Advanced Science最新文献

Advanced in vitro platforms incorporating vascularized tumors offer a promising approach to dissect biological interactions between cancer, stromal, and immune components, as well as for biological drug testing. Here, we employed a vascularized 3D bioreactor system to evaluate the impact of allogeneic peripheral blood mononuclear cell (PBMC) perfusion on breast cancer spheroids embedded within self-organizing endothelial and stromal matrices. PBMC introduction results in rapid vascular regression, with reduced vessel density and interconnectivity of the self-assembled networks. Tumor spheroids exposed to PBMC show increased apoptosis and pyroptosis, resulting in spheroid size reduction. Interestingly, this is accompanied by enhanced peripheral tumor cell proliferation and invasive dissemination into the surrounding matrix. While tumor spheroids alone stabilize vascular networks and activate stromal components, PBMC perfusion triggers further stromal activation and desmoplasia, indicating inflammation and immune-mediated cytotoxicity. This approach demonstrates the multifaceted impact of allogeneic immune cell perfusion, including tumor suppression, vascular regression, stromal activation, and invasive tumor behavior, collectively reshaping the tumor microenvironment through innate immune-driven inflammation. These findings emphasize the importance of accounting for donor mismatch and innate immune activation in designing translationally relevant vascularized tumor models, and they support the development of autologous systems.

Immune homeostasis is indispensable for preserving organismal integrity, orchestrated through complex molecular networks encompassing immune cell dynamics, microbial cues, and epigenetic regulation. Among these, the gut microbiota-non-coding RNA (ncRNA) axis has recently garnered substantial attention as a multifaceted modulator of host immunity. Emerging evidence indicates that microbial-derived metabolites can reprogram ncRNA expression, thereby modulating immune cell differentiation, activation, and effector responses. Notably, dysregulation of this axis has been mechanistically implicated in the etiology of diverse immune-related pathologies, including colorectal cancer, sepsis, atherosclerosis, and neuroimmune conditions. Particularly intriguing is its translational potential: both microbial signatures and ncRNA profiles are being leveraged as diagnostic biomarkers and actionable targets for immune modulation. In this review, we delineate the molecular frameworks underpinning the gut microbiota-ncRNA-immune and explore how its perturbation contributes to pathogenesis. We further highlight emerging therapeutic strategies targeting this axis, underscoring its significance in precision immunology and host-microbiota co-regulation.

Polyethylene nanoplastics (NP) and lead (Pb) increasingly co-occur in agriculture, where their effects exacerbate phytotoxic impacts. We tested whether the endophytic entomopathogenic fungus, Metarhizium anisopliae, can mitigate individual or combined stress of NP and Pb in rice by examining fungus-soil-plant mechanisms using physiological assays, transcriptomics, metabolomics, and rhizosphere microbiome profiling. Rice seedlings were grown under eight treatments (individual or combined stress of Pb and NP, with or without M. anisopliae). Individual and combined Pb and NP stress reduced seedling growth, chlorophyll content, and hormonal levels, while increasing oxidative damage. Pb and NP interactions showed synergistic toxicity, causing severe growth suppression and lipid peroxidation, and repressing photosynthesis and hormone-related pathways. M anisopliae inoculation alleviated these effects and enhanced rice growth by reducing Pb uptake and translocation, restoring antioxidant and hormonal balance, and up-regulating pathways including flavonoid biosynthesis, ABC transporters, and hormone signaling. Pb measurements showed fungal inoculation restricted Pb uptake as a protective mechanism. M. anisopliae reshaped the soil bacterial community, enriching taxa associated with plant growth promotion and contaminant tolerance. These findings identify M. anisopliae seed inoculation as a strategy to mitigate Pb and NP phytotoxicity in rice by integrating contaminant uptake control with plant and rhizosphere reprogramming.

