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1.
Circ Heart Fail ; 14(1): e007300, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33464954

RESUMO

BACKGROUND: Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies. Here, we explore the effects of chronic PDE9 inhibition with CRD-733 in the mouse transverse aortic constriction pressure overload HF model. METHODS: Adult male C57BL/6J mice were subjected to transverse aortic constriction and developed significant left ventricular (LV) hypertrophy after 7 days (P<0.001). Mice then received daily treatment with CRD-733 (600 mg/kg per day; n=10) or vehicle (n=17), alongside sham-operated controls (n=10). RESULTS: CRD-733 treatment reversed existing LV hypertrophy compared with vehicle (P<0.001), significantly improved LV ejection fraction (P=0.009), and attenuated left atrial dilation (P<0.001), as assessed by serial echocardiography. CRD-733 prevented elevations in LV end diastolic pressures (P=0.037) compared with vehicle, while lung weights, a surrogate for pulmonary edema, were reduced to sham levels. Chronic CRD-733 treatment increased plasma cGMP levels compared with vehicle (P<0.001), alongside increased phosphorylation of Ser273 of cardiac myosin binding protein-C, a cGMP-dependent protein kinase I phosphorylation site. CONCLUSIONS: The PDE9 inhibitor, CRD-733, improves key hallmarks of HF including LV hypertrophy, LV dysfunction, left atrial dilation, and pulmonary edema after pressure overload in the mouse transverse aortic constriction HF model. Additionally, elevated plasma cGMP may be used as a biomarker of target engagement. These findings support future investigation into the therapeutic potential of CRD-733 in human HF.

2.
Parasit Vectors ; 14(1): 41, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430945

RESUMO

BACKGROUND: Despite the licensure of the world's first dengue vaccine and the current development of additional vaccine candidates, successful Aedes control remains critical to the reduction of dengue virus transmission. To date, there is still limited literature that attempts to explain the spatio-temporal population dynamics of Aedes mosquitoes within a single city, which hinders the development of more effective citywide vector control strategies. Narrowing this knowledge gap requires consistent and longitudinal measurement of Aedes abundance across the city as well as examination of relationships between variables on a much finer scale. METHODS: We utilized a high-resolution longitudinal dataset generated from Singapore's islandwide Gravitrap surveillance system over a 2-year period and built a Bayesian hierarchical model to explain the spatio-temporal dynamics of Aedes aegypti and Aedes albopictus in relation to a wide range of environmental and anthropogenic variables. We also created a baseline during our model assessment to serve as a benchmark to be compared with the model's out-of-sample prediction/forecast accuracy as measured by the mean absolute error. RESULTS: For both Aedes species, building age and nearby managed vegetation cover were found to have a significant positive association with the mean mosquito abundance, with the former being the strongest predictor. We also observed substantial evidence of a nonlinear effect of weekly maximum temperature on the Aedes abundance. Our models generally yielded modest but statistically significant reductions in the out-of-sample prediction/forecast error relative to the baseline. CONCLUSIONS: Our findings suggest that public residential estates with older buildings and more nearby managed vegetation should be prioritized for vector control inspections and community advocacy to reduce the abundance of Aedes mosquitoes and the risk of dengue transmission.

