Science China Life Sciences最新文献

Graft-versus-host disease (GVHD) remains a major challenge in successful allogeneic hematopoietic stem cell transplantation. Here, we report that inhibiting sphingosine kinase 1 (SPHK1), an enzyme that phosphorylates sphingosine to bioactive sphingosine-1-phosphate (S1P), effectively ameliorates acute GVHD (aGVHD) without compromising the graft-versus-leukemia effect. The absence of SPHK1 in the host exerts a beneficial effect on maintaining gut homeostasis by limiting intestinal epithelial cell (IEC) and intestinal stem cell (ISC) injury. This reduces gut permeability and prevents bacterial translocation, decreasing MHC II levels in IECs and donor T-cell infiltration. Persistent endoplasmic reticulum (ER) stress is observed during GVHD in the gastrointestinal tract and contributes to IEC injury. SPHK1 deficiency attenuates IEC damage by alleviating ER stress, which can be reversed by supplementation with exogenous S1P. FTY720, an S1P receptor antagonist, significantly inhibits ER stress-induced IEC injury. Our findings highlight the pathogenic role of host SPHK1 in gastrointestinal injury during aGVHD and suggest that targeting SPHK1 could be a therapeutic strategy for managing this condition.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory loss, and behavioral disturbances, eventually leading to dementia and severely diminishing quality of life. With the global population aging, AD has become an unprecedented challenge for society and families. Recent advances in the development of amyloid-beta (Aβ)-targeting monoclonal anti-bodies, like lecanemab and donanemab, provided hope for slowing or even halting disease progression. However, these treatments have not yet achieved the ultimate goal of reversing cognitive deterioration and restoring normal function. The complexity of AD stems from multiple contributing factors, with Aβ deposition and tau protein tangles being central to its pathology, while genetic predispositions, aging, and systemic factors further drive disease progression. Addressing AD by targeting a single factor has proven insufficient, highlighting the need for a comprehensive understanding of its multifaceted mechanisms. This review explores the latest advances in AD mechanistic research and therapeutic development, focusing on key areas such as amyloid precursor protein (APP) metabolism, Aβ dynamics, Aβ antibody immunotherapy, tau protein dysfunction, genetic influences, aging mechanisms, and systemic factors. By critically examining these aspects, we aim to provide insights that support more holistic approaches to AD diagnosis and treatment, ultimately laying the groundwork for innovative strategies to combat this debilitating disease.

Chimeric antigen receptor-T (CAR-T) cell therapy has made considerable advancements in the treatment of malignant tumors; however, its clinical application continues to face challenges such as low response rates and relapse, which are critical issues requiring urgent resolution. The insufficient functionality of CAR-T cells remains a core factor affecting their clinical efficacy. This article provides a systematic review of various strategies to enhance CAR-T cell functionality, including structural modification and gene editing of chimeric antigen receptor CAR molecules, optimization of manufacturing processes, enhancement of CAR-T cells to counteract the inhibitory tumor immune microenvironment, and combination therapies with other drugs. In terms of optimizing CAR molecules, particularly the development of dual-target CARs, this approach not only effectively prevents antigen escape but also significantly enhances the activation, proliferation, and anti-tumor efficacy of CAR-T cells. Gene editing technology offers new opportunities to improve the persistence, proliferative capacity, and anti-tumor activity of CAR-T cells, thereby enhancing their function and reducing disease relapse. Furthermore, epigenetic regulation augments the adaptability of CAR-T cells, strengthening their anti-tumor effects. Simultaneously, combining CAR-T cell therapy with other immunotherapies provides fresh perspectives for improving overall treatment efficacy. However, challenges remain in areas such as the precision of gene editing, reversibility of epigenetic regulation, and optimization of CAR structures. Future research should focus on refining these strategies and exploring their synergistic applications to maximize the therapeutic potential of CAR-T cell therapy. With ongoing technological advancements, CAR-T cell therapy is poised to achieve groundbreaking applications in a broader range of malignant tumor treatments, offering new hope to patients.