Noncompressible hemorrhage is a leading cause of death in both combat and lay settings, primarily due to the challenges in accessing and treating injuries deep within abdominal tissues where traditional compression-based methods are ineffective. Existing hemostatic materials fail to address the needs of large wound cavities, necessitating the development of advanced materials with rapid expansion and superior hemostatic properties. Here we report an expandable hemostat engineered from a nanocomposite-coated shape memory foam. This material exhibits rapid expansion, achieving a ~5X increase in volume within 3 min in vitro, and demonstrates notable shape recovery in vivo. The material's hemostatic efficacy is evident through a ~70% reduction in clotting time compared to untreated controls, primarily due to the ability to adhere platelets and red blood cells. Moreover, the composite material displays excellent hemocompatibility and cytocompatibility, with low hemolysis rates and high cellular viability. In vivo assessments further confirm its effectiveness, showing an accelerated clotting time (~80% reduction) and decreased blood loss (~50% decrease), alongside minimal inflammation and necrosis in histological analyses. Additionally, the composite demonstrates good biocompatibility following subcutaneous implantation, illustrating its efficacy in vivo. Overall, the synergistic effect of rapid expansion by shape memory foam, along with the excellent procoagulant ability of the nanocomposite makes this biocompatible, expandable hemostat a promising treatment for noncompressible hemorrhage.

Bone is the most common destination of metastatic breast cancer cells. Upon dissemination to the bone, cancer cells may either colonize aggressively or enter a quiescent state, depending on interactions with the bone microenvironment. This study revealed how the osteoblastic microenvironment determines the fate of cancer cells disseminated in the bone marrow. Cancer cells remain quiescent as disseminated tumor cells (DTCs) or as micrometastases within an inactive osteoblastic microenvironment (homeostasis) but colonize the bone in an active, nonmineralized osteoblastic (osteogenic) microenvironment. In a highly mineralized osteoblastic microenvironment, basal-like tumor cells remain quiescent, whereas luminal-like cancer cells survive and invade the bone. These findings provide a comprehensive explanation for the divergent outcomes of disseminated cancer cells in the bone, focusing on whether they colonize, reside in quiescence, or reactivate from dormancy. Moreover, in a supportive osteogenic microenvironment, both cancer cells and well-differentiated osteoblasts were demonstrated to activate osteoclasts, leading to osteolytic lesions. Cellular (osteoblasts) and matrix (bone matrix) components exhibited distinct roles in bone colonization. Furthermore, the therapeutic potential of disrupting integrin-mediated interactions between tumor cells and the bone matrix was evaluated in animal experiments to prevent the reactivation of quiescent tumor cells and their colonization of the bone.

Breast cancer incidence is rising globally, presenting challenges such as treatment side effects and drug resistance. Bufalin is a bufadienolides compound with potential anti-cancer effects. This study shows that bufalin inhibits malignant proliferation of MDA-MB-231 and MCF-7 cells and protects mice against breast cancer. Of note, GTF3C4 was identified as the target protein by Limited Proteolysis-Mass Spectrometry. GTF3C4 is overexpressed in breast cancer and associated with poor prognosis. RNA sequencing analysis reveals that the PI3K/AKT signaling pathway is a key contributor. Using cell thermal shift assays, drug affinity response target stability assays, and surface plasmon resonance, it was verified that bufalin can specifically bind to GTF3C4. Bufalin reduces GTF3C4 protein levels in vivo and in vitro, effectively inhibiting breast cancer progression by suppressing the PI3K/AKT signaling pathway. After the knockdown of GTF3C4, the PI3K/AKT signaling pathway is also suppressed, thereby inhibiting the proliferation of breast cancer cells and promoting apoptosis. Single-cell RNA sequencing results indicated that bufalin reduces the proportions of macrophages, neutrophils, and monocytes, and affects the strength of receptor-ligand signals between cells. Collectively, this study demonstrates that bufalin targets GTF3C4 to inhibit the PI3K/AKT pathway and remodels the tumor microenvironment, thereby hindering the malignant progression of breast cancer.