3.
PLoS One ; 16(1): e0245220, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33507965

RESUMO

Population and economic growth in Asia has led to increased urbanisation. Urbanisation has many detrimental impacts on ecosystems, especially when expansion is unplanned. Singapore is a city-state that has grown rapidly since independence, both in population and land area. However, Singapore aims to develop as a 'City in Nature', and urban greenery is integral to the landscape. While clearing some areas of forest for urban sprawl, Singapore has also reclaimed land from the sea to expand its coastline. Reclaimed land is usually designated for future urban development, but must first be left for many years to stabilise. During the period of stabilisation, pioneer plant species establish, growing into novel forest communities. The rate of this spontaneous vegetation development has not been quantified. This study tracks the temporal trends of normalized difference vegetation index (NDVI), as a proxy of vegetation maturity, on reclaimed land sensed using LANDSAT images. Google Earth Engine was used to mosaic cloud-free annual LANDSAT images of Singapore from 1988 to 2015. Singapore's median NDVI increased by 0.15 from 0.47 to 0.62 over the study period, while its land area grew by 71 km2. Five reclaimed sites with spontaneous vegetation development showed variable vegetation covers, ranging from 6% to 43% vegetated cover in 2015. On average, spontaneous vegetation takes 16.9 years to develop to a maturity of 0.7 NDVI, but this development is not linear and follows a quadratic trajectory. Patches of spontaneous vegetation on isolated reclaimed lands are unlikely to remain forever since they are in areas slated for future development. In the years that these patches exist, they have potential to increase urban greenery, support biodiversity, and provide a host of ecosystem services. With this knowledge on spontaneous vegetation development trajectories, urban planners can harness the resource when planning future developments.

4.
Arterioscler Thromb Vasc Biol ; : ATVBAHA120315322, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33054395

RESUMO

OBJECTIVE: The superoxide-generating Nox2 (NADPH oxidase-2) is expressed in multiple cell types. Previous studies demonstrated distinct roles for cardiomyocyte, endothelial cell, and leukocyte cell Nox2 in ANG II (angiotensin II)-induced cardiovascular remodeling. However, the in vivo role of fibroblast Nox2 remains unclear. Approach and Results: We developed a novel mouse model with inducible fibroblast-specific deficiency of Nox2 (Fibro-Nox2KO mice) and investigated the responses to chronic ANG II stimulation. Fibro-Nox2KO mice showed no differences in basal blood pressure or vessel wall morphology, but the hypertensive response to ANG II infusion (1.1 mg/[kg·day] for 14 days) was substantially reduced as compared to control Nox2-Flox littermates. This was accompanied by a significant attenuation of aortic and resistance vessel remodeling. The conditioned medium of ANG II-stimulated primary fibroblasts induced a significant increase in vascular smooth muscle cell, which was inhibited by the shRNA-mediated knockdown of fibroblast Nox2. Mass spectrometric analysis of the secretome of ANG II-treated primary fibroblasts identified GDF6 (growth differentiation factor 6) as a potential growth factor that may be involved in these effects. Recombinant GDF6 induced a concentration-dependent increase in vascular smooth muscle cell growth while chronic ANG II infusion in vivo significantly increased aortic GDF6 protein levels in control mice but not Fibro-Nox2KO animals. Finally, silencing GDF6 in fibroblasts prevented the induction of vascular smooth muscle cell growth by fibroblast-conditioned media in vitro. CONCLUSIONS: These results indicate that fibroblast Nox2 plays a crucial role in the development of ANG II-induced vascular remodeling and hypertension in vivo. Mechanistically, fibroblast Nox2 may regulate paracrine signaling to medial vascular smooth muscle cells via factors, such as GDF6.

5.
Mol Ther Methods Clin Dev ; 18: 607-619, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32775495

RESUMO

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase A (GLA) gene, which encodes the exogalactosyl hydrolase, alpha-galactosidase A (α-Gal A). Deficient α-Gal A activity results in the progressive, systemic accumulation of its substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), leading to renal, cardiac, and/or cerebrovascular disease and early demise. The current standard treatment for Fabry disease is enzyme replacement therapy, which necessitates lifelong biweekly infusions of recombinant enzyme. A more long-lasting treatment would benefit Fabry patients. Here, a gene therapy approach using an episomal adeno-associated viral 2/6 (AAV2/6) vector that encodes the human GLA cDNA driven by a liver-specific expression cassette was evaluated in a Fabry mouse model that lacks α-Gal A activity and progressively accumulates Gb3 and Lyso-Gb3 in plasma and tissues. A detailed 3-month pharmacology and toxicology study showed that administration of a clinical-scale-manufactured AAV2/6 vector resulted in markedly increased plasma and tissue α-Gal A activities, and essentially normalized Gb3 and Lyso-Gb3 at key sites of pathology. Further optimization of vector design identified the clinical lead vector, ST-920, which produced several-fold higher plasma and tissue α-Gal A activity levels with a good safety profile. Together, these studies provide the basis for the clinical development of ST-920.

