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Secondary pneumonia, a common complication of sepsis-induced immunosuppression (SII), is closely linked to alveolar macrophage (AM) dysfunction primarily due to impaired glycolytic activity. However, the underlying molecular mechanisms remain unclear. In this study, it is found that exosomal RNA component of the mitochondrial RNA processing endoribonuclease (Rmrp), derived from type II alveolar epithelial cells (AEC-IIs), drives glycolytic defects and immune tolerance in AMs following cecal ligation and puncture (CLP) sepsis. Targeted depletion of Rmrp in either AEC-IIs or AMs alleviated SII and secondary pneumonia induced by Pseudomonas aeruginosa infection 48 h post CLP. Mechanistically, Rmrp interacts with and inhibits the ubiquitination and degradation of the RNA-binding protein zinc finger protein 36 (ZFP36). This results in ZFP36 upregulation, subsequently accelerating the decay of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3 ) mRNA by binding to its AU-rich elements in the 3′ untranslated region. The degradation of Pfkfb3 mRNA leads to impaired glycolysis and suppresses immune responses in AMs after sepsis. Additionally, it is found that exosomal Rmrp levels are correlated with AM immune tolerance and the prognosis of patients with sepsis. These findings highlight the critical role of AEC-II-derived exosomal Rmrp in the pathogenesis of SII and secondary pneumonia. Importantly, the study suggests that exosomal Rmrp may serve as a biomarker for predicting and managing SII in clinical settings.

Sacha inchi shell extract (SISE), whose main active substance is a polysaccharide, has been reported to have hypotensive effects. Consequently, a novel acidic arabinogalactan, termed SISP, was isolated from SISE, and its efficacy in protecting vascular endothelial cells was investigated. SISP had a molecular weight of 57.51 kDa and was composed mainly of Gal, Rha, Ara, and GalA. The main backbone of SISP was composed of →6)-β-D-Galp-(1→, →3,6)-β-D-Galp-(1→, →2)-α-L-Rhap-(1 → and →4)-α-D-GalAp-(1→, and the side chains were branched at the O-3 position of →3,6)-β-D-Galp-(1 → mainly by [α-L-Araf-(1 → 5)-α-L-Araf-(1 → 5,2)-α-L-Araf-(1→], α-L-Araf-(1 → and β-D-Galp-(1→. Compared with the angiotensin II group, high-dose SISP alleviated endothelial cell dysfunction by increasing the vasodilator nitric oxide level by 30.49 % and decreasing the vasoconstrictor endothelin-1 secretion by 53.66 %. Furthermore, SISP protected vascular endothelial cells by reducing oxidative damage via ROS reduction and SOD activity enhancement, inhibiting endothelial cell migration, and activating the ACE2-Ang (1–7)-MasR-AKT-eNOS-NO pathway. Additionally, molecular docking results revealed that SISP could form 23 hydrogen bonds with the central kinase domain of AKT. Therefore, SISP can be potentially used as a vasodilator for the treatment of cardiovascular diseases associated with endothelial dysfunction.

Background Hypertensive intracerebral hemorrhage (HICH) is a life-threatening disease and lacks effective treatments. Previous studies have confirmed that metabolic profiles altered after ischemic stroke, but how brain metabolism changes after HICH was unclear. This study aimed to explore the metabolic profiles after HICH and the therapeutic effects of soyasaponin I on HICH.Methods HICH model was established first. Hematoxylin and eosin staining was used to estimate the pathological changes after HICH. Western blot and Evans blue extravasation assay were applied to determine the integrity of the blood–brain barrier (BBB). Enzyme-linked immunosorbent assay was used to detect the activation of the renin–angiotensin–aldosterone system (RAAS). Next, liquid chromatography–mass spectrometry-untargeted metabolomics was utilized to analyze the metabolic profiles of brain tissues after HICH. Finally, soyasaponin I was administered to HICH rats, and the severity of HICH and activation of the RAAS were further assessed.Results We successfully constructed HICH model. HICH significantly impaired BBB integrity and activated RAAS. HICH increased PE(14:0/24:1(15Z)), arachidonoyl serinol, PS(18:0/22:6(4Z, 7Z, 10Z, 13Z, 16Z, and 19Z)), PS(20:1(11Z)/20:5(5Z, 8Z, 11Z, 14Z, and 17Z)), glucose 1-phosphate, etc., in the brain, whereas decreased creatine, tripamide, D-N-(carboxyacetyl)alanine, N-acetylaspartate, N-acetylaspartylglutamic acid, and so on in the hemorrhagic hemisphere. Cerebral soyasaponin I was found to be downregulated after HICH and supplementation of soyasaponin I inactivated the RAAS and alleviated HICH.Conclusion The metabolic profiles of the brains changed after HICH. Soyasaponin I alleviated HICH via inhibiting the RAAS and may serve as an effective drug for the treatment of HICH in the future.

