The FASEB Journal最新文献

Acute kidney injury is one of the most common complications of sepsis, characterized by high incidence and mortality. There is an urgent need for novel therapeutic strategies to improve the outcomes for patients with sepsis-associated acute kidney injury (SA-AKI). Our previous study demonstrated that magnesium sulfate (MgSO₄) exerts renoprotective effects in septic patients. This study aimed to explore the underlying protective mechanisms of MgSO₄ in SA-AKI. C57BL/6J mice were randomly assigned to five groups: the control group, the lipopolysaccharide (LPS, 10 mg/kg) group, and three MgSO₄ treatment groups receiving low, medium, and high dose (50, 100, 150 mg/kg, respectively). Renal function, histopathology, inflammatory markers, oxidative stress, mitochondrial function, and apoptosis were assessed. The results demonstrated that MgSO₄ significantly improved renal function, reducing kidney injury following LPS challenge. MgSO₄ also suppressed systemic and renal inflammation, as evidenced by decreased TNF-α, IL-6, or IL-1β levels in HK-2 cells, serum, and kidney tissues. Mechanistically, MgSO₄ alleviated oxidative stress and mitochondrial dysfunction in HK-2 cells, reducing mitochondrial Ca²⁺ loading and ROS production while restoring ATP content, antioxidant capacity, and mitochondrial membrane potential. Transcriptomic profiling of renal tissue identified inflammation and cell death related pathways as major LPS-responsive signatures and suggested NF-κB signaling as a potential MgSO₄-modulated axis. MgSO₄ inhibited intrinsic apoptosis both in vitro and in vivo, reflected by a reduced Bax/Bcl-2 ratio, decreased caspase-9 activation and cleaved caspase-3 signals, and fewer TUNEL-positive cells. Consistently, immunohistochemistry and immunoblotting confirmed that MgSO₄ inhibited renal NF-κB activation, reflected by reduced phosphorylation of p65 (p-p65). Collectively, these findings suggest that MgSO₄ mitigates SA-AKI by dampening inflammation, oxidative stress, mitochondrial dysfunction, and apoptosis, at least in part through inhibition of NF-κB signaling, supporting its therapeutic potential for SA-AKI.

Essential meiotic structure-specific endonuclease 1 (EME1) is integral to the maintenance of genomic stability in various cancers. However, its biological role and expression profile of this molecule in nasopharyngeal carcinoma (NPC) remain to be explored. In this study, we found that EME1 was overexpressed in NPC specimens compared to adjacent noncancerous tissues and was correlated with poorer overall survival outcomes. Furthermore, EME1 knockdown significantly inhibited the proliferation and migration of NPC cells in vitro and in vivo, with a corresponding sensitization to either camptothecin (CPT) or olaparib, evidenced by a further suppression of proliferation upon drug treatment. Notably, silencing EME1 significantly increased the sensitivity of NPC cell lines to CPT by enhancing ATM-CHEK2 phosphorylation and inducing nuclear abnormalities. Collectively, our findings suggest that combining EME1 modulation with agents such as CPT or olaparib could be an effective treatment strategy for NPC patients.

