along stem lineages to major artiodactylan crown clades. Shortest trees place Cetacea within Artiodactyla and close to Indohyus, with Mesonychia outside of Artiodactyla. The relationships of Mesonychia and Indohyus are highly unstable, however--in trees only two steps longer than minimum length, Mesonychia falls inside Artiodactyla and displaces Indohyus from a position close to Cetacea. Trees based only on data that fossilize continue to show the classic arrangement of relationships within Artiodactyla with Cetacea grouping outside the clade, a signal incongruent with the molecular data that dominate the total evidence result. CONCLUSIONS/SIGNIFICANCE: Integration of new fossil material of Indohyus impacts placement of another extinct clade Mesonychia, pushing it much farther down the tree. The phylogenetic position of Indohyus suggests that the cetacean stem lineage included herbivorous and carnivorous aquatic species. We also conclude that extinct members of Cetancodonta (whales+hippopotamids) shared a derived ability to hear underwater sounds, even though several cetancodontans lack a pachyostotic auditory bulla. We revise the taxonomy of living and extinct artiodactylans and propose explicit node and stem-based definitions for the ingroup

Preliminary imaging results from the second Mercury encounter

The second Mercury encounter has resulted in the acquisition of about 360 pictures of the south polar regions which provide a reliable cartographic and geologic tie between the two sides of the planet photographed on the first encounter. Stereoscopic coverage of large areas of the southern hemisphere was obtained by combining Mercury 1 and 2 pictures taken at different viewing angles. The south polar regions consist of heavily cratered terrain and intercrater plains interspersed with patches of smooth plains. No large areas of smooth plains similar to those surrounding Caloris occur in the south polar regions. No new types of terrain have been recognized, but lobate scarps are common. The second largest basin seen by Mariner 10 (∼600-km diameter) has been confirmed on the new photography. At high solar elevations the surface displays an abundance of rays and rayed craters

Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

Abstract Background It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection. Results Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember™, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced. Conclusions Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.http://deepblue.lib.umich.edu/bitstream/2027.42/78314/1/1750-1326-5-45.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/2/1750-1326-5-45.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/3/1750-1326-5-45-S1.PDFPeer Reviewe

Suppression of cancer stemness p21-regulating mRNA and microRNA signatures in recurrent ovarian cancer patient samples

<p>Abstract</p> <p>Background</p> <p>Malignant ovarian disease is characterised by high rates of mortality due to high rates of recurrent chemoresistant disease. Anecdotal evidence indicates this may be due to chemoresistant properties of cancer stem cells (CSCs). However, our understanding of the role of CSCs in recurrent ovarian disease remains sparse. In this study we used gene microarrays and meta-analysis of our previously published microRNA (miRNA) data to assess the involvement of cancer stemness signatures in recurrent ovarian disease.</p> <p>Methods</p> <p>Microarray analysis was used to characterise early regulation events in an embryonal carcinoma (EC) model of cancer stemness. This was then compared to our previously published microarray data from a study of primary versus recurrent ovarian disease. In parallel, meta-analysis was used to identify cancer stemness miRNA signatures in tumor patient samples.</p> <p>Results</p> <p>Microarray analysis demonstrated a 90% difference between gene expression events involved in early regulation of differentiation in murine EC (mEC) and embryonic stem (mES) cells. This contrasts the known parallels between mEC and mES cells in the undifferentiated and well-differentiated states. Genelist comparisons identified a cancer stemness signature set of genes in primary versus recurrent data, a subset of which are known p53-p21 regulators. This signature is present in primary and recurrent or in primary alone but essentially never in recurrent tumors specifically. Meta-analysis of miRNA expression showed a much stronger cancer stemness signature within tumor samples. This miRNA signature again related to p53-p21 regulation and was expressed prominently in recurrent tumors. Our data indicate that the regulation of p53-p21 in ovarian cancer involves, at least partially, a cancer stemness component.</p> <p>Conclusion</p> <p>We present a p53-p21 cancer stemness signature model for ovarian cancer. We propose that this may, at least partially, differentially regulate the p53-p21 mechanism in ovarian disease. Targeting CSCs within ovarian cancer represents a potential therapeutic avenue.</p

Could MicroRNAs be Useful Tools to Improve the Diagnosis and Treatment of Rare Gynecological Cancers? A Brief Overview

Gynecological cancers pose an important public health issue, with a high incidence among women of all ages. Gynecological cancers such as malignant germ-cell tumors, sex-cord-stromal tumors, uterine sarcomas and carcinosarcomas, gestational trophoblastic neoplasia, vulvar carcinoma and melanoma of the female genital tract, are defined as rare with an annual incidence of <6 per 100,000 women. Rare gynecological cancers (RGCs) are associated with poor prognosis, and given the low incidence of each entity, there is the risk of delayed diagnosis due to clinical inexperience and limited therapeutic options. There has been a growing interest in the field of microRNAs (miRNAs), a class of small non-coding RNAs of 22 nucleotides in length, because of their potential to regulate diverse biological processes. miRNAs usually induce mRNA degradation and translational repression by interacting with the 30 untranslated region (30-UTR) of target mRNAs, as well as other regions and gene promoters, as well as activating translation or regulating transcription under certain conditions. Recent research has revealed the enormous promise of miRNAs for improving the diagnosis, therapy and prognosis of all major gynecological cancers. However, to date, only a few studies have been performed on RGCs. In this review, we summarize the data currently available regarding RGCs.peer-reviewe

