Advanced Science最新文献

BTB domain and CNC homolog 1 (BACH1) belongs to the family of basic leucine zipper proteins and is expressed in most mammalian tissues. It can regulate its own expression and play a role in transcriptionally activating or inhibiting downstream target genes. It has a crucial role in various biological processes, such as oxidative stress, cell cycle, heme homeostasis, and immune regulation. Recent research highlights BACH1's significant regulatory roles in a series of conditions, including stem cell pluripotency maintenance and differentiation, growth, senescence, and apoptosis. BACH1 is closely associated with cardiovascular diseases and contributes to angiogenesis, atherosclerosis, restenosis, pathological cardiac hypertrophy, myocardial infarction, and ischemia/reperfusion (I/R) injury. BACH1 promotes tumor cell proliferation and metastasis by altering tumor metabolism and the epithelial-mesenchymal transition phenotype. Moreover, BACH1 appears to show an adverse role in diseases such as neurodegenerative diseases, gastrointestinal disorders, leukemia, pulmonary fibrosis, and skin diseases. Inhibiting BACH1 may be beneficial for treating these diseases. This review summarizes the role of BACH1 and its regulatory mechanism in different cell types and diseases, proposing that precise targeted intervention of BACH1 may provide new strategies for human disease prevention and treatment.

Single-cell chromatin conformation capture (scHi-C) techniques have evolved to provide significant insights into the structural organization and regulatory mechanisms in individual cells. Although many scHi-C protocols have been developed, they often involve intricate procedures and the resulting data are sparse, leading to computational challenges for systematic data analysis and limited applicability. This review provides a comprehensive overview, quantitative evaluation of thirteen protocols and practical guidance on computational topics. It is first assessed the efficiency of these protocols based on the total number of contacts recovered per cell and the cis/trans ratio. It is then provided systematic considerations for scHi-C quality control and data imputation. Additionally, the capabilities and implementations of various analysis methods, covering cell clustering, A/B compartment calling, topologically associating domain (TAD) calling, loop calling, 3D reconstruction, scHi-C data simulation and differential interaction analysis is summarized. It is further highlighted key computational challenges associated with the specific complexities of scHi-C data and propose potential solutions.

Pericytes are a key player in vascularization, protecting endothelial cells from external harm and promoting the formation of new vessels when necessary. However, pericytic identity and its relationship with other cell types, such as mesenchymal stromal/stem cells, is highly debated. This study compares the role of pericytes and unselected stromal cells in vascularization using multichannel microfluidic chips. In both angiogenesis and vasculogenesis, pericytes promote more vessel formation than stromal cells. Pericytes can wrap around endothelial vessels acting as mural cells, while stromal cells remain separated. Whole-transcriptome sequencing confirms an upregulation of pro-vascularization genes in endothelial cell-pericyte co-cultures, while metabolism increases and inflammation decreases in stromal cell co-cultures. Treatment of stromal-endothelial cell co-cultures with either conditioned media or isolated extracellular vesicles from pericytes replicates the increase in vasculogenesis of the direct co-cultures. Cytokine quantification reveals that interleukin 6 (IL-6) is significantly increased in pericyte conditions. Blocking it with siltuximab results in a reduction of pericyte vasculogenic potential comparable to stromal cell levels, revealing that pericyte pro-vascularization is mediated by IL-6. This study provides new insights into the relationship between pericytes and endothelial cells and the elusive identity of mesenchymal stromal cells. These findings are relevant for both vascular biology and tissue engineering.

Zinc plays a central role in the hematological development. Therapeutic interventions with zinc are shown to improve the health status of patients with malignancies by stimulating the immune system and reducing side effects. Despite the abnormal zinc homeostasis in leukemia, the role and mechanisms of zinc signaling in leukemia development remain poorly understood. Recently, some important breakthroughs are made in laboratory and clinical studies of zinc in leukemia, such as the role of zinc in regulating ferroptosis and the effects of zinc in immunotherapy. Zinc-based strategies are urgently needed to refine the current zinc intervention regimen for side-effect free therapy in chemotherapy-intolerant patients. This review provides a comprehensive overview of the role of zinc homeostasis in leukemia patients and focuses on the therapeutic potential of zinc signaling modulation in leukemia.

Liver disease poses a significant threat to global public health, with arsenic (As) recognized as a major environmental toxin contributing to liver injury. However, the specific mechanisms and the protective effects of α-lipoic acid (LA) remain unclear. Therefore, this study employs network toxicology and network pharmacology to comprehensively analyze the hepatotoxic mechanism of As and the hepatoprotective mechanism of LA, and further verifies the mechanisms of peroxisomal β-oxidation and lipophagy in the process. The network analysis results show that As induces liver damage mainly through autophagy, apoptosis, lipid metabolism, and oxidative stress, whereas LA exerts its hepatoprotective properties mainly by regulating lipid metabolism. Further verifications find that As inhibits SIRT1 expression, activates the P53 and Notch pathways, damages mitochondria, inhibits peroxisomal β-oxidation, increases lipid accumulation, and enhances lipophagy in the liver, while LA intervention alleviates As-induced lipid accumulation and enhances lipophagy by targeting SIRT1, ameliorating mitochondrial damage, enhancing peroxisomal β-oxidation, thereby alleviating As-induced liver damage. This study further clarifies the mechanism of As hepatotoxicity and provides a theoretical basis for LA as a potential hepatoprotective agent.