Ovarian cancer (OC) is often detected at an advanced stage and has a high recurrence rate after surgery or chemotherapy. Thus, it is essential to develop new strategies for OC treatment. This study tended to investigate the effects of endothelial cell-specific molecule 1 (ESM1) in OC. The impact of ESM1 on lipid metabolism was investigated through the regulation of ESM1 expression. Differential genes regulated by ESM1 were screened by mRNA sequencing. The role of autophagy in ESM1 regulation on lipid metabolism was explored using autophagy inhibitor chloroquine (CQ). Co-IP, dual-luciferase reporter assay, actinomycin D treatment assay, and others were used to analyze the mechanism of ESM1 regulation on lipid metabolism. The xenograft mouse model was constructed to explore the impact of ESM1 regulation on OC development. The regulatory mechanism of ESM1 in OC patient samples was verified by using microarray analysis and the Log-rank (Mantel-Cox) test. After ESM1 silencing, cholesterol synthesis decreased and lipolysis increased. mRNA sequencing revealed that ESM1 regulation on lipid metabolism was related to Beclin 1 (BECN1). In vitro experiments, ESM1 inhibited lipolysis by suppressing BECN1-mediated autophagy. BECN1 expression was regulated by the transcription factor Kruppel-like factor 10 (KLF10). The competitive binding between BECN1 and HSPA5 promoted the ubiquitination degradation of HMGCR, thereby inhibiting cholesterol production. The intervention experiment with exogenous cholesterol showed a positive correlation between m6A reader IGF2BP3 expression and cholesterol content. Mechanistically, IGF2BP3 regulated the stability of ESM1 mRNA. In vivo experiments, ESM1 modified by m6A methylation promoted cholesterol synthesis and inhibited lipolysis. High expression of ESM1 predicted poor prognosis in OC patients. ESM1 regulated lipid metabolism through IGF2BP3/ESM1/KLF10/BECN1 positive feedback, which was a promising target for OC treatment.

Pathogenesis exploration and timely intervention of lung injury is quite necessary as it has harmed human health worldwide for years. Ficolin B (Fcn B) is a recognition molecule that can recognize a variety of ligands and play an important role in mediating the cell cycle, immune response, and tissue homeostasis in the lung. However, the role of Fcn B in bleomycin (BLM)-induced lung injury is obscure. This study aims to investigate the sources of Fcn B and its mechanism in BLM-induced lung injury. WT, Fcna -/- , and Fcnb -/- mice were selected to construct the BLM-induced lung injury model. Lung epithelial cells were utilized to construct the BLM-induced cell model. Exosomes that were secreted from alveolar macrophages (AMs) were applied for intervention by transporting Fcn B. Clinical data suggested M-ficolin (homologous of Fcn B) was raised in plasma of interstitial lung disease (ILD) patients. In the mouse model, macrophage-derived Fcn B aggravated BLM-induced lung injury and fibrosis. Fcn B further promoted the development of autophagy and ferroptosis. Remarkably, cell experiment results revealed that Fcn B transported by BLM-induced AMs exosomes accelerated autophagy and ferroptosis in lung epithelial cells through the activation of the cGAS-STING pathway. In contrast, the application of 3-Methyladenine (3-MA) reversed the promotion effect of Fcn B from BLM-induced AMs exosomes on lung epithelial cell damage by inhibiting autophagy-dependent ferroptosis. Meanwhile, in the BLM-induced mice model, the intervention of Fcn B secreted from BLM-induced AMs exosomes facilitated lung injury and fibrosis via ferroptosis. In summary, this study demonstrated that Fcn B transported by exosomes from AMs exacerbated BLM-induced lung injury by promoting lung epithelial cells ferroptosis through the cGAS-STING signaling pathway.