6.
ACS Sens ; 5(9): 2701-2723, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32838523

RESUMO

Driven by complex and interconnected factors, including population growth, climate change, and geopolitics, infectious diseases represent one of the greatest healthcare challenges of the 21st century. Diagnostic technologies are the first line of defense in the fight against infectious disease, providing critical information to inform epidemiological models, track diseases, decide treatment choices, and ultimately prevent epidemics. The diagnosis of infectious disease at the genomic level using nucleic acid disease biomarkers has proven to be the most effective approach to date. Such methods rely heavily on enzymes to specifically amplify or detect nucleic acids in complex samples, and significant effort has been exerted to harness the power of enzymes for in vitro nucleic acid diagnostics. Unfortunately, significant challenges limit the potential of enzyme-assisted nucleic acid diagnostics, particularly when translating diagnostic technologies from the lab toward the point-of-use or point-of-care. Herein, we discuss the current state of the field and highlight cross-disciplinary efforts to solve the challenges associated with the successful deployment of this important class of diagnostics at or near the point-of-care.

7.
Nat Commun ; 11(1): 4260, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848150

RESUMO

Mangrove forests hold some of the highest densities of carbon recorded in any ecosystem, but have experienced widespread deforestation through conversion to aquaculture and agriculture. Alongside deforestation, mangroves have shown simultaneous natural expansion in some parts of the world, and considerable investments have been made into restoration programmes. Here we estimate net changes in the global mangrove carbon stock due to land cover change between 1996 and 2016, using data on mangrove deforestation and forestation, and proportional changes in carbon stock during processes of mangrove loss and gain. The global mangrove carbon stock declined by 158.4 Mt (95% CI = -156.8-525.9 Mt); a reduction of 1.8% of the stock present in 1996. Efforts to conserve and restore mangroves appear to have had some success, and - along with natural forestation - have contributed to relatively low net losses of mangrove carbon stocks over two decades.

8.
J Card Fail ; 26(9): 769-775, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32464187

RESUMO

BACKGROUND: Combined angiotensin receptor/neprilysin inhibition with sacubitril/valsartan (Sac/Val) has emerged as a therapy for heart failure. The presumed mechanism of benefit is through prevention of natriuretic peptide degradation, leading to increased cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) signaling. However, the specific requirement of PKG for Sac/Val effects remains untested. METHODS AND RESULTS: We examined Sac/Val treatment in mice with mutation of the cGMP-dependent protein kinase I (PKGI)α leucine zipper domain, which is required for cGMP-PKGIα antiremodeling actions in vivo. Wild-type (WT) or PKG leucine zipper mutant (LZM) mice were exposed to 56-day left ventricular (LV) pressure overload by moderate (26G) transaortic constriction (TAC). At day 14 after TAC, mice were randomized to vehicle or Sac/Val by oral gavage. TAC induced the same degree of LV pressure overload in WT and LZM mice, which was not affected by Sac/Val. Although LZM mice, but not WT, developed LV dilation after TAC, Sac/Val improved cardiac hypertrophy and LV fractional shortening to the same degree in both the WT and LZM TAC mice. CONCLUSION: These findings indicate the beneficial effects of Sac/Val on LV structure and function in moderate pressure overload. The unexpected finding that PKGIα mutation does not abolish the Sac/Val effects on cardiac hypertrophy and on LV function suggests that signaling other than natriuretic peptide- cGMP-PKG mediates the therapeutic benefits of neprilysin inhibition in heart failure.

