Conventional therapies for colorectal cancer (CRC) are often constrained by limited specificity, while the hypoxic, acidic, and immunosuppressive commonly contributes to immunotherapy resistance. Herein, a dual-responsive nanosystem with oxygen vacancies (AgFeO2-PVP, termed Vo-AFP) was engineered against CRC. This system is selectively activated within the tumor microenvironment (TME) by H2S and acidic conditions, triggering Fe2+ release to induce ferroptosis and forming a dual-vacancy structure composed of iron and oxygen vacancies. These defects introduce sub-bandgap (intermediate energy bands) that facilitate two-step single-photon absorption under 1064 nm laser irradiation and promote non-radiative electron-hole recombination, boosting photothermal conversion efficiency from 17.03% to 34. 15%. Density functional theory (DFT) calculations confirm that the dual-vacancy configuration induces charge redistribution, enhancing localized surface plasmon resonance (LSPR) in the Near-infrared II (NIR-II) window. The synergy between defect-assisted sub-bandgap absorption and LSPR enhancement enables effective photothermal ablation of deep tumors. In vivo results show that localized heating further accelerates Fe2+ release and suppresses the GPX4-mediated antioxidant pathway, augmenting ferroptotic death. This photothermal-enhanced ferroptosis significantly sensitizes tumors to aPD-L1 checkpoint blockade, remodels the immunosuppressive microenvironment, activates systemic antitumor immunity, and inhibits tumors and pulmonary lesions. Vo-AFP thus provides an integrated theranostic platform and a new paradigm for activatable, defect-engineered nanosystem in CRC immunotherapy.

BACKGROUND AND PURPOSE:Previous studies have highlighted the significance of the bile acid receptor TGR5 (also known as Takeda G protein-coupled receptor 5) in regulating inflammation and mitochondrial homeostasis in various diseases, whereas the specific involvement of TGR5 in spinal cord injury (SCI) remains unclear. This study aimed to elucidate the effects of TGR5 on SCI, as well as the underlying mechanisms. EXPERIMENTAL APPROACH:The TGR5 agonist INT-777 was used to activate TGR5 in a mouse model of SCI, induced by contusion injury to T9-T10 vertebrae, and cultured cells. To determine the mechanism of TGR5 activation after SCI, public dataset analysis, behaviour assessment, histology and biochemical analysis relating to inflammation, pyroptosis and mitochondrial function were performed. KEY RESULTS:TGR5 levels were increased in a mouse model of spinal cord injury (SCI), and in primary microglia and BV2 cells treated with tert-butyl hydroperoxide. Furthermore, TGR5 activation by INT-777 improved functional recovery and tissue repair in SCI mice. Mechanistically, INT-777-mediated TGR5 activation exerted a neuroprotective effect by regulating cAMP/AMPK signalling, resulted in suppression of mitochondrial dysfunction and mitochondrial DNA (mtDNA) release, which inhibited absent in melanoma 2 (AIM2)-driven pyroptosis and the inflammatory response. Notably, AIM2 overexpression partly blocked the neuroprotective effects of TGR5 activation in SCI mice. Additionally, AMPK inhibition by dorsomorphin aggravated neural injury and inflammation was alleviated in AIM2 deletion mice following SCI. CONCLUSIONS AND IMPLICATIONS:INT-777 exerts anti-inflammatory and neuroprotective effects in the injured spinal cord by activating the TGR5/cAMP/AMPK pathway, thereby maintaining mitochondrial homeostasis and suppressing AIM2-mediated pyroptosis.

Traumatic spinal cord injuries (SCIs) exhibit marked differences in severity, yet objective biomarkers reflecting early pathological status remain limited. Here, we identify syntaxin-17 (STX17), a key autophagosomal SNARE protein, as a severity-associated biomarker and functional regulator of autophagic flux following SCI. Proteomic profiling and experimental validation revealed that moderate SCI is characterized by increased autophagic flux accompanied by increased neuronal STX17 expression, whereas severe SCI is characterized by STX17 downregulation, impaired autophagosome–lysosome fusion, and exacerbated neuronal necroptosis. Notably, serum STX17 levels in both SCI patients and mouse models correlated with injury severity, highlighting its translational potential as a biomarker. Mechanistically, restoring STX17 expression reestablished autophagic flux, suppressed necroptosis, and promoted axonal regeneration and functional recovery after severe SCI. We further identified an upstream circRNA–miRNA regulatory mechanism that modulates STX17 expression in neurons. Collectively, our findings establish STX17 as a previously unrecognized biomarker and therapeutic target that links autophagic flux dysregulation to injury severity and neuronal fate after traumatic SCI.

