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1.
Nature ; 615(7952): 436-442, 2023 03.
Article in English | MEDLINE | ID: mdl-36922608

ABSTRACT

The globally important carbon sink of intact, old-growth tropical humid forests is declining because of climate change, deforestation and degradation from fire and logging1-3. Recovering tropical secondary and degraded forests now cover about 10% of the tropical forest area4, but how much carbon they accumulate remains uncertain. Here we quantify the aboveground carbon (AGC) sink of recovering forests across three main continuous tropical humid regions: the Amazon, Borneo and Central Africa5,6. On the basis of satellite data products4,7, our analysis encompasses the heterogeneous spatial and temporal patterns of growth in degraded and secondary forests, influenced by key environmental and anthropogenic drivers. In the first 20 years of recovery, regrowth rates in Borneo were up to 45% and 58% higher than in Central Africa and the Amazon, respectively. This is due to variables such as temperature, water deficit and disturbance regimes. We find that regrowing degraded and secondary forests accumulated 107 Tg C year-1 (90-130 Tg C year-1) between 1984 and 2018, counterbalancing 26% (21-34%) of carbon emissions from humid tropical forest loss during the same period. Protecting old-growth forests is therefore a priority. Furthermore, we estimate that conserving recovering degraded and secondary forests can have a feasible future carbon sink potential of 53 Tg C year-1 (44-62 Tg C year-1) across the main tropical regions studied.


Subject(s)
Carbon Sequestration , Carbon , Conservation of Natural Resources , Forests , Humidity , Trees , Tropical Climate , Carbon/metabolism , Conservation of Natural Resources/methods , Conservation of Natural Resources/statistics & numerical data , Conservation of Natural Resources/trends , Trees/metabolism , Forestry/statistics & numerical data , Satellite Imagery , Temperature , Rainforest , Borneo , Africa, Central , Brazil
2.
Development ; 149(20)2022 10 15.
Article in English | MEDLINE | ID: mdl-35997536

ABSTRACT

Complex organ development depends on single lumen formation and its expansion during tubulogenesis. This can be achieved by correct mitotic spindle orientation during cell division, combined with luminal fluid filling that generates hydrostatic pressure. Using a human 3D cell culture model, we have identified two regulators of these processes. We find that pleckstrin homology leucine-rich repeat protein phosphatase (PHLPP) 2 regulates mitotic spindle orientation, and thereby midbody positioning and maintenance of a single lumen. Silencing the sole PHLPP family phosphatase in Drosophila melanogaster, phlpp, resulted in defective spindle orientation in Drosophila neuroblasts. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) is the main channel regulating fluid transport in this system, stimulated by phosphorylation by protein kinase A and inhibited by the AMP-activated protein kinase AMPK. During lumen expansion, CFTR remains open through the action of PHLPP1, which stops activated AMPK from inhibiting ion transport through CFTR. In the absence of PHLPP1, the restraint on AMPK activity is lost and this tips the balance in the favour of channel closing, resulting in the lack of lumen expansion and accumulation of mucus.


Subject(s)
AMP-Activated Protein Kinases , Cystic Fibrosis Transmembrane Conductance Regulator , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Animals , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Humans , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Phosphoprotein Phosphatases/genetics , Phosphoprotein Phosphatases/metabolism , Phosphoric Monoester Hydrolases/metabolism , Phosphorylation
3.
Neuroscience ; 497: 215-227, 2022 08 10.
Article in English | MEDLINE | ID: mdl-35276307