9.
Nanoscale ; 12(21): 11647-11658, 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32436550

RESUMO

Antibody-targeted nanoparticles have shown exceptional promise as delivery vehicles for anticancer drugs, although manufacturability challenges have hampered clinical progress. These include the potential for uncontrolled and random antibody conjugation, resulting in masked or inactive paratopes and unwanted Fc domain interactions. To circumvent these issues, we show that the interchain disulfide of cetuximab F(ab) may be selectively re-bridged with a strained alkyne handle, to permit 'click' coupling to azide-capped nanoparticles in a highly uniform and oriented manner. When compared to conventional carbodiimide chemistry, this conjugation approach leads to the generation of nanoparticles with a higher surface loading of cetuximab F(ab) and with markedly improved ability to bind to the target epidermal growth factor receptor. Moreover, we show that entrapment of a camptothecin payload within these nanoparticles can enhance drug targeting to antigen-expressing pancreatic cancer cells, resulting in superior cytotoxicity versus the conventional nanoformulation. Collectively, this work highlights the critical need to develop refined methods for the construction of targeted nanoparticles that will accelerate their clinical translation through improved performance and manufacturability.

10.
Sci Rep ; 10(1): 7117, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32346000

RESUMO

Fragmentation is a major driver of ecosystem degradation, reducing the capacity of habitats to provide many important ecosystem services. Mangrove ecosystem services, such as erosion prevention, shoreline protection and mitigation of climate change (through carbon sequestration), depend on the size and arrangement of forest patches, but we know little about broad-scale patterns of mangrove forest fragmentation. Here we conduct a multi-scale analysis using global estimates of mangrove density and regional drivers of mangrove deforestation to map relationships between habitat loss and fragmentation. Mangrove fragmentation was ubiquitous; however, there are geographic disparities between mangrove loss and fragmentation; some regions, like Cambodia and the southern Caribbean, had relatively little loss, but their forests have been extensively fragmented. In Southeast Asia, a global hotspot of mangrove loss, the conversion of forests to aquaculture and rice plantations were the biggest drivers of loss (>50%) and fragmentation. Surprisingly, conversion of forests to oil palm plantations, responsible for >15% of all deforestation in Southeast Asia, was only weakly correlated with mangrove fragmentation. Thus, the management of different deforestation drivers may increase or decrease fragmentation. Our findings suggest that large scale monitoring of mangrove forests should also consider fragmentation. This work highlights that regional priorities for conservation based on forest loss rates can overlook fragmentation and associated loss of ecosystem functionality.

11.
Landsc Urban Plan ; 200: 103837, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32341614

RESUMO

Urban ecosystem service (UES) is becoming an influential concept to guide the planning, design, and management of urban landscapes towards urban sustainability. However, its use is hindered by definitional ambiguity, and the conceptual bases underpinning its application remain weak. This is exemplified by two different but equally valid interpretations of UES: "urban ecosystem services", referring to ecosystem services from analogs of natural and semi-natural ecosystems within urban boundaries, and "urban ecosystem services", a much broader term that includes the former group as well as urban services in a city. While we recognize that a single definition of UES is not possible nor necessary as its application is context-dependent, it is nevertheless useful to clarify the relationships between these interpretations to promote consistent use, and importantly, explore how a broader interpretation of UES might advance its applications in areas that have been neglected. We developed a conceptual framework that links UES to natural and human-derived capital to explain the relationships between the dual meanings of UES and proposed three normative propositions to guide its application: (1) integrate holistically multiple components of natural capital to provide UES, (2) reduce dependence on non-renewable abiotic resources and human-derived capital, and (3) enhance UES through technology. The framework we developed helps to resolve the current ambiguity in the meanings of UES, highlights the need to recognise neglected aspects of natural capital important for UES, and can be used to clarify relationships with related concepts conveying dependence of human well-being on nature.

