摘要: Neutrophil extracellular traps (NETs) act as a vital first line of defence against tissue damage and pathogens, playing a significant role in improving diseases such as intestinal ischemia reperfusion injury (IRI). However, we observed that after intestinal injury, intestinal bacteria and lipopolysaccharides (LPS) can enter the circulatory system, leading to a significant secondary increase in NETs production and the subsequent activation of a coagulation cascade. This phenomenon contributes to a pathological process known as the 'second strike' of NETs, which exaggerates intestinal damage and microcirculation disturbance. Selectively mitigating the detrimental effects associated with this second strike presents a promising therapeutic strategy. We developed an innovative conjugate of stroke-homing peptide (SHp) and DNase1 (SHp-DNase1) to enhance the stability of DNase in the bloodstream while selectively targeting NETs in thromboembolic events. The effects of SHp-DNase1 on blood flow, ischemia, and vascular leakage were evaluated in a mouse model using laser Doppler flowmetry and an in vivo imaging system. Levels of LPS and NETs were elevated in patients with IRI. Similarly, the expression of NETs and LPS was upregulated in mice with intestinal IRI. In vivo imaging revealed disturbances in intestinal microcirculation, accompanied by intestinal leakage, which were effectively reversed by the administration of SHp-DNase1. Almost all of the SHp-DNase1 localised to the gastrointestinal tract, demonstrating the effective targeting of DNase1 to the site of intestinal injury via SHp guidance. Furthermore, the combination of SHp-DNase1 and CRO significantly reduced the expression of ischemia-inducible factors, leading to a marked decrease in mortality in the mouse model. These findings suggest that intestinal LPS leakage correlated with NETs exacerbation plays a critical role in IRI. The combination of SHp-DNase1 and CRO is an effective treatment strategy by simultaneously controlling inflammation and addressing microcirculatory disorders induced by NETs in the therapy of IRI.

摘要: The brain and gut are sensory organs responsible for sensing, transmitting, integrating, and responding to signals from the internal and external environment. In-depth analysis of brain-gut axis interactions is important for human health and disease prevention. Current research on the brain-gut axis primarily relies on animal models. However, animal models make it difficult to study disease mechanisms due to inherent species differences, and the reproducibility of experiments is poor because of individual animal variations, which leads to a significant limitation of real-time sensory responses. Organ-on-a-chip platforms provide an innovative approach for disease treatment and personalized research by replicating brain and gut ecosystems in vitro. This enables a precise understanding of their biological functions and physiological responses. In this article, we examine the history and most current developments in brain, gut, and gut-brain chips. The importance of these systems for understanding pathophysiology and developing new drugs is emphasized throughout the review. This article also addresses future directions and present issues with the advancement and application of gut-brain-on-a-chip technologies. In this article, we examine the history and most current developments in brain, gut, and gut-brain chips. The importance of these systems for understanding pathophysiology and developing new drugs is emphasized throughout the review.image

摘要: Traumatic optic neuropathy refers to optic nerve (ON) injury by trauma, including explosion and traffic accident. Retinal ganglion cell (RGC) death is the critical pathological cause of irreversible visual impairment and blindness in ON injury. We previously investigated the patterns of 11 modes of cell death in mouse retina post-ON injury. Here we aimed to identify additional signalling pathways regulating RGC survival in rodents post-ON injury. RNA sequencing analysis identified the upregulation of inflammation and cellular senescence-related genes in retina post-ON injury, which were confirmed by immunoblotting and immunofluorescence analyses. Increased expression of senescence-associated beta-galactosidase (SA-beta gal) in RGCs and activation of microglia were also found. Transforming growth factor-beta receptor type II inhibitor (LY2109761) treatment suppressed p15Ink4b and p21Cip1 protein and SA-beta gal expression and promoted RGC survival post-ON injury with decreasing the expression of cell death markers in retina. Consistently, senolytics (dasatinib and quercetin) treatments can promote RGC survival and alleviate the reduction of ganglion cell complex thickness and pattern electroretinography activity post-ON injury with reducing SA-beta gal, p15Ink4b, p21Cip1, microglial activation and cell death marker expression. In summary, this study revealed the activation of cellular senescence in rodent retina post-ON injury and contribute to RGC survival regulation. Targeting cellular senescence can promote RGC survival after ON injury, suggesting a potential treatment strategy for traumatic optic neuropathy. This study revealed the activation of cellular senescence in rodent retina post-optic nerve injury and contribute to retinal ganglion cell survival regulation. Senolytics and TGF-beta receptor inhibitor can be the potential treatment strategies promoting retinal ganglion cell survival after optic nerve injury by targeting cellular senescence. image