ABSTRACT

Spaced training, which involves long inter-trial intervals, has positive effects on memories. One of the main attributes of long-term memories (LTM) is persistence. Here, to identify the process that promotes LTM persistence by spaced learning, we used the spatial object recognition (SOR) task in rats. The protocol consisted of a first strong training session that induced LTM formation (tested 1 day after training), but not LTM persistence (tested 7 or 14 days after training); and a second weak training session that promoted memory persistence when applied 1 day, but not 7 days, after the first training. We propose that the promotion of memory persistence is based on the Behavioral Tagging (BT) mechanism operating when the memory trace is retrieved. BT involves the setting of a tag induced by learning which gives rise to input selectivity, and the use of plasticity-related proteins (PRPs) to establish the mnemonic trace. We postulate that retraining will mainly retag the sites initially activated by the original learning, where the PRPs needed for memory expression and/or induced by retrieval would be used to maintain a persistent mnemonic trace. Our results suggest that the mechanism of memory expression, but not those of memory reinforcement or reconsolidation, is necessary to promote memory persistence after retraining. The molecular mechanisms involve ERKs1/2 activity to set the SOR learning tag, and the availability of GluA2-containing AMPA receptor. In conclusion, both the synthesis of PRPs and the setting of learning tags are key processes triggered by retraining that allow SOR memory persistence.


Subject(s)
Memory, Long-Term , Spatial Memory , Animals , Hippocampus , Rats , Rats, Wistar , Spatial Learning
4.
Eur Respir J ; 2022 May 12.
Article in English | MEDLINE | ID: mdl-35144988

ABSTRACT

BACKGROUND: There is an emerging understanding that coronavirus disease 2019 (COVID-19) is associated with increased incidence of pneumomediastinum. We aimed to determine its incidence among patients hospitalised with COVID-19 in the United Kingdom and describe factors associated with outcome. METHODS: A structured survey of pneumomediastinum and its incidence was conducted from September 2020 to February 2021. United Kingdom-wide participation was solicited via respiratory research networks. Identified patients had SARS-CoV-2 infection and radiologically proven pneumomediastinum. The primary outcomes were to determine incidence of pneumomediastinum in COVID-19 and to investigate risk factors associated with patient mortality. RESULTS: 377 cases of pneumomediastinum in COVID-19 were identified from 58 484 inpatients with COVID-19 at 53 hospitals during the study period, giving an incidence of 0.64%. Overall 120-day mortality in COVID-19 pneumomediastinum was 195/377 (51.7%). Pneumomediastinum in COVID-19 was associated with high rates of mechanical ventilation. 172/377 patients (45.6%) were mechanically ventilated at the point of diagnosis. Mechanical ventilation was the most important predictor of mortality in COVID-19 pneumomediastinum at the time of diagnosis and thereafter (p<0.001) along with increasing age (p<0.01) and diabetes mellitus (p=0.08). Switching patients from continuous positive airways pressure support to oxygen or high flow nasal oxygen after the diagnosis of pneumomediastinum was not associated with difference in mortality. CONCLUSIONS: Pneumomediastinum appears to be a marker of severe COVID-19 pneumonitis. The majority of patients in whom pneumomediastinum was identified had not been mechanically ventilated at the point of diagnosis.

5.
Nat Commun ; 12(1): 1785, 2021 03 19.
Article in English | MEDLINE | ID: mdl-33741981

ABSTRACT

Tropical secondary forests sequester carbon up to 20 times faster than old-growth forests. This rate does not capture spatial regrowth patterns due to environmental and disturbance drivers. Here we quantify the influence of such drivers on the rate and spatial patterns of regrowth in the Brazilian Amazon using satellite data. Carbon sequestration rates of young secondary forests (<20 years) in the west are ~60% higher (3.0 ± 1.0 Mg C ha-1 yr-1) compared to those in the east (1.3 ± 0.3 Mg C ha-1 yr-1). Disturbances reduce regrowth rates by 8-55%. The 2017 secondary forest carbon stock, of 294 Tg C, could be 8% higher by avoiding fires and repeated deforestation. Maintaining the 2017 secondary forest area has the potential to accumulate ~19.0 Tg C yr-1 until 2030, contributing ~5.5% to Brazil's 2030 net emissions reduction target. Implementing legal mechanisms to protect and expand secondary forests whilst supporting old-growth conservation is, therefore, key to realising their potential as a nature-based climate solution.