Skeletal muscle atrophy, a debilitating complication of COPD, is closely linked to cigarette smoke (CS) exposure. The epigenetic regulator HDAC2 has been implicated, but the upstream regulatory mechanisms and precise downstream pathways are unclear. Using a CS-induced mouse atrophy model and C2C12 myotubes treated with cigarette smoke extract (CSE), we systematically investigated the role of USP47/HDAC2/CYP1A1/ROS axis through gain/loss-of-function studies, RNA-seq, ChIP-qPCR, co-immunoprecipitation, and ubiquitination assays. HDAC2 was downregulated in atrophic muscle, and its overexpression mitigated CS-induced atrophy, improved grip strength, and enhanced muscle regeneration. HDAC2 acted as a transcriptional repressor of CYP1A1 by deacetylating H3K9 and H3K27 at the promoter, thus curtailing ROS-driven excessive autophagy. We further discovered that the deubiquitinase USP47 is the key upstream regulator of HDAC2. USP47 directly interacted with HDAC2, promoted its deubiquitination, and enhanced its protein stability. Consequently, USP47 overexpression phenocopied the benefits of HDAC2 overexpression, which were effectively nullified by restoring CYP1A1 expression. In conclusion, we delineate a previously unrecognized signaling axis wherein USP47 stabilizes HDAC2 to inhibit the CYP1A1/ROS/autophagy cascade, ultimately protecting against CS-induced skeletal muscle atrophy. Targeting the USP47-HDAC2 interface presents a novel therapeutic strategy for combating muscle wasting in COPD.

Gastrodia elata BI., which is an edible plant, has been reported in previous studies to possess a strong capacity for alleviating the symptoms of Alzheimer's disease (AD). This study focuses on ginger-processed and fermented Gastrodia elata BI. (FGGE) to investigate its effects on behaviour, brain neuroregulation, and the gut microbiota in an AlCl 3 -induced AD rat model, and to explore the underlying mechanisms. Results indicate that FGGE significantly improved novel object recognition and the correct alternation rate in the Y-maze test for AD rats. In addition, FGGE alleviated brain oxidative stress and restored the anti-inflammatory response, cholinergic function, and tissue morphology in the hippocampus. Furthermore, FGGE activated the cAMP response element–binding protein/brain-derived neurotrophic factor signalling pathway, reversing neural network abnormalities and enhancing neural regulation. FGGE also promoted the proliferation of bacteria negatively associated with AD, such as Methanosphaera and Lactobacillus , thereby restoring gut microbiota balance. The mechanisms by which FGGE alleviates AD may involve the modulation of the gut-brain axis, ultimately mitigating AD symptoms. FGGE represents an innovative functional food with significant therapeutic potential and promising application prospects.

Background Pulmonary fibrosis (PF) is a progressive interstitial lung disease marked by extracellular matrix accumulation and epithelial damage, with limited therapeutic options. Alveolar epithelial cell apoptosis is a key pathological hallmark of PF, but the upstream regulators driving this process remain unclear. Caspase-9, a central initiator of the intrinsic apoptotic pathway, has been implicated in fibrotic diseases across multiple organs. However, its role in lung fibrosis and its molecular interactions are not fully elucidated. Methods Caspase-9 expression was analyzed in human PF lung tissues, bleomycin (BLM)-induced mouse models, and TGF-β1-treated MLE-12 alveolar epithelial cells. Functional studies included pharmacological inhibition, siRNA knockdown, and overexpression of Caspase-9. Fibrosis and apoptosis were assessed using Western blot, qPCR, immunohistochemistry, TUNEL, and electron microscopy. Interaction with β-catenin was examined via co-localization, modulation, and rescue experiments. Results Caspase-9 and cleaved-Caspase-9 were significantly upregulated in fibrotic lungs and TGF-β1-stimulated epithelial cells. Caspase-9 inhibition reduced collagen deposition, improved lung architecture, and suppressed pro-fibrotic markers in mice. In MLE-12 cells, Caspase-9 knockdown attenuated TGF-β1-induced apoptosis, restored E-cadherin, and downregulated fibrotic genes. Conversely, Caspase-9 overexpression aggravated fibrosis and apoptosis. Mechanistically, Caspase-9 interacted with β-catenin, enhanced its nuclear accumulation, and promoted downstream fibrotic signaling. β-catenin silencing reversed Caspase-9-induced fibrosis, while β-catenin activation nullified the protective effects of Caspase-9 inhibition both in vitro and in vivo. These results identify a functional Caspase-9/β-catenin axis in PF progression. Conclusions Caspase-9 drives pulmonary fibrosis by promoting epithelial apoptosis and activating β-catenin signaling. Targeting the Caspase-9/β-catenin axis may offer a promising therapeutic strategy for PF. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-025-07020-1.