Glial metabolic reprogramming is essential for axonal regeneration post-spinal cord injury (SCI). While olfactory mucosa mesenchymal stem cell-derived exosomal lncRNA RMRP (OM-MSC-exo-RMRP) exhibits therapeutic potential for SCI, its involvement in glial metabolic reprogramming requires elucidation. OM-MSC-derived exosomes (OM-MSC-exos) were extracted and identified. Astrocytes (CTX-TNA2) were stimulated with TNF-α, treated with OM-MSC-exos, and co-cultured with dorsal root ganglion neuron (DRGns) to model glia–neuron interactions. DRGn axonal regeneration was assessed using immunofluorescence staining and western blotting. Astrocyte metabolism was assessed by detecting ECAR, OCR, glucose consumption, lactate production, and LDH activity. Molecular interactions among RMRP, WTAP, and p53 were determined by qPCR, western blotting, RNA immunoprecipitation, MeRIP-qPCR, and actinomycin D assays. A SCI mouse model was built and administered OM-MSC-exos, followed by histopathological evaluations using H&E, Nissl staining, and BMS scoring. RMRP was enriched in OM-MSC-exos and down-regulated in TNF-α-stimulated astrocytes. OM-MSC-exo treatment elevated RMRP expression, ECAR, glucose consumption, lactate production, LDH activity, decreased OCR in TNF-α-stimulated astrocytes, and promoted axonal regeneration. However, these effects were abolished when RMRP was down-regulated in OM-MSC-exos. Mechanistically, RMRP bound to WTAP in astrocytes, reducing WTAP expression and subsequent m⁶A of p53 mRNA, thereby destabilizing p53. WTAP or p53 overexpression could reverse RMRP overexpression-induced astrocyte metabolic reprogramming and DRGn axonal regeneration. In vivo assays indicated that OM-MSC-exo treatment promoted motor function, glycolysis, and axonal regeneration after SCI by transferring RMRP, with decreased WTAP and p53 expressions. OM-MSC-exo-RMRP mediates metabolic reprogramming to promote post-SCI axonal regeneration via inhibiting WTAP-mediated p53 m⁶A.

The cornea is highly susceptible to spaceflight-induced stress, compromising visual acuity and mission safety. Here, we identify endoplasmic reticulum (ER) and mitochondrial dysfunction as key mediators of corneal degeneration under simulated microgravity (SMG). SMG exposure led to corneal epithelial thinning, reduced nerve fiber density, and delayed wound healing. Multi-omics profiling and cellular assays revealed aberrant ER–mitochondrial crosstalk, characterized by excessive formation of mitochondria-associated membranes (MAMs) and activation of stress signaling pathways. Notably, treatment with low-intensity ultrasound (LIUS) restored corneal epithelial integrity by modulating MAM dynamics, alleviating organelle stress, and normalizing cellular homeostasis. These findings identify a novel molecular axis in microgravity-induced ocular degeneration and propose LIUS as a deployable, non-invasive countermeasure for preserving corneal health during deep spaceflight.

Available studies have found associations between several cytokines and calcific aortic valvular stenosis (CAVS). To better comprehend the causal link between circulating cytokines and CAVS, we performed a bidirectional Mendelian randomization (MR) study. Genetic variants associated with 41 cytokines were obtained from public genome-wide association study (GWAS), and summary statistics for GWAS of CAVS were obtained from the FinnGen consortium. Forward MR analysis was conducted to determine the impacts of 41 cytokines on CAVS risk and reverse MR analysis was used to determine whether genetic susceptibility to CAVS altered the levels of these cytokines. Inverse-variance weighting (IVW) was implemented as the primary method, and several different sensitivity analyses were used to verify the reliability of the findings. Our results found no significant association between 41 cytokines and CAVS risk. However, increased levels of interleukin-18 (IL-18) (odds ratio [OR] = 1.080, 95% CI: 1.024–1.139) and interferon-gamma (IFN-γ) (OR = 1.157, 95% CI: 1.028–1.302) had suggestive connections with an elevated risk of CAVS, and increased levels of IL-13 (OR = 0.942, 95% CI: 0.890–0.997) and IL-5 (OR = 0.892, 95% CI: 0.804–0.990) had suggestive associations with a reduced risk of CAVS. A reverse MR analysis found that CAVS had a suggestive relationship with a reduced level of platelet-derived growth factor BB (PDGF-BB) (OR = 0.920, 95% CI: 0.853–0.993) and IL-4 (OR = 0.925, 95% CI: 0.856–1.000). Our findings suggest the causal effects of IL-18, IFN-γ, IL-13, and IL-5 on CAVS risk, and genetic predisposition of CAVS may reduce the levels of PDGF-BB and IL-4.