12.
PLoS One ; 15(4): e0231576, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32339175

RESUMO

Urban residents can benefit from spending time in outdoor spaces and engaging with nature-related activities. Such engagement can improve health and well-being, support community cohesion, and improve environmentally-friendly behaviours. However, engagement with nature may not be equal amongst different members of society. We investigated individual variation in engagement with nature in Singapore, a high-density city in tropical Southeast Asia. Through a survey of 1000 residents, we analysed relationships between demographic factors such as age, income, and sex, and the frequency of visitation to different ecosystem types, and the frequency of engagement with different nature-related activities. Parks and neighbourhood open spaces were among the most commonly-visited outdoor spaces, with nature reserves and other natural areas being visited less frequently. Common activities included sitting outdoors, art and photography, and running, while hiking and nature recreation were less frequent. In contrast with previous studies, we found relatively small differences among different groups of the population in their preferred types of outdoor activities. Older people, those with lower incomes, and without degrees were less likely to visit most types of outdoor space and engage with most types of nature-related activities. In the case of nature reserves, the distance from the visitor's home had a significantly negative influence on the frequency of visitation. These findings demonstrate that the benefits of engagement with nature are not equally enjoyed by all demographic groups, and that some groups lack engagement across the board. Strategies to increase nature engagement in tropical cities could include increasing the local availability and accessibility of different types of outdoor space, and education and public outreach programmes to encourage participation.


Assuntos
Meio Ambiente , Recreação , População Urbana/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Viés , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Singapura , Fatores Socioeconômicos
13.
Org Biomol Chem ; 18(12): 2215-2218, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32150198

RESUMO

Due to their homogeneity, tuneable properties, low cost and ease of manufacture, thermally induced phase separation (TIPS) polymeric microparticles are emerging as an exciting class of injectable device for the treatment of damaged tissue or complex diseases, such as cancer. However, relatively little work has explored enhancing surface functionalisation of this system. Herein, we present the functionalisation of TIPS microparticles with both small molecules and an antibody fragment of Herceptin™, via a heterobifunctional pyridazinedione linker capable of participating in SPAAC "click" chemistry, and compare it to the traditional method of preparing active-targeted microparticle systems, that is, physisorption of antibodies to the microparticle surface. Antigen-binding assays demonstrated that functionalisation of microparticles with Herceptin Fab, via a pyridazinedione linker, provided an enhanced avidity to HER2+ when compared to traditional physisorption methods.

14.
Sci Rep ; 10(1): 4125, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139774

RESUMO

Humans may have evolved a need to connect with nature, and nature provides substantial cultural and social values to humans. However, quantifying the connection between humans and nature at a global scale remains challenging. We lack answers to fundamental questions: how do humans experience nature in different contexts (daily routines, fun activities, weddings, honeymoons, other celebrations, and vacations) and how do nature experiences differ across countries? We answer these questions by coupling social media and artificial intelligence using 31,534 social media photographs across 185 countries. We find that nature was more likely to appear in photographs taken during a fun activity, honeymoon, or vacation compared to photographs of daily routines. More importantly, the proportion of photographs with nature taken during fun activities is associated with national life satisfaction scores. This study provides global evidence of the biophilia hypothesis by showing a connection between humans and nature that contributes to life satisfaction and highlights how nature serves as background to many of our positive memories.


Assuntos
Mídias Sociais , Inteligência Artificial , Humanos , Satisfação Pessoal , Fotografação
15.
Sci Rep ; 10(1): 808, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31965008

RESUMO

Urban parks and green spaces are among the few places where city dwellers can have regular contact with nature and engage in outdoor recreation. Social media data provide opportunities to understand such human-environment interactions. While studies have demonstrated that geo-located photographs are useful indicators of recreation across different spaces, recreation behaviour also varies between different groups of people. Our study used social media to assess behavioural patterns across different groups of park users in tropical Singapore. 4,674 users were grouped based on the location and content of their photographs on the Flickr platform. We analysed how these groups varied spatially in the parks they visited, as well as in their photography behaviour. Over 250,000 photographs were analysed, including those uploaded and favourited by users, and all photographs taken at city parks. There were significant differences in the number and types of park photographs between tourists and locals, and between user-group axes formed from users' photograph content. Spatial mapping of different user groups showed distinct patterns in the parks they were attracted to. Future work should consider such variability both within and between data sources, to provide a more context-dependent understanding of human-environment interactions and preferences for outdoor recreation.