Subject(s)
Carbon Sequestration , Carbon/metabolism , Climate Change , Forests , Tropical Climate , Algorithms , Biomass , Brazil , Conservation of Natural Resources/methods , Ecosystem , Fires , Forestry , Geography , Models, Theoretical , Satellite Imagery/methods , Trees/growth & development , Trees/metabolism
7.
Sci Data ; 7(1): 287, 2020 08 28.
Article in English | MEDLINE | ID: mdl-32859937

ABSTRACT

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

8.
Sci Data ; 7(1): 269, 2020 08 14.
Article in English | MEDLINE | ID: mdl-32796858

ABSTRACT

The restoration and reforestation of 12 million hectares of forests by 2030 are amongst the leading mitigation strategies for reducing carbon emissions within the Brazilian Nationally Determined Contribution targets assumed under the Paris Agreement. Understanding the dynamics of forest cover, which steeply decreased between 1985 and 2018 throughout Brazil, is essential for estimating the global carbon balance and quantifying the provision of ecosystem services. To know the long-term increment, extent, and age of secondary forests is crucial; however, these variables are yet poorly quantified. Here we developed a 30-m spatial resolution dataset of the annual increment, extent, and age of secondary forests for Brazil over the 1986-2018 period. Land-use and land-cover maps from MapBiomas Project (Collection 4.1) were used as input data for our algorithm, implemented in the Google Earth Engine platform. This dataset provides critical spatially explicit information for supporting carbon emissions reduction, biodiversity, and restoration policies, enabling environmental science applications, territorial planning, and subsidizing environmental law enforcement.

9.
Front Psychol ; 11: 48, 2020.
Article in English | MEDLINE | ID: mdl-32063874

ABSTRACT

One of the top challenges in education and neuroscience consists in translating laboratory results into strategies to improve learning and memory in teaching environments. In that sense, during the last two decades, researchers have discovered specific temporal windows around learning, during which the intervention with some experiences induces modulatory effects on the formation and/or persistence of memory. Based on these results, the aim of the present study was to design a specific strategy to improve the memory of students in a high-school scenario, by assessing the effect of a novel situation experienced close to learning. We found that the long-term memory about a geometrical figure was more precise in the group of students that faced a novel situation 1 h before or after learning the figure than the control group of students who did not face the novelty. This enhancement was probably triggered by processes acting on memory formation mechanisms that remained evident 45 days after learning, indicating that the improvement was sustained over time. In addition, our results showed that novelty no longer improved the memory if it was experienced 4 h before or after learning. However, far beyond this window of efficacy, when it was faced around 10 h after learning, the novel experience improved the memory persistence tested 7 days later. In summary, our findings characterized different temporal windows of the effectiveness of novelty acting on memory processing, providing a simple and inexpensive strategy that could be used to improve memory formation and persistence in high-school students.

10.
Am J Public Health ; 110(2): 216-221, 2020 02.
Article in English | MEDLINE | ID: mdl-31855479

ABSTRACT

Objectives. To describe methods employed to track infants enrolled in the New York State Zika Pregnancy and Infant Registry (NYSZPIR) and demonstrate the benefits of population databases to improve the process.Methods. We used patient medical records and provider outreach, New York State Immunization Information System (NYSIIS), and New York State Early Hearing Detection and Intervention Information System (NYEHDI-IS) to gather medical information. We used descriptive statistics to summarize variables and the McNemar test to determine statistical significance (P < .05).Results. We identified 109 live births from NYSZPIR mothers. Provider information was documented for 106 (97.2%) infants in NYSIIS compared with 72 (66.1%) through chart review. Collected results of newborn hearing screening increased from 82 (75.2%) to 106 (97.2%) using NYEHDI-IS. The amount of data obtained was significantly higher (P < .001) when including NYSIIS and NYEHDI-IS compared with using medical records alone.Conclusions. Public health surveillance systems can be used to track infants using data sources such as NYSIIS and NYEHDI-IS in addition to traditional methods. Using medical records alone is inadequate for locating and tracking infants and may result in high lost to follow-up rates.


