Jingjing Zhang

Pericyte specification and expansion must be coordinated with vascular growth to establish a functional cerebrovascular network, yet how endothelial signals control these distinct developmental transitions remains incompletely understood. Here, using genetic manipulation, single-cell transcriptomic analysis, and longitudinal in vivo imaging in zebrafish, we identify ligand-specific endothelial Notch signaling as a mechanism coordinating brain pericyte development. Endothelial Jag2b is required for efficient pericyte specification from pericerebral progenitor pools and subsequently promotes Notch-dependent pericyte proliferation and population expansion. By contrast, endothelial Dll4 restrains pericyte proliferation and functionally opposes Jag2b-dependent expansion, demonstrating that distinct endothelial Notch ligands generate different developmental outputs. Endothelial Notch activation increases jag2b expression, and genetic interaction analyses establish Jag2b as an important mediator of Notch-dependent pericyte expansion. Moreover, genetic disruption of piezo1 reduces brain pericyte abundance, whereas endothelial jag2b expression rescues this phenotype, placing Jag2b downstream of Piezo1-dependent hemodynamic signaling. Together, these findings reveal a ligand-specific endothelial Notch program that integrates hemodynamic cues with endothelial–pericyte communication to coordinate the specification and expansion of brain pericytes during cerebrovascular development.

Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a prevalent and serious hepatic disorder affecting approximately 30% of the global population. Despite its high prevalence, the precise pathophysiological mechanisms underlying MASLD development remain incompletely understood. Previous studies have shown that A1M regulates endoplasmic reticulum stress and oxidative responses in hepatocytes, thereby influencing liver homeostasis. However, the roles of AMBP, the precursor of both A1M and Bikunin, in MASLD pathogenesis and progression remain poorly characterized. Here, we generated ambp knockout ( ambp ^−/− ) zebrafish, subjected them to a high‐fat diet (HFD), and found that loss of ambp attenuated the development of MASLD under HFD feeding. Mechanistically, Ambp deficiency induced the production of reactive oxygen species (ROS) at homeostatic levels, which subsequently activated the peroxisome proliferator‐activated receptor α (PPARα) signaling pathway, which suppressed oxidative stress and maintained lipid homeostasis. Collectively, our results demonstrate that Ambp is a critical regulator of MASLD pathogenesis, suggesting that inhibiting AMBP function represents a potential therapeutic strategy for MASLD treatment.

Background/Objectives: Osteoporosis is a metabolic bone disease characterized by reduced bone mass and impaired bone microarchitecture. It has become a major clinical challenge due to the limitations of current therapeutic approaches. Isoimperatorin (ISO), a naturally occurring and biologically active furanocoumarin extracted from various traditional herbals, exhibits therapeutic potential in combating osteoporosis. However, toxicity limits its application. Methods: In vivo, compound B15 was evaluated in an Ovariectomy (OVX) mice model, where treatment was associated with changes in bone microarchitecture parameters, modulation of serum bone metabolism markers, and alterations in the histopathological features of bone tissue. Results: In this study, a new series of furanocoumarin derivatives was designed and synthesized for the treatment of osteoporosis. Compared with ISO, compound B15 has less toxicity and better ability to inhibit osteoclast formation in vitro. Compound B15 could decelerate the progression of osteoporosis in ovariectomized mice. It is worth mentioning that the expression of estradiol in the serum of mice with excised ovaries was significantly increased by compound B15. Conclusions: These results imply that the novel furanocoumarin derivative B15 is a promising therapeutic option for osteoporosis.

The vertebrate brain requires precisely patterned vasculature, yet the molecular and cellular dynamics of cerebrovascular development remain incompletely understood. While single-cell studies have profiled brain vasculature, integrating these data across molecular, cellular, and architectural scales remains challenging. We combine in situ sequencing, single-cell transcriptomics, and 3D vascular reconstruction to map zebrafish brain endothelial development (3-11 dpf). Quantitative 3D analysis reveals a developmental shift from lateral vascularization to intraparenchymal angiogenesis, coinciding with blood-brain barrier (BBB) maturation. We identify 6 endothelial subtypes with conserved mammalian signatures, showing capillary endothelial cells (CapECs), the predominant intracranial subtype exhibiting stage-specific enrichment of transporter and tight junction modules. Spatial transcriptomics show progressive CapEC enrichment in mesencephalic/metencephalic regions versus arterial EC accumulation in prosencephalic vessels. Functional assays confirm BBB competency by 11 dpf, while genetic perturbation of three uncharacterized CapEC-enriched genes (slc16a1a, zgc:158423, cldc1) disrupts vascular patterning and BBB integrity. This multidimensional atlas provides an evolutionary perspective on cerebrovascular development, bridges molecular profiles with vascular architecture, and offers insights into developmental dynamics across scales.

