Based on WGCNA and machine learning studies, SMURF2 drives NSCLC malignant transformation, ferroptosis, and macrophage polarization by ubiquitinating SPP1.

Sepsis-induced myopathy (SIM) is a common and life-threatening complication, but its underlying mechanisms remain poorly understood. PACS2, a key resident protein at mitochondria-associated endoplasmic reticulum membranes (MAMs), regulates ER homeostasis under various pathological conditions. However, whether sepsis disrupts PACS2-dependent MAM integrity, thereby triggering ER dysfunction and muscle wasting, remains unexplored. We established a sepsis mouse model via cecal ligation and puncture (CLP) and assessed muscle function using compound muscle action potential (CMAP) recording and grip strength measurements. Muscle atrophy was evaluated by H&E staining and Western blotting. PACS2 expression was determined by Western blotting, immunohistochemistry and qRT-PCR. MAM integrity was assessed by immunofluorescence co-localization of IP3R and VDAC1, and ER-phagy (reticulophagy) activation was evaluated by transmission electron microscopy, Western blotting and fluorescence microscopy. To investigate the functional role of PACS2, adeno-associated virus (AAV)-mediated PACS2 overexpression was performed in mouse tibialis anterior muscle and gastrocnemius muscles, followed by RNA-sequencing analysis. The MAPK pathway proteins p-ERK, p-P38 and p-JNK levels were assessed by Western blotting, and the involvement of ERK-MAPK signalling was tested pharmacologically via intraperitoneal injection of the ERK inhibitor SCH772984. Septic mice developed progressive skeletal muscle atrophy (p < 0.001) and dysfunction (p < 0.01), accompanied by 56% reduction in PACS2 expression at 96 h post-CLP (p < 0.01), 25% decrease in MAM integrity (p < 0.05) and subsequent activation of FAM134B-mediated ER-phagy (p < 0.01). AAV-mediated PACS2 overexpression significantly alleviated muscle atrophy by restoring MAM integrity by 28% (p < 0.01), reducing FAM134B expression by 43% (p < 0.01) and attenuating ER-phagy (p < 0.01). Co-immunoprecipitation revealed no detectable direct protein-protein interaction between PACS2 and FAM134B. Transcriptome sequencing and Western blotting analysis demonstrated that PACS2 overexpression specifically activated the ERK-MAPK signalling pathway (55% increase in p-ERK, p < 0.01) without affecting p-P38 or p-JNK levels (p>0.05), which suppressed FAM134B-mediated ER-phagy (p < 0.05) and ameliorated muscle atrophy (p < 0.05) by inhibiting nuclear translocation of TFEB (p < 0.01). Pharmacological ERK inhibition with SCH772984 abolished the protective effects of PACS2 by promoting TFEB nuclear translocation (p < 0.001) and TFEB-mediated FAM134B expression (p < 0.001). Our findings demonstrate that SIM is closely associated with disrupted MAM integrity. PACS2 plays a critical role in maintaining MAM structural integrity and regulating FAM134B-mediated ER-phagy through the ERK-MAPK-TFEB signalling axis, thereby providing novel mechanistic insights and potential therapeutic targets for SIM.

