Myocardial infarction is the most common form of acute coronary syndrome. Blockage of a coronary artery due to blood clotting leads to ischemia and subsequent cell death in the form of necrosis, ...apoptosis, necroptosis and ferroptosis. Revascularization by coronary artery bypass graft surgery or non-surgical percutaneous coronary intervention combined with pharmacotherapy is effective in relieving symptoms and decreasing mortality. However, reactive oxygen species (ROS) are generated from damaged mitochondria, NADPH oxidases, xanthine oxidase, and inflammation. Impairment of mitochondria is shown as decreased metabolic activity, increased ROS production, membrane permeability transition, and release of mitochondrial proteins into the cytoplasm. Oxidative stress activates Nrf2 transcription factor, which in turn mediates the expression of mitofusin 2 (Mfn 2) and proteasomal genes. Increased expression of Mfn2 and inhibition of mitochondrial fission due to decreased Drp1 protein by proteasomal degradation contribute to mitochondrial hyperfusion. Damaged mitochondria can be removed by mitophagy via Parkin or p62 mediated ubiquitination. Mitochondrial biogenesis compensates for the loss of mitochondria, but requires mitochondrial DNA replication and initiation of transcription or translation of mitochondrial genes. Experimental evidence supports a role of Nrf2 in mitophagy, via up-regulation of PINK1 or p62 gene expression; and in mitochondrial biogenesis, by influencing the expression of PGC-1α, NResF1, NResF2, TFAM and mitochondrial genes. Oxidative stress causes Nrf2 activation via Keap1 dissociation, de novo protein translation, and nuclear translocation related to inactivation of GSK3β. The mechanism of Keap 1 mediated Nrf2 activation has been hijacked for Nrf2 activation by small molecules derived from natural products, some of which have been shown capable of mitochondrial protection. Multiple lines of evidence support the importance of Nrf2 in protecting mitochondria and preserving or renewing energy metabolism following tissue injury.
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•Myocardial ischemia and reperfusion produce ROS via mitochondria and oxidases.•ROS activates Nrf2 transcript factor by protein translation or protein stabilization.•Nrf2 increases Mfn2, PINK1, p62, PGC-1α, NResF1 and mitochondrial gene expression.•Nrf2 aids in regulation of mitochondrial hyerfusion, mitophagy and biogenesis.•Nrf2 inducers show mitochondrial protection in animal models of cardiac injury.
Myocardial ischemia or reperfusion increases the generation of reactive oxygen species (ROS) from damaged mitochondria, NADPH oxidases, xanthine oxidase, and inflammation. ROS can be removed by eight ...endogenous antioxidant and redox systems, many components of which are expressed under the influence of the activated Nrf2 transcription factor. Transcriptomic profiling, sequencing of Nrf2-bound DNA, and Nrf2 gene knockout studies have revealed the power of Nrf2 beyond the antioxidant and detoxification response, from tissue recovery, repair, and remodeling, mitochondrial turnover, and metabolic reprogramming to the suppression of proinflammatory cytokines. Multifaceted regulatory mechanisms for Nrf2 protein levels or activity have been mapped to its functional domains, Nrf2-ECH homology (Neh)1–7. Oxidative stress activates Nrf2 via nuclear translocation, de novo protein translation, and increased protein stability due to removal of the Kelch-like ECH-associated protein 1 (Keap1) checkpoint, or the inactivation of β-transducin repeat-containing protein (β-TrCP), or Hmg-CoA reductase degradation protein 1 (Hrd1). The promise of small-molecule Nrf2 inducers from natural products or derivatives is discussed here. Experimental evidence is presented to support Nrf2 as a lead target for drug development to further improve the treatment outcome for myocardial infarction (MI).
Myocardial ischemic reperfusion leads to increased oxidative stress and cell death by necrosis, apoptosis, and necroptosis.During oxidative stress, the activity of Nrf2 as a transcription factor is regulated by protein stability, translation, nuclear localization, and protein–protein interactions.The Nrf2 transcription factor controls the expression of key components in eight antioxidant and redox systems for the removal of reactive oxygen species.The genes under the influence of Nrf2 status suggest its involvement in mitochondrial turnover, tissue recovery, repair, or remodeling, metabolic reprogramming, and the limitation of proinflammatory cytokines.Small-molecule Nrf2 inducers have shown promise in eliciting cardiac protection and inhibiting inflammation in experimental animals, suggesting a future direction for the development of nontoxic Nrf2 inducers using modern technologies.