摘要: A specialised microenvironment, termed niche, provides extrinsic signals for the maintenance of residential stem cells. However, how residential stem cells maintain niche homeostasis and whether stromal niche cells could convert their fate into stem cells to replenish lost stem cells upon systemic stem cell loss remain largely unknown. Here, through systemic identification of JAK/STAT downstream targets in adult Drosophila testis, we show that Escargot (Esg), a member of the Snail family of transcriptional factors, is a putative JAK/STAT downstream target. esg is intrinsically required in cyst stem cells (CySCs) but not in germline stem cells (GSCs). esg depletion in CySCs results in CySC loss due to differentiation and non-cell autonomous GSC loss. Interestingly, hub cells are gradually lost by delaminating from the hub and converting into CySCs in esg-defective testes. Mechanistically, esg directly represses the expression of socs36E, the well-known downstream target and negative regulator of JAK/STAT signalling. Finally, further depletion of socs36E completely rescues the defects observed in esg-defective testes. Collectively, JAK/STAT target Esg suppresses SOCS36E to maintain CySC fate and repress niche cell conversion. Thus, our work uncovers a regulatory loop between JAK/STAT signalling and its downstream targets in controlling testicular niche homeostasis under physiological conditions.

摘要: Metabolic balance is essential for oocyte maturation and acquisition of developmental capacity. Suboptimal conditions of in vitro cultures would lead to lipid accumulation and finally result in disrupted oocyte metabolism. However, the effect and mechanism underlying lipid catabolism in oocyte development remain elusive currently. In the present study, we observed enhanced developmental capacity in Procyanidin B2 (PCB2) treated oocytes during in vitro maturation. Meanwhile, reduced oxidative stress and declined apoptosis were found in oocytes after PCB2 treatment. Further studies confirmed that oocytes treated with PCB2 preferred to lipids catabolism, leading to a notable decrease in lipid accumulation. Subsequent analyses revealed that mitochondrial uncoupling was involved in lipid catabolism, and suppression of uncoupling protein 1 (UCP1) would abrogate the elevated lipid consumption mediated by PCB2. Notably, we identified peroxisome proliferator-activated receptor gamma (PPAR gamma) as a potential target of PCB2 by docking analysis. Subsequent mechanistic studies revealed that PCB2 improved oocyte development capacity and attenuated oxidative stress by activating PPAR gamma mediated mitochondrial uncoupling. Our findings identify that PCB2 intricately improves oocyte development capacity through targeted activation of the PPAR gamma/UCP1 pathway, fostering uncoupling lipid catabolism while concurrently mitigating oxidative stress.

摘要: Aurora Kinase A (AURKA) plays a central role as a serine/threonine kinase in regulating cell cycle progression and mitotic functions. Over the years, extensive research has revealed the multifaceted roles of AURKA in cancer development and progression. AURKA's dysregulation is frequently observed in various human cancers, including hepatocellular carcinoma (HCC). Its overexpression in HCC has been associated with aggressive phenotypes and poor clinical outcomes. This review comprehensively explores the molecular mechanisms underlying AURKA expression in HCC and its functional implications in cell migration, invasion, epithelial-to-mesenchymal transition, metastasis, stemness, and drug resistance. This work focuses on the clinical significance of AURKA as a diagnostic and prognostic biomarker for HCC. High levels of AURKA expression have been correlated with shorter overall and disease-free survival in various cohorts, highlighting its potential utility as a sensitive prognostic indicator. Recent insights into AURKA's role in modulating the tumour microenvironment, particularly immune cell recruitment, may provide valuable information for personalized treatment strategies. AURKA's critical involvement in modulating cellular pathways and its overexpression in cancer makes it an attractive target for anticancer therapies. This review discusses the evidence about novel and selective AURKA inhibitors for more effective treatments for HCC. Aurora kinase A (AURKA) is a crucial protein that controls cell growth and division. It plays a major role in cancer development and progression, causing abnormal cell behaviour. AURKA is often overexpressed in hepatocellular carcinoma (HCC), making it a potential diagnostic and prognostic marker of disease severity. Increasing evidence is exploring the use of AURKA as a target for new anticancer treatments in HCC. Understanding the role of AURKA in cancer may improve liver tumour management and treatment, offering hope for better outcomes for patients in the future. image