Radiotherapy activates both the PI3K/AKT pathway and autophagy in cervical cancer, contributing to radioresistance. To address this, EM2, a dual AKT/autophagy inhibitor, was investigated for its potential to enhance radiosensitivity. RNA-Seq, Western blot, qRT-PCR, and transmission electron microscopy were employed to analyze PI3K/AKT and autophagy pathways following irradiation, while CCK8, clone formation, and flow cytometry assays evaluated proliferation, apoptosis, and cell cycle effects. KEGG and GSEA analyses confirmed irradiation-induced activation of the PI3K/AKT pathway. Both PI3K and autophagy inhibitors significantly improved efficacy, whereas EM2 suppressed AKT pathway activation and autophagy, synergistically inducing G2/M phase arrest, and increasing apoptosis. In vivo experiments using a nude mouse xenograft model demonstrated that EM2 combined with irradiation effectively suppressed tumor growth, PI3K/AKT activation, and autophagy without significant toxicity. These results underscore EM2 as a promising therapeutic agent to overcome radioresistance by simultaneously targeting the PI3K/AKT pathway and autophagy.

Exposure to small independent space (SIS) causes stress-related behavioral and neural abnormalities, but the time-dependent mechanisms and gut microbiota-hippocampus interactions remain unclear. To investigate the time-dependent effects of acute and chronic restraint stress (CRS) on mouse behavior, neuroendocrine function, gut microbiota, and hippocampal activity. Behavioral assessments were conducted using the open field test and tail suspension test. Meanwhile, enzyme-linked immunosorbent assay (ELISA) was applied to measure neurotransmitters, hypothalamic–pituitary–adrenal (HPA) axis markers, and inflammatory factors; 16S rRNA sequencing was used for gut microbiota analysis; liquid chromatography–tandem mass spectrometry (LC–MS/MS) for metabolite identification; and immunofluorescence staining for hippocampal structure observation. Acute SIS induced depression-like behaviors. Chronic SIS showed peak despair at 4 days (d), followed by persistent depression at 8 d. Norepinephrine (NE) increased while 5-hydroxytryptamine (5-HT) decreased; NE depletion at 4 d coincided with reduced hippocampal glucocorticoid receptor (GR) expression. Both acute (2 h) and chronic (4 d) SIS reduced gut microbiota diversity and disrupted tyrosine metabolism. Hippocampal tests showed neuronal compensation at 6 h post-acute stress and neuronal apoptosis with glial dysfunction after 4 d of chronic stress. SIS damages via the “gut microbiota-tyrosine metabolism-hippocampus axis,” with 4 d of chronic exposure as a critical decompensation point, offering a time-specific intervention target.

Mechanical force induces a series of biological responses such as inflammation in force-loaded tissues and cells. The periodontal ligament (PDL) fibroblasts act as vital sensors and transducers in response to mechanical loading within periodontium. Studies have shown that PDL fibroblasts also participate in mediating periodontal inflammatory responses under physiological or pathological conditions. Mitophagy is a selective form of autophagy that eliminates damaged or dysfunctional mitochondria to maintain cellular health. It plays a vital role in inflammation alleviation, cell survival, and tissue homeostasis. However, whether mitophagy is involved in mechanical force-related inflammation and the precise mechanisms remain unclear. In addition, the elucidation of the interplay between mitophagy and periodontal inflammation during mechanical loading is of great significance for maintaining periodontal homeostasis under systemic conditions. In our study, we first focused on validating the crosstalk between mitophagy and inflammation in PDL fibroblasts under mechanical loading and aimed to elucidate the upstream regulatory role of adenosine monophosphate-activated protein kinase (AMPK). Moreover, based on both in vivo and in vitro experiments, we found that high glucose conditions exacerbated inflammation by suppressing mitophagy. Additionally, targeted activation of AMPK enhanced mitochondrial turnover through mitophagy, thereby disrupting proinflammatory cascades and offering a promising strategy for inflammation resolution in periodontal diseases, especially those combined with diabetic conditions.