16.
PLoS One ; 15(1): e0227227, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978114

RESUMO

Many conflicting reports about the involvement of serum amyloid P component (SAP) in amyloid diseases have been presented over the years; SAP is known to be a universal component of amyloid aggregates but it has been suggested that it can both induce and suppress amyloid formation. By using our Drosophila model of systemic lysozyme amyloidosis, SAP has previously been shown to reduce the toxicity induced by the expression of the disease-associated lysozyme variant, F57I, in the Drosophila central nervous system. This study further investigates the involvement of SAP in modulating lysozyme toxicity using histochemistry and spectral analyses on the double transgenic WT and F57I lysozyme flies to probe; i) formation of aggregates, ii) morphological differences of the aggregated lysozyme species formed in the presence or absence of SAP, iii) location of lysozyme and iv) co-localisation of lysozyme and SAP in the fly brain. We found that SAP can counteract the toxicity (measured by the reduction in the median survival time) induced by F57I lysozyme by converting toxic F57I species into less toxic amyloid-like structures, as reflected by the spectral changes that p-FTAA undergoes when bound to lysozyme deposits in F57I-F57I-SAP flies as compared to F57I-F57I flies. Indeed, when SAP was introduced to in vitro lysozyme fibril formation, the endpoint fibrils had enhanced ThT fluorescence intensity as compared to lysozyme fibrils alone. This suggests that a general mechanism for SAP's role in amyloid diseases may be to promote the formation of stable, amyloid-like fibrils, thus decreasing the impact of toxic species formed along the aggregation pathway.


Assuntos
Amiloidose/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Muramidase/metabolismo , Componente Amiloide P Sérico/metabolismo , Amiloide/genética , Amiloide/metabolismo , Amiloide/ultraestrutura , Amiloidose/genética , Amiloidose/patologia , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Humanos , Muramidase/genética , Agregados Proteicos , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia
17.
Cardiovasc Res ; 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31821410

RESUMO

AIMS: Chronic pressure or volume overload induce concentric versus eccentric left ventricular (LV) remodelling, respectively. Previous studies suggest that distinct signalling pathways are involved in these responses. NADPH oxidase-4 (Nox4) is a reactive oxygen species (ROS)-generating enzyme that can limit detrimental cardiac remodelling in response to pressure overload. This study aimed to assess its role in volume overload-induced remodelling. METHODS AND RESULTS: We compared the responses to creation of an aortocaval fistula (Shunt) to induce volume overload in Nox4-null mice (Nox4-/-) versus wild-type (WT) littermates. Induction of Shunt resulted in a significant increase in cardiac Nox4 mRNA and protein levels in WT mice as compared to Sham controls. Nox4-/- mice developed less eccentric LV remodelling than WT mice (echocardiographic relative wall thickness: 0.30 vs 0.27, p < 0.05), with less LV hypertrophy at organ level (increase in LV weight/tibia length ratio of 25% vs 43%, p < 0.01) and cellular level (cardiomyocyte cross-sectional area: 323 µm2 vs 379 µm2, p < 0.01). LV ejection fraction, foetal gene expression, interstitial fibrosis, myocardial capillary density and levels of myocyte apoptosis after Shunt were similar in the two genotypes. Myocardial phospho-Akt levels were increased after induction of Shunt in WT mice whereas levels decreased in Nox4-/- mice (+29% vs -21%, p < 0.05), associated with a higher level of phosphorylation of the S6 ribosomal protein (S6) and the eIF4E-binding protein 1 (4E-BP1) in WT compared to Nox4-/- mice. We identified that Akt activation in cardiac cells is augmented by Nox4 via a Src kinase-dependent inactivation of protein phosphatase 2A (PP2A). CONCLUSION: Endogenous Nox4 is required for the full development of eccentric cardiac hypertrophy and remodelling during chronic volume overload. Nox4-dependent activation of Akt and its downstream targets S6 and 4E-BP1 may be involved in this effect. TRANSLATIONAL PERSPECTIVE: Cardiac volume overload resulting, for example, from aortic or mitral regurgitation contributes to the development of heart failure. Its underlying pathophysiology differs from that of cardiac pressure overload. Our study identifies the reactive oxygen species generating enzyme NADPH oxidase-4 (Nox4) as an important regulator of volume overload-induced cardiac remodelling by promoting eccentric LV hypertrophy, an adaptive response to the increased volume. As Nox inhibition is currently being developed as a potential therapeutic approach for several human diseases (e.g. lung fibrosis), our findings highlight the importance of assessing the potential impact on cardiac function in patients with co-existent valvular regurgitation.

