Pre-eclampsia (PE) is a dangerous pathological status that occurs during pregnancy and is a leading reason for both maternal and fetal death. Autophagy is necessary for cellular survival in the face ...of environmental stress as well as cellular homeostasis and energy management. Aberrant microRNA (miRNA) expression is crucial in the pathophysiology of PE. Although studies have shown that miRNA (miR)-190a-3p function is tissue-specific, the precise involvement of miR-190a-3p in PE has yet to be determined. We discovered that miR-190a-3p was significantly lower and death-associated protein kinase 1 (DAPK1) was significantly higher in PE placental tissues compared to normal tissues, which is consistent with the results in cells. The luciferase analyses demonstrated the target-regulatory relationship between miR-190a-3p and DAPK1. The inhibitory effect of miR-190a-3p on autophagy was reversed by co-transfection of si-DAPK1 and miR-190a-3p inhibitors. Thus, our data indicate that the hypoxia-dependent miR-190a-3p/DAPK1 regulatory pathway is implicated in the development and progression of PE by promoting autophagy in trophoblast cells.
To improve the effect of English learning in the context of smart education, this study combines speech coding to improve the intelligent speech recognition algorithm, builds an intelligent English ...learning system, combines the characteristics of human ears, and studies a coding strategy of a psychoacoustic masking model based on the characteristics of human ears. Moreover, this study analyzes in detail the basic principles and implementation process of the psychoacoustic model coding strategy based on the characteristics of the human ear and completes the channel selection by calculating the masking threshold. In addition, this study verifies the effectiveness of the algorithm in this study through simulation experiments. Finally, this study builds a smart speech recognition system based on this model and uses simulation experiments to verify the effect of smart speech recognition on English learning. To improve the voice recognition effect of smart speech, band-pass filtering and envelope detection adopt the gammatone filter bank and Meddis inner hair cell model in the mathematical model of the cochlear system; at the same time, the masking effect model of psychoacoustics is introduced in the channel selection stage to prevent noise. Sex has been improved, and the recognition effect of smart voice has been improved. The analysis shows that the intelligent speech recognition system proposed in this study can effectively improve the effect of English learning. In particular, it has a great effect on improving the effect of oral learning.
Ischemic stroke is a leading cause of morbidity and mortality worldwide. Resident microglia are the principal immune cells of the brain, and the first to respond to the pathophysiological changes ...induced by ischemic stroke. Traditionally, it has been thought that microglial activation is deleterious in ischemic stroke, and therapies to suppress it have been intensively explored. However, increasing evidence suggests that microglial activation is also critical for neurogenesis, angiogenesis, and synaptic remodeling, thereby promoting functional recovery after cerebral ischemia. Here, we comprehensively review the dual role of microglia during the different phases of ischemic stroke, and the possible mechanisms controlling the post-ischemic activity of microglia. In addition, we discuss the dynamic interactions between microglia and other cells, such as neurons, astrocytes, oligodendrocytes, and endothelial cells within the brain parenchyma and the neurovascular unit.
Activation of the phagocytosis of macrophages to tumor cells is an attractive strategy for cancer immunotherapy, but the effectiveness is limited by the fact that many tumor cells express an ...increased level of anti‐phagocytic signals (e.g., CD47 molecules) on their surface. To promote phagocytosis of macrophages, a pro‐phagocytic nanoparticle (SNPACALR&aCD47) that concurrently carries CD47 antibody (aCD47) and a pro‐phagocytic molecule calreticulin (CALR) is constructed to simultaneously modulate the phagocytic signals of macrophages. SNPACALR&aCD47 can achieve targeted delivery to tumor cells by specifically binding to the cell‐surface CD47 and block the CD47‐SIRPα pathway to inhibit the “don't eat me” signal. Tumor cell‐targeted delivery increases the exposure of recombinant CALR on the cell surface and stimulates an “eat me” signal. Simultaneous modulation of the two signals enhances the phagocytosis of 4T1 tumor cells by macrophages, which leads to significantly improved anti‐tumor efficacy in vivo. The findings demonstrate that the concurrent blockade of anti‐phagocytic signals and activation of pro‐phagocytic signals can be effective in macrophage‐mediated cancer immunotherapy.
The phagocytosis of tumor cells by macrophages requires both the coordinated disruption of “don't eat me” signals and simultaneous activation of “eat me” signals. Herein, a nanoparticle‐enabled strategy is proposed to concurrently modulate the cell surface levels of calreticulin (CALR) and CD47 to improve macrophage phagocytosis for improved cancer immunotherapy.
Abstract
Ischemic stroke is caused primarily by an interruption in cerebral blood flow, which induces severe neural injuries, and is one of the leading causes of death and disability worldwide. Thus, ...it is of great necessity to further detailly elucidate the mechanisms of ischemic stroke and find out new therapies against the disease. In recent years, efforts have been made to understand the pathophysiology of ischemic stroke, including cellular excitotoxicity, oxidative stress, cell death processes, and neuroinflammation. In the meantime, a plethora of signaling pathways, either detrimental or neuroprotective, are also highly involved in the forementioned pathophysiology. These pathways are closely intertwined and form a complex signaling network. Also, these signaling pathways reveal therapeutic potential, as targeting these signaling pathways could possibly serve as therapeutic approaches against ischemic stroke. In this review, we describe the signaling pathways involved in ischemic stroke and categorize them based on the pathophysiological processes they participate in. Therapeutic approaches targeting these signaling pathways, which are associated with the pathophysiology mentioned above, are also discussed. Meanwhile, clinical trials regarding ischemic stroke, which potentially target the pathophysiology and the signaling pathways involved, are summarized in details. Conclusively, this review elucidated potential molecular mechanisms and related signaling pathways underlying ischemic stroke, and summarize the therapeutic approaches targeted various pathophysiology, with particular reference to clinical trials and future prospects for treating ischemic stroke.