Spinal cord injury (SCI) is accompanied by a significant microglia-associated inflammatory response that is associated with secondary tissue damage and poorer functional outcomes. Serum and glucocorticoid-regulated kinase 1 (SGK1) has been implicated in the regulation of cell survival and neuronal excitability in various diseases. However, the role and cell-specific mechanism of SGK1 in SCI remain to be elucidated. In this study, we observed that SGK1 was predominantly expressed in microglia located at the lesion margin during the early phase of SCI in a mouse contusion model. Inhibition of SGK1 by GSK650394 has been shown to promote neural repair while simultaneously suppressing neuroinflammation and mitochondrial oxidative stress. Mechanistically, the inhibition of SGK1 results in a reduction of FoxO1 phosphorylation and the promotion of nuclear import, consequently inducing microglial mitophagy and promoting mitochondrial homeostasis, leading to the suppression of absent in melanoma 2 (AIM2) related pyroptosis and the conversion of microglia into a neuroprotective M2 phenotype. In particular, AIM2 overexpression or deletion effectively interfered with the influence of SGK1-FoxO1 on the modulation of SCI. In conclusion, the present findings provide a potential therapeutic strategy for the treatment of SCI.

Trophoblast cells serve as the foundation for placental development. We analyzed published multiomics sequencing data and found that trophoblast cells highly expressed RRS1 compared to primitive endoderm and epiblast. We used HTR-8/SVneo cells for further investigation, and Western blot and immunofluorescence staining confirmed that HTR-8/SVneo cells highly expressed RRS1. RRS1 was successfully knocked down in HTR-8/SVneo cells using siRNA. Using IncuCyte S3 live-cell analysis system based on continuous live-cell imaging and real-time data, we observed that proliferation, migration, and invasion abilities were all significantly decreased in RRS1-knockdown cells. RNA-seq revealed that knockdown of RRS1 affected the gene transcription, and upregulated pathways in extracellular matrix organization, DNA damage response, and intrinsic apoptotic signaling, downregulated pathways in embryo implantation, trophoblast cell migration, and wound healing. Differentially expressed genes were enriched in diseases related to placental development. Consistent with these findings, human chorionic villus samples collected from spontaneous abortion cases exhibited significantly reduced RRS1 expression compared to normal controls. Our results highlight the functional importance of RRS1 in human trophoblasts and suggest that its deficiency contributes to early pregnancy loss.

Ultrasound-responsive drug delivery systems have emerged as a promising approach in cancer therapy, offering enhanced targeting precision, controlled drug release, and reduced systemic toxicity. These systems utilize the mechanical and thermal effects of ultrasound to enable the spatiotemporally triggered release of therapeutic payloads in tumor sites. This review provides an overview of the key mechanisms underlying ultrasound-responsive drug delivery, including the activation of sonosensitizers and prodrugs, as well as the role of ultrasound-responsive nanocarriers such as liposomes, micelles, nanobubbles, and metal-organic frameworks. We explore the biophysical effects of ultrasound, including mechanical cavitation and thermal effects, that enable localized drug release and their application in enhancing the permeability of tumor tissues. Additionally, the combination of ultrasound with other therapeutic modalities such as chemotherapy, immunotherapy, and gene therapy is discussed, highlighting the synergistic potential of multimodal treatment strategies. Despite the promising preclinical findings, challenges remain, such as optimizing ultrasound parameters, improving nanocarrier stability, and ensuring clinical translation. Future research is directed toward overcoming these limitations and expanding the clinical applicability of ultrasound-responsive drug delivery systems in cancer treatment. Integrating ultrasound-triggered systems with advanced imaging technologies offers a pathway toward precision medicine, allowing for tailored cancer therapies with minimized off-target effects.