The NFE2L2 gene encodes the transcription factor Nrf2 best known for regulating the expression of antioxidant and detoxification genes. Gene knockout approaches have demonstrated its universal ...cytoprotective features. While Nrf2 has been the topic of intensive research in cancer biology since its discovery in 1994, understanding the role of Nrf2 in cardiovascular disease has just begun. The literature concerning Nrf2 in experimental models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, heart failure, and diabetes supports its cardiac protective character. In addition to antioxidant and detoxification genes, Nrf2 has been found to regulate genes participating in cell signaling, transcription, anabolic metabolism, autophagy, cell proliferation, extracellular matrix remodeling, and organ development, suggesting that Nrf2 governs damage resistance as well as wound repair and tissue remodeling. A long list of small molecules, most derived from natural products, have been characterized as Nrf2 inducers. These compounds disrupt Keap1-mediated Nrf2 ubquitination, thereby prohibiting proteasomal degradation and allowing Nrf2 protein to accumulate and translocate to the nucleus, where Nrf2 interacts with sMaf to bind to ARE in the promoter of genes. Recently alternative mechanisms driving Nrf2 protein increase have been revealed, including removal of Keap1 by autophagy due to p62/SQSTM1 binding, inhibition of βTrCP or Synoviolin/Hrd1-mediated ubiquitination of Nrf2, and de novo Nrf2 protein translation. We review here a large volume of literature reporting historical and recent discoveries about the function and regulation of Nrf2 gene. Multiple lines of evidence presented here support the potential of dialing up the Nrf2 pathway for cardiac protection in the clinic.
Summary
Submergence is an abiotic stress that limits agricultural production world‐wide. Plants sense oxygen levels during submergence and postsubmergence reoxygenation and modulate their responses. ...Increasing evidence suggests that completely submerged plants are often exposed to low‐light stress, owing to the depth and turbidity of the surrounding water; however, how light availability affects submergence tolerance remains largely unknown.
Here, we showed that Arabidopsis thaliana MYB DOMAIN PROTEIN30 (MYB30) is an important transcription factor that integrates light signaling and postsubmergence stress responses.
MYB DOMAIN PROTEIN30 protein abundance decreased upon submergence and accumulated during reoxygenation. Under submergence conditions, CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1), a central regulator of light signaling, caused the ubiquitination and degradation of MYB30. In response to desubmergence, however, light‐induced MYB30 interacted with MYC2, a master transcription factor involved in jasmonate signaling, and activated the expression of the VITAMIN C DEFECTIVE1 (VTC1) and GLUTATHIONE SYNTHETASE1 (GSH1) gene families to enhance antioxidant biosynthesis. Consistent with this, the myb30 knockout mutant showed increased sensitivity to submergence, which was partially rescued by overexpression of VTC1 or GSH1.
Thus, our findings uncover the mechanism by which the COP1‐MYB30 module integrates light signals with cellular oxidative homeostasis to coordinate plant responses to postsubmergence stress.
Metal-support interaction is of great significance for catalysis as it can induce charge transfer between metal and support, tame electronic structure of supported metals, impact adsorption energy of ...reaction intermediates, and eventually change the catalytic performance. Here, we report the metal size-dependent charge transfer reversal, that is, electrons transfer from platinum single atoms to sulfur-doped carbons and the carbon supports conversely donate electrons to Pt when their size is expanded to ~1.5 nm cluster. The electron-enriched Pt nanoclusters are far more active than electron-deficient Pt single atoms for catalyzing hydrogen evolution reaction, exhibiting only 11 mV overpotential at 10 mA cm
and a high mass activity of 26.1 A mg
at 20 mV, which is 38 times greater than that of commercial Pt/C. Our work manifests that the manipulation of metal size-dependent charge transfer between metal and support opens new avenues for developing high-active catalysts.
Upper gastrointestinal cancers (including oesophageal cancer and gastric cancer) are the most common cancers worldwide. Artificial intelligence platforms using deep learning algorithms have made ...remarkable progress in medical imaging but their application in upper gastrointestinal cancers has been limited. We aimed to develop and validate the Gastrointestinal Artificial Intelligence Diagnostic System (GRAIDS) for the diagnosis of upper gastrointestinal cancers through analysis of imaging data from clinical endoscopies.
This multicentre, case-control, diagnostic study was done in six hospitals of different tiers (ie, municipal, provincial, and national) in China. The images of consecutive participants, aged 18 years or older, who had not had a previous endoscopy were retrieved from all participating hospitals. All patients with upper gastrointestinal cancer lesions (including oesophageal cancer and gastric cancer) that were histologically proven malignancies were eligible for this study. Only images with standard white light were deemed eligible. The images from Sun Yat-sen University Cancer Center were randomly assigned (8:1:1) to the training and intrinsic verification datasets for developing GRAIDS, and the internal validation dataset for evaluating the performance of GRAIDS. Its diagnostic performance was evaluated using an internal and prospective validation set from Sun Yat-sen University Cancer Center (a national hospital) and additional external validation sets from five primary care hospitals. The performance of GRAIDS was also compared with endoscopists with three degrees of expertise: expert, competent, and trainee. The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of GRAIDS and endoscopists for the identification of cancerous lesions were evaluated by calculating the 95% CIs using the Clopper-Pearson method.