DNA methylation plays a critical role in gene regulation, affecting cellular differentiation and disease progression, particularly in non-coding regions. However, predicting the epigenetic consequences of non-coding mutations at single-cell resolution remains a challenge. Existing tools have limited prediction capacity and struggle to capture dynamic, cell-type-specific regulatory changes that are crucial for understanding disease mechanisms. Here, Methven, a deep learning framework designed is presented to predict the effects of non-coding mutations on DNA methylation at single-cell resolution. Methven integrates DNA sequence with single-cell ATAC-seq data and models SNP-CpG interactions over 100 kbp genomic distances. By using a divide-and-conquer approach, Methven accurately predicts both short- and long-range regulatory interactions and leverages the pre-trained DNA language model for enhanced precision in classification and regression tasks. Methven outperforms existing methods and demonstrates robust generalizability to monocyte datasets. Importantly, it identifies CpG sites associated with rheumatoid arthritis, revealing key pathways involved in immune regulation and disease progression. Methven's ability to detect progressive epigenetic changes provides crucial insights into gene regulation in complex diseases. These findings demonstrate Methven's potential as a powerful tool for basic research and clinical applications, advancing this understanding of non-coding mutations and their role in disease, while offering new opportunities for personalized medicine.

In patients with major depressive disorder (MDD) and animal models of depression, key pathological hallmarks include activation of microglia as well as atrophy and loss of astrocytes. Under certain pathological conditions, microglia can inflict damage to neurons and astrocytes. However, the precise mechanisms underlying how activated microglia induced astrocyte atrophy and loss remain enigmatic. In this study, a depression model induced by chronic social defeat stress (CSDS) is utilized. The results show that CSDS induces significant anxiety- and depression-like behaviors, along with notable astrocyte atrophy and apoptosis, microglial activation, and elevated levels of microglial interleukin-6 (IL-6). Subsequent studies demonstrate that IL-6 released from activated microglia promotes astrocyte apoptosis. Furthermore, the knockdown of the P2X7 receptor P2X7 receptor (P2X7R) in microglia, which is implicated in the stress response, reduces stress-induced microglial activation, IL-6 release, and astrocyte apoptosis. Direct inhibition of microglia by minocycline corroborates these effects. The selective knockdown of IL-6 in microglia and IL-6 receptors in astrocytes effectively mitigates depression-like behaviors and reduces astrocyte atrophy. This study identifies microglial IL-6 as a key factor that contributes to astrocyte apoptosis and depressive symptoms. Consequently, the IL-6/IL-6R pathway has emerged as a promising target for the treatment of depression.

Little is known about plant-parasitic animal-derived pathogen-associated molecular pattern (PAMP)/ pattern-recognition receptor (PRR) pairs. Additionally, mitochondrial proteins have not previously been reported to be secreted into hosts by pathogens. Here, it is found that the Meloidogyne javanica elongation factor thermo unstable (EF-Tu) (MjEF-Tu) located in the nematode mitochondria is up-regulated and secreted into the host plant during nematode parasitism. MjEF-Tu interacts with the PRR Arabidopsis thaliana EF-Tu receptor (AtEFR), triggering the plant hallmark defence responses mediated by AtEFR. An 18-aa sequence (Nelf18) in the N terminus of the nematode EF-Tu contributes to the immunogenic activity. M. javanica water extract and mitochondrial extract also induce plant immunity sensed by AtEFR, owing to the presence of MjEF-Tu. In addition, Nelf18 enhances plant resistance to nematode, virus, and bacterial infections depending on AtEFR. These findings first demonstrate that mitochondrial proteins from pathogens can be secreted into hosts and function as a cross-kingdom signal and identified the first plant-parasitic animal-derived proteinaceous PAMP/PRR pair, providing novel insights into host-pathogen interactions.

Meibomian gland dysfunction (MGD) is a leading cause of evaporative dry eye disease, presenting a challenge for targeted treatment. Traditional topical ocular drug delivery methods often fail to effectively reach the meibomian glands (MGs). To address this, the study has developed a soluble microneedles (MN) patch comprising poly(vinyl alcohol), cyclodextrin modified polyacrylic acid, and new indocyanine green. This innovative MN patch facilitates the transdermal release of peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, such as rosiglitazone in response to near-infrared ray induced temperature changes. By safely optimizing temperature, the patch effectively liquefied meibum lips, thereby alleviating duct obstruction while releasing the drug. MN patches exhibit sufficient mechanical strength for effective skin penetration, and its biosafety for eyelid application has been rigorously assessed in vitro and in vivo. The therapeutic efficiency of rosiglitazone loaded MN (ROSI-MN) treatment for MGD is evaluated in high-fat mice. After three months of treatments, ROSI-MN administration significantly alleviated MGD clinical manifestations, including ocular surface damage, lipid deposits, glandular hypertrophy, and inflammatory infiltration, ultimately improving the microstructure and biofunction of MGs. In conclusion, the soluble MN patches hold promise as an effective drug delivery strategy for treating ocular surface diseases beyond MGD.

Basal-like breast cancer (BLBC), overlapping with the subgroup of estrogen receptor (ER), progesterone receptor (PR), and HER2 triple-negative breast cancer, has the worst prognosis and limited therapeutics. The XPO1 gene encodes nuclear export protein 1, a promising anticancer target which mediates nucleus-cytoplasm transport of nuclear export signal containing proteins such as tumor suppressor RB1 and some RNAs. Despite drugs targeting XPO1 are used in clinical, the regulation of XPO1 expression and functional mechanism is poorly understood, especially in BLBC. This study finds that KLF5 is a transcription factor of XPO1, which increases RB1 nuclear export and cell proliferation in BLBC cells. Furthermore, XPO1 interacts with the RNA-binding protein PTBP1 to export FOXO1 mRNA to cytoplasm and thus activates the FOXO1-KLF5 axis as a feedback. This work demonstrates that XPO1 inhibitor KPT-330 in combination with CDK4/6 inhibitor additively suppressed BLBC tumor growth in vivo. These results reveal a novel positive feedback regulation loop between KLF5 and XPO1 and provide a novel treatment strategy for BLBC.