Meat quality and lean meat percentage are important to pig industry. Muscle and adipose tissues are regarded as secretory organs that release myokines and adipokines to mediate muscle-adipose tissue crosstalk, which regulates lipid deposition and skeletal muscle development. The Taoyuan Black (TB) pig, a Chinese indigenous breed, exhibits abundant lipid deposition and is known for excellent meat quality. The aim of this study was to explore the dynamics of muscle development and lipid deposition in TB pigs at different ages and to identify myokines and adipokines that contribute to lipid accumulation. Forty TB and 40 Duroc pigs were fed the same diet and slaughtered for analysis at age of 60, 120, 180, and 210 d. The “window phase” of lipid deposition in TB pigs was defined from 120 to 180 d of age according to carcass traits, intramuscular fat (IMF), and adipocyte area. Comparative transcriptome of the longissimus dorsi (LD) muscle and subcutaneous adipose revealed upregulated energy and lipid metabolism pathways in TB pigs at 180 d compared to 120 d ( P < 0.05). Many myokines and adipokines associated with IMF and peripheral fat deposition have been identified via database comparison. Myokine IGF2 in TB pigs was downregulated at 180 d compared to 120 d ( P < 0.05) and had negative correlation with backfat thickness, perirenal fat percentage, and fat percentage ( P < 0.05), adipokines SFRP5 and AGT were upregulated in TB pigs at 180 d compared to 120 d and different between TB and Duroc pigs ( P < 0.05). This study provides new insights into the interaction between muscle and adipose tissues, as well as potential targets for nutritional regulation of IMF, lean meat percentage, and meat quality.

Background The molecular mechanisms underlying lymph node metastasis (LNM) in gastric cancer (GC) remain poorly understood. This study investigated HOXA9’s role in driving LNM via metabolic reprogramming. Methods Integrated analysis of gastric cancer RNA sequencing data and clinical specimens was performed. Functional validation involved HOXA9 overexpression and knockdown in AGS and HGC-27 cell lines, c-MYC silencing by siRNA, and glycolytic inhibition using 2-deoxyglucose (2-DG, 2.5 mM). In vitro assays evaluated proliferation (CCK-8), apoptosis (Annexin V/PI), migration/invasion (Transwell), lymphangiogenesis (HLEC tubulogenesis), and metabolism (Seahorse analyser). In vivo, effects were evaluated using a popliteal LNM mouse model ( n  = 6/group) and administered exogenous lactate (20 mM) to restore levels. Results HOXA9 was significantly upregulated in LNM-positive GC tissues (1.3-fold, p  = 0.0006) and predicted poor survival (HR = 1.57, p  = 1.7 × 10⁻⁵). HOXA9 overexpression enhanced GC cell proliferation (2.5-fold, p  < 0.0001), invasion (1.6-fold, p  = 0.0002), and migration (2.0-fold, p  < 0.0001), while suppressing apoptosis. Mechanistically, HOXA9 directly bound the c-MYC promoter, thereby upregulating glycolytic enzymes (HIF-1α, HK2, GLUT1, PDK1, LDHA) and increasing lactate secretion (1.7-fold, p  = 0.005). The resultant lactate-rich microenvironment stimulated lymphangiogenesis (1.4-fold, p  < 0.01) and endothelial cell migration (1.8-fold, p  < 0.001). These effects were significantly reversed by c-MYC knockdown or 2-DG treatment, with 2-DG reducing lymphangiogenesis by 37.56% ( p  < 0.0001). In vivo, HOXA9 knockdown reduced LNM burden (66% reduction in node volume, 83% lower metastasis rate), and this effect was markedly rescued by lactate supplementation. Conclusions HOXA9 promotes GC LNM by activating the c-MYC-glycolysis-lactate axis, which remodels the lymphatic niche. This axis represents a targetable pathway for GC therapy.