Mitochondrial oxidative stress and the absent in melanoma 2 (AIM2) inflammasome play crucial roles in the regulation of secondary injury in patients with spinal cord injury (SCI). AIM2 responds to oxidative stress-mediated DNA damage, and this response leads to neuroinflammation. Salt-inducible kinase 2 (SIK2) is an AMPK-related protein kinase that plays a role in modulating cell metabolism and homeostasis. SIK2 and AIM2 are key molecules involved in metabolic regulation and the innate immune response, respectively. There is a potential association between SIK2 and AIM2 in terms of the cellular stress response, DNA damage repair and inflammatory signal transduction. However, the detailed role and mechanisms remain to be fully elucidated in the context of SCI. The present study revealed that SIK2 and AIM2 increase the number of microglia after SCI. Moreover, pharmacological inhibition of SIK2 or genetic deletion of AIM2 improves functional recovery. In addition, the SIK2 inhibitor ARN-3236, which alleviates the neuroinflammatory response, attenuates mitochondrial dysfunction and represses AIM2 activation in microglia. Mechanistically, SIK2 inhibition reduces Drp1-dependent mitochondrial fission through the CRTC1/CREB pathway, thereby decreasing mitochondrial DNA (mtDNA) leakage and AIM2 inflammasome activation, which inhibits the release of pyroptosis-related proteins and proinflammatory cytokines, ultimately mitigating neuroinflammation after SCI. Furthermore, SIK2-mediated neuroinflammation and functional recovery are related to AIM2. Thus, modulating microglial function through inhibition of SIK2 may be a viable therapeutic strategy for promoting functional recovery after SCI.

AIM:The purpose of this study was to investigate the value of the tissue annular motion displacement (TMAD) parameter in assessing left ventricular systolic function in patients with severe aortic stenosis (AS) and to investigate the risk factors for major adverse cardiovascular events (MACEs) in patients with severe AS with a biplane Simpson's method ejection fraction (LVEF-Simpson) ≥ 50%. METHODS:We enrolled 81 patients diagnosed with severe AS and 22 controls. Comparative analyses were performed between the groups, and longitudinal follow-up assessments tracked the incidence of MACEs. Survival analysis, utilizing Kaplan-Meier curves, was employed to determine the prognostic significance of TMAD parameters. RESULTS:TMAD parameters showed negative linear correlations with left ventricle global longitudinal strain (LVGLS). Overall, 69 patients (85.2%) underwent successful transcatheter aortic valve replacement (TAVR), which significantly improves myocardial longitudinal systolic function. MACE occurred in 12 (14.8%) AS patients during the follow-up period. CONCLUSION:TMAD parameters allowed early detection of left ventricle systolic dysfunction (LVSF) in severe AS patients with normal ejection fraction and correlated well with LVGLS, and TMADmid-A4C was a strong predictor of MACE in severe AS patients with preserved LVEF.

ObjectivesThe study aimed to evaluate the effect of GeLMA/bFGF hydrogel loaded with dental pulp stem cells (DPSCs) on the repair and regeneration of traumatic optic nerve injury.Materials and methodsGeLMA/bFGF hydrogel was photo-cross-linked by LED light. The physical–chemical properties and cytocompatibility of GeLMA/bFGF hydrogel after being squeezed (GeLMA/bFGF-SQ) were evaluated by SEM and degradation analyses, as well as live/dead and CCK-8 assays, respectively. The axon growth of PC12 cells was evaluated by MAP2 staining. The GeLMA/bFGF/DPSCs-SQ hydrogel was injected in situ into the lesion site to observe the repair of optic nerve injury. The number of retinal ganglion cells (RGCs) was calculated by βIII-tubulin staining. The length of regenerated axons was observed by CTB staining. Tissue recovery and axon growth of the optic nerve were observed by HE and TEM analyses, respectively.ResultsGeLMA/bFGF-SQ hydrogel had a porous structure and great degradability, as well as good cytocompatibility. Meanwhile, DPSCs-conditioned medium (DPSCs-CM) could promote the axon growth of PC12 cells. Moreover, the number of RGCs and the regeneration of axons of the optic nerve were the highest in the GeLMA/bFGF/DPSCs-SQ group. HE and TEM data revealed abundant newly and orderly arrangement of optic nerve axons that was observed in the damaged area of the GeLMA/bFGF/DPSCs-SQ group.ConclusionTransplantation of GeLMA/bFGF/DPSCs-SQ in situ provided an appropriate microenvironment for the repair and regeneration of injured optic nerves. Moreover, DPSCs combined with bFGF protected the RGCs from apoptosis and promoted optic nerve regeneration by secreting a series of neurotrophic factors.