Subject(s)
Data Collection , Population Surveillance , Registries , Zika Virus Infection/congenital , Zika Virus Infection/epidemiology , Databases, Factual , Female , Humans , Infant , Infant, Newborn , Male , Mothers/statistics & numerical data , New York/epidemiology , Pregnancy , Zika Virus/isolation & purification
11.
Ecotoxicol Environ Saf ; 154: 19-26, 2018 Jun 15.
Article in English | MEDLINE | ID: mdl-29453161

ABSTRACT

The biological effects of gamma radiation may exert damage beyond that of the individual through its deleterious effects on reproductive function. Impaired reproductive performance can result in reduced population size over consecutive generations. In a continued effort to investigate reproductive and heritable effects of ionizing radiation, we recently demonstrated adverse effects and genomic instability in progeny of parents exposed to gamma radiation. In the present study, genotoxicity and effects on the reproduction following subchronic exposure during a gametogenesis cycle to 60Co gamma radiation (27 days, 8.7 and 53 mGy/h, total doses 5.2 and 31 Gy) were investigated in the adult wild-type zebrafish (Danio rerio). A significant reduction in embryo production was observed one month after exposure in the 53 mGy/h exposure group compared to control and 8.7 mGy/h. One year later, embryo production was significantly lower in the 53 mGy/h group compared only to control, with observed sterility, accompanied by a regression of reproductive organs in 100% of the fish 1.5 years after exposure. Histopathological examinations revealed no significant changes in the testis in the 8.7 mGy/h group, while in 62.5% of females exposed to this dose rate the oogenesis was found to be only at the early previtellogenic stage. The DNA damage determined in whole blood, 1.5 years after irradiation, using a high throughput Comet assay, was significantly higher in the exposed groups (1.2 and 3-fold increase in 8.7 and 53 mGy/h females respectively; 3-fold and 2-fold increase in 8.7 and 53 mGy/h males respectively) compared to controls. A significantly higher number of micronuclei (4-5%) was found in erythrocytes of both the 8.7 and 53 mGy/h fish compared to controls. This study shows that gamma radiation at a dose rate of ≥ 8.7 mGy/h during gametogenesis causes adverse reproductive effects and persistent genotoxicity (DNA damage and increased micronuclei) in adult zebrafish.


Subject(s)
DNA Damage , Gametogenesis/radiation effects , Gamma Rays/adverse effects , Reproduction/drug effects , Zebrafish/genetics , Animals , Comet Assay , Dose-Response Relationship, Radiation , Female , Gametogenesis/genetics , Genomic Instability/radiation effects , Male , Ovum/radiation effects , Reproduction/genetics , Testis/radiation effects , Zebrafish/growth & development
12.
NPJ Sci Learn ; 3: 19, 2018.
Article in English | MEDLINE | ID: mdl-30631480

ABSTRACT

The influence of a given event on long-term memory formation of another one has been a relevant topic of study in the neuroscience field in recent years. Students at school learn contents which are usually tested in exam format. However, exam elevates the arousal state of the students acting as a mild stressor that could influence another memory formation ongoing process. Thus, in this study we examine in high school students the effect of exams on long-term retention of unrelated information, learned at different times before or after the exams. Our results show that exams are not innocuous and that they could improve or reduce the retention of temporarily associated content. These effects did not show gender differences. Our findings should alert teachers about the side effects of exams on the learning of other content within the same school day.

13.
Fish Shellfish Immunol ; 70: 638-647, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28935599

ABSTRACT

A viral responsive protein (MjVRP) was characterized from Marsupenaeus japonicus haemocytes. In amino acid homology and phylogenetic tree analyses, MjVRP clustered in the same group with the viral responsive protein of Penaeus monodon (PmVRP15), showing 34% identity. MjVRP transcripts were mainly expressed in haemocytes and the lymphoid organ. Western blotting likewise showed that MjVRP was strongly expressed in haemocytes and the lymphoid organ. Immunostaining detected MjVRP within the cytosol next to the perinuclear region in some haemocytes. Experimental challenge with white spot syndrome virus (WSSV) significantly up-regulated the mRNA level of MjVRP in the M. japonicus haemocytes at 6 and 48 h. Flow cytometry and indirect immunofluorescence assays revealed that the ratio of MjVRP+ haemocytes significantly increased 24 and 48 h post-WSSV infection. These results suggest that MjVRP+ haemocytes have a supporting role in the pathogenesis of WSSV.


