130 research outputs found

    Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy

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    Background and Purpose: Cannabis has been used to treat epilepsy for millennia, with such use validated by regulatory approval of cannabidiol (CBD) for Dravet syndrome. Unregulated artisanal cannabis-based products used to treat children with intractable epilepsies often contain relatively low doses of CBD but are enriched in other phytocannabinoids. This raises the possibility that other cannabis constituents might have anticonvulsant properties. Experimental Approach: We used the Scn1a+/− mouse model of Dravet syndrome to investigate the cannabis plant for phytocannabinoids with anticonvulsant effects against hyperthermia-induced seizures. The most promising, cannabigerolic acid (CBGA), was further examined against spontaneous seizures and survival in Scn1a+/− mice and in electroshock seizure models. Pharmacological effects of CBGA were surveyed across multiple drug targets. Key Results: The initial screen identified three phytocannabinoids with novel anticonvulsant properties: CBGA, cannabidivarinic acid (CBDVA) and cannabigerovarinic acid (CBGVA). CBGA was most potent and potentiated the anticonvulsant effects of clobazam against hyperthermia-induced and spontaneous seizures, and was anticonvulsant in the MES threshold test. However, CBGA was proconvulsant in the 6-Hz threshold test and a high dose increased spontaneous seizure frequency in Scn1a+/− mice. CBGA was found to interact with numerous epilepsy-relevant targets including GPR55, TRPV1 channels and GABAA receptors. Conclusion and Implications: These results suggest that CBGA, CBDVA and CBGVA may contribute to the effects of cannabis-based products in childhood epilepsy. Although these phytocannabinoids have anticonvulsant potential and could be lead compounds for drug development programmes, several liabilities would need to be overcome before CBD is superseded by another in this class

    Cyprus women's health research (COHERE) initiative: determining the relative burden of women's health conditions and related co-morbidities in an Eastern Mediterranean population

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    Background: There is lack of population level data on prevalence and distribution of common benign women's health conditions such as endometriosis, uterine fibroids, polycystic ovary syndrome from the Eastern Mediterranean region despite their significant consequences on quality of life. In particular, there is complete absence of any health statistics from Northern Cyprus, which is an emerging region in Europe. The Cyprus Women's Health Research (COHERE) Initiative is the first large-scale cross-sectional study in the region, aiming to determine the relative burden of benign women's health conditions and related co-morbidities in women living in Northern Cyprus. Methods: The COHERE Initiative is a cross-sectional study aiming to recruit 8000 women aged 18 55 years and residing for at least the past 5 years in Northern Cyprus. The study is composed of two main steps: (1) Baseline recruitment, including (i) completion of a detailed health questionnaire, which is an expanded version of the World Endometriosis Research Foundation (WERF) Endometriosis Phenome Harmonisation Project (EPHect) standardised questionnaire, including questions on demographics, menstrual history, hormone use, pregnancy, pain (pelvic pain, bladder and bowel pain, migraine), medical history, family history of illnesses, medication use, life-style factors in relation to a wide range of reproductive and endocrine conditions, resource use (ii) measurement of weight, height, waist/hip circumference and blood pressure, (iii) collection of saliva samples for genotyping. (2) Gynaecology clinic follow up, including a pelvic ultrasound scan (USS). There is also a follow-up food frequency questionnaire (FFQ) targeted to all women taking part in the baseline recruitment with an aim to collect more detailed data on dietary habits. Discussion: The COHERE Initiative will generate prevalence rates for conditions, define the clinical profiles for women's health conditions, and estimate the economic burden of these conditions in Northern Cyprus. The results will also provide insights into the current status of health-care among women living in a currently under-investigated region. The genetic findings will inform future gene mapping studies for investigation of the heritable component of conditions in this population/region. Moreover, the results will be compared with other centres collecting data using EPHect tools globally and will help determine population differences and similarities in disease patterns and clinical profiles. The COHERE Initiative will serve as a resource to conduct hypothesis-driven follow-up studies investigating effect of the Mediterranean life-style' as well as genetic factors on common benign women's health conditions that maybe specific to Eastern Mediterranean populations

    Getting ‘Smad' about obesity and diabetes

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    Recent findings on the role of transforming growth factor (TGF)-β/Smad3 signaling in the pathogenesis of obesity and type 2 diabetes have underscored its importance in metabolism and adiposity. Indeed, elevated TGF-β has been previously reported in human adipose tissue during morbid obesity and diabetic neuropathy. In this review, we discuss the pleiotropic effects of TGF-β/Smad3 signaling on metabolism and energy homeostasis, all of which has an important part in the etiology and progression of obesity-linked diabetes; these include adipocyte differentiation, white to brown fat phenotypic transition, glucose and lipid metabolism, pancreatic function, insulin signaling, adipocytokine secretion, inflammation and reactive oxygen species production. We summarize the recent in vivo findings on the role of TGF-β/Smad3 signaling in metabolism based on the studies using Smad3−/− mice. Based on the presence of a dual regulatory effect of Smad3 on peroxisome proliferator-activated receptor (PPAR)β/δ and PPARγ2 promoters, we propose a unifying mechanism by which this signaling pathway contributes to obesity and its associated diabetes. We also discuss how the inhibition of this signaling pathway has been implicated in the amelioration of many facets of metabolic syndromes, thereby offering novel therapeutic avenues for these metabolic conditions

    Oncogenic Signaling Pathways in The Cancer Genome Atlas.

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    Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy

    Treatment of hyperprolactinemia: a systematic review and meta-analysis

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