本周hzangs在最新文献中选取了9篇分享给大家，第1篇文章介绍了肝脏中鞘磷脂磷酸二酯酶3通过调控膜鞘磷脂代谢，影响脂质摄取和细胞外囊泡释放来促进肝脂肪性肝炎；第3篇文章介绍了ATG9A囊泡可以递送半乳糖凝集素 9；第6篇文章介绍了脂质不对称性丧失与膜起泡的关系；第9篇文章评估了HEK293F 衍生的细胞外囊泡作为药物输送载体的稳定性和安全性。
- Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism.
肝鞘磷脂磷酸二酯酶 3 通过破坏膜鞘脂代谢来促进脂肪性肝炎。
[Cell Metab] PMID: 40015281
Abstract: Metabolic-dysfunction-associated steatohepatitis (MASH) remains a major health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption or pharmacological inhibition of SMPD3 alleviates MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. Although healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses sirtuin 1 (SIRT1), triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes disease progression by enhancing caveolae-dependent lipid uptake and extracellular vesicle secretion from steatotic hepatocytes to exacerbate inflammation and fibrosis. Consequently, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid metabolism and holds great promise for developing novel MASH therapies.
- Babesiosis and sickle red blood cells: loss of deformability, altered osmotic fragility, and hypervesiculation.
巴贝斯虫病和镰状红细胞：变形能力丧失、渗透脆性改变和囊泡增多。
[Blood] PMID: 39869831
Abstract: Babesiosis in sickle cell disease (SCD) is marked by severe anemia but the underlying red blood cell (RBC) rheologic parameters remain largely undefined. Here, we describe altered RBC deformability from both primary (host RBC sickle hemoglobin mediated) and secondary changes (Babesia parasite infection mediated) to the RBC membrane using wild-type AA, sickle trait AS, and sickle SS RBCs. Our ektacytometry analysis demonstrates that the changes in the host RBC biomechanical properties, before and after Babesia infection, reside on a spectrum of severity, with wild-type infected AA cells, despite showing a significant reduction of deformability under both shear and osmolarity gradients, exhibiting only a mild phenotype, compared with infected AS RBCs that show median changes in deformability and infected SS RBCs that exhibit the most dramatic impact of infection on cellular rheology, including an increase in point of sickling values. Furthermore, using ImageStream cytometric technology to quantify changes in cellular shape and area along with a tunable resistive pulse sensor to measure release of extracellular vesicles from these host RBCs, before and after infection, we offer a potential mechanistic basis for this extreme SS RBC rheologic profile, which include enhanced sickling rates and altered osmotic fragility, loss of RBC surface area, and hypervesiculation in infected SS host RBCs. These results underline the importance of understanding the impact of intraerythrocytic parasitic infections of SCD RBCs, especially on their cellular membranes and studying the mechanisms that lead to hyperhemolysis and extreme anemia in patients with SCD.
- Autophagy-independent role of ATG9A vesicles as carriers for galectin-9 secretion.
ATG9A囊泡作为半乳糖凝集素 9 分泌载体作用。
[Nat Commun] PMID: 40335523
Abstract: Galectins play vital roles in cellular processes such as adhesion, communication, and survival, yet the mechanisms underlying their unconventional secretion remain poorly understood. This study identifies ATG9A, a core autophagy protein, as a key regulator of galectin-9 secretion via a mechanism independent of classical autophagy, secretory autophagy, or the LC3-dependent extracellular vesicle loading and secretion pathway. ATG9A vesicles function as specialized carriers, with the N-terminus of ATG9A and both carbohydrate recognition domains of galectin-9 being critical for the process. TMED10 mediates the incorporation of galectin-9 into ATG9A vesicles, which then fuse with the plasma membrane via the STX13-SNAP23-VAMP3 SNARE complex. Furthermore, ATG9A regulates the secretion of other proteins, including galectin-4, galectin-8, and annexin A6, but not IL-1β, galectin-3, or FGF2. This mechanism is potentially conserved across other cell types, including monocytic cells, which underscores its broader significance in unconventional protein secretion.
- Microbiota fasting-related changes ameliorate cognitive decline in obesity and boost ex vivo microglial function through the gut-brain axis.