Macrophage extracellular traps (METs) are highly correlated with the inflammatory response following central nervous system (CNS) injury. However, how to effectively target and inhibit the formation of METs remains a significant challenge. This study investigated the development of a tailored “combination of internal and external” strategy through the design of multifunctional nanozymes (DNase I@CeO 2 /Man) to inhibit and degrade METs after spinal cord injury (SCI). The DNase I@CeO 2 /Man construct consisted of hollow cerium dioxide (CeO 2 ) nanoparticles decorated with mannan (Man) and loaded with deoxyribonuclease I (DNase I). The presence of Man on the surface of the nanomedicine facilitated selective internalization by microglia rather than neurons. Hollow CeO 2 nanoparticles loaded with DNase I exhibited strong reactive oxygen species (ROS) scavenging capabilities and enabled the sustained release of DNase I, thereby effectively inhibiting the formation and promoting the degradation of METs. Furthermore, DNase I@CeO 2 /Man preserved mitochondrial homeostasis to reduce the leakage of mitochondrial DNA (mtDNA) and inhibited the cGAS/Sting signaling pathway, thereby mitigating the formation of METs from inside microglia. The released DNase I efficiently eliminated METs from the external environment of microglia. Moreover, DNase I@CeO 2 /Man is capable of modulating the anti‐inflammatory phenotypic transformation of microglia, suppressing inflammatory cascades, and subsequently restructuring the microglia‐neuronal cell axis by regulating the c‐Caspase 1‐GSDMD‐IL‐1β/IL‐18 pathway to prevent neuronal pyroptosis. In a murine model of SCI, the administration of DNase I@CeO 2 /Man significantly enhanced motor function and promoted axonal regeneration. In summary, this study not only presents a novel approach for inhibiting METs but also establishes a new framework for the treatment of other CNS injury‐related disorders.

Carbonic anhydrase IX (CAIX) and cysteine desulfurase (NFS1) are a synthetic lethal pair for cancer treatment. The suppression of NFS1 upregulates the iron starvation response and enriches intracellular Fe2+, leading to increased lipid peroxidation. However, the potency of the NFS1 inhibitor is compromised by the hypoxic microenvironment. To address this issue, we report a mechano-responsive ferrocene-bearing micelle that mimics the CAIX/NFS1 axis via ultrasound-activated iron release and the co-delivery of SLC-0111, a CAIX inhibitor. Upon ultrasound stimulation, the micelles disassemble in acidic lysosomes, releasing ferrous ions and SLC-0111, triggering intracellular acidification, reactive oxygen species accumulation, and lipid peroxidation. Moreover, the liberation of Fe2+ is facilitated by the presence of hydrogen peroxide and further enhanced by mechanical force. SLC-0111 leads to intracellular acidification and synergizes with Fe2+ to boost the Fenton reaction. This cascade disrupted redox homeostasis and induced multiple cell death pathways, including ferroptosis, apoptosis, pyroptosis, and necroptosis, in a tumor-selective manner. The in vivo efficacy studies in a 4T1 breast cancer model confirmed potent tumor suppression with minimal systemic toxicity. This work introduces a mechanical force-controlled strategy as a substitute for CAIX/NFS1 synthetic lethality therapy without the interference of oxygen level, holding promise for advancing tumor-specific therapy.