The testicular interstitium relies on coordinated signaling among vascular, steroidogenic, and structural cells, yet the regulatory role of testicular endothelial cells (TECs) in maintaining this homeostasis remains unclear. Here, we identify TECs as a central signaling hub that orchestrates intercellular communication within the human testis. Integrative single-cell transcriptomic analysis of healthy and diabetic testes reveals that diabetes disrupts platelet-derived growth factor (PDGF) signaling. TECs in diabetes undergo endothelial-to-mesenchymal transition and exhibit reduced PDGFB expression, while Leydig and testicular peritubular cells downregulate PDGFRB, collectively weakening intercellular connectivity. This disruption silences the JUND-MCL1 survival program in Leydig cells, leading to apoptosis, extracellular matrix accumulation, and testosterone insufficiency, while impairing the contractility of testicular peritubular cells. Importantly, exogenous PDGF-BB supplementation reactivates the JUND-MCL1 axis, protects Leydig cells, alleviates fibrosis, and partially restores testosterone production and peritubular function. Together, these findings establish endothelial PDGF dysregulation as a key driver of diabetic testicular pathology and highlight PDGF-BB supplementation as a mechanistically grounded therapeutic strategy to restore interstitial and endocrine function in the context of diabetes.

Cyclic nucleotide-gated (CNG) channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are key members of the cyclic nucleotide-activated ion channel family that translate intracellular cyclic nucleotide binding into electrical signals. Functionally, CNG channels drive large inward currents in photoreceptors and olfactory sensory neurons, whereas HCN channels are best known for their roles in pacemaker activity in the heart and the regulation of neuronal excitability. Despite their considerable sequence similarity and conserved overall architecture, these channels exhibit striking differences in ion conductance, K⁺ selectivity, and voltage dependence. Here, we performed microsecond-timescale atomistic molecular dynamics (MD) simulations to directly compare the ion conduction mechanisms of HCN and CNG channels, using the prototypical K⁺-selective channel MthK as a reference. Our simulations reproduced key features observed in single-channel patch-clamp electrophysiology and revealed that distinct selectivity filter architectures and dynamic behaviors are the primary determinants underlying the divergence in ion conductance and K⁺ selectivity between HCN and CNG channels. Together, these results provide a mechanistic framework for understanding the physiological roles of these channels and pave the way for the rational design of cation channels with tailored functional properties.

Germanium (Ge) stands out as a promising anode due to its high theoretical capacity combined with intrinsically superior ionic and electronic conductivities. Nevertheless, the high cost and pronounced volume expansion upon lithiation pose significant challenges for its practical implementation. Herein, sodium hydride (NaH)-driven multiphasic reduction is introduced to synthesize micrometre Ge with a tailored porous and hybrid nanocrystalline-amorphous structure, which uniquely emerges under off-stoichiometric reduction conditions. By elucidating the underlying multiphase reaction pathways, this structural evolution can be attributed to the dual role of NaH decomposition, where hydrogen regulates porosity and crystallinity while metallic Na acts as the primary reductant for germanium dioxide. This synthesized Ge exhibits outstanding reversibility and an exceptionally cycling stability even at high current density compared to commercial Ge microparticles, while also preserving the electrode integrity throughout cycling. This study offers mechanistic insights into extending NaH-driven reduction beyond GeO₂ to other metal oxides, paving the way for the development of high-capacity anodes.

High-grade meningiomas remain clinically challenging due to their aggressive behavior and limited therapeutic options. Although mutations and dysregulation of KMT2 family members have been implicated in various cancers, their functional significance in meningioma remains unclear. While NF2 alterations are the most common drivers of meningioma pathogenesis, the mechanisms regulating NF2 transcription in NF2-intact tumors are poorly understood. Here, we demonstrate that KMT2C expression is markedly reduced in high-grade meningiomas and that loss of KMT2C promotes proliferation and invasion in NF2-wild-type meningioma cells. Mechanistically, KMT2C deficiency suppresses NF2 transcription and inactivates Hippo signaling, leading to enhanced oncogenic activity and increased sensitivity to ferroptosis. Loss of KMT2C impairs the acetyltransferase activity of CBP/EP300, resulting in a global reduction of H3K27ac and transcriptional silencing of NF2. Pharmacological restoration of histone acetylation with the HDAC inhibitor Trichostatin A (TSA) effectively suppressed tumor growth. Collectively, our findings identify KMT2C as a key epigenetic regulator linking promoter histone acetylation, NF2-Hippo pathway activity, and ferroptosis susceptibility. These results provide mechanistic insights into high-grade meningioma progression and highlight ferroptosis induction and epigenetic modulation as promising therapeutic strategies for NF2-wild-type, KMT2C-deficient meningiomas.