微生物群禁食相关的变化可改善肥胖症的认知能力下降，并通过肠脑轴增强体外小胶质细胞的功能。
[Gut] PMID: 40335161
Abstract: Background: Obesity-related cognitive decline is linked to gut microbiota dysbiosis, with emerging evidence suggesting that dietary interventions may ameliorate cognitive impairment via gut-brain axis modulation. The role of microglial cells in this process remains underexplored. Objective: To investigate how diet-induced changes in gut microbiota influence cognitive function in individuals with obesity and their microglial activity, and to determine the impact of specific dietary interventions. Design: This study included 96 participants with obesity who were randomised into three dietary intervention groups: Mediterranean diet (Med), alternate-day fasting (ADF) and ketogenic diet (Keto). Cognitive performance and microbiota composition were assessed pre-intervention and post-intervention. The effects of microbiota-related changes on microglial function were further evaluated in mice models through faecal transplantation and in vitro model with microbiota exosome treatment. Results: Both the Keto and ADF groups demonstrated significant weight loss, but cognitive performance improved most notably in the ADF group, in association with reduced inflammation. Diet-related microbiota composition was correlated with the cognitive outcomes in the human study. Mice models confirmed that the cognitive benefits of ADF were microbiota-dependent and linked to enhanced microglial phagocytic capacity and reduced inflammation, accompanied by changes in microglia morphology. Conclusion: Fasting-induced modifications in gut microbiota contribute to cognitive improvement in individuals with obesity, with microglial cells playing a crucial mediatory role. Among the interventions, ADF most effectively enhanced microglial function and cognitive performance, suggesting its potential as a therapeutic strategy for obesity-related cognitive decline. Further studies are required to fully elucidate the underlying mechanisms.
- Heat Shock Strengthens the Protective Potential of MSCs in Liver Injury by Promoting EV Release Through Upregulated Autophagosome Formation.
热休克通过上调自噬体形成促进 EV 释放，增强 MSCs 在肝损伤中的保护潜力。
[J Extracell Vesicles] PMID: 40326673
Abstract: Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show powerful potential in the treatment of multiple diseases. However, the low yield of MSC-EVs severely restricts their clinical application. Here, heat shock (HS), a moderate external stimulus, can enhance EVs release of MSCs by upregulating autophagosome formation. Mechanistically, HS elevates TRPV2 expression to induce Ca2+influx and then promotes the activity of two succinylases, SUCLG2 and OXCT1, followed by increasing the succinylation of YWHAZ (a 14-3-3 protein) at lysine 11 (K11). Acting as an adaptor protein, YWHAZ's succinylation at K11 inhibits its degradation, reinforcing YWHAZ-ULK1 binding, which upregulates ULK1 S555 phosphorylation to promote autophagosome formation and enhance EV release of MSCs. Additionally, the improved therapeutic efficacy of HS-treated MSCs via EV release has been shown in two liver injury models-hepatic ischemia/reperfusion injury (HIRI) and acetaminophen-induced liver injury. These findings proved that HS, an easily implementable and cost-effective method, can be used to elevate MSC-EV yield in mass production.
- Loss of lipid asymmetry facilitates plasma membrane blebbing by decreasing membrane lipid packing.
脂质不对称性的丧失通过减少膜脂质包装促进了质膜起泡。
[Proc Natl Acad Sci U S A] PMID: 40324083
Abstract: Membrane blebs have important roles in cell migration, apoptosis, and intercellular communication through extracellular vesicles (EVs). While plasma membranes (PM) typically maintain phosphatidylserine (PS) on their cytoplasmic leaflet, most blebs have PS exposed on their outer leaflet, revealing that loss of steady-state lipid asymmetry often accompanies PM blebbing. How these changes in PM lipid organization regulate membrane properties and affect bleb formation remains unknown. We confirmed that lipid scrambling through the scramblase TMEM16F is essential for chemically induced membrane blebbing across cell types, with the kinetics of PS exposure being tightly coupled to the kinetics of bleb formation. Measurement of lipid packing with environment-sensitive probes revealed that lipid scrambling changes the physical properties of the PM, reducing lipid packing and facilitating the bilayer bending required for bleb formation. Accordingly, reducing lipid packing of the PM through cholesterol extraction, elevated temperature, or treatment with biological amphiphiles promoted blebbing in the absence of TMEM16F. Consistent with these cellular observations, blebbing inCaenorhabditis elegans embryos measured via EV production was significantly reduced by depleting the TMEM16-homolog ANOH-2. Our findings suggest that changing membrane biophysical properties by lipid scrambling is an important contributor to the formation of blebs and EVs and potentially other cellular processes involving PM deformation.
- Fate reversal: Exosome-driven macrophage rejuvenation and bacterial-responsive drug release for infection immunotherapy in diabetes.
