Is there evidence for bacterial transfer via the placenta and any role in the colonization of the infant gut? - a systematic review.

With the important role of the gut microbiome in health and disease, it is crucial to understand key factors that establish the microbial community, including gut colonization during infancy. It has been suggested that the first bacterial exposure is via a placental microbiome. However, despite many publications, the robustness of the evidence for the placental microbiome and transfer of bacteria from the placenta to the infant gut is unclear and hence the concept disputed. Therefore, we conducted a systematic review of the evidence for the role of the placental, amniotic fluid and cord blood microbiome in healthy mothers in the colonization of the infant gut. Most of the papers which were fully assessed considered placental tissue, but some studied amniotic fluid or cord blood. Great variability in methodology was observed especially regarding sample storage conditions, DNA/RNA extraction, and microbiome characterization. No study clearly considered transfer of the normal placental microbiome to the infant gut. Moreover, some studies in the review and others published subsequently reported little evidence for a placental microbiome in comparison to negative controls. In conclusion, current data are limited and provide no conclusive evidence that there is a normal placental microbiome which has any role in colonization of infant gut

A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability

SummaryCircadian clocks regulate membrane excitability in master pacemaker neurons to control daily rhythms of sleep and wake. Here, we find that two distinctly timed electrical drives collaborate to impose rhythmicity on Drosophila clock neurons. In the morning, a voltage-independent sodium conductance via the NA/NALCN ion channel depolarizes these neurons. This current is driven by the rhythmic expression of NCA localization factor-1, linking the molecular clock to ion channel function. In the evening, basal potassium currents peak to silence clock neurons. Remarkably, daily antiphase cycles of sodium and potassium currents also drive mouse clock neuron rhythms. Thus, we reveal an evolutionarily ancient strategy for the neural mechanisms that govern daily sleep and wake

TRPV6 Determines the Effect of Vitamin D3 on Prostate Cancer Cell Growth

Despite remarkable advances in the therapy and prevention of prostate cancer it is still the second cause of death from cancer in industrialized countries. Many therapies initially shown to be beneficial for the patients were abandoned due to the high drug resistance and the evolution rate of the tumors. One of the prospective therapeutical agents even used in the first stage clinical trials, 1,25-dihydroxyvitamin D3, was shown to be either unpredictable or inefficient in many cases. We have already shown that TRPV6 calcium channel, which is the direct target of 1,25-dihydroxyvitamin D3 receptor, positively controls prostate cancer proliferation and apoptosis resistance (Lehen'kyi et al., Oncogene, 2007). However, how the known 1,25-dihydroxyvitamin D3 antiproliferative effects may be compatible with the upregulation of pro-oncogenic TRPV6 channel remains a mystery. Here we demonstrate that in low steroid conditions 1,25-dihydroxyvitamin D3 upregulates the expression of TRPV6, enchances the proliferation by increasing the number of cells entering into S-phase. We show that these pro-proliferative effects of 1,25-dihydroxyvitamin D3 are directly mediated via the overexpression of TRPV6 channel which increases calcium uptake into LNCaP cells. The apoptosis resistance of androgen-dependent LNCaP cells conferred by TRPV6 channel is drastically inversed when 1,25-dihydroxyvitamin D3 effects were combined with the successful TRPV6 knockdown. In addition, the use of androgen-deficient DU-145 and androgen-insensitive LNCaP C4-2 cell lines allowed to suggest that the ability of 1,25-dihydroxyvitamin D3 to induce the expression of TRPV6 channel is a crucial determinant of the success or failure of 1,25-dihydroxyvitamin D3-based therapies

Nouveaux mécanismes de régulation de la concentration calcique réticulaire : implication dans la physiopathologie de la prostate humaine.