Mutations in ribosome biogenesis-related genes or functional defects in ribosomal proteins can lead to a class of autosomal genetic disorders characterized by tissue-specific defects, termed ribosomopathies. NOC4L, a critical factor in ribosome biogenesis, participates in the maturation of the 40S small ribosomal subunit. However, its functions in neural and cartilage development remain incompletely understood. In this study, through generation and phenotypic characterization of a zebrafish noc4l knockout model, we identified severe developmental abnormalities including microcephaly, micrognathia, and embryonic lethality. Further analyses revealed that noc4l loss-of-function results in reduced proliferation, differentiation blockade, and apoptotic activation. Mechanistically, sucrose gradient analysis demonstrated the disrupted ribosome biogenesis in noc4l mutants, with significantly reduced 40S/80S subunits and polysome levels, ultimately leading to overall translational inhibition and concurrent suppression of metabolic pathways. Pharmacological PPARγ activation via rosiglitazone partially rescued craniofacial malformations, ameliorated neurodevelopmental defects, and prolonged mutant life span. Although inhibition of the p53 pathway can partially rescue the phenotype, the p53 pathway and metabolic pathways are likely independent contributing factors. Our study reveals the molecular basis of developmental defects in noc4l mutants through impaired ribosome assembly and demonstrates the therapeutic potential of metabolic interventions for ribosomopathies.

Ciliogenesis requires an orchestrated interaction between the Golgi apparatus and centrioles via vesicle trafficking, yet this process is still poorly understood. Phosphatidylinositol 4-kinase β (PI4KB) is a conserved kinase that localizes to the Golgi for generating phosphatidylinositol 4-phosphate, an important lipid component related to cilium formation. Here, we demonstrate a previously uncharacterized mechanism of PI4KB in regulating Rab11a to enable proper ciliogenesis. PI4KB kinase activity maintains the normal vesicle density around the Golgi and Rab11a localization to centrioles in ciliogenesis. Inhibition of PI4KB activity leads to the reduced centriole localization but accumulation of Rab11a on the Golgi. We identified that the activation of Rab11a relies on PI4KB activity, while inactive Rab11a–guanosine diphosphate stably associates with Golgi and fails to undergo outward delivery. Autosomal-dominant nonsyndromic sensorineural hearing loss mutations in PI4KB abnormally intensify PI4KB interaction with Rab11a, leading to the aberrant subcellular Rab11a localization and defective ciliogenesis. Collectively, our study delineates a critical role for PI4KB in post–Golgi vesicle formation and ciliogenesis.

Background: Bronchiectasis is characterized by chronic cough and bronchial dilation. It has evolved from an orphan disease to a common condition, with a long history of research. This study employed bibliometric and visualization analyses to comprehensively examine the research dynamics, hotspots, and development trends in bronchiectasis research. Methods: Articles on bronchiectasis published between 2005 and 2024 were collected from the Web of Science Core Collection (WoSCC). The co-occurrence and clustering of keywords, co-citations of literature, and cooperation relationships among countries and institutions were analyzed and visualized via R-Bibliometric and VOSviewer. Results: A total of 127 countries/regions participated in the research on bronchiectasis, with 6,331 articles included in the analysis, published in 1,350 journals. The results showed that the number of research achievements on bronchiectasis had been increasing over the past 20 years. The United States of America was the country with the highest number of publications and citations. The top high-frequency keywords are sorted by frequency of occurrence: “bronchiectasis”, “cystic fibrosis”, “COPD”, “CT”, “asthma”, “children”, “primary ciliary dyskinesia”, “exacerbation”, “Pseudomonas aeruginosa”, and “interstitial lung disease”. The co-citation analysis suggested that the co-cited literature primarily focused on the establishment and evolution of the Bronchiectasis Severity Index, as well as the publication of guidelines for bronchiectasis. Conclusions: Research in the field of bronchiectasis is growing rapidly. The causes of decreased respiratory function might be the focus of subsequent research and the direction of development. This study encapsulates the developmental trajectories in the realm of bronchiectasis research, offering references for ongoing and forthcoming studies relevant to bronchiectasis.