Astragalus membranaceus (Fisch.) Bunge is a fundamental herb in traditional Chinese medicine. It has a long history of use in clinical practice for treating stroke and its associated sequelae. Notably, Formononetin (FN) has been identified as a primary bioactive isoflavone in this herb. However, its specific function in cerebral ischemia‒reperfusion injury remains unclear, especially regarding the area of immunometabolic regulation. Ischemic stroke remains a major cause of neurological disability worldwide. Although reperfusion is crucial for salvaging the ischemic penumbra, it also contributes to secondary injury driven by microglial activation. Emerging evidence suggests that targeting metabolic immune interactions may help mitigate postreperfusion neuroinflammation. This study aimed to investigate whether FN attenuates cerebral ischemia‒reperfusion injury by modulating microglial metabolism and polarization. A transient middle cerebral artery occlusion (tMCAO) model was established in mice. Formononetin (FN) was administered immediately after reperfusion. Neurological deficit scores were assessed daily for three days. Twenty-four hours after reperfusion, pathological injury was evaluated by hematoxylin and eosin (H&E) staining and a TUNEL assay. Microglial polarization markers were analyzed using immunofluorescence and Western blotting. Inflammatory cytokines were measured by real-time quantitative polymerase chain reaction (RT‒qPCR) and enzyme-linked immunosorbent assay (ELISA). RNA sequencing was performed on peri-infarct cortical tissue to identify affected pathways. Glycolytic protein levels in the same region were measured by western blotting. Molecular docking was employed to predict key bioactive compounds and their potential targets. These predictions were further validated by Western blot analysis. For in vitro studies, BV2 cells were subjected to oxygen‒glucose deprivation and reperfusion (OGD/R). Polarization markers were subsequently detected by flow cytometry and RT‒qPCR. Cellular ATP and lactate levels, glucose uptake, the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) were measured. An AMPK inhibitor was used for intervention in both in vivo and in vitro experiments. Key indicators related to AMPK signaling, microglial polarization, and glycolysis were examined via immunofluorescence and Western blotting. FN treatment improved neurological function scores, reduced infarct volume, and attenuated pathological injury in tMCAO mice. Both in vivo and in vitro, FN treatment inhibited glycolysis and enhanced mitochondrial oxidative metabolism. It also decreased M1-like polarization while increasing M2-like polarization markers, leading to a reduction in proinflammatory cytokine production. RNA sequencing and molecular docking analysis revealed the AMPK/mTOR/HIF-1⍺ pathway, which was subsequently confirmed at the protein level. An AMPK inhibitor reversed the FN-induced changes in both metabolic and microglial phenotypes. FN suppresses glycolytic metabolism in microglia through AMPK signaling, thereby influencing microglial polarization and attenuating neuroinflammation.

M2 macrophage-derived migrasomes enhance bone regeneration by directing osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs).

This study aimed to investigate the effect of downhill running on mitophagic flux and autophagosome-lysosome fusion in rat soleus muscle. Sprague-Dawley rats were trained on a treadmill at a speed of 16 m·min -1 and a decline of -16° for 90 min, and the soleus muscle was sampled at 0 h, 12 h, 24 h, 48 h, and 72 h after exercise. Mitochondrial ultrastructural changes were observed by using a transmission electron microscope. Protein levels of Cathepsin D, Vacuolar H + -ATPase (V-ATPase), mitochondrial respiratory complex Ⅰ (NDUFB8), complex Ⅲ (UQCRC2), and microtubule-associated protein 1 light chain 3 (LC3) were determined by Western blot. Mitochondria co-localizations with LC3 and lysosomal-associated membrane protein 2 (LAMP2), syntaxin 17 (STX17) co-localizations with LC3, LAMP2, SNAP29, and vesicle-associated membrane protein 8 (VAMP8), as well as the SNAP29 co-localizations with VAMP8, were measured by immunofluorescence. To assess mitophagic flux in vivo , colchicine or saline was injected intraperitoneally 3 d before exercise, and the protein expression of mitochondrial LC3-Ⅱ was detected by Western blot. After downhill running, mitochondrial structure appeared to be abnormal and contained autophagosomes and autophagolysosomes. The expression levels of Cathepsin D, Vacuolar H + -ATPase, and mitochondrial LC3, as well as the co-localizations of STX17 with LC3 and SNAP29 were significantly higher, whereas the expression levels of mitochondrial NDUFB8, UQCRC2, and LAMP2, along with the co-localizations of STX17 with LAMP2 and VAMP8 were significantly lower than those in the control group. Specifically, mitochondrial LC3-Ⅱ flux was significantly lower following downhill running. A bout of downhill running may block mitophagic flux by impairing mitophagosome-lysosome fusion, which is accompanied by increased recruitment of STX17 and SNAP29 to autophagosome and reduced co-localizations of STX17 and SNAP29 with lysosomal VAMP8.