Prostate cancer is the second cancer-related cause of decease. Nowadays, treatments aim at decreasing the androgen action on this organ. Unfortunately, with time, patients develop an androgen-independent cancer with fatal issue. Calcium (Ca2+), an ubiquitary second messenger, is involved in several processes such as apoptosis and proliferation. Endoplasmic Reticulum (ER) is a major actor in Ca2+ signalling. Thus, the study of ER channels is critical for developing new therapeutic strategies. Our work led to the identification of two new ER proteins: the translocon and TRPM8 channel (Transient Receptor Potential Melastatin 8). These two channels could represent fundamental elements of calcium signalisation by regulating Ca2+ concentration in the ER. Moreover, the study of Ca2+ signature evolution during prostate carcinogenesis led us to show that Orai1 (identified here as the main carrier of capacitative Ca2+ entry) expression is decreased in advanced prostate cancer. Reversely, TRPV6 (Transient Receptor Potential Vanilloid 6), a Ca2+ channel involved in constitutive Ca2+ entry, is over expressed in prostate cancer later stages. Thus, variations in these proteins expression could be responsible respectively for apoptosis resistance or an increase in prostate cancer cells proliferation. This might explain the evolution of prostate cancer to more aggressive stages.Le cancer de la prostate est la seconde cause de mortalité par cancer chez l'homme. Actuellement, les traitements hormonaux visent à diminuer le taux d'androgènes actifs. Malheureusement, avec le temps, les patients développent un cancer androgènes dont l'issue est fatale. Le calcium (Ca2+), second messager ubiquitaire, est impliqué dans de nombreux processus tels que l'apoptose ou la prolifération. Le Réticulum Endoplasmique (RE) est un acteur essentiel de la signalisation calcique. Ainsi, l'étude de canaux calciques réticulaires est fondamentale dans le développement de nouvelles stratégies thérapeutiques. Les travaux effectués ont permis d'identifier deux nouvelles protéines sur le RE : le translocon et le canal TRPM8 (Transient Receptor Potential Melastatin 8). Ces deux protéines seraient des éléments majeurs de la signalisation calcique en régulant la concentration de Ca2+ du RE. Par ailleurs, l'étude de l'évolution de la signature calcique au cours de la cancérogenèse prostatique a permis de mettre en évidence qu'Orai1 (identifié ici comme étant la protéine responsable de l'Entrée Capacitive de Ca2+) est moins exprimée dans les cancers les plus agressifs. A l'opposé, TRPV6 (Transient receptor potential Vanilloid 6), canal calcique impliqué dans l'entrée constitutive de Ca2+, est surexprimé dans des stades avancés de cancer. Ainsi, les variations d'expression de ces protéines seraient responsables respectivement d'un défaut d'apoptose ou d'une augmentation de la prolifération des cellules cancéreuses prostatiques androgéno-indépendantes. Ceci permettrait d'expliquer l'évolution du cancer de la prostate vers des stades plus agressifs

Nouveaux mécanismes de régulation de la concentration calcique réticulaire (implication dans la physiopathologie de la prostate humaine)

Le cancer de la prostate est la seconde cause de mortalité par cancer chez l'homme. Actuellement, les traitements hormonaux visent à diminuer le taux d'androgènes actifs. Malheureusement, avec le temps, les patients développent un cancer androgéno-indépendant dont l'issue est fatale. Le calcium (Ca2+), second messager ubiquitaire, est impliqué dans de nombreux processus tels que l'apoptose ou la prolifération. Le Réticulum Endoplasmique (RE) est un acteur essentiel de la signalisation calcique. Ainsi, l'étude de canaux calciques réticulaires est fondamentale dans le développement de nouvelles stratégies thérapeutiques. Les travaux effectués ont permis d'identifier deux nouvelles protéines sur le RE : le translocon et le canal TRPM8 (Transient Receptor Potential Melastatin 8). Ces deux protéines seraient des éléments majeurs de la signalisation calcique en régulant la concentration de Ca2+ du RE. Par ailleurs, l'étude de l'évolution de la signature calcique au cours de la cancérogenèse prostatique a permis de mettre en évidence qu'Orail (identifié ici comme étant la protéine responsable de l'Entrée Capacitive de Ca2+) est moins exprimée dans les cancers les plus agressifs. A l'opposé, TRPV6 (Transient receptor potential Vanilloid 6), canal calcique impliqué dans l'entrée constitutive de Ca2+, est surexprimé dans des stades avancés de cancer. Ainsi, les variations d'expression de ces protéines seraient responsables respectivement d'un défaut d'apoptose ou d'une augmentation de la prolifération des cellules cancéreuses prostatiques androgéno-indépendantes. Ceci permettrait d'expliquer l'évolution du cancer de la prostate vers des stades plus agressifsLILLE1-BU (590092102) / SudocSudocFranceF

Insights into Ca(2+) homeostasis of advanced prostate cancer cells.

