The cell‐to‐cell transfer of α‐synuclein (α‐Syn) greatly contributes to Parkinson's disease (PD) pathogenesis and underlies the spread of α‐Syn pathology. During this process, extracellular α‐Syn can ...activate microglia and neuroinflammation, which plays an important role in PD. However, the effect of extracellular α‐Syn on microglia autophagy is poorly understood. In the present study, we reported that extracellular α‐Syn inhibited the autophagy initiation, as indicated by LC3‐II reduction and p62 protein elevation in BV2 and cultured primary microglia. The in vitro findings were verified in microglia‐enriched population isolated from α‐Syn‐overexpressing mice induced by adeno‐associated virus (AAV2/9)‐encoded wildtype human α‐Syn injection into the substantia nigra (SN). Mechanistically, α‐Syn led to microglial autophagic impairment through activating toll‐like receptor 4 (Tlr4) and its downstream p38 and Akt‐mTOR signaling because Tlr4 knockout and inhibition of p38, Akt as well as mTOR prevented α‐Syn‐induced autophagy inhibition. Moreover, inhibition of Akt reversed the mTOR activation but failed to affect p38 phosphorylation triggered by α‐Syn. Functionally, the in vivo evidence showed that lysozyme 2 Cre (Lyz2cre)‐mediated depletion of autophagy‐related gene 5 (Atg5) in microglia aggravated the neuroinflammation and dopaminergic neuron losses in the SN and exacerbated the locomotor deficit in α‐Syn‐overexpressing mice. Taken together, the results suggest that extracellular α‐Syn, via Tlr4‐dependent p38 and Akt‐mTOR signaling cascades, disrupts microglial autophagy activity which synergistically contributes to neuroinflammation and PD development.
Autophagy‐dependent and independent machinery synergistically contribute to hα‐Syn‐caused neuroinflammation in PD. The basal autophagy activity restricts microglia inflammation. Extracellular hα‐Syn interacts with and activates Tlr4, resulting in inflammatory responses, as well as autophagy suppression in microglia via Tlr4‐dependent p38 and Akt/mTOR signaling cascades. This impairs the inhibitory effect of autophagy on inflammation, and thus aggravating hα‐Syn‐induced inflammatory responses.
Alzheimer’s disease (AD), the most common type of dementia, is a progressive disease beginning with mild memory loss, possibly leading to loss of the ability to carry on a conversation and respond to ...environments. It can seriously affect a person’s ability to carry out daily activities. Therefore, early diagnosis of AD is conducive to better treatment and avoiding further deterioration of the disease. Magnetic resonance imaging (MRI) has become the main tool for humans to study brain tissues. It can clearly reflect the internal structure of a brain and plays an important role in the diagnosis of Alzheimer’s disease. MRI data is widely used for disease diagnosis. In this paper, based on MRI data, a method combining a 3D convolutional neural network and ensemble learning is proposed to improve the diagnosis accuracy. Then, a data denoising module is proposed to reduce boundary noise. The experimental results on ADNI dataset demonstrate that the model proposed in this paper improves the training speed of the neural network and achieves 95.2% accuracy in AD vs. NC (normal control) task and 77.8% accuracy in sMCI (stable mild cognitive impairment) vs. pMCI (progressive mild cognitive impairment) task in the diagnosis of Alzheimer’s disease.
Nighttime light (NTL) intensity is highly associated with the unique footprint of human activities, reflecting the development of socioeconomic and urbanization. Therefore, better understanding of ...the relationship between NTL intensity and human activities can help extend the applications of NTL remote sensing data. Different from the global effect of human activities on NTL intensity discussed in previous studies, we focused more attention to the local effect caused by the spatial heterogeneity of human activities with the support of the multiscale geographically weighted regression (MGWR) model in this study. In particular, the Suomi National Polar Orbiting Partnership/Visible Infrared Imaging Radiometer Suite (NPP/VIIRS) NTL data within Chongqing, China were taken as example, and the point of interest (POI) data and road network data were adopted to characterize the intensity of human activity type. Our results show that there is significant spatial variation in the effect of human activities to the NTL intensity, since the accuracy of fitted MGWR (adj.R2: 0.86 and 0.87 in 2018 and 2020, respectively; AICc: 4844.63 and 4623.27 in 2018 and 2020, respectively) is better than that of both the traditional ordinary least squares (OLS) model and the geographically weighted regression (GWR) model. Moreover, we found that almost all human activity features show strong spatial heterogeneity and their contribution to NTL intensity varies widely across different regions. For instance, the contribution of road network density is more homogeneous, while residential areas have an obviously heterogeneous distribution which is associated with house vacancy. In addition, the contributions of the commercial event and business also have a significant spatial heterogeneity distribution, but show a distinct decrement when facing the COVID-19 pandemic. Our study successfully explores the relationship between NTL intensity and human activity features considering the spatial heterogeneity, which aims to provide further insights into the future applications of NTL data.