TNKS1 mediates the PTEN-PI3K/AKT pathway to regulate glycolysis and proliferation in gliomas.

Identification of three novel linear B-cell epitopes located on the glycoprotein of Micropterus salmoides rhabdovirus using monoclonal antibodies.

To investigate the mechanism by which BRD4 accelerates acute lung injury (ALI) by promoting ferroptosis mediated by ANP32B/H3K27ac/MYC/HOXB8/BACH1 in alveolar epithelial cells. Gene co-expression was analyzed with bioinformatics. Eighteen SPF-grade C57BL/6J male mice (6-8 weeks old, 20 ± 4 g) were divided into three groups: Sham, Model, and Model-JQ1. Lung function was analyzed post-anesthesia; after euthanasia, lung tissues were collected for TEM to observe structural changes. HE staining assessed cellular morphology and pathology, while Prussian blue staining evaluated iron deposition. Western Blot detected BRD4, ANP32B, MYC, HOXB8, and BACH1 protein expression. ELISA measured GSH, MDA, lipid ROS, Fe2+, and LPO levels. MLE-12 cells were cultured and divided into four groups: NC, LPS, LPS-JQ1, and LPS-JQ1-BACH1-OE. Western Blot and immunofluorescence analyzed protein expression, and TEM observed cell ultrastructure. ELISA assessed oxidative stress markers. HOXB8 regulates BACH1, impacting oxidative stress and iron metabolism genes. LPS induced significant cell damage, alleviated by BRD4 inhibition. JQ1 improved lung injury and function, reduced iron accumulation, and oxidative damage. Western Blot and ELISA showed LPS upregulated key proteins, reversed by BRD4 inhibition. JQ1 inhibited LPS-induced stress in cells; BACH1 overexpression partially reversed this. Immunofluorescence showed BRD4 inhibition suppressed BACH1 and promoted SLC7A11 expression. ALI is accelerated by BRD4 through the promotion of ANP32B/H3K27ac/MYC/HOXB8/BACH1-mediated ferroptosis in alveolar epithelial cells. A deeper understanding of the role of BRD4 in alveolar epithelial cell injury is provided by these findings, and potential therapeutic targets for the treatment of ALI may be identified.

Daidzein attenuates hepatic ischemia/reperfusion injury via HMGB1-TLR4 signaling pathway.

ALOX5 knockdown alleviates cartilage damage in osteoarthritis by inhibiting the NF-κB signaling pathway.

The impact of heterodimeric G protein G12 family on proliferation, migration, and invasion in human oral squamous cell carcinoma cells.

MST1 modulates inflammation by inhibiting BNIP3 -dependent mitophagy via the JNK/p53 pathway in acute lung injury.

The combination of Huangqi and Danggui alleviates cerebral ischemia/reperfusion injury by inhibiting pyroptosis via NOX4-mediated ROS accumulation in rats.

Piezo1 Mediates Mechanical Strain-Induced Bone Remodeling in TMJ Condylar Cartilage via PI3K/Akt Signaling.

Linggan Wuwei Jiangxin Decoction attenuates chronic obstructive pulmonary disease via modulation of the AGE/RAGE signaling pathway.

Intermittent fasting attenuates ovarian chronic inflammation in obese mice by inhibiting the CXCL12-CXCR4 axis.

Role of PTP1B in coordinating synaptic plasticity and ferroptosis: A mechanism underlying the antidepressant effect of spinosin from Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou.

SRPRB can regulate proliferation and migration in Triple-Negative breast cancer cells.

Endothelial Nitric Oxide Synthase Restores Diabetic Dentin Regeneration via AKT/Endothelial Nitric Oxide Synthase Axis.

Inonotus obliquus (Ach. ex Pers.) Pilát aqueous extract alleviates acute cold exposure/rewarming-induced myocardial injury by regulating mitochondrial dynamics via liver kinase B1/adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator-1 alpha signaling pathway activation.