BackgroundCentral nervous system (CNS) injury causes severe organ damage due to both damage resulting from the injury and subsequent cell death. However, there are currently no effective treatments for countering the irreversible loss of cell function. Parthanatos is a poly (ADP-ribose) polymerase 1 (PARP-1)-dependent form of programmed cell death that is partly responsible for neural cell death. Consequently, the mechanism by which parthanatos promotes CNS injury has attracted significant scientific interest.Aim of reviewOur review aims to summarize the potential role of parthanatos in CNS injury and its molecular and pathophysiological mechanisms. Understanding the role of parthanatos and related molecules in CNS injury is crucial for developing effective treatment strategies and identifying important directions for future in-depth research.Key scientific concepts of reviewParthanatos (from Thanatos, the personification of death according to Greek mythology) is a type of programmed cell death that is initiated by the overactivation of PARP-1. This process triggers a cascade of reactions, including the accumulation of poly(ADP-ribose) (PAR), the nuclear translocation of apoptosis-inducing factor (AIF) after its release from mitochondria, and subsequent massive DNA fragmentation caused by migration inhibitory factor (MIF) forming a complex with AIF. Secondary molecular mechanisms, such as excitotoxicity and oxidative stress-induced overactivation of PARP-1, significantly exacerbate neuronal damage following initial mechanical injury to the CNS. Furthermore, parthanatos is not only associated with neuronal damage but also interacts with various other types of cell death. This review focuses on the latest research concerning the parthanatos cell death pathway, particularly considering its regulatory mechanisms and functions in CNS damage. We highlight the associations between parthanatos and different cell types involved in CNS damage and discuss potential therapeutic agents targeting the parthanatos pathway.

Spinal cord injury (SCI) is a destructive neurological trauma that induces permanent sensory and motor impairment as well as a deficit in autonomic physiological function. Melanocortin receptor 4 (MC4R) is a G protein-linked receptor that is extensively expressed in the neural system and contributes to inhibiting inflammation, regulating mitochondrial function, and inducing programmed cell death. However, the effect of MC4R in the modulation of oxidative stress and whether this mechanism is related to the role of absent in melanoma 2 (AIM2) in SCI are not confirmed yet. In the current study, we demonstrated that MC4R is significantly increased in the neurons of spinal cords after trauma and oxidative stimulation of cells. Further, activation of MC4R by RO27‐3225 effectively improved functional recovery, inhibited AIM2 activation, maintained mitochondrial homeostasis, repressed oxidative stress, and prevented Drp1 translocation to the mitochondria. Meanwhile, treating Drp1 inhibitors would be beneficial in reducing AIM2 activation, and activating AIM2 could abolish the protective effect of MC4R on neuron homeostasis. In conclusion, we demonstrated that MC4R protects against neural injury through a novel process by inhibiting mitochondrial dysfunction, oxidative stress, as well as AIM2 activation, which may serve as an available candidate for SCI therapy.

Lysosomes play a crucial role in various intracellular pathways as their final destination. Various stressors, whether mild or severe, can induce lysosomal membrane permeabilization (LMP), resulting in the release of lysosomal enzymes into the cytoplasm. LMP not only plays a pivotal role in various cellular events but also significantly contributes to programmed cell death (PCD). Previous research has demonstrated the participation of LMP in central nervous system (CNS) injuries, including traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid hemorrhage (SAH), and hypoxic-ischemic encephalopathy (HIE). However, the mechanisms underlying LMP in CNS injuries are poorly understood. The occurrence of LMP leads to the activation of inflammatory pathways, increased levels of oxidative stress, and PCD. Herein, we present a comprehensive overview of the latest findings regarding LMP and highlight its functions in cellular events and PCDs (lysosome-dependent cell death, apoptosis, pyroptosis, ferroptosis, and autophagy). In addition, we consolidate the most recent insights into LMP in CNS injury by summarizing and exploring the latest advances. We also review potential therapeutic strategies that aim to preserve LMP or inhibit the release of enzymes from lysosomes to alleviate the consequences of LMP in CNS injury. A better understanding of the role that LMP plays in CNS injury may facilitate the development of strategic treatment options for CNS injury.