Trichostatin A (TSA) possess histone deacetylase (HDAC) inhibitory potential, can reverse the deactivation of tumor suppressor genes and inhibit tumor cell proliferation. We evaluated the effect of ...TSA on HDAC expression, tumor cell proliferation, and cancer stem cells (CSCs) activities in pancreatic ductal adenocarnoma (PDAC) cells. The PDAC cell lines MiaPaCa-2 and PANC-1 were distinctly sensitive to TSA, with enhanced apoptosis, compared to SAHA. TSA or SAHA inhibited vimentin, HDACs 1, 7 and 8, upregulated E-cadherin mRNA and protein levels in the PDAC cells, and time-dependently downregulated Oct-4, Sox-2, and Nanog, as well as inhibited PDAC tumorsphere formation. TSA also induces accumulation of acetylated histones, while increasing histone 3 lysine 4 or 9 dimethylation levels in PDAC cells and enhancing the epigenetic activity of SAHA. The anti-CSCs effect of TSA was like that obtained by silencing HDAC-1 or 7 using siRNA, and enhances Gemcitabine activity. Our study highlights the molecular targetability of HDACs 1, 7, and 8, confirm their PDAC-CSCs maintaining role, and demonstrate that compared to SAHA, TSA modulates the epigenetically- mediated oncogenic activity of PDAC-CSCs, and potentiate Gemcitabine therapeutic activity, making a case for further exploration of TSA activity alone or in combination with Gemcitabine in PDAC therapy.
Alzheimer’s disease (AD), a neuropsychiatric disorder, continually arises in the elderly. To date, no targeted medications have been developed for AD. Early and fast diagnosis of AD plays a pivotal ...role in identifying potential AD patients, enabling timely medical interventions, and mitigating disease progression. Computer-aided diagnosis (CAD) becomes possible with the burgeoning of deep learning. However, the existing CAD models for processing 3D Alzheimer’s disease images usually have the problems of slow convergence, disappearance of gradient, and falling into local optimum. This makes the training of 3D diagnosis models need a lot of time, and the accuracy is often poor. In this paper, a novel 3D aggregated residual network with accelerated mirror descent optimization is proposed for diagnosing AD. First, a novel unbiased subgradient accelerated mirror descent (SAMD) optimization algorithm is proposed to speed up diagnosis network training. By optimizing the nonlinear projection process, our proposed algorithm can avoid the occurrence of the local optimum in the non-Euclidean distance metric. The most notable aspect is that, to the best of our knowledge, this is the pioneering attempt to optimize the AD diagnosis training process by improving the optimization algorithm. Then, we provide a rigorous proof of the SAMD’s convergence, and the convergence of SAMD is better than any existing gradient descent algorithms. Finally, we use our proposed SAMD algorithm to train our proposed 3D aggregated residual network architecture (ARCNN). We employed the ADNI dataset to train ARCNN diagnostic models separately for the AD vs. NC task and the sMCI vs. pMCI task, followed by testing to evaluate the disease diagnostic outcomes. The results reveal that the accuracy can be improved in diagnosing AD, and the training speed can be accelerated. Our proposed method achieves 95.4% accuracy in AD diagnosis and 79.9% accuracy in MCI diagnosis; the best results contrasted with several state-of-the-art diagnosis methods. In addition, our proposed SAMD algorithm can save about 19% of the convergence time on average in the AD diagnosis model compared with the gradient descent algorithms, which is very momentous in clinic.
