The antioxidant trolox inhibits aging and enhances prostaglandin E-2 secretion in mesenchymal stem cells

Mesenchymal stem cells(MSCs)have been widely used in regenerative medicine and clinical therapy due to their capabilities of proliferation,differentiation,and immune regulation.However,during in vitro expansion,MSCs are prone to aging,which largely limits their application.Prostaglandin E-2(PGE-2)is a key effector secreted by MSCs to exert immunomodulatory effects.By screening the compound library for PGE-2 secretion,the antioxidant trolox was verified as a stimulator of MSCs to secrete PGE-2.The effect of antioxidant trolox on biological characteristics of MSCS,including aging,proliferation,and gene expression,was examined.The results demonstrated that trolox can resist aging,promote proliferation,and enhance PGE-2 secretion of MSCs without affecting their surface marker expression.Furthermore,trolox treatment up-regulates miR-17-92 clusters in MSCs and may contribute to its anti-aging effects.Thus,trolox addition might be beneficial for MSCs expansion and their application.

Suppression of cell pyroptosis by omeprazole through PDE4-mediated autophagy in gastric epithelial cells

Helicobacter pylori is a risk factor for the development of peptic ulcers with autophagy dysfunction.Omeprazole was widely known as the first-line regimen for H.pylori-associated gastritis.Objectives:The objective of this work was to assess the role of omeprazole on cell pyroptosis and autophagy.Methods:The clinical samples were collected.Quantitative polymerase chain reaction,western blotting,enzyme linked immunosorbent assay,and immunofluorescence(IF)analysis were conducted to reveal the mechanism of omeprazole on cell pyroptosis and autophagy.Results:The results revealed that omeprazole could decrease cell pyroptosis,which was attributed to the downregulation of cleaved caspase-1 expression,resulting in the inhibition of gasdermin E and interleukin-18/1βmaturation and secretion as well as the resolution of inflammation.Mechanistically,omeprazole treatment led to drastic downregulation of mammalian target of rapamycin(mTOR)activity was observed in BGC823 cells,leading to enhanced autophagy characterized by increased LC3II expression,which further reduced cell pyroptosis.This omeprazole-mediated phenomenon was enhanced after phosphodiesterase-4(PDE4)inhibitor dipyridamole(DIP)treatment.In addition,activation of mTOR by MHY1485 could rescue the suppression of cell pyroptosis induced by omeprazole.Most importantly,IF analysis suggested that phosphorylation of mTOR and PDE4 activity and caspase-1 were enhanced in H.pylori-infected gastric mucosa.Conclusion:These findings indicate that omeprazole suppresses cell pyroptosis through PDE4-mediated autophagy in gastric epithelial cells,and DIP enhanced the omeprazole-mediated inhibition of cell pyroptosis,implying that DIP is an alternative combined therapy strategy in improving the treatment of patients with H.pylori infection.

Gene regulatory network inference based on causal discovery integrating with graph neural network

Gene regulatory network (GRN) inference from gene expression data is asignificant approach to understanding aspects of the biological system.Compared with generalized correlation-based methods, causality-inspiredones seem more rational to infer regulatory relationships. We proposeGRINCD, a novel GRN inference framework empowered by graph representationlearning and causal asymmetric learning, considering both linearand non-linear regulatory relationships. First, high-quality representation ofeach gene is generated using graph neural network. Then, we apply theadditive noise model to predict the causal regulation of each regulator-targetpair. Additionally, we design two channels and finally assemble them forrobust prediction. Through comprehensive comparisons of our frameworkwith state-of-the-art methods based on different principles on numerousdatasets of diverse types and scales, the experimental results show that ourframework achieves superior or comparable performance under variousevaluation metrics. Our work provides a new clue for constructing GRNs,and our proposed framework GRINCD also shows potential in identifyingkey factors affecting cancerdevelopment.

Warburg Effects in Cancer and Normal Proliferating Cells:Two Tales of the Same Name

It has been observed that both cancer tissue cells and normal proliferating cells(NPCs)have the Warburg effect.Our goal here is to demonstrate that they do this for different reasons.To accomplish this,we have analyzed the transcriptomic data of over 7000 cancer and control tissues of 14 cancer types in TCGA and data of five NPC types in GEO.Our analyses reveal that NPCs accumulate large quantities of ATPs produced by the respiration process before starting the Warburg effect,to raise the intracellular pH from 6.8 to 7.2 and to prepare for cell division energetically.Once cell cycle starts,the cells start to rely on glycolysis for ATP generation followed by ATP hydrolysis and lactic acid release,to maintain the elevated intracellular pH as needed by cell division since together the three processes are pH neutral.The cells go back to the normal respirationbased ATP production once the cell division phase ends.In comparison,cancer cells have reached their intracellular pH at 7.4 from top down as multiple acid-loading transporters are up-regulated and most acid-extruding ones except for lactic acid exporters are repressed.Cancer cells use continuous glycolysis for ATP production as way to acidify the intracellular space since the lactic acid secretion is decoupled from glycolysis-based ATP generation and is pH balanced by increased expressions of acid-loading transporters.Co-expression analyses suggest that lactic acid secretion is regulated by external,non-pH related signals.Overall,our data strongly suggest that the two cell types have the Warburg effect for very different reasons.

Fenton reactions drive nucleotide and ATP syntheses in cancer

We present a computational study of tissue transcriptomic data of 14 cancer types to address： what may drive cancer cell division？ Our analyses point to that persistent disruption of the intraceUular pH by Fenton reactions may be at the root of cancer development. Specifically, we have statistically demonstrated that Fenton reactions take place in cancer cytosoi and mitochondria across all the 14 cancer types, based on cancer tissue gene-expression data integrated via the Michaelis-Menten equation. In addition, we have shown that （i） Fenton reactions in cytosol of the disease cells will continuously increase their pH, to which the cells respond by generating net protons to keep the pH stable through a combination of synthesizing glycolytic ATPs and consuming them by nucleotide syntheses, which may drive cell division to rid of the continuously synthesized nucleotides; and （ii） Fenton reactions in mitochondria give rise to novel ways for ATP synthesis with electrons ultimately coming from H2O2, largely originated from immune cells. A model is developed to link these to cancer development, where some mutations may be selected to facilitate cell division at rates dictated by Fenton reactions.

Assessment of cognitive dysfunction in traumatic brain injury patients:a review

Traumatic brain injury(TBI)is one of the major causes of human mortality and morbidity in the world.Brain injury could affect the core of a person’s being–their thinking,memory,personality and behaviour.Electrophysiological markers from the human electroencephalogram and brain imaging provide a rich source of data which helps to elucidate specific processing impairments in TBI patients.To assess the cognitive and social function in traumatic brain injury patients,this review will focus on some of methods for assessing the disabling cognitive and social function deficits induced by TBI.There are many new technologies available to address TBI and recognition related questions.Integration of the various techniques will help to facilitate our comprehending of TBI,cognitive function and social function,and improve treatment and rehabilitation.