Search progress of pyruvate kinase M2 (PKM2) in organ fibrosis.

Fibrosis is characterized by abnormal deposition of the extracellular matrix (ECM), leading to organ structural remodeling and loss of function. The principal cellular effector in fibrosis is activated myofibroblasts, which serve as the main source of matrix proteins. Metabolic reprogramming, transitioning from mitochondrial oxidative phosphorylation to aerobic glycolysis, is widely observed in rapidly dividing cells such as tumor cells and activated myofibroblasts and is increasingly recognized as a fundamental pathogenic basis in organ fibrosis. Targeting metabolism represents a promising strategy to mitigate fibrosis. PKM2, a key enzyme in glycolysis, plays a pivotal role in metabolic reprogramming through allosteric regulation, impacting both metabolic and non-metabolic pathways. Therefore, metabolic reprogramming induced by PKM2 activation is involved in the occurrence and development of fibrosis in various organs. A comprehensive understanding of the role of PKM2 in fibrotic diseases is crucial for seeking new anti-fibrotic therapeutic targets. In this context, we summarize PKM2's role in glycolysis, mediating the intricate mechanisms underlying fibrosis in multiple organs, and discuss the potential value of PKM2 inhibitors and allosteric activators in future clinical treatments, aiming to identify novel therapeutic targets for proliferative fibrotic diseases.

Bacterial quorum-sensing signal IQS induces host cell apoptosis by targeting POT1-p53 signalling pathway.

Pseudomonas aeruginosa, an opportunistic life-threatening human bacterial pathogen, employs quorum-sensing (QS) signal molecules to modulate virulence gene expression. 2-(2-hydroxyphenyl)-thiazole-4-carbaldehyde (IQS) is a recently identified QS signal that integrates the canonical lasR-type QS of P. aeruginosa and host phosphate stress response to fine-tune its virulence production for a successful infection. To address the role of IQS in pathogen-host interaction, we here present that IQS inhibits host cell growth and stimulates apoptosis in a dosage-dependent manner. By downregulating the telomere-protecting protein POT1 in host cells, IQS activates CHK1, CHK2, and p53 in an Ataxia telangiectasia mutated (ATM)/ATM and RAD3-related (ATR)-dependent manner and induces DNA damage response. Overexpression of POT1 in host cells presents a resistance to IQS treatment. These results suggest a pivotal role of IQS in host apoptosis, highlighting the complexity of pathogenesis mechanisms developed by P. aeruginosa during infection.

iTRAQ-based differential proteomic analysis in Mongolian gerbil brains chronically infected with Toxoplasma gondii.

The aim of our study was to detect differentially regulated proteins and specific signaling pathways in Mongolian gerbil brains during chronic Toxoplasma gondii (T.gondii) PRU strain infection. We use a iTRAQ-based strategy to detecte 4935 proteins, out of which 110 proteins were differentially expressed (>/=2.0-fold, p value <0.05) when the brain of gerbils infected with T.gondii was compared to control brain tissues. We confirmed the authenticity and the accuracy of iTRAQ results through quantitative real-time PCR and western blot (WB), which was consistent with mass spectrometry analysis. Pathway analysis and GO (Gene Ontology) annotations indicated the deregulation of several pathways related to immune response, metabolism and neurological processes, like neuronal growth and neurotransmitter transport. Through the iTRAQ-based strategy, we obtained a comparative proteome profile of brain tissues from Mongolian gerbils with chronic infection of T.gondii. Several differentially expressed proteins involved in neurological pathways, like Parvalbumin, Drebrin or Synaptotagmin, can be further investigated to enhance our understanding of central nervous system (CNS) injury caused by T.gondii. BIOLOGICAL SIGNIFICANCE: T.gondii can infect almost all nucleated cells with a preference for the CNS, which can induce Toxoplasma encephalitis (TE). However, the pathogenesis and mechanisms between the parasite and host associated with TE are largely unexplored. Around 30% of the world population is considered to have latent infection with T.gondii and >90% patients died of TE, while the proportion of secondary paralysis is also high. Patients of TE may have highly varied neurological symptoms with both focal and diffuse neurological lesions, while mental symptoms and behavior disorders are frequently accompanied, like the Alzheimer's disease (AD). We present a comparative proteomics analysis to explore the differences of protein expression caused by chronic T.gondii infection. The results of this analysis can be helpful for identifying key proteins involved in the pathogenesis of TE. In addition, the study can contribute to a better understanding of molecular mechanisms underlying the host-parasite relationship in chronic infection of T.gondii and facilitate further development of new therapies for TE.