命运逆转：外泌体驱动的巨噬细胞再生和细菌反应性药物释放用于糖尿病感染免疫治疗。
[J Control Release] PMID: 40250625
Abstract: Superficial surgical site infection (SSI) is a significant risk factor for the development of periprosthetic joint infection (PJI), particularly in diabetic patients. A high-glucose microenvironment is observed to compromise phagocytosis by inducing cellular senescence, which leads to impaired antibacterial immune function. Exosomes derived from umbilical cord stem cells (H-Exos) can reverse the immunosuppressive microenvironment by rejuvenating senescent cells, thereby terminating excessive, persistent, and ineffective inflammatory responses. Thus, a novel exosome-based immunotherapeutic antibacterial strategy to reverse fate is proposed. Vancomycin & lysostaphin-loaded exosomes are incorporated in a customizable microneedle patch (ExoV-ExoL@MN) for controlled release, enabling tailored treatments for diverse clinical scenarios. While rejuvenating macrophage senescent phenotype, the antibiotics encapsulated within exosomes can be responsively released by the hemolysin secreted by bacteria, triggering rapid bacterial killing. Post-infection clearance, they induce a shift from M1 to M2 macrophage polarization, thereby enhancing anti-inflammatory and reparative responses. Furthermore, the components can be mixed on demand and at any time, allowing for real-time customization and fabrication directly at the clinic (fabrication@clinic). This strategy reverses the immunosuppressive microenvironment by rejuvenating senescent macrophages and effectively combats bacterial invasion into deep tissues through bacteria-responsive antibiotic release, providing a promising approach for preventing and treating SSI-induced PJI.
- Pathogen-targeting biomineralized bacterial outer membrane vesicles for eradicating both intracellular and extracellular Staphylococcus aureus.
针对病原体的生物矿化细菌外膜囊泡，用于消灭细胞内和细胞外的金黄色葡萄球菌。
[J Control Release] PMID: 40189054
Abstract: Intracellular Staphylococcus aureus is associated with recurrent infections and antibiotic resistance. Conventional antibiotics are ineffective against such intracellular bacterial pathogens, which calls for exploration of new approaches to treat these infections. Here, we report the development of pathogen-targeting biomineralized bacterial outer membrane vesicle (OMV) for targeted antibiotic delivery and eradicating both intracellular and extracellular S. aureus. These OMVs were derived from E. coli, and chemically modified with hydroxamate-type siderophore to target the intracellular S. aureus. The surface of OMV was coated with pH-sensitive calcium carbonate (CaCO3) to target the infection microenvironment. The CaCO3-coated siderophore-OMV (SOMV@CaCO3) was loaded with the antimicrobial drugs lysostaphin (Lsn) and mupirocin (Mup) (Lsn-SOMV@CaCO3-Mup) and administration of these OMVs resulted in effective eradication of both extracellular and intracellular S. aureus. Thus, Lsn-SOMV@CaCO3-Mup provides a novel and promising strategy for the treatment of invasive S. aureus infections.
- A comprehensive evaluation of stability and safety for HEK293F-derived extracellular vesicles as promising drug delivery vehicles.
全面评估 HEK293F 衍生的细胞外囊泡作为有前景的药物输送载体的稳定性和安全性。
[J Control Release] PMID: 40169120
Abstract: HEK293F-derived extracellular vesicles (HEK293F-EVs) have great potential as next-generation drug delivery vehicles. A comprehensive understanding of their batch stability and in vivo safety is prerequisite for clinical translation. HEK293F-EVs were purified using ultracentrifugation combined with size exclusion chromatography, and their physicochemical properties, such as morphology, size distribution, and biomarkers, were thoroughly characterized. Raman spectroscopy and multi-omics analyses were employed to elaborate their molecular composition. Blood kinetics and biodistribution were assessed via IVIS spectrum imaging. Additionally, long-term in vivo safety was evaluated following multiple-dose administration through hematology, serum biochemistry, cytokine/chemokine profiling, and histopathology. HEK293F-EVs exhibited stable yields, purity, physicochemical properties (morphology, size, zeta potential, and marker proteins), and chemical composition across different cell passages (P10, P20, P30), with no significant variations. Content profiling, including protein, miRNA, metabolite, and lipid, confirmed consistent molecular stability across five production batches. GO, Reactome, and KEGG analyses revealed minimal enrichment in pathways related to acute immune response or cytotoxicity. Blood kinetics studies indicated rapid clearance of HEK293F-EVs from circulation, though slightly slower than PEG-Liposomes. Organ biodistribution was comparable between HEK293F-EVs and PEG-Liposomes, with HEK293F-EVs potentially having longer retention times. Importantly, HEK293F-EVs exhibited a favorable preclinical long-term safety profile, showing low immunogenicity and fewer tissue lesions compared to PEG-Liposomes. Our study demonstrates that HEK293F-EVs maintain stable physicochemical characteristics and compositions across batches and possess a superior safety profile, suggesting their significant potential as a safe and reliable drug delivery platform for clinical applications.
今天的整理就到这里。希望大家可以有所收获。大家下周见！
