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Merged inside sarcoma manages Genetic replication timing and kinetics.
Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC (300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis, insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor (INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3β signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC (250 μmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC's beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model. Long-term (90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3β pathway.Insulin therapy plays an essential role in the treatment of diabetes mellitus. However, frequent injections required to effectively control the glycemic levels lead to substantial inconvenience and low patient compliance. In order to improve insulin delivery, many efforts have been made, such as developing the nanoparticles (NPs)-based release systems and oral insulin. Although some improvements have been achieved, the ultimate results are still unsatisfying and none of insulin-loaded NPs systems have been approved for clinical use so far. Recently, nano‒protein interactions and protein corona formation have drawn much attention due to their negative influence on the in vivo fate of NPs systems. As the other side of a coin, such interactions can also be used for constructing advanced drug delivery systems. Herein, we aim to provide an insight into the advance and flaws of various NPs-based insulin delivery systems. Particularly, an interesting discussion on nano‒protein interactions and its potentials for developing novel insulin delivery systems is initiated.S-adenosylmethionine (SAM) is ubiquitous in living organisms and is of great significance in metabolism as a cofactor of various enzymes. Methyltransferases (MTases), a major group of SAM-dependent enzymes, catalyze methyl transfer from SAM to C, O, N, and S atoms in small-molecule secondary metabolites and macromolecules, including proteins and nucleic acids. MTases have long been a hot topic in biomedical research because of their crucial role in epigenetic regulation of macromolecules and biosynthesis of natural products with prolific pharmacological moieties. However, another group of SAM-dependent enzymes, sharing similar core domains with MTases, can catalyze nonmethylation reactions and have multiple functions. Herein, we mainly describe the nonmethylation reactions of SAM-dependent enzymes in biosynthesis. First, we compare the structural and mechanistic similarities and distinctions between SAM-dependent MTases and the non-methylating SAM-dependent enzymes. Second, we summarize the reactions catalyzed by these enzymes and explore the mechanisms. Finally, we discuss the structural conservation and catalytical diversity of class I-like non-methylating SAM-dependent enzymes and propose a possibility in enzymes evolution, suggesting future perspectives for enzyme-mediated chemistry and biotechnology, which will help the development of new methods for drug synthesis.The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-γ (IFN-γ), macrophages, and T cell-dependent immune responses, play a vital role in tumor growth by affecting the HH signaling pathway. Moreover, inhibition of proliferating cancer-associated fibroblasts (CAFs) and inflammatory factors can normalize the TME by suppressing HH signaling. Furthermore, aberrant HH signaling activation is favorable to both the proliferation of cancer stem cells (CSCs) and the drug resistance of gastrointestinal tumors. This review discusses the current understanding of the role and mechanism of aberrant HH signaling activation in gastrointestinal carcinogenesis, the gastrointestinal TME, tumor immune tolerance and drug resistance and highlights the underlying therapeutic opportunities.Redox-altered plasticity refers to redox-dependent reversible changes in synaptic plasticity via altering functions of key proteins, such as N-methyl-d-aspartate receptor (NMDAR). Age-related cognitive disorders includes Alzheimer's disease (AD), vascular dementia (VD), and age-associated memory impairment (AAMI). Based on the critical role of NMDAR-dependent long-term potentiation (LTP) in memory, the increase of reactive oxygen species in cognitive disorders, and the sensitivity of NMDAR to the redox status, converging lines have suggested the redox-altered NMDAR-dependent plasticity might underlie the synaptic dysfunctions associated with cognitive disorders. read more In this review, we summarize the involvement of redox-altered plasticity in cognitive disorders by presenting the available evidence. According to reports from our laboratory and other groups, this "redox-altered plasticity" is more similar to functional changes rather than organic injuries, and strategies targeting redox-altered plasticity using pharmacological agents might reverse synaptic dysfunctions and memory abnormalities in the early stage of cognitive