18.
J Med Chem ; 62(19): 8711-8732, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31532644

RESUMO

Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.


Assuntos
Isoquinolinas/farmacologia , Receptores de Dopamina D1/agonistas , Acetilcolina/metabolismo , Administração Oral , Regulação Alostérica/efeitos dos fármacos , Animais , Sítios de Ligação , Cristalografia por Raios X , AMP Cíclico/metabolismo , Células HEK293 , Meia-Vida , Humanos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Rim/efeitos dos fármacos , Rim/metabolismo , Locomoção/efeitos dos fármacos , Camundongos , Conformação Molecular , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Ratos , Receptores de Dopamina D1/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade
19.
Chem Commun (Camb) ; 55(53): 7671-7674, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31204425

RESUMO

Herein we report the construction of a nanoparticle-based drug delivery system which targets a key regulator in tumour angiogenesis. We exploit a Variable New Antigen Receptor (VNAR) domain, conjugated using site-specific chemistry, to direct poly lactic acid-co-glycolic acid-polyethylene glycol (PLGA-PEG) nanoparticles to delta like canonical Notch ligand 4 (DLL4). The importance of site-specific chemistry is demonstrated.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Receptores de Antígenos/química , Humanos , Estrutura Molecular
20.
Sci Rep ; 9(1): 5844, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971724

RESUMO

Transverse aortic constriction (TAC) is a well-established model of pressure overload-induced cardiac hypertrophy and failure in mice. The degree of constriction "tightness" dictates the TAC severity and is determined by the gauge (G) of needle used. Though many reports use the TAC model, few studies have directly compared the range of resulting phenotypes. In this study adult male mice were randomized to receive TAC surgery with varying degrees of tightness: mild (25G), moderate (26G) or severe (27G) for 4 weeks, alongside sham-operated controls. Weekly echocardiography and terminal haemodynamic measurements determined cardiac remodelling and function. All TAC models induced significant, severity-dependent left ventricular hypertrophy and diastolic dysfunction compared to sham mice. Mice subjected to 26G TAC additionally exhibited mild systolic dysfunction and cardiac fibrosis, whereas mice in the 27G TAC group had more severe systolic and diastolic dysfunction, severe cardiac fibrosis, and were more likely to display features of heart failure, such as elevated plasma BNP. We also observed renal atrophy in 27G TAC mice, in the absence of renal structural, functional or gene expression changes. 25G, 26G and 27G TAC produced different responses in terms of cardiac structure and function. These distinct phenotypes may be useful in different preclinical settings.


Assuntos
Aorta Torácica/cirurgia , Modelos Animais de Doenças , Insuficiência Cardíaca/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Miocárdio/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Constrição Patológica , Fibrose/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Distribuição Aleatória
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