A Targeted Library Screen Reveals a New Inhibitor Scaffold for Protein Kinase D

Protein kinase D (PKD) has emerged as a potential therapeutic target in multiple pathological conditions, including cancer and heart diseases. Potent and selective small molecule inhibitors of PKD are valuable for dissecting PKD-mediated cellular signaling pathways and for therapeutic application. In this study, we evaluated a targeted library of 235 small organic kinase inhibitors for PKD1 inhibitory activity at a single concentration. Twenty-eight PKD inhibitory chemotypes were identified and six exhibited excellent PKD1 selectivity. Five of the six lead structures share a common scaffold, with compound 139 being the most potent and selective for PKD vs PKC and CAMK. Compound 139 was an ATP-competitive PKD1 inhibitor with a low double-digit nanomolar potency and was also cell-active. Kinase profiling analysis identified this class of small molecules as pan-PKD inhibitors, confirmed their selectivity again PKC and CAMK, and demonstrated an overall favorable selectivity profile that could be further enhanced through structural modification. Furthermore, using a PKD homology model based on similar protein kinase structures, docking modes for compound 139 were explored and compared to literature examples of PKD inhibition. Modeling of these compounds at the ATP-binding site of PKD was used to rationalize its high potency and provide the foundation for future further optimization. Accordingly, using biochemical screening of a small number of privileged scaffolds and computational modeling, we have identified a new core structure for highly potent PKD inhibition with promising selectivity against closely related kinases. These lead structures represent an excellent starting point for the further optimization and the design of selective and therapeutically effective small molecule inhibitors of PKD. © 2012 Tandon et al

The Association between Metformin Use and Risk of Developing Severe Dementia among AD Patients with Type 2 Diabetes

This study explores the potential impact of metformin on the development of severe dementia in individuals with Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM). With an emerging interest in the role of the APOE genotype in mediating metformin’s effects on cognitive decline in AD patients, we sought to investigate whether metformin usage is associated with a reduced risk of severe dementia. Using data from the National Alzheimer’s Coordinating Center (NACC) database (2005–2021), we identified 1306 participants with both AD and T2DM on diabetes medications. These individuals were categorized based on metformin usage, and a propensity score-matched cohort of 1042 participants was analyzed. Over an average follow-up of 3.6 years, 93 cases of severe dementia were observed. A Kaplan–Meier analysis revealed that metformin users and non-users had similar probabilities of remaining severe dementia-free (log-rank p = 0.56). Cox proportional hazards models adjusted for covariates showed no significant association between metformin usage and a lower risk of severe dementia (HR, 0.96; 95% CI, 0.63–1.46; p = 0.85). A subgroup analysis based on APOE ε4 carrier status demonstrated consistent results, with metformin use not correlating with a reduced severe dementia risk. In conclusion, our findings from a substantial cohort of AD and T2DM patients suggest that metformin usage is not significantly associated with a decreased risk of severe dementia. This observation persists across APOE ε4 carriers and non-carriers, indicating a lack of genotype-mediated effect

Identifying Key Areas of Green Space for Ecological Restoration Based on Ecological Security Patterns in Fujian Province, China

Urban expansion has resulted in the fragmentation of green spaces. Based on the concept of a living community that integrates mountains, rivers, forests, farmlands, lakes, and grasslands, the extraction of key elements in green spaces of regional ecosystems provides core scientific support for the ecological restoration of territorial spaces. According to the ecological service function importance and ecological sensitivity, the ecological sources were identified in this study. Furthermore, we distinguished the ecological corridors using the minimum cumulative resistance (MCR) model and identified the key areas of green spaces using the circuit theory model. The result showed that (1) 62 ecological sources were present with a total area of 4696 km2, of which green space accounted for 98.19%; meanwhile, 151 ecological corridors (optimal path) were densely distributed in the southwest region around the Daimao and Bopingling mountains. (2) The key areas of ecological restoration in the study area included 17 key ecological sources and 19 key ecological corridors. The area covered by ecological pinch points was 1327 km2, among which 77.54% of green space comprised forest area. The area of ecological barriers was 9647 km2, and the forest area still accounted for the highest proportion (63.92%). (3) Based on a comprehensive analysis of the spatial distribution of key areas of ecological restoration and green spaces, we formulated classified ecological restoration measures. The study findings are expected to provide a reference for planning the ecological restoration of territorial spaces

Identifying Key Areas of Green Space for Ecological Restoration Based on Ecological Security Patterns in Fujian Province, China