Subject(s)
Arthropod Proteins/genetics , Arthropod Proteins/immunology , Gene Expression Regulation/immunology , Immunity, Innate/genetics , Penaeidae/genetics , White spot syndrome virus 1/physiology , Amino Acid Sequence , Animals , Arthropod Proteins/chemistry , Flow Cytometry , Fluorescent Antibody Technique , Gene Expression Profiling , Hemocytes/metabolism , Penaeidae/immunology , Phylogeny , Sequence Alignment
14.
Nat Commun ; 7: 13889, 2016 12 22.
Article in English | MEDLINE | ID: mdl-28004827

ABSTRACT

A fundamental question is how autophagosome formation is regulated. Here we show that the PX domain protein HS1BP3 is a negative regulator of autophagosome formation. HS1BP3 depletion increased the formation of LC3-positive autophagosomes and degradation of cargo both in human cell culture and in zebrafish. HS1BP3 is localized to ATG16L1- and ATG9-positive autophagosome precursors and we show that HS1BP3 binds phosphatidic acid (PA) through its PX domain. Furthermore, we find the total PA content of cells to be significantly upregulated in the absence of HS1BP3, as a result of increased activity of the PA-producing enzyme phospholipase D (PLD) and increased localization of PLD1 to ATG16L1-positive membranes. We propose that HS1BP3 regulates autophagy by modulating the PA content of the ATG16L1-positive autophagosome precursor membranes through PLD1 activity and localization. Our findings provide key insights into how autophagosome formation is regulated by a novel negative-feedback mechanism on membrane lipids.


Subject(s)
Autophagy/physiology , Nerve Tissue Proteins/metabolism , Phosphatidic Acids/metabolism , Animals , Animals, Genetically Modified , Autophagosomes/metabolism , Autophagy-Related Proteins/metabolism , Cell Line , Cortactin/metabolism , HEK293 Cells , HeLa Cells , Humans , Membrane Lipids/metabolism , Models, Biological , Nerve Tissue Proteins/chemistry , Phospholipase D/metabolism , Protein Domains , Zebrafish , Zebrafish Proteins/metabolism
15.
Adv Exp Med Biol ; 916: 411-37, 2016.
Article in English | MEDLINE | ID: mdl-27165364

ABSTRACT

Colorectal cancer, encompassing colon and rectal cancer, arises from the epithelial lining of the large bowel. It is most prevalent in Westernised societies and is increasing in frequency as the world becomes more industrialised. Unfortunately, metastatic colorectal cancer is not cured by chemotherapy and the annual number of deaths caused by colorectal cancer, currently 700,000, is expected to rise. Our understanding of the contribution that genetic mutations make to colorectal cancer, although incomplete, is reasonably well advanced. However, it has only recently become widely appreciated that in addition to the ongoing accumulation of genetic mutations, chronic inflammation also plays a critical role in the initiation and progression of this disease. While a robust and tractable genetic model of colorectal cancer in zebrafish, suitable for pre-clinical studies, is not yet available, the identification of genes required for the rapid proliferation of zebrafish intestinal epithelial cells during development has highlighted a number of essential genes that could be targeted to disable colorectal cancer cells. Moreover, appreciation of the utility of zebrafish to study intestinal inflammation is on the rise. In particular, zebrafish provide unique opportunities to investigate the impact of genetic and environmental factors on the integrity of intestinal epithelial barrier function. With currently available tools, the interplay between epigenetic regulators, intestinal injury, microbiota composition and innate immune cell mobilisation can be analysed in exquisite detail. This provides excellent opportunities to define critical events that could potentially be targeted therapeutically. Further into the future, the use of zebrafish larvae as hosts for xenografts of human colorectal cancer tissue, while still in its infancy, holds great promise that zebrafish could one day provide a practical, preclinical personalized medicine platform for the rapid assessment of the metastatic potential and drug-sensitivity of patient-derived cancers.