Blood‐brain barrier (BBB) disruption is central to neurodegenerative and cerebrovascular diseases, but its causal role and therapeutic targeting remain challenging. Bromodomain and extraterminal domain (BET) proteins, particularly Brd4, regulate transcription via dual bromodomains (BD1, BD2). While BD1 antagonists are explored for tumors and BD2 antagonists for inflammation, their impact on cerebrovascular integrity is unclear. Crucially, opposing BBB effects of domain‐specific BET antagonism: the BD2 antagonist RVX208 disrupt the BBB, whereas the BD1 antagonist MS436 significantly reduces leakage and improves neurological outcomes, revealing therapeutic potential is demonstrated. Mechanistically, endothelial Brd4 critically suppresses BBB stability. Its ablation upregulates tight junction (TJ) proteins. Brd4, acting exclusively through its BD1 domain, destabilizes TJs via Rnf43 is identified, which promotes β‐catenin and TJ protein degradation. This defines a novel Brd4 BD1/Rnf43/β‐catenin axis essential for BBB integrity. The findings establish Brd4 BD1 inhibition as a novel BBB‐protective strategy and position MS436 for repurposing in cerebrovascular diseases, necessitating reevaluation of domain‐specific BET targeting for neurovascular pathologies.

The blood‐brain barrier (BBB) maintains brain homeostasis through specialized functions including tight junction formation and selective transport of brain endothelial cells (ECs). While ECs are generally thought to rely primarily on glycolysis for energy production, the transcriptional mechanisms underlying their metabolic specialization in the brain endothelium remain poorly understood, especially considering the brain's extraordinary energy demands. Through comparative transcriptomic analysis, it is demonstrated that brain endothelial cells are enriched for mitochondrial function genes, with forkhead box protein 1 (FOXQ1) being selectively expressed in cerebral vasculature. Conditional knockout of Foxq1 in endothelial cells results in severe mitochondrial dysfunction, including disrupted cristae morphology, reduced oxygen consumption, and impaired adenosine triphosphate (ATP) production. Mechanistically, FOXQ1 directly regulates two key pathways: calcium signaling through huntingtin‐associated protein (HAP1)‐mediated endoplasmic reticulum (ER)‐mitochondrial calcium transfer, and mitochondrial structural integrity via AarF domain‐containing protein kinase 1 (ADCK1)‐dependent cristae organization. These findings reveal that brain endothelial cells rely on oxidative phosphorylation rather than glycolysis alone, challenging the prevailing metabolic paradigm for endothelial cells. This work establishes FOXQ1 as an important regulator of brain endothelial metabolism and provides new insights into the molecular basis of cerebrovascular specialization, with implications for understanding vascular dysfunction in neurological diseases.

Brain metastasis (BM) remains a significant challenge in breast cancer (BC) management. While conventional metastatic routes primarily involve hematogenous dissemination, emerging evidence suggests that BC cells can also migrate along the abluminal surface of blood vessels, bypassing the blood-brain barrier (BBB). To investigate this phenomenon, we established a zebrafish xenograft model utilizing GFP-labeled MDA-MB-231 cells, allowing real-time observation of BC cell migration along the posterior cerebral veins. Our findings revealed that LRP8, an apolipoprotein E receptor, is upregulated in BC patients with brain metastasis. Functional studies demonstrated that LRP8 knockdown significantly inhibited proliferation, migration, and invasion of triple-negative breast cancer (TNBC) cells both in vitro and in vivo. Mechanistically, LRP8 promotes the activation of CDC42, enhancing filopodia formation and cell motility, a process influenced by the neuronal extracellular matrix protein, Reelin. Furthermore, we demonstrated the therapeutic potential of MEN 10207, a neurokinin-2 receptor antagonist, in inhibiting TNBC cell migration and suppressing BM formation in both zebrafish and mouse models. These findings provide novel insights into the mechanisms underlying extravascular brain dissemination of BC, highlighting the Reelin-LRP8-CDC42 axis as a potential therapeutic target for this devastating complication.