摘要: Cardiovascular disease (CVD) is a group of diseases that primarily affect the heart or blood vessels, with high disability and mortality rates, posing a serious threat to human health. The causative factors, pathogenesis, and characteristics of common CVD differ, but they all involve common pathological processes such as inflammation, oxidative stress, and fibrosis. S100A9 belongs to the S100 family of calcium-binding proteins, which are mainly secreted by myeloid cells and bind to the Toll-like receptor 4 and receptor for advanced glycation end products and is involved in regulating pathological processes such as inflammatory response, fibrosis, vascular calcification, and endothelial barrier function in CVD. The latest research has found that S100A9 is a key biomarker for diagnosing and predicting various CVD. Therefore, this article reviews the latest research progress on the diagnostic and predictive, and therapeutic value of S100A9 in inflammatory-related CVD such as atherosclerosis, myocardial infarction, and arterial aneurysm and summarizes its molecular mechanisms in the progression of CVD, aiming to explore new predictive methods and to identify potential intervention targets for CVD in clinical practice.

摘要: Irreversible damage to hair cells (HCs) in the cochlea leads to hearing loss. Cochlear supporting cells (SCs) in the murine cochlea have the potential to differentiate into HCs. Neuron membrane glycoprotein M6B (Gpm6b) as a four-transmembrane protein is a potential regulator of HC regeneration according to our previous research. In this study, we found that AAV-ie-mediated Gpm6b overexpression promoted SC-derived organoid expansion. Enhanced Gpm6b prevented the normal decrease in SC plasticity as the cochlea develops by supporting cells re-entry cell cycle and facilitating the SC-to-HC transformation. Also, overexpression of Gpm6b in the organ of Corti through the round window membrane injection facilitated the trans-differentiation of Lgr5+ SCs into HCs. In conclusion, our results suggest that Gpm6b overexpression promotes HC regeneration and highlights a promising target for hearing repair using the inner ear stem cells combined with AAV.

摘要: Increased expression of CD24 and MET, markers for cancer stem-like cells (CSCs), are each associated with ovarian cancer severity. However, whether CD24 and MET are co-expressed in ovarian CSCs and, if so, how they are related to CSC phenotype manifestation remains unknown. Our immunohistochemistry analysis showed that the co-expression of CD24 and MET was associated with poorer patient survival in ovarian cancer than those without. In addition, analyses using KM plotter and ROC plotter presented that the overexpression of CD24 or MET in ovarian cancer patients was associated with resistance to platinum-based chemotherapy. In our miRNA transcriptome and putative target genes analyses, miR-181a was downregulated in CD24-high ovarian cancer cells compared to CD24-low and predicted to bind to CD24 and MET 3'UTRs. In OV90 and SK-OV-3 cells, CD24 downregulated miR-181a expression by Src-mediated YY1 activation, leading to increased expression of MET. And, CD24 or MET knockdown or miR-181a overexpression inhibited the manifestation of CSC phenotypes, cellular quiescence-like state and chemoresistance, in OV90 and SK-OV-3 cells: increased colony formation, decreased G0/G1 phase cell population and increased sensitivity to Cisplatin and Carboplatin. Our findings suggest that CD24-miR-181a-MET may consist of a signalling route for ovarian CSCs, therefore being a combinatory set of markers and therapeutic targets for ovarian CSCs.

摘要: The rapid advancement of human stem cell research and its expansion into emerging areas has resulted in an escalation of ethical challenges associated with these studies. As a result, there has been a corresponding increase in both the volume and complexity of institutional ethics reviews, coupled with higher expectations for the quality of the review process. In response to these challenges, this standard provides a comprehensive outline of the fundamental principles, content, types, and procedures of ethics review, specifically focusing on non-clinical human stem cell research. Its purpose is to provide clear operational and procedural guidelines, as well as recommendations, for the ethics review of such studies. The document was originally published by the Chinese Society for Cell Biology on August 30, 2022. It is our hope that the publication of these guidelines will facilitate the integration of ethical considerations and evaluations in a structured manner throughout the entire process of stem cell research, ultimately fostering a healthy and orderly development of the field.