Aim： A previous report shows that emodin extracted from the Chinese herbs rhubarb and giant knotweed rhizome can ameliorate the anticancer drug cisplatin-induced injury of HEK293 cells. In this ...study, we investigated whether and how emodin could protect renal tubular epithelial cells against cisplatin-induced nephrotoxicity in vitro. Methods： The viability and apoptosis of normal rat renal tubular epithelial cells （NRK-52E） were detected using formazan assay and flow cytometry analysis, respectively. The expression levels of cleaved caspase-3, autophagy maker LC3 1/11, and AMPK/mTOR signal- ing pathway-related proteins were measured with Western blot analysis. The changes of morphology and RFP-LC3 fluorescence were observed under microscopy. Results： Cisplatin （10-50 pmol/L） dose-dependently induced cell damage and apoptosis in NRK-52E cells, whereas emodin （10 and 100 pmol/L） significantly ameliorated cisplatin-induced cell damage, apoptosis and caspase-3 cleavage. Emodin dose-dependently increased LC3-11 levels and induced RFP-LC3-containing punctate structures in NRK-52E cells. Furthermore, the protective effects of emodin were abolished by bafilomycin A1 （10 nmol/L）, and mimicked by rapamycin （100 nmol/L）. Moreover, emodin increased the phosphorylation of AMPK and suppressed the phosphorylation of mTOR. The AMPK inhibitor compound C （10 pmol/L） not only abol- ished emodin-induced autophagy activation, but also emodin-induced anti-apoptotic effects. Conclusion： Emodin ameliorates cisplatin-induced apoptosis of rat renal tubular cells in vitro through modulating the AMPK/mTOR sig- naling pathways and activating autophagy. Emodin may have therapeutic potential for the prevention of cisplatin-induced nephro- toxicity.
Bacterial infections pose mounting public health concerns and cause an enormous medical and financial burden today. Rapid and sensitive detection of pathogenic bacteria at the point of care (POC) ...remains a paramount challenge. Here, we report a novel concept of bacteria-instructed click chemistry and employ it for POC microbial sensing. In this concept of bacteria-instructed click chemistry, we demonstrate for the first time that pathogenic bacteria can capture and reduce exogenous Cu2+ to Cu+ by leveraging their unique metabolic processes. The produced Cu+ subsequently acts as a catalyst to trigger the click reaction between gold nanoparticles (AuNPs) modified with azide and alkyne functional molecules, resulting in the aggregation of nanoparticles with a color change of the solution from red to blue. In this process, signal amplification from click chemistry is complied with the aggregation of functionalized AuNPs, thus presenting a robust colorimetric strategy for sensitive POC sensing of pathogenic bacteria. Notably, this colorimetric strategy is easily integrated in a smartphone app as a portable platform to achieve one-click detection in a mobile way. Moreover, with the help of the magnetic preseparation process, this smartphone app-assisted platform enables rapid (within 1 h) detection of Escherichia coli with high sensitivity (40 colony-forming units/mL) in the complex artificial sepsis blood samples, showing great potential for clinical early diagnosis of bacterial infections.
Cancer is a leading cause of death, affecting people in both developed and developing countries. It is a challenging disease due to its complicated pathophysiological mechanism. Many anti-cancer ...drugs are used to treat cancer and reduce mortality rates, but their toxicity limits their administration. Drugs made from natural products, which act as multi-targeted therapy, have the ability to target critical signaling proteins in different pathways. Natural compounds possess pharmacological activities such as anti-cancer activity, low toxicity, and minimum side effects.
is a medicinal plant whose extracts and phytochemicals are used to treat cancer, cardiovascular disorders, blood stasis, easing inflammation, edema, and pain.
's secondary metabolites target cancer's dysregulated pathways, causing cancer cell death. In this review, we focused on several ginsenosides extracted from
that have been evaluated against various cancer cell lines, with the aim of cancer treatment. Furthermore, an
investigation of these ginsenosides should be conducted to gain insight into the dysregulation of several pathways, followed by clinical trials for the potential and effective treatment of cancer.
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