Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with ...mitochondrial amyloid-beta protein (Abeta) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Abeta- and Ca(2+)-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from Abeta- and oxidative stress-induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer's disease mouse model and alleviates Abeta-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer's disease. Blockade of CypD may be a therapeutic strategy in Alzheimer's disease.
Our previous animal studies found that the preventive effects of lactoferrin (Lf) on alcoholic liver injury (ALI) are associated with nuclear factor E2-related factor 2 (Nrf2). To further explore the ...causality, experiments were performed using rat normal liver BRL-3A cells. Lf treatment reduced ethanol-induced death and apoptosis; meanwhile, Lf treatment alleviated excessive LDH release. These findings confirmed the protection of Lf against ethanol-induced injury in BRL-3A cells. Mechanistically, Lf treatment reversed the reduction in nuclear Nrf2 induced by ethanol without affecting the cytoplasmic Nrf2 level, which led to antioxidant enzyme activity restoration. However, the blocking of Nrf2 nuclear translocation by ML385 eliminated the protective effects of Lf. In a conclusion, Lf protects BRL-3A cells from ethanol-induced injury via promoting Nrf2 nuclear translocation.
Nanotechnology-enabled pesticide delivery systems have been widely studied and show great prospects in modern agriculture. Nanodelivery systems not only achieve the controlled release of ...agrochemicals but also possess many unique characteristics. This study presents the development of a pH-responsive pesticide nanoformulation utilizing hollow mesoporous silica nanoparticles (HMSNs) as a nanocarrier. The nanocarrier was loaded with the photosensitive pesticide prochloraz (Pro) and then combined with ZnO quantum dots (ZnO QDs) through electrostatic interactions. ZnO QDs serve as both the pH-responsive gatekeeper and the enhancer of the pesticide. The results demonstrate that the prepared nanopesticide exhibits high loading efficiency (24.96%) for Pro. Compared with Pro technical, the degradation rate of Pro loaded in HMSNs@Pro@ZnO QDs was reduced by 26.4% after 24 h ultraviolet (UV) exposure, indicating clearly improved photostability. In a weak acidic environment (pH 5.0), the accumulated release of the nanopesticide after 48 h was 2.67-fold higher than that in a neutral environment. This indicates the excellent pH-responsive characteristic of the nanopesticide. The tracking experiments revealed that HMSNs can be absorbed by rice leaves and subsequently transported to other tissues, indicating their potential for effective systemic distribution and targeted delivery. Furthermore, the bioactivity assays confirmed the fungicidal efficacy of the nanopesticide against rice blast disease. Therefore, the constructed nanopesticide holds great prospect in nanoenabled agriculture, offering a novel strategy to enhance pesticide utilization.
Aβ40 and Aβ42 are the predominant Aβ species in the human body. Toxic Aβ42 oligomers and fibrils are believed to play a key role in causing Alzheimer's disease (AD). However, the role of Aβ40 in AD ...pathogenesis is not well established. Emerging evidence indicates a protective role for Aβ40 in AD pathogenesis. Although Aβ40 is known to inhibit Aβ42 fibril formation, it is not clear whether the inhibition acts on the non-toxic monomer or acts on the toxic Aβ42 oligomers. In contrast to conventional methods that detect the appearance of fibrils, in our study Aβ42 aggregation was monitored by the decreasing NMR signals from Aβ42 monomers. In addition, differential NMR isotope labelling enabled the selective observation of Aβ42 aggregation in a mixture of Aβ42 and Aβ40. We found Aβ40 monomers inhibit the aggregation of non-toxic Aβ42 monomers, in an Aβ42/Aβ40 ratio-dependent manner. NMR titration revealed that Aβ40 monomers bind to Aβ42 aggregates with higher affinity than Aβ42 monomers. Aβ40 can also release Aβ42 monomers from Aβ42 aggregates. Thus, Aβ40 likely protects Aβ42 monomers by competing for the binding sites on pre-existing Aβ42 aggregates. Combining our data with growing evidence from transgenic mice and human genetics, we propose that Aβ40 plays a critical, protective role in Alzheimer's by inhibiting the aggregation of Aβ42 monomer. Aβ40 itself, a peptide already present in the human body, may therefore be useful for AD prevention and therapy.