1 036 496 endoscopy images from 84 424 individuals were used to develop and test GRAIDS. The diagnostic accuracy in identifying upper gastrointestinal cancers was 0·955 (95% CI 0·952–0·957) in the internal validation set, 0·927 (0·925–0·929) in the prospective set, and ranged from 0·915 (0·913–0·917) to 0·977 (0·977–0·978) in the five external validation sets. GRAIDS achieved diagnostic sensitivity similar to that of the expert endoscopist (0·942 95% CI 0·924–0·957 vs 0·945 0·927–0·959; p=0·692) and superior sensitivity compared with competent (0·858 0·832–0·880, p<0·0001) and trainee (0·722 0·691–0·752, p<0·0001) endoscopists. The positive predictive value was 0·814 (95% CI 0·788–0·838) for GRAIDS, 0·932 (0·913–0·948) for the expert endoscopist, 0·974 (0·960–0·984) for the competent endoscopist, and 0·824 (0·795–0·850) for the trainee endoscopist. The negative predictive value was 0·978 (95% CI 0·971–0·984) for GRAIDS, 0·980 (0·974–0·985) for the expert endoscopist, 0·951 (0·942–0·959) for the competent endoscopist, and 0·904 (0·893–0·916) for the trainee endoscopist.
GRAIDS achieved high diagnostic accuracy in detecting upper gastrointestinal cancers, with sensitivity similar to that of expert endoscopists and was superior to that of non-expert endoscopists. This system could assist community-based hospitals in improving their effectiveness in upper gastrointestinal cancer diagnoses.
The National Key R&D Program of China, the Natural Science Foundation of Guangdong Province, the Science and Technology Program of Guangdong, the Science and Technology Program of Guangzhou, and the Fundamental Research Funds for the Central Universities.
Noncoding RNAs (ncRNAs) represent a large segment of the human transcriptome and have been shown to play important roles in cellular physiology and disease pathogenesis. Increasing evidence on the ...functional roles of ncRNAs in cancer progression emphasizes the potential of ncRNAs for cancer treatment. Here, we summarize the roles of ncRNAs in disease relapse and resistance to current standard chemotherapy and radiotherapy; the current research progress on ncRNAs for clinical and/or potential translational applications, including the identification of ncRNAs as therapeutic targets; therapeutic approaches for ncRNA targeting; and ncRNA delivery strategies in potential clinical translation. Several ongoing clinical trials of novel RNA-based therapeutics were also emphasized. Finally, we discussed the perspectives and obstacles to different target combinations, delivery strategies, and system designs for ncRNA application. The next approved nucleic acid drug to treat cancer patients may realistically be on the horizon.
N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects the fates of modified RNAs, ...including their stability, splicing, and/or translation, and thus plays important roles in posttranscriptional regulation. To date, m6A methyltransferases have been reported to execute m6A deposition on distinct RNAs by their own or forming different complexes with additional partner proteins. In this review, we summarize the function of these m6A methyltransferases or complexes in regulating the key genes and pathways of cancer biology. We also highlight the progress in the use of m6A methyltransferases in mediating therapy resistance, including chemotherapy, targeted therapy, immunotherapy and radiotherapy. Finally, we discuss the current approaches and clinical potential of m6A methyltransferase-targeting strategies. Keywords: m6A, m6A methyltransferase, Cancer, Therapy resistance, Drug discovery
This paper analyzes the power mechanism of tourism to help rural revitalization by elaborating the core content of rural tourism and rural revitalization. It also combines the advantages of the Lasso ...regression method and ridge regression method to form a flexible regression network model, which is used to predict the amount of tourists and tourists’ demand for rural tourism so as to put forward the implementation path of the tourism industry to help rural revitalization development. To verify the effectiveness of the proposed algorithm, data analysis is carried out in rural areas of L city as an example. The results show that compared with the Lasso regression model, the average absolute percentage error decreased by 2.41%, the average absolute error decreased by 2,233, and the root-mean-square error decreased by 2,967, which indicates that the elasticity regression network prediction model has a stronger generalization ability and a better prediction ability, and it can predict the number of tourists more accurately, and it can provide data for the tourism industry to contribute to rural revitalization and development. Reference.
Accelerating the data acquisition of dynamic magnetic resonance imaging leads to a challenging ill-posed inverse problem, which has received great interest from both the signal processing and machine ...learning communities over the last decades. The key ingredient to the problem is how to exploit the temporal correlations of the MR sequence to resolve aliasing artifacts. Traditionally, such observation led to a formulation of an optimization problem, which was solved using iterative algorithms. Recently, however, deep learning-based approaches have gained significant popularity due to their ability to solve general inverse problems. In this paper, we propose a unique, novel convolutional recurrent neural network architecture which reconstructs high quality cardiac MR images from highly undersampled k-space data by jointly exploiting the dependencies of the temporal sequences as well as the iterative nature of the traditional optimization algorithms. In particular, the proposed architecture embeds the structure of the traditional iterative algorithms, efficiently modeling the recurrence of the iterative reconstruction stages by using recurrent hidden connections over such iterations. In addition, spatio-temporal dependencies are simultaneously learnt by exploiting bidirectional recurrent hidden connections across time sequences. The proposed method is able to learn both the temporal dependence and the iterative reconstruction process effectively with only a very small number of parameters, while outperforming current MR reconstruction methods in terms of reconstruction accuracy and speed.
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