As a lipophilic tumour, ovarian cancer (OC) preferentially metastasizes to adipose-rich environments including the omentum and the peritoneum. Current research regarding the OC microenvironment has focused primarily on tumour-associated immune cells, whereas little attention has been given to the adipose tissue and the adipose-derived stem cells (ADSCs) within it. Here, from the perspective of senescence, we hypothesized that the continuous presence and accumulation of tumour cells disrupts the homeostasis of adipose tissue by intercellular interactions. Through a series of in vitro and in vivo experiments, we found that OC cells induce adipose tissue ageing and ADSC senescence, leading to adipose tissue dysfunction, glucose intolerance, and insulin resistance. OC extracellular vesicle (OC-EV) and ADSC coculture revealed that OC-EVs trigger ADSC ageing and dysfunction. Moreover, coculture promoted the formation of inflammasomes in ADSCs and increased the levels of the inflammatory factors IL-1β and IL-18. RNA-sequencing and bioinformatics analysis revealed that the nuclear factor kappa B (NF-κB) signalling pathway is involved in ADSC senescence induced by OC cells. Immunofluorescence staining and Western blotting confirmed that increased expression of NF-κB signalling-related proteins is associated with senescent ADSCs. Further mechanistic studies revealed that OC-EVs deliver IL-1β to promote ADSC senescence and regulate the NF-κB signalling pathway in ADSCs. On the basis of these findings, we attempted to ameliorate the ovarian cancer microenvironment by eliminating senescent ADSCs, aiming to develop a therapeutic strategy against ovarian cancer. Both treatment with the senolytic cocktail dasatinib plus quercetin and treatment with the NF-κB inhibitor resveratrol (RSV) alleviated adipose tissue ageing, improved glucose tolerance and insulin sensitivity, and ultimately decreased OC progression and metastasis. Together, these results indicate an important role of ovarian cancer in adipose tissue ageing, and identify the elimination of senescent ADSCs in adipose tissue as a new potential strategy for the treatment of OC.

Recurrent implantation failure (RIF) poses a substantial challenge in assisted reproductive technologies, causing serious psychological burden and economic pressure to patients with infertility. However, the pathogenesis of RIF remains unclear; therefore, in-depth research on RIF is crucial for guiding clinical treatment. Recent studies have indicated that reproductive tract microbiota imbalance is closely related to RIF, making it a new and promising research direction to explore. The present study shows that during the secretory phase, alpha diversity of the endometrial microbiota (EnM) significantly differed (P=0.022) between the RIF and control groups. Moreover, beta diversity analysis found significant differences in both the EnM and uterine lavage fluid microbiota (UfM) (both P<0.05). Further comparing the endometrial tissue metabolites of the RIF and control groups in the secretory phase, 34 metabolites were significantly increased, while 19 others, such as dimethylglycine (DMG), were significantly decreased in the RIF group. Correlation analysis revealed significant correlations between differentially abundant microbiota and metabolites in the endometrium. Furthermore, transplantation of EnM from the RIF group into the uterine cavity of SD rats significantly altered the microecological environment of the uterine cavity, decreasing Hoxa-10 and Lif and reducing embryonic implantation sites. Further exploration of the mechanism revealed that this transplantation decreased the proportion of uterine regulatory T (Treg) cells and the expression of DMG. Additionally, DMG supplementation is expected to mitigate the reduction in Treg and the impairment of endometrial receptivity caused by endometrial tissue microbiota disorders. Therefore, alterations in EnM in patients with RIF may alter endometrial metabolites, decrease Treg-cell proportions, affect endometrial receptivity, and ultimately induce recurrent implantation failure.

Why some flowers are so fragrant remains mysterious. The hypothesis of pollinator-mediated selection suggests that floral scent offers olfactory signals attracting pollen vectors, but it may be susceptible to pollen consumers. To explore the filtering hypothesis of floral scent that lures potential pollinators but repels pollinivores, here we provide the first report that thrips were the only effective pollinators for Osmanthus fragrans (Oleaceae), a famous fragrant tree whose flowers produce no nectar, although co-flowering species were pollinated by diverse insects, including honeybees, in both wild and cultivated populations. A series of experimental tests of ecological functions in floral scent demonstrate that two major aromatic compounds, β-ionone and linalool, both deter honeybee visits, but β-ionone attracts thrips. Honeybees obviously avoided O. fragrans, and ceased re-visiting Hibiscus mutabilis flowers that were artificially added linalool or β-ionone, illustrating a push-pull strategy using floral scent to recruit thrips pollinators but repel pollen feeders to reduce pollen consumption. The finding of β-ionone as an olfactory signal filtering pollen vectors highlights that the diversity of floral volatiles could also be selected by antagonists via pollen protection from pollinivore repellence.