Cannabidiol stimulates AML-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner

Glioma stem-like cells (GSCs) correspond to a tumor cell subpopulation, involved in glioblastoma multiforme (GBM) tumor ini- tiation and acquired chemoresistance. Currently, drug-induced differentiation is considered as a promising approach to eradi- cate this tumor-driving cell population. Recently, the effect of cannabinoids (CBs) in promoting glial differentiation and inhibiting gliomagenesis has been evidenced. Herein, we demonstrated that cannabidiol (CBD) by activating transient receptor potential vanilloid-2 (TRPV2) triggers GSCs differentiation activating the autophagic process and inhibits GSCs proliferation and clonogenic capability. Above all, CBD and carmustine (BCNU) in combination overcome the high resistance of GSCs to BCNU treatment, by inducing apoptotic cell death. Acute myeloid leukemia (Aml-1) transcription factors play a pivotal role in GBM proliferation and differentiation and it is known that Aml-1 control the expression of several nociceptive receptors. So, we evaluated the expression levels of Aml-1 spliced variants (Aml-1a, b and c) in GSCs and during their differentiation. We found that Aml-1a is upregulated during GSCs differentiation, and its downregulation restores a stem cell phenotype in differ- entiated GSCs. Since it was demonstrated that CBD induces also TRPV2 expression and that TRPV2 is involved in GSCs differ- entiation, we evaluated if Aml-1a interacted directly with TRPV2 promoters. Herein, we found that Aml-1a binds TRPV2 promoters and that Aml-1a expression is upregulated by CBD treatment, in a TRPV2 and PI3K/AKT dependent manner. Alto- gether, these results support a novel mechanism by which CBD inducing TRPV2-dependent autophagic process stimulates Aml-1a-dependent GSCs differentiation, abrogating the BCNU chemoresistance in GSCs

The Neurospora crassa carotenoid biosynthetic gene (albino 3) reveals highly conserved regions among prenyltransferases.

In the filamentous fungus Neurospora crassa the biosynthesis of carotenoids is regulated by blue light. Here we report the characterization of the albino-3 (al-3) gene of N. crassa, which encodes the carotenoid biosynthetic enzyme geranylgeranyl-pyrophosphate synthetase. This is the first geranylgeranyl-pyrophosphate synthetase gene isolated. Nucleotide sequence comparison of al-3 genomic and cDNA clones revealed that the al-3 gene is not interrupted by introns. Transcription of the al-3 gene has been examined in dark-grown and light-induced mycelia. The analysis revealed that the al-3 gene is not expressed in the dark and that its transcription is induced by blue light (Nelson, M. A., Morelli, G., Carattoli, A., Romano, N., and Macino, G. (1989) Mol. Cell. Biol. 9, 1271-1276). The al-3 gene encodes a polypeptide of 428 amino acids. Comparison of the deduced amino acid sequence of al-3 with the sequences of prenyltransferases of other species, from bacteria to humans, showed three highly conserved homologous regions. These homologous regions may be involved in the formation of the catalytic site of the prenyltransferases

ATHB2 is a negative regulator of germination in Arabidopsis thaliana seeds

The germination timing of seeds is of the utmost adaptive importance for plant populations. Light is one of the best characterized factors promoting seed germination in several species. The germination is also fnely regulated by changes in hormones levels, mainly those of gibberellin (GA) and abscisic acid (ABA). Here, we performed physiological, pharmacological, and molecular analyses to uncover the role of ATHB2, an HD-ZIP II transcription factor, in germination of Arabidopsis seeds. Our study demonstrated that ATHB2 is a negative regulator and sustains the expression of transcription factors to block germination promoted by light. Besides, we found that ATHB2 increases ABA sensitivity. Moreover, ABA and auxin content in athb2-2 mutant is higher than wild-type in dry seeds, but the diferences disappeared during the imbibition in darkness and the frst hours of exposition to light, respectively. Some ABA and light transcription factors are up-regulated by ATHB2, such as ABI5, ABI3, XERICO, SOMNUS and PIL5/PIF1. In opposition, PIN7, an auxin transport, is down-regulated. The role of ATHB2 as a repressor of germination induced by light afecting the gemination timing, could have diferential efects on the establishment of seedlings altering the competitiveness between crops and weeds in the feld.Fil: Tognacca, Rocío Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Monica, Carabelli. Consiglio Nazionale delle Ricerche; ItaliaFil: Giorgio, Morelli. Research Centre for Genomics and Bioinformatics, Council for Agricultural Research and Economics; ItaliaFil: Ida, Ruberti. Consiglio Nazionale delle Ricerche; ItaliaFil: Botto, Javier Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentin

Advances in transient receptor potential vanilloid-2 channel expression and function in tumor growth and progression.

