Abstract
A novel coronavirus disease (COVID-19), caused by infection with SARS-CoV-2, has swept across 31 provinces in China and over 40 countries worldwide. The transition from first symptoms to ...acute respiratory distress syndrome (ARDS) is highly likely to be due to uncontrolled cytokine release. There is an urgent need to identify safe and effective drugs for treatment. Chloroquine (CQ) exhibits a promising inhibitory effect. However, the clinical use of CQ can cause severe side effects. We propose that hydroxychloroquine (HCQ), which exhibits an antiviral effect highly similar to that of CQ, could serve as a better therapeutic approach. HCQ is likely to attenuate the severe progression of COVID-19, inhibiting the cytokine storm by suppressing T cell activation. It has a safer clinical profile and is suitable for those who are pregnant. It is cheaper and more readily available in China. We herein strongly urge that clinical trials are performed to assess the preventive effects of HCQ in both disease infection and progression.
Hypoxia and the acidic microenvironment play a vital role in tumor metastasis and angiogenesis, generally compromising the chemotherapeutic efficacy. This provides a tantalizing angle for the design ...of platinum(IV) prodrugs for the effective and selective killing of solid tumors. Herein, two carbonic anhydrase IX (CAIX)‐targeting platinum(IV) prodrugs have been developed, named as CAIXplatins. Based on their strong affinity for and inhibition of CAIX, CAIXplatins can not only overcome hypoxia and the acidic microenvironment, but also inhibit metabolic pathways of hypoxic cancer cells, resulting in a significantly enhanced therapeutic effect on hypoxic MDA‐MB‐231 tumors both in vitro and in vivo compared with cisplatin/oxaliplatin, accompanied with excellent anti‐metastasis and anti‐angiogenesis activities. Furthermore, the cancer selectivity indexes of CAIXplatins are 70–90 times higher than those of cisplatin/oxaliplatin with effectively alleviated side‐effects.
Tumor microenvironment and metabolism regulation can be achieved by targeting carbonic anhydrase IX with platinum(IV) prodrugs, termed CAIXplatins. This strategy could be used to treat hypoxic and aggressive tumors. The advantages of CAIXplatins in comparison to cisplatin/oxaliplatin include the greatly increased cancer selectivity index, enhanced therapeutic efficiency, reduced level of side‐effects, as well as the excellent anti‐angiogenesis activity.
Abstract
High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung ...cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.
Summary
Cataract is one of the most important causes of blindness worldwide, with age‐related cataract being the most common one. Agents preventing cataract formation are urgently required. ...Substantial evidences point out aggravated oxidative stress as a vital factor for cataract formation. Nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2)/Kelch‐like erythroid‐cell‐derived protein with CNC homology (ECH)‐associated protein 1 (Keap1) system is considered as one of the main cellular defense mechanisms against oxidative stresses. This review discusses the role of Nrf2 pathway in the prevention of cataracts and highlights that Nrf2 suppressors may augment oxidative stress of the lens, and Nrf2 inducers may decrease the oxidative stress and prevent the cataract formation. Thus, Nrf2 may serve as a promising therapeutic target for cataract treatment.
The aging of population has become an issue of great concern because of its rapid increase. Aging is an important risk factor of many chronic diseases. Resveratrol could be found in many foods, such ...as grapes, red wine, peanuts, and blueberries. Many studies reported that resveratrol possessed various bioactivities, such as antioxidant, anti-inflammatory, cardiovascular protection, anticancer, antidiabetes mellitus, antiobesity, neuroprotection, and antiaging effects. The antiaging mechanisms of resveratrol were mainly ameliorating oxidative stress, relieving inflammatory reaction, improving mitochondrial function, and regulating apoptosis. Resveratrol could be an effective and safe compound for the prevention and treatment of aging and age-related diseases. In this review, we summarize the effects of resveratrol on aging, life extension, and several age-related diseases, with special attention paid to the mechanisms of antiaging action.
As big data mining technology is known to directly change the development direction and internal management, and the behaviour of college students’ political wisdom network has also changed ...significantly, hence the application and analysis of data mining technology becomes indispensable. Bidirectional gated cyclic cell network can solve the gradient disappearance or gradient explosion existing in traditional models, but can also make up for the deficiency of extracting the contextual semantic information of long text effectively. Using the combination of big data-based mining technology and college students’ network ideology and politics, this paper designed a set of BiGRU_Attention framework based on college students’ network ideological wisdom framework and adopted big data mining technology to collect data. First, according to the Internet technology and information collection, design a complete set of college students’ ideological wisdom framework. Then, the GRU structure, BiGRU framework and Attention mechanism combined with BiGRU_Attention model are introduced. Meanwhile, Word2Vec is used to train the Chinese word vector. Finally, the BiGRU_Attention proposed in this paper is compared with several models. Experimental results show that the BiGRU_Attention proposed in this paper has a better accuracy of 96.32% over other models. The experimental results also show that the framework of ideological and political intelligence proposed in this paper can be applied to the campus environment of college students.