International audienceProstate cancer is the second cancer-related cause of death. Nowadays, the aim of treatments is to decrease the effects of androgens on this organ. Unfortunately, over time, patients develop an androgen-independent cancer with a fatal outcome. The main features of late stage prostate cancer are an increased cell proliferation and apoptosis resistance. It is well known that calcium (Ca(2+)), a ubiquitous secondary messenger, is involved in several processes such as apoptosis and proliferation. In this mini review, we will focus on the changes in Ca(2+) homeostasis of prostate cancer epithelial cells during prostate cancer evolution

TRPV6 channel controls prostate cancer cell proliferation via Ca(2+)/NFAT-dependent pathways.: Role of TRPV6 in prostate cancer

International audienceThe transient receptor potential channel, subfamily V, member 6 (TRPV6), is strongly expressed in advanced prostate cancer and significantly correlates with the Gleason >7 grading, being undetectable in healthy and benign prostate tissues. However, the role of TRPV6 as a highly Ca(2+)-selective channel in prostate carcinogenesis remains poorly understood. Here, we report that TRPV6 is directly involved in the control of prostate cancer cell (LNCaP cell line) proliferation by decreasing: (i) proliferation rate; (ii) cell accumulation in the S-phase of cell cycle and (iii) proliferating cell nuclear antigen (PCNA) expression. We demonstrate that the Ca(2+) uptake into LNCaP cells is mediated by TRPV6, with the subsequent downstream activation of the nuclear factor of activated T-cell transcription factor (NFAT). TRPV6-mediated Ca(2+) entry is also involved in apoptosis resistance of LNCaP cells. Our results suggest that TRPV6 expression in LNCaP cells is regulated by androgen receptor, however, in a ligand-independent manner. We conclude that the upregulation of TRPV6 Ca(2+) channel in prostate cancer cells may represent a mechanism for maintaining a higher proliferation rate, increasing cell survival and apoptosis resistance as well.Oncogene (2007) 26, 7380-7385; doi:10.1038/sj.onc.1210545; published online 28 May 2007

PSA reduces prostate cancer cell motility by stimulating TRPM8 activity and plasma membrane expression.

International audienceAlthough the transient receptor potential melastatin 8 (TRPM8) cold receptor is highly expressed in prostate cancer (PCa) and constitutes a promising diagnostic and prognostic indicator, the natural agonists of this channel in the prostate, as well as its physiological and pathological functions, remain unknown. In this study, we identified the well-known PCa marker, prostate-specific antigen (PSA), as a physiological TRPM8 agonist. Electrophysiological and Ca(2+) imaging studies demonstrated that PSA activated TRPM8-mediated current by the bradykinin 2 receptor signaling pathway. Further investigation of this mechanism by cell-surface biotinylation revealed that the increase in TRPM8 current induced by PSA was due to an increase in the number of functional TRPM8 channels on the plasma membrane. Importantly, wound-healing and migration assays revealed that TRPM8 activation by PSA reduced motility of the PC3 PCa cell line, suggesting that plasma membrane TRPM8 has a protective role in PCa progression. Consequently, PSA was identified as a natural TRPM8 agonist in the prostate and we propose a putative physiological role for both of these proteins in carcinogenesis, making this pathway a potentially important target for anticancer agent development.Oncogene advance online publication, 7 June 2010; doi:10.1038/onc.2010.210

Dual PDF signaling pathways reset clocks via TIMELESS and acutely excite target neurons to control circadian behavior.

Molecular circadian clocks are interconnected via neural networks. In Drosophila, PIGMENT-DISPERSING FACTOR (PDF) acts as a master network regulator with dual functions in synchronizing molecular oscillations between disparate PDF(+) and PDF(-) circadian pacemaker neurons and controlling pacemaker neuron output. Yet the mechanisms by which PDF functions are not clear. We demonstrate that genetic inhibition of protein kinase A (PKA) in PDF(-) clock neurons can phenocopy PDF mutants while activated PKA can partially rescue PDF receptor mutants. PKA subunit transcripts are also under clock control in non-PDF DN1p neurons. To address the core clock target of PDF, we rescued per in PDF neurons of arrhythmic per⁰¹ mutants. PDF neuron rescue induced high amplitude rhythms in the clock component TIMELESS (TIM) in per-less DN1p neurons. Complete loss of PDF or PKA inhibition also results in reduced TIM levels in non-PDF neurons of per⁰¹ flies. To address how PDF impacts pacemaker neuron output, we focally applied PDF to DN1p neurons and found that it acutely depolarizes and increases firing rates of DN1p neurons. Surprisingly, these effects are reduced in the presence of an adenylate cyclase inhibitor, yet persist in the presence of PKA inhibition. We have provided evidence for a signaling mechanism (PKA) and a molecular target (TIM) by which PDF resets and synchronizes clocks and demonstrates an acute direct excitatory effect of PDF on target neurons to control neuronal output. The identification of TIM as a target of PDF signaling suggests it is a multimodal integrator of cell autonomous clock, environmental light, and neural network signaling. Moreover, these data reveal a bifurcation of PKA-dependent clock effects and PKA-independent output effects. Taken together, our results provide a molecular and cellular basis for the dual functions of PDF in clock resetting and pacemaker output