Aim of this review is to study the role of the TRPV2 channel, a member of the TRPV subfamily of TRP channels, in tumor progression. Physiologically, the triggering of TRPV2 by agonists/activators (e.g., growth factors, hormones and cannabinoids), by inducing TRPV2 translocation from the endosome to the plasmatic membrane, inhibit cell proliferation and induce necrosis and/or apoptosis. Thus, loss or alterations of TRPV2 proliferative and apoptotic signals, results in uncontrolled proliferation and augmented resistance to apoptotic stimuli. For example in prostate cancer cells, the TRPV2 activation following lysophospholipid or adrenomedullin stimulation enhances the invasiveness of cancer cells; furthermore, the increased malignancy of castration-resistant prostate cancer cells was associated with enhanced TRPV2 expression, mainly in metastatic prostate cancer cells. In addition, the TRPV2 cellular functions may also to be related to the presence of TRPV2 variants, able to interfere with the physiological functions of normal TRPV2 channels. In this regard, bladder cancer tumors show loss or reduction of a short TRPV2 variant during cancer progression, with increased malignancy and invasiveness. High expression of TRPV2 was also observed more frequently in esophageal squamous cell carcinoma patients with advanced pT stage, lymph node metastasis and advanced pathological stage

Cooperative Interaction between the Alpha1-Adrenoceptors (ñ1-AR) andTransient Receptor Potential (TRP) Triggers a Proliferative Cell Signal inProstate Cancer Cell Lines

Calcium (Ca2+) increases the proliferation of human advanced prostate cancer (PCa) cells but the ion channels involved are unknown. Santoni and Quaglia groups investigated the correlation between alpha1D-adrenergic receptor (α1D-AR) and the transient receptor potential vanilloid type 1 (TRPV1) ion channel expression in PCa cells. The α1D-AR and TRPV1 mRNAs are increased in PCa compared to BPH. α1D-AR and TRPV1 are co-expressed in PCa cells. Norepinephrine (NE) induced α1D-AR- and TRPV1-dependent protons release, Ca2+ flux in PC3 cells and activation of PLC, PKC and ERK path-ways that stimulated PC3 cell proliferation. Similarly, a role for TRPC6 or GPR55 in α1-AR-dependent proliferation of mesangial cells and PCa cells was reported. Overall, a crosstalk between α1-AR and TRPs in PCa cells, involved in the control of cell proliferation has been demonstrated. These data strongly promote a putative novel pharmacological approach in the treatment of PCa by targeting both α1-AR and TRP channels

High CTLA-4 expression correlates with poor prognosis in thymoma patients

Thymomas, tumors that arise from epithelial cells of the thymus gland, are the most common neoplasms of the anterior mediastinum, with an incidence rate of approximately 2.5 per million/year. Cytotoxic T Lymphocyte Antigen 4 (CTLA-4 or CD152) exerts inhibitory activity on T cells, and since its oncogenic role in the progression of different types of tumors, it has emerged as a potential therapeutic target in cancer patients. In this study, we assessed the expression of CTLA-4 both at mRNA and protein levels in paraffin embedded-tissues from patients with thymomas. Furthermore, we evaluated the relationship between CTLA-4 expression and the clinical-pathologic characteristics and prognosis in patients with thymomas. Sixty-eight patients with median age corresponding to 62 years were included in this analysis. Thymomas were classified accordingly to the WHO and Masaoka-Koga for histochemical analysis and for prognostic significance. A statistical difference was found between CTLA-4 mRNA levels in human normal thymus compared with thymoma specimens. CTLA-4 expression was statistically found to progressively increase in A, B1, B2, AB and it was maximal in B3 thymomas. According to Masaoka-Koga pathological classification, CTLA-4 expression was lower in I, IIA and IIB, and higher in invasive III and IV stages. By confocal microscopy analysis we identified the expression of CTLA-4 both in tumor cells and in CD45+ tumor-infiltrating leukocytes, mainly in B3 and AB thymomas. Finally, CTLA-4 overexpression significantly correlates with reduced overall survival in thymoma patients and in atypical thymoma subgroup, suggesting that it represents a negative prognostic factor