Tart cherry supplement enhances skeletal muscle glutathione peroxidase expression and functional recovery after muscle damage

Introduction: Montmorency cherry concentrate (MCC) supplementation enhances functional recovery from exercise, potentially due to antioxidant and anti-inflammatory effects. However, to date, supporting empirical evidence for these mechanistic hypotheses is reliant on indirect blood biomarkers. This study is the first to investigate functional recovery from exercise alongside molecular changes within the exercised muscle following MCC supplementation. Methods: Ten participants completed two maximal unilateral eccentric knee extension trials following MCC or placebo supplementation for 7 days prior to and 48 hours following exercise. Knee extension maximum voluntary isometric contractions (MVC), maximal isokinetic contractions, single leg jumps, and soreness measures were assessed before, immediately, 24 and 48 h after exercise. Venous blood and vastus lateralis muscle samples were collected at each time point. Plasma concentrations of IL-6, TNF-⍺, C-reactive protein, creatine kinase, and phenolic acids were quantified. Intramuscular mRNA expression of SOD 1 and 3, GPX1, 3, 4 and 7, Catalase, and Nrf2 and relative intramuscular protein expression of SOD1, Catalase and GPX3 were quantified. Results: MCC supplementation enhanced recovery of normalized MVC 1s average compared to placebo (Post- Exercise PLA: 59.5±18.0% vs MCC: 76.5±13.9%; 24 h PLA: 69.8±15.9% vs MCC: 80.5±15.3%; supplementation effect p=0.024). MCC supplementation increased plasma hydroxybenzoic, hippuric and vanillic acid concentrations (supplementation effect p = 0.028, p = 0.002, p= 0.003); SOD3, GPX3, GPX4, GPX7 (supplement effect p < 0.05) and GPX1 (interaction effect p = 0.017) gene expression; and GPX3 protein expression (supplementation effect p = 0.004) versus placebo. There were no significant differences between conditions for other outcome measures. Conclusion: MCC supplementation conserved isometric muscle strength and upregulated antioxidant gene and protein expression in parallel with increased phenolic acid concentrations

Shatavari supplementation in postmenopausal women improves handgrip strength and increases vastus lateralis myosin regulatory light chain phosphorylation but does not alter markers of bone turnover

Abstract: Shatavari has long been used as an Ayurvedic herb for women’s health, but empirical evidence for its effectiveness has been lacking. Shatavari contains phytoestrogenic compounds that bind to the estradiol receptor. Postmenopausal estradiol deficiency contributes to sarcopenia and osteoporosis. In a randomised double-blind trial, 20 postmenopausal women (68.5 ± 6 years) in-gested either placebo (N = 10) or shatavari (N = 10; 1000 mg/d, equivalent to 26,500 mg/d fresh weight shatavari) for 6 weeks. Handgrip and knee extensor strength were measured at baseline and at 6 weeks. Vastus lateralis (VL) biopsy samples were obtained. Data are presented as difference scores (Week 6 – baseline, median ± interquartile range). Handgrip, (but not knee extensor) strength was improved by shatavari supplementation (shatavari +0.7 ± 1.1 kg, placebo -0.4 ± 1.3 kg; p=0.04). Myosin regulatory light chain phosphorylation, a known marker of improved myosin contractile function, was increased in VL following shatavari supplementation (immunoblotting; placebo -0.08 ± 0.5 a.u. shatavari +0.3 ± 1 arbitrary units (a.u.); p = 0.03). Shatavari increased phosphorylation of Aktser473 (Aktser473 (placebo -0.6 ± 0.6 a.u. shatavari +0.2 ± 1.3 a.u; p = 0.03) in VL. Shatavari supplementation did not alter plasma markers of bone turnover (P1NP, β-CTX) and stimulation of human osteoblasts with pooled sera (N = 8 per condition) from placebo and shatavari supplementation conditions did not alter cytokine or metabolic markers of osteoblast activity. Shatavari may improve muscle function and contractility via myosin conformational change and warrants further investigation in larger and more diverse cohorts of its utility in conserving and enhancing musculoskeletal functio

Guillain-Barré syndrome: a century of progress

In 1916, Guillain, Barré and Strohl reported on two cases of acute flaccid paralysis with high cerebrospinal fluid protein levels and normal cell counts — novel findings that identified the disease we now know as Guillain–Barré syndrome (GBS). 100 years on, we have made great progress with the clinical and pathological characterization of GBS. Early clinicopathological and animal studies indicated that GBS was an immune-mediated demyelinating disorder, and that severe GBS could result in secondary axonal injury; the current treatments of plasma exchange and intravenous immunoglobulin, which were developed in the 1980s, are based on this premise. Subsequent work has, however, shown that primary axonal injury can be the underlying disease. The association of Campylobacter jejuni strains has led to confirmation that anti-ganglioside antibodies are pathogenic and that axonal GBS involves an antibody and complement-mediated disruption of nodes of Ranvier, neuromuscular junctions and other neuronal and glial membranes. Now, ongoing clinical trials of the complement inhibitor eculizumab are the first targeted immunotherapy in GBS