Subject(s)
Colorectal Neoplasms/pathology , Disease Models, Animal , Animals , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/therapy , Prevalence , Zebrafish
16.
Biochem J ; 461(3): 383-90, 2014 Aug 01.
Article in English | MEDLINE | ID: mdl-24840251

ABSTRACT

Previously, we have shown that the phosphoinositide metabolizing enzymes PIKfyve (phosphoinositide 5-kinase, FYVE finger containing) and MTMR3 (myotubularin-related protein 3), together with their lipid product PtdIns5P, are important for migration of normal human fibroblasts. As these proteins are a kinase and a phosphatase respectively, and thereby considered druggable, we wanted to test their involvement in cancer cell migration and invasion. First, we showed that PIKfyve and MTMR3 are expressed in most cancer cells. Next, we demonstrated that depletion of PIKfyve or MTMR3 resulted in decreased velocity in three different cancer cell lines by using new software for cell tracking. Inhibition of the enzymatic activity of PIKfyve by the inhibitor YM201636 also led to a strong reduction in cell velocity. Mechanistically, we show that PIKfyve and MTMR3 regulate the activation of the Rho family GTPase Rac1. Further experiments also implicated PtdIns5P in the activation of Rac1. The results suggest a model for the activation of Rac1 in cell migration where PIKfyve and MTMR3 produce PtdIns5P on cellular membranes which may then serve to recruit effectors to activate Rac1. Finally, in an invasion assay, we demonstrate that both PIKfyve and MTMR3 are implicated in invasive behaviour of cancer cells. Thus PIKfyve and MTMR3 could represent novel therapeutic targets in metastatic cancer.


Subject(s)
Carcinoma/metabolism , Neoplasm Proteins/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol Phosphates/metabolism , Protein Tyrosine Phosphatases, Non-Receptor/metabolism , Sarcoma/metabolism , rac1 GTP-Binding Protein/agonists , Carcinoma/drug therapy , Carcinoma/pathology , Cell Line , Cell Line, Tumor , Cell Movement/drug effects , Cell Polarity , Computational Biology , Databases, Genetic , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Expert Systems , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Invasiveness , Neoplasm Proteins/agonists , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Phosphatidylinositol 3-Kinases/genetics , Phosphoinositide-3 Kinase Inhibitors , Protein Tyrosine Phosphatases, Non-Receptor/antagonists & inhibitors , Protein Tyrosine Phosphatases, Non-Receptor/genetics , RNA Interference , Sarcoma/drug therapy , Sarcoma/pathology , Software , rac1 GTP-Binding Protein/metabolism
18.
EMBO Rep ; 14(1): 57-64, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23154468

ABSTRACT

Although phosphatidylinositol 5-phosphate (PtdIns5P) is present in many cell types and its biogenesis is increased by diverse stimuli, its precise cellular function remains elusive. Here we show that PtdIns5P levels increase when cells are stimulated to move and we find PtdIns5P to promote cell migration in tissue culture and in a Drosophila in vivo model. First, class III phosphatidylinositol 3-kinase, which produces PtdIns3P, was shown to be involved in migration of fibroblasts. In a cell migration screen for proteins containing PtdIns3P-binding motifs, we identified the phosphoinositide 5-kinase PIKfyve and the phosphoinositide 3-phosphatase MTMR3, which together constitute a phosphoinositide loop that produces PtdIns5P via PtdIns(3,5)P(2). The ability of PtdIns5P to stimulate cell migration was demonstrated directly with exogenous PtdIns5P and a PtdIns5P-producing bacterial enzyme. Thus, the identified phosphoinositide loop defines a new role for PtdIns5P in cell migration.