Cross-talk between microRNAs, long non-coding RNAs and p21Cip1 in glioma: diagnostic, prognostic and therapeutic roles

Glioblastoma multiforme is considered one of the most common malignant primary intracranial tumors. Despite treatment with a combination of surgery, chemotherapy and radiotherapy, patients with glioblastoma multiform have poor prognosis. It has been widely accepted that the occurrence, progression, and even recurrence of glioblastoma multiforme strictly depends on the presence of glioma cancer stem cells. The presence of glioma stem cells reduces the efficacy of standard therapies, thus increasing the imperative to identify new targets and therapeutic strategies in glioblastoma patients. In this regard, the p21Cip1 pathway has been found to play an important role in the maintenance of the glioma stem cells. It has been shown that this pathway regulates cancer stem cell pool by preventing hyperproliferation and exhaustion. MicroRNAs, endogenous small non-coding RNAs, and long non-coding RNAs, regulate post-transcription gene expression. These are not only altered in glioma, but also in other cancer types, and are involved in tumor development and progression. Notably, they have also been shown to modulate the expression of proteins in the p21Cip1 signaling pathway. This review highlights the extent and complexity of cross-talk between microRNAs, long non-coding RNAs and the p21Cip1 pathway, and demonstrates how such interplay orchestrates the regulation of protein expression and functions in glioma and glioma stem cells

Cardiovascular features of possible autonomous cortisol secretion in patients with adrenal incidentalomas

Background: Low-grade incomplete post-dexamethasone cortisol suppression in patients with adrenal incidentalomas – recently defined as possible autonomous cortisol secretion (pACS) – has been associated with increased cardiovascular events and mortality. However, prospective studies documenting cardiac abnormalities in these patients are lacking. Subjects and methods: Between July 2016 and September 2017, 71 consecutive patients with adrenal lesions were prospectively screened for hypercortisolism by dexamethasone suppression test (NCT 02611258). Complete anthropometric, metabolic and hormonal parameters were recorded along with full cardiac ultrasound assessment and noninvasive measurement of arterial stiffness. All patients underwent chemical-shift magnetic resonance imaging to characterize the lesions. Cardiovascular outcomes were recorded in blind. Results: According to post-dexamethasone suppression cortisol values (post-DST), 34 patients had pACS and 37 nonfunctioning adenomas (NFA). The two groups were similar in sex, BMI, age distribution, cardiovascular risk factors and comorbidities. Left ventricular mass index (LVMIBSA) was increased in pACS compared to NFA (P=0.006) and mildly correlated to the post-DST cortisol level (rho=0.347; P=0.004). The post-DST cortisol levels explained up to 13.7% of LVMIBSAvariance (P=0.002). Compared to NFA, patients with pACS had a higher prevalence of diastolic dysfunction (35.1% vs 82.6%; P=0.001) and worse arterial stiffness assessed by pulse wave velocity (P=0.033). Conclusions: In apparently asymptomatic patients, mild autonomous cortisol secretion can sustain early cardiac and vascular remodeling, independently of other risk factors. The morphological and functional cardiovascular changes observed in pACS underline the need for further studies to correctly define the long-term management of this relatively common condition

Surname analysis of the Corsican population reveals an agreement with geographical and linguistic structure

The surname is a cultural trait that is extremely useful for historical and linguistic studies and can effectively be used as a genetic marker. In many human populations the surname is inherited in the paternal lineage, and can therefore be considered a marker for the Y chromosome. In this study, surnames were recorded from the white pages of telephone directories in current use in Corsica in 1993. All surnames present in thirteen villages scattered over the whole island and covering the main historical regions were transcribed. Surname variability was found to be higher in coastal villages, and lower in more isolated communities. The isonymy detected among the thirteen villages allowed the calculation of kinship values, visualized in a tree showing two main clusters, one referring to the northern villages and one encompassing the villages of the south. The pattern reflects the administrative division of the island, with the exception of Vico, which belongs to the southern administrative region but is geographically close to the northern villages, and Ghisoni, which belongs to the northern district but is more similar to the village of Bastelica in the southern district. The data presented here show a structure in the surname distribution that is in substantial agreement with the geographical patterns. The kinship values are consistent with a moderated gene flow among villages producing a surname structure according to the geographic features of the territory