Urban expansion has resulted in the fragmentation of green spaces. Based on the concept of a living community that integrates mountains, rivers, forests, farmlands, lakes, and grasslands, the extraction of key elements in green spaces of regional ecosystems provides core scientific support for the ecological restoration of territorial spaces. According to the ecological service function importance and ecological sensitivity, the ecological sources were identified in this study. Furthermore, we distinguished the ecological corridors using the minimum cumulative resistance (MCR) model and identified the key areas of green spaces using the circuit theory model. The result showed that (1) 62 ecological sources were present with a total area of 4696 km2, of which green space accounted for 98.19%; meanwhile, 151 ecological corridors (optimal path) were densely distributed in the southwest region around the Daimao and Bopingling mountains. (2) The key areas of ecological restoration in the study area included 17 key ecological sources and 19 key ecological corridors. The area covered by ecological pinch points was 1327 km2, among which 77.54% of green space comprised forest area. The area of ecological barriers was 9647 km2, and the forest area still accounted for the highest proportion (63.92%). (3) Based on a comprehensive analysis of the spatial distribution of key areas of ecological restoration and green spaces, we formulated classified ecological restoration measures. The study findings are expected to provide a reference for planning the ecological restoration of territorial spaces

Influence of Landscape Pattern Evolution on Soil Conservation in a Red Soil Hilly Watershed of Southern China

The Tingjiang Watershed is a typical mountainous area with red soil in the south of China. Due to the high rainfall intensity, significant cultivated land expansion, and accelerated urbanization, ecological problems such as soil erosion are prominent in the study area. Based on the land use, precipitation, digital elevation model (DEM), normalized difference vegetation Index (NDVI), and soil types in 2000, 2010, and 2020, the landscape pattern and soil conservation in the Tingjiang Watershed were assessed at the sub-watershed scale. The spatial correlation between soil conservation and landscape pattern was analyzed using GeoDA software. The results show the following: (1) From 2000 to 2020, the total amount of soil conservation decreased by 4.15 × 108 t. In terms of spatial analysis, the amount of soil conservation in the Tingjiang Watershed showed an upward and then downward trend in the north and a downward trend in the south, with the most obvious downward trend in the southeast and the northeast. (2) Fragmentation of the overall landscape pattern in the Tingjiang Watershed has increased. The discrete degree and homogeneity of patches decreased in Changting County, while landscape heterogeneity and homogeneity increased in Shanghang, Liancheng, and Yongding Counties. (3) Soil conservation was significantly correlated with the landscape indices patch density (PD), landscape shape index (LSI), mean patch area (AREA_MN), patch cohesion index (COHESION), splitting index (SPLIT), and Shannon evenness index (SHEI). Sub-watersheds with low soil conservation had landscape splitting index, landscape dispersion, patch type richness, and boundary complexity. These areas were mainly distributed in the southern part of the watershed. Sub-watersheds with higher soil conservation were characterized by low patch fragmentation and strong connectivity of dominant patches, which were mainly located in the northern part of the watershed. (4) The spatial error model (SEM) fit better in 2000, 2010, and 2020 compared with the spatial lag model (SLM) and ordinary least squares regression (OLS). The diagnostic results of the SEM model show that among the six landscape indices, PD, SHEI, and AREA_MN are the main influencing factors affecting soil conservation in the watershed to different degrees. The purpose of this study was to investigate the response state of soil conservation capacity as landscape patterns evolve in the Tingjiang Watershed, with the goal of providing a reference for landscape planning and management as well as soil erosion management in the watershed

Exploring Urban Green Space Optimization of the Urban Walking Life Circle in Fuzhou, China

The spatial distribution of urban green spaces (UGS) is closely related to the health of residents and the ecological pattern of cities. Exploring the equity of UGSs plays an important role in urban planning and also provides guidance for urban development. Taking the main urban area of Fuzhou City as an example, this study uses network big data and census data to pinpoint the population demand, evaluates the accessibility and equity of UGS within the basic living circle, neighborhood living circle and daily living circle of residents at the scale of residential and sub-districts. Based on the G2SFCA model, we also quantify the actual effective UGS’s service capacity. Then, using the scale and travel range as the entry point, we further discuss the similarities and differences under different scales and different travel ranges. Finally, optimization strategies are proposed for the construction status. The results show that: (1) The spatial allocation of urban green space resources varies significantly, and there is a serious inequity in the spatial distribution of urban green space under pedestrian conditions; (2) The results of UGS accessibility, equity, and service capacity in Fuzhou at both residential and sub-district scales are consistent; (3) Urban construction should be multi-level overall planning, combined with local economic and social development factors in accordance with local conditions to take measures. The results of the study can provide a scientific reference for the optimization of the spatial distribution of UGS

Selectivity profiling of compounds 122 and 140.

<p>Listed in this table are all the protein kinases that bound compound <b>122</b> at over 50% at 10 µM. Their competition by compound <b>140</b> is listed in parallel. Compound <b>140</b> exhibited greater selectivity as compared to compound <b>122</b>. The data were obtained from profiling of a total of 353 kinases in the kinome. Enzymes competed by compound <b>140</b> at 99–100% are bolded.</p

Structures and PKD1 inhibitory activities of selected small molecule inhibitors identified in previous HTS assays.

<p>Structures and PKD1 inhibitory activities of selected small molecule inhibitors identified in previous HTS assays.</p