Abstract
The chromobox (CBX) proteins mediate epigenetic gene silencing and have been implicated in the cancer development. By analyzing eight CBX family members in TCGA dataset, we found that ...chromobox 7 (CBX7) was the most strikingly downregulated CBX family member in urinary bladder cancer (UBC), as compared to normal tissues. Though dysregulation of CBX7 has been reported in multiple cancers, its specific role and clinical relevance in UBC remain unclear. Herein, we found that frequent downregulation of CBX7 in UBC specimens, which was due to its promoter hypermethylation, was correlated with poor prognosis. The ectopic expression of CBX7 suppressed UBC cell proliferation, migration, invasion, and cancer stemness, whereas CBX7 depletion promoted cancer cell aggressiveness. Importantly, CBX7 overexpression in UBC cells inhibited tumorigenicity, whereas CBX7 depletion promoted the tumor development, indicating its tumor-suppressive role in UBC. Using RNA-seq and chromosome immunoprecipitation (ChIP) assays, we identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of CBX7, which was negatively modulated by CBX7 in a PRC1-dependent manner and involved in stimulating ERK signaling. Consistently, AKR1B10 overexpression induced cancer cell aggressiveness, whereas suppression of AKR1B10 by siRNA or its small molecular inhibitor, oleanolic acid, reversed the CBX7 deficiency-induced cellular effects. AKR1B10 overexpression was negatively associated with CBX7 downregulation and predicted poor clinical outcomes in UBC patients. Taken together, our results indicate that CBX7 functions as a tumor suppressor to downregulate AKR1B10 and further inactivates ERK signaling. This CBX7/AKR1B10/ERK signaling axis may provide a new therapeutic strategy against UBC.
In recent years, China has suffered from frequent extreme precipitation events, and predicting their future trends has become an essential part of the current research on this issue. Because of the ...inevitable uncertainties associated with individual models for climate prediction, this study uses a machine learning approach to integrate and fit multiple models. The results show that the use of several evaluation metrics provides better results than the traditional ensemble median method. The correlation coefficients with the actual observations were found to improve from about 0.8 to 0.9, while the correlation coefficients of the precipitation amount (PRCPTOT), very heavy precipitation days (R20mm), and extreme precipitation intensity (SDII95) reached 0.95. Based on this, the precipitation simulations of moderate forced scenario for sharing socio-economic path (SSP2-4.5) from 27 coupled models in the Coupled Model Intercomparison Project Phase 6 (CMIP6) were used to explore potential changes in future extreme precipitation events in China and to calculate the distribution and trends of the PRCPTOT, extreme precipitation amount (R95pTOT), maximum consecutive 5-day precipitation (Rx5day), precipitation intensity (SDII), SDII95, and R20mm for the early 21st century (2023–2050), mid-21st century (2051–2075), and late 21st century (2076–2100), respectively. The results showed that the most significant increase in extreme precipitation indices is expected to occur by the end of the century, with the R95pTOT, Rx5day, and SDII95 increasing by 13.73%, 9.43%, and 9.34%, respectively, from the base period. The remaining three precipitation indexes, the PRCPTOT, SDII, and R20mm, also showed increases of 8.77%, 6.84%, and 4.02%, respectively. Additionally, there were apparent differences in the spatial variation of extreme precipitation. There were significant increasing trends of extreme precipitation indexes in central China and northeast China in the three periods, among which the total annual precipitation showed an increasing trend in central and northern China and a decreasing trend in western and south China. An increasing trend of annual precipitation intensity was found to be mainly concentrated in central China and south China, and the annual precipitation frequency showed a larger increasing trend at the beginning of this century. The annual precipitation frequency showed an increasing trend in the early part of this century. In general, all the indices showed an overall increasing trend in the future period, with the PRCPTOT, Rx5day, and SDII95 showing the most significant overall increasing trends.
Abstract
Background
Enolase is an essential enzyme in the process of glycolysis and has been implicated in cancer progression. Though dysregulation of ENOs has been reported in multiple cancers, ...their prognostic value and specific role in bladder cancer (BLCA) remain unclear.
Methods
Multiple databases were employed to examine the expression of ENOs in BLCA. The expression of ENO1 was also validated in BLCA cell lines and tissue samples by western blotting and immunohistochemistry. Kaplan–Meier analysis, ROC curve, univariate and multivariate Cox regression were performed to evaluate the predictive capability of the ENO1. Gene ontology (GO) and Gene Set Enrichment Analyses (GSEA) analysis were employed to perform the biological processes enrichment. Function experiments were performed to explore the biological role of ENO1 in BLCA. The correlation of ENO1 with immune cell infiltration was explored by CIBERSORT.
Results
By analyzing three ENO isoforms in multiple databases, we identified that ENO1 was the only significantly upregulated gene in BLCA. High expression level of ENO1 was further confirmed in BLCA tissue samples. Aberrant ENO1 overexpression was associated with clinicopathological characteristics and unfavorable prognosis. Functional studies demonstrated that ENO1 depletion inhibited cancer cell aggressiveness. Furthermore, the expression level of ENO1 was correlated with the infiltration levels of immune cells and immune-related functions.