Subject(s)
Cell Movement/physiology , Drosophila melanogaster/metabolism , Fibroblasts/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol Phosphates/biosynthesis , Protein Tyrosine Phosphatases, Non-Receptor/metabolism , Animals , Binding Sites , Cell Line , Class III Phosphatidylinositol 3-Kinases/genetics , Class III Phosphatidylinositol 3-Kinases/metabolism , Drosophila melanogaster/genetics , Fibroblasts/cytology , Gene Expression Regulation , Humans , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol Phosphates/metabolism , Protein Binding , Protein Interaction Domains and Motifs , Protein Tyrosine Phosphatases, Non-Receptor/antagonists & inhibitors , Protein Tyrosine Phosphatases, Non-Receptor/genetics , RNA, Small Interfering/genetics , Signal Transduction
19.
Cell Oncol ; 32(1-2): 11-27, 2010.
Article in English | MEDLINE | ID: mdl-20203370

ABSTRACT

BACKGROUND: Androgen receptor (AR) and the phosphatidylinositol-3 kinase (PI3K) signaling are two of the most important pathways implicated in prostate cancer. Previous work has shown that there is crosstalk between these two pathways; however, there are conflicting findings and the molecular mechanisms are not clear. Here we studied the AR-PI3K pathway crosstalk in prostate cancer cells in vitro as well as in vivo. METHODS: Quantitative PCR, Western analysis, reporter assays, and proliferation analyses in vitro and in vivo were used to evaluate the effect of PI3K pathway inhibition on AR signaling and cell growth. RESULTS: Transcriptional activity of AR was increased when the PI3K pathway was inhibited at different levels. In the androgen responsive prostate cancer cell line LNCaP, androgen and the mTOR inhibitor rapamycin synergistically activated androgen target genes. Despite increased androgen signaling, rapamycin treatment reduced LNCaP cell growth; the AR antagonist bicalutamide potentiated this effect. Furthermore, the rapamycin derivative CCI-779 reduced the growth of CWR22 prostate cancer xenografts while increasing AR target gene expression. CONCLUSION: These findings suggest that inhibition of the PI3K pathway activates AR signaling. Despite the increase in AR signaling which has proliferative effects, the result of PI3K pathway inhibition is antiproliferative. These findings suggest that the PI3K pathway is dominant over AR signaling in prostate cancer cells which should be considered in developing novel therapeutic strategies for prostate cancer.


Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Prostatic Neoplasms/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Androgen/metabolism , Signal Transduction , Animals , Cell Line, Tumor , Cell Proliferation , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Phosphatidylinositol 3-Kinases/genetics , Prostatic Neoplasms/genetics , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins c-akt/genetics , Receptors, Androgen/genetics , TOR Serine-Threonine Kinases , Transcriptional Activation
20.
Curr Med Chem ; 16(26): 3341-58, 2009.
Article in English | MEDLINE | ID: mdl-19548874

ABSTRACT

The L-type Ca(2+) channel plays a critical role in cardiac function as the main route for entry of calcium into cardiac myocytes. It is essential to excitability as it shapes the long plateau phase of the cardiac action potential that is unique to cardiac ventricular myocytes. It is necessary for contraction as it triggers the release of calcium from sarcoplasmic reticulum stores for actin-myosin interaction. The L-type Ca(2+) channel also regulates cytoplasmic calcium levels. It is well recognised that an increase in intracellular calcium is involved in the activation of growth-promoting signal pathways. Recently reactive oxygen species have been implicated in the activation of signal pathways and the development of pathological hypertrophy. There is now evidence that implicates activation of the L-type Ca(2+) channel with persistent alterations in calcium homeostasis and cellular reactive oxygen species production as a possible trigger of cardiac hypertrophy. A number of different approaches have been used to modify channel function with the view to preventing ischemia-reperfusion injury, cardiac hypertrophy or cardiac failure providing good evidence that the L-type Ca(2+) channel may be an efficacious target in the prevention of cardiac pathology.


Subject(s)
Calcium Channels, L-Type/metabolism , Heart Diseases/drug therapy , Amino Acid Sequence , Animals , Calcium/metabolism , Calcium Channel Agonists/therapeutic use , Calcium Channels, L-Type/physiology , Cardiomegaly/pathology , Dogs , Heart Diseases/pathology , Humans , Molecular Sequence Data , Rats , Reactive Oxygen Species/metabolism , Reactive Oxygen Species/toxicity , Signal Transduction
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