This paper investigates a dynamic event-triggered distributed observer for linear systems including two groups of local observers: one can access the local outputs and another cannot. By the ...detectability decomposition, the proposed observer contains a detectable sub-state (DSS) observer and a distributed undetectable sub-state (USS) observer. The dynamic event-triggered mechanism (DETM) for the outputs only requires a copy of the DSS observer with low dimension. Besides, only the USS estimate is transmitted to the neighbors which can reduce the communication burden. Positive minimum inter-event times are prescribed previously in the DETMs, and piece-wise dynamics for internal dynamic variables are employed. By modeling the error systems as hybrid systems, the exponential stability of the proposed observer is assured with the utilization of time-triggering method and event-triggering method.
•A dynamic event-triggered distributed observer is proposed.•Outputs and estimates are transmitted by dynamic event-triggering mechanisms.•Positive minimum inter-event time is prescribed previously.•The exponential stability of the proposed observer is obtained.
Metabolic diseases are serious threats to public health and related to gut microbiota. Probiotics, prebiotics, synbiotics, and postbiotics (PPSP) are powerful regulators of gut microbiota, thus ...possessing prospects for preventing metabolic diseases. Therefore, the effects and mechanisms of PPSP on metabolic diseases targeting gut microbiota are worth discussing and clarifying. Generally, PPSP benefit metabolic diseases management, especially obesity and type 2 diabetes mellitus. The underlying gut microbial-related mechanisms are mainly the modulation of gut microbiota composition, regulation of gut microbial metabolites, and improvement of intestinal barrier function. Moreover, clinical trials showed the benefits of PPSP on patients with metabolic diseases, while the clinical strategies for gestational diabetes mellitus, optimal formula of synbiotics and health benefits of postbiotics need further study. This review fully summarizes the relationship between probiotics, prebiotics, synbiotics, postbiotics, and metabolic diseases, presents promising results and the one in dispute, and especially attention is paid to illustrates potential mechanisms and clinical effects, which could contribute to the next research and development of PPSP.
BackgroundMetabolically healthy obese phenotype (MHO) refers to obese individuals with absence of metabolic abnormalities such as dyslipidaemia, insulin resistance and hypertension. Many studies ...reported the long-term prognosis of MHO on diseases and mortality with inconsistent results.MethodsWe performed a meta-analysis to assess the risks of cardiovascular (CV) events and all-cause mortality for MHO individuals. Original prospective observational studies were searched in Medline, EMBASE, Web of Science and Cochrane library up to 30 September 2015. In this meta-analysis, the relative risk (RR) calculated on the basis of the incident number of disease events and deaths in participants and the corresponding multivariable-adjusted HR were both extracted to calculate pooled risk estimates. A random-effects model was used if there was heterogeneity among studies; otherwise, the fixed-effects model was used.Results22 prospective studies, involving 584 799 participants, were archived in the analyses. With metabolically healthy normal weight as the reference, the MHO phenotype was associated with a higher risk of CV events (RR 1.50, 95% CI 1.27 to 1.77; HR 1.60, 95% CI 1.38 to 1.84). However, MHO individuals were not associated with increased risk of all-cause mortality (RR 1.18, 95% CI 0.83 to 1.66; HR 1.07, 95% CI 0.92 to 1.25).ConclusionsThe meta-analysis confirms a positive association between a metabolically healthy obese phenotype and the risk of CV events. However, higher risk for all-cause mortality is not evident in metabolically healthy obese individuals.
The digestive system cancers are leading cause of cancer‐related death worldwide, and have high risks of morbidity and mortality. More and more long non‐coding RNAs (lncRNAs) have been studied to be ...abnormally expressed in cancers and play a key role in the process of digestive system tumour progression. Plasmacytoma variant translocation 1 (PVT1) seems fairly novel. Since 1984, PVT1 was identified to be an activator of MYC in mice. Its role in human tumour initiation and progression has long been a subject of interest. The expression of PVT1 is elevated in digestive system cancers and correlates with poor prognosis. In this review, we illustrate the various functions of PVT1 during the different stages in the complex process of digestive system tumours (including oesophageal cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma and pancreatic cancer). The growing evidence shows the involvement of PVT1 in both proliferation and differentiation process in addition to its involvement in epithelial to mesenchymal transition (EMT). These findings lead us to conclude that PVT1 promotes proliferation, survival, invasion, metastasis and drug resistance in digestive system cancer cells. We will also discuss PVT1's potential in diagnosis and treatment target of digestive system cancer. There was a great probability PVT1 could be a novel biomarker in screening tumours, prognosis biomarkers and future targeted therapy to improve the survival rate in cancer patients.
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