Conventional tumor markers for non-invasive diagnosis of gastric cancer (GC) exhibit insufficient sensitivity and specificity to facilitate detection of early gastric cancer (EGC). We aimed to ...identify EGC-specific exosomal lncRNA biomarkers that are highly sensitive and stable for the non-invasive diagnosis of EGC. Hence, in the present study, exosomes from the plasma of five healthy individuals and ten stage I GC patients and from culture media of four human primary stomach epithelial cells and four gastric cancer cells (GCCs) were isolated. Exosomal RNA profiling was performed using RNA sequencing to identify EGC-specific exosomal lncRNAs. A total of 79 and 285 exosomal RNAs were expressed at significantly higher levels in stage I GC patients and GCCs, respectively, than that in normal controls. Through combinational analysis of the RNA sequencing results, we found two EGC-specific exosomal lncRNAs, lncUEGC1 and lncUEGC2, which were further confirmed to be remarkably up-regulated in exosomes derived from EGC patients and GCCs. Furthermore, stability testing demonstrates that almost all the plasma lncUEGC1 was encapsulated within exosomes and thus protected from RNase degradation. The diagnostic accuracy of exosomal lncUEGC1 was evaluated, and lncUEGC1 exhibited AUC values of 0.8760 and 0.8406 in discriminating EGC patients from healthy individuals and those with premalignant chronic atrophic gastritis, respectively, which was higher than the diagnostic accuracy of carcinoembryonic antigen. Consequently, exosomal lncUEGC1 may be promising in the development of highly sensitive, stable, and non-invasive biomarkers for EGC diagnosis.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a low survival rate. The therapeutic effect of chemotherapy and immunotherapy for PDAC is disappointing due to the ...presence of dense tumor stroma and immunosuppressive cells in the tumor microenvironment (TME). Herein, a tumor‐penetrating nanoparticle is reported to modulate the deep microenvironment of PDAC for improved chemoimmunotherapy. The tumor pH‐sensitive polymer is synthesized by conjugating N,N‐dipentylethyl moieties and monomethoxylpoly(ethylene glycol) onto PAMAM dendrimer, into whose cavity a hydrophobic gemcitabine (Gem) prodrug is accommodated. They self‐assemble into nanoparticles (denoted as SPN@Pro‐Gem) with the size around 120 nm at neutral pH, but switch into small particles (≈8 nm) at tumor site to facilitate deep delivery of Gem into the tumor parenchyma. In addition to killing cancer cells that resided deeply in the tumor tissue, SPN@Pro‐Gem could modulate the TME by reducing the abundance of tumor‐associated macrophages and myeloid‐derived suppressor cells as well as upregulating the expression level of PD‐L1 of tumor cells. This collectively facilitates the infiltration of cytotoxic T cells into the tumors and renders checkpoint inhibitors more effective in previously unresponsive PDAC models. This study reveals a promising strategy for improving the chemoimmunotherapy of pancreatic cancer.
A tumor penetrating nanomedicine SPN@Pro‐Gem is designed for deep tumor delivery of gemcitabine prodrug (Pro‐Gem) through tumor pH‐sensitive size switching. The SPN@Pro‐Gem not only potentiates chemotherapy of Gem, but also reduces the infiltration of immunosuppressive cells and upregulates PD‐L1 expression on tumor cells. Combining SPN@Pro‐Gem with anti‐PD‐1 antibody improves the chemoimmunotherapy of pancreatic cancer.
In response to various types of environmental and cellular stress, microglia rapidly activate and exhibit either pro- or anti-inflammatory phenotypes to maintain tissue homeostasis. Activation of ...microglia can result in changes in morphology, phagocytosis capacity, and secretion of cytokines. Furthermore, microglial activation also induces changes to cellular energy demand, which is dependent on the metabolism of various metabolic substrates including glucose, fatty acids, and amino acids. Accumulating evidence demonstrates metabolic reprogramming acts as a key driver of microglial immune response. For instance, microglia in pro-inflammatory states preferentially use glycolysis for energy production, whereas, cells in anti-inflammatory states are mainly powered by oxidative phosphorylation and fatty acid oxidation. In this review, we summarize recent findings regarding microglial metabolic pathways under physiological and pathological circumtances. We will then discuss how metabolic reprogramming can orchestrate microglial response to a variety of central nervous system pathologies. Finally, we highlight how manipulating metabolic pathways can reprogram microglia towards beneficial functions, and illustrate the therapeutic potential for inflammation-related neurological diseases.
In this paper, a novel dual-band dual-polarized array antenna with low frequency ratio and integrated filtering characteristics is proposed. By employing a dual-mode stub-loaded resonator (SLR) to ...feed and tune with two patches, the two feed networks for each polarization can be combined, resulting in the reduction of the feed networks and the input ports. In addition, owing to the native dual resonant features of the SLR, the proposed antenna exhibits second-order filtering characteristics with improved bandwidth and out-of-band rejections. The antenna is synthesized and the design methodology is explained. The coupling coefficients between the SLR and the patches are investigated. To verify the design concept, a C-/X-band element and a 2 \times 2 array are optimized and prototyped. Measured results agree well with the simulations, showing good performance in terms of bandwidth, filtering, harmonic suppression, and radiation at both bands. Such an integrated array design can be used to simplify the feed of a reflector antenna. To prove the concept, a paraboloid reflector fed by the proposed array is conceived and measured directivities of 24.6 dBi (24.7 dBi) and 28.6 dBi (29.2 dBi) for the X-polarization (Y-polarization) are obtained for the low- and high-band operations, respectively.
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