disorders. Targeting redox modifications for NMDARs may serve as a novel therapeutic strategy for memory deficits.The aim of this research is to investigate the relationships between the counts of cases with Covid-19 and the deaths due to it in seven countries that are severely affected from this pandemic disease. First, the Pearson's correlation is used to determine the relationships among these countries. Then, the factor analysis is applied to categorize these countries based on their relationships.This work studies a new SEIR type mathematical model for SARS-CoV-2. We show how immigration, protection, death rate, exposure, cure rate and interaction of infected people with healthy people affect the population. Our model has four classes including susceptible, exposed, infected and recovered respectively. Here, we find the basic reproduction number and local stability through jacobean matrix. Lyapunov function theory is used to calculate the global stability for the problem under investigation. Also an attempt is made to derive some numerical interpretation under fractional derivative by using fractional order nonstandard finite difference (NSFD) sachem. The graphical presentations are given for some real data.In this paper, we consider a mathematical model to explain, understanding, and to forecast the outbreaks of COVID-19 in India. The model has four components leading to a system of fractional order differential equations incorporating the refuge concept to study the lockdown effect in controlling COVID-19 spread in India. We investigate the model using the concept of Caputo fractional-order derivative. The goal of this model is to estimate the number of total infected, active cases, deaths, as well as recoveries from COVID-19 to control or minimize the above issues in India. The existence, uniqueness, non-negativity, and boundedness of the solutions are established. In addition, the local and global asymptotic stability of the equilibrium points of the fractional-order system and the basic reproduction number are studied for understanding and prediction of the transmission of COVID-19 in India. The next step is to carry out sensitivity analysis to find out which parameter is the most dominant to affect the disease's endemicity. The results reveal that the parameters η , μ and ρ are the most dominant sensitivity indices towards the basic reproductive number. A numerical illustration is presented via computer simulations using MATLAB to show a realistic point of view.Middle East respiratory syndrome coronavirus has been persistent in the Middle East region since 2012. In this paper, we propose a deterministic mathematical model to investigate the effect of media coverage on the transmission and control of Middle Eastern respiratory syndrome coronavirus disease. In order to do this we develop model formulation. Basic reproduction number R 0 will be calculated from the model to assess the transmissibility of the (MERS-CoV). We discuss the existence of backward bifurcation for some range of parameters. We also show stability of the model to figure out the stability condition and impact of media coverage. We show a special case of the model for which the endemic equilibrium is globally asymptotically stable. Finally all the theoretical results will be verified with the help of numerical simulation for easy understanding.Most cardiovascular disease (CVD) events can be prevented with appropriate risk management. Existing evidence suggests women are less likely than men to receive guideline-recommended medications, however data on sex-differences in preventive medication use following a CVD event are lacking. Relative risks (RRs) comparing use of blood pressure- and lipid-lowering medications in men and women at 3-, 6-, 9- and 12-months following hospitalisation for myocardial infarction (MI) or stroke from 2012 to 2017 were quantified using linked data from 8,278 participants enrolled in the Australian 45 and Up Study. Overall, 51% of women and 58% of men were using both blood-pressure- and lipid-lowering medications three months after a MI or stroke event, decreasing to 48% and 53%, respectively, at 12 months after an event. Adjusting for potential confounders, women were 9% less likely than men (RR = 0.91 [95% CI 0.87, 0.95]) to be using both medications and 19% more likely (RR = 1.19 [95% CI 1.07, 1.32]) to use neither medication three months after a MI or stroke event. At the 12-month mark, women were 8% less likely (RR = 0.92 [95% CI 0.88, 0.97]) to be using both medications and 14% more likely (RR = 1.14 [95% CI 1.03, 1.26]) to use neither medication. Women were consistently less likely to use both preventive medications and more likely to use neither medication at each follow-up time point. Overall, there were major shortfalls in basic preventive medication use post-CVD event and sex disparities are likely to further jeopardise efforts to reduce CVD events in the community.
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