Conclusions
Taken together, our results indicated that ENO1 might serve as a promising prognostic biomarker for prognosticating prognosis associated with the tumor immune microenvironment, suggesting that ENO1 could be a potential immune-related target against BLCA.
In recent decades, the hydrological processes on the Loess Plateau have undergone significant changes due to the combined effects of climate change and human activities. This study investigates the ...Qin River basin, the core area of the Loess Plateau. Between 1971 and 2000, the hydrometeorology of the flood season in the Qin basin on the Loess Plateau in China changed abruptly in 1982 and 1992. This study uses distributed hydrologic modeling and statistical analysis to distinguish the spatial and temporal impacts of climate change and human activities. The fastest dynamic changes in land use occurred in grassland and construction land, accounting for 0.36% and −0.1%, respectively, from 1982 to 1991. From 1992 to 2000, it was 0.29% and 0.3%, respectively. The increase in basin area where the Normalized Difference Vegetation Index increased was 95%. However, except for significant changes in runoff from 1981 to 1992, there were no significant changes in precipitation, runoff, and temperature during other flood seasons. During the two studied variation periods, from 1982 to 1991 and from 1992 to 2000, the contribution rate of climate change to flood season runoff (CClimate) decreased from 83.26% to 74.47%, while the contribution rate of human activity disturbance to flood season runoff (Chuman) increased from 16.74% to 25.53%. In terms of spatial distribution, from 1982 to 1991, areas with a Chuman > 50% were primarily concentrated in the upper reaches of the basin, while from 1992–2000, these areas shifted to the lower reaches. This study offers valuable insights for water resource planning and soil conservation measures in the Loess Plateau and similar arid regions worldwide, aiming to ensure water resource safety and sustainability in response to climate change and human interference.
Iron overload, as a risk factor for osteoporosis, can result in the up-regulation of Hepcidin, and Hepcidin knockout mice display defects in their bone microarchitecture. However, the molecular and ...genetic mechanisms underlying Hepcidin deficiency-derived bone loss remain unclear. Here, we show that hepcidin knockdown in zebrafish using morpholinos leads to iron overload. Furthermore, a mineralization delay is observed in osteoblast cells in hepcidin morphants, and these defects could be partially restored with microinjection of hepcidin mRNA. Quantitative real-time PCR analyses revealed the osteoblast-specific genes alp, runx2a, runx2b, and sp7 in morphants are down-regulated. Furthermore, we confirmed qRT-PCR results by in situ hybridization and found down-regulated genes related to osteoblast function in hepcidin morphants. Most importantly, we revealed that hepcidin was capable of removing whole-body iron which facilitated larval recovery from the reductions in bone formation and osteogenesis induced by iron overload.
•First use morpholino of hepcidin.•First discover mineralization delay by iron overload in zebrafish.•First reveal iron overload downregulate ossification genes.
This study is the first in the region to use Global Precipitation Mission Dual-Frequency Precipitation Radar (GPM-DPR) and Fengyun-2G (FY-2G) observations to qualitatively and quantitatively study ...the Southwest Vortex evolution characteristics during the flood season from 2019 to 2021. Furthermore, vertical characteristics of the two main precipitation types in the Southwest Vortex, stratiform and convective, were statistically analyzed at different life stages, including horizontal and vertical distribution of precipitation particles, droplet spectrum characteristics, and vertically layered precipitation contribution. The results showed that: (1) The typical convective precipitation (CP) in the developing and mature stages has strong reflectivity distribution centers in the upper and lower layers, showing characteristics related to terrain. Additionally, the high-level hydrometeor particles are mainly solid precipitation particles, and particles in the lower layers collide and coalesce in the violent vertical motion of the airflow. (2) For the three stages of CP, the reflectivity below melting layer (ML) first showed a rapid weakening trend toward the surface and then remained unchanged, significantly changing its vertical structure. The main rainfall type of the Southwest Vortex system was stratiform precipitation (SP) in the three stages. (3) In the two types of cloud precipitation, the developing stage is generally composed of large and sparse precipitation particles, the mature stage of large and dense precipitation particles, and the dissipating stage of small and sparse precipitation particles. The findings of this study reveal the three-dimensional refined structure and vertical variation characteristics of different life stages of the Southwest Vortex precipitation cloud system and provide important tools and references for improving the accuracy of numerical models and the forecast level of short-term heavy precipitation under complex terrain.
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