Background and purpose: Autophagy is a protective factor for controlling neuronal damage, while necroptosis promotes neuroinflammation after spinal cord injury (SCI). DADLE (D-Ala(2) , D-Leu(5) ]-enkephalin) is a selective agonist for delta (delta) opioid receptor and has been identified as a promising drug for neuroprotection. The aim of this study was to investigate the mechanism/s by which DADLE causes locomotor recovery following SCI.Experimental approach: Spinal cord contusion model was used and DADLE was given by i.p. (16 mgkg(-1) ) in mice for following experiments. Motor function was assessed by footprint and Basso mouse scale (BMS) score analysis. Western blotting used to evaluate related protein expression. Immunofluorescence showed the protein expression in each cell and its distribution. Network pharmacology analysis was used to find the related signalling pathways.Key results: DADLE promoted functional recovery after SCI. In SCI model of mice, DADLE significantly increased autophagic flux and inhibited necroptosis. Concurrently, DADLE restored autophagic flux by decreasing lysosomal membrane permeabilization (LMP). Additionally, chloroquine administration reversed the protective effect of DADLE to inhibit necroptosis. Further analysis showed that DADLE decreased phosphorylated cPLA(2) , overexpression of cPLA(2) partially reversed DADLE inhibitory effect on LMP and necroptosis, as well as the promotion autophagy. Finally, AMPK/SIRT1/p38 pathway regulating cPLA(2) is involved in the action DADLE on SCI and naltrindole inhibited DADLE action on delta receptor and on AMPK signalling pathway.Conclusion and implication: DADLE causes its neuroprotective effects on SCI by promoting autophagic flux and inhibiting necroptosis by decreasing LMP via activating delta receptor/AMPK/SIRT1/p38/cPLA(2) pathway.

The dose‐dependent cardiomyopathy of adriamycin (doxorubicin) limits its long‐term clinical use, which is revealed as a consequence of cardiomyocyte ferroptosis. As a ferrous iron (Fe 2 + )‐dependent regulated cell death pathway, ferroptosis is induced by the tailored lipid peroxides in the cell membranes. Herein, iron‐chelating polymer micelles are reported for concurrent doxorubicin delivery and cardiotoxicity reduction. The amphiphilic polymer consists of methoxy poly (ethylene glycol)‐ co ‐poly (glutamic acid) copolymer as the backbone and deferiprone analog as the side chain. The chiral polymer adopted the α‐helix conformation to enable prolonged retention in the cell membranes, resulting in efficient iron chelation, ferroptosis inhibition, and cardiotoxicity reduction. The co‐encapsulation of doxorubicin and coenzyme Q 10 (CoQ 10 ) in micelles further alleviates the cardiotoxicity because the reduced CoQ 10 can act as a radical trapping agent to constrain lipid peroxidation and cardiomyocyte ferroptosis. The reduction of cardiotoxicity is accompanied by enhanced anticancer efficacy in an in vivo murine breast cancer model. The chiral iron‐chelating polymer micelles can be a promising platform for enhanced doxorubicin delivery and reduced cardiac adverse effects.

Background: Necroptosis and pyroptosis, two types of proinflammatory programmed cell death, were recently found to play important roles in spinal cord injury (SCI). Moreover, cyclic helix B peptide (CHBP) was designed to maintain erythropoietin (EPO) activity and protect tissue against the adverse effects of EPO. However, the protective mechanism of CHBP following SCI is still unknown. This research explored the necroptosis- and pyroptosis-related mechanism underlying the neuroprotective effect of CHBP after SCI. Methods: Gene Expression Omnibus (GEO) datasets and RNA sequencing were used to identify the molecular mechanisms of CHBP for SCI. A mouse model of contusion SCI was constructed, and HE staining, Nissl staining, Masson staining, footprint analysis and the Basso Mouse Scale (BMS) were applied for histological and behavioural analyses. qPCR, Western blot analysis, immunoprecipitation and immunofluorescence were utilized to analyse the levels of necroptosis, pyroptosis, autophagy and molecules associated with the AMPK signalling pathway. Results: The results revealed that CHBP significantly improved functional restoration, elevated autophagy, suppressed pyroptosis, and mitigated necroptosis after SCI. 3-Methyladenine (3-MA), an autophagy inhibitor, attenuated these beneficial effects of CHBP. Furthermore, CHBP-triggered elevation of autophagy was mediated by the dephosphorylation and nuclear translocation of TFEB, and this effect was due to stimulation of the AMPKFOXO3a-SPK2-CARM1 and AMPK-mTOR signalling pathways. Conclusion: CHBP acts as a powerful regulator of autophagy that improves functional recovery by alleviating proinflammatory cell death after SCI and thus might be a prospective therapeutic agent for clinical application.

Osteoarthritis (OA) is a chronic and costly disease characterized by cartilaginous degradation and inflammation in the joints. Syringic acid (SA), which is extracted from Morus nigra and Daphne gnidioides, possesses several health benefits, including antioxidant, antibacterial, and anticancer activities. Previous research has demonstrated that SA can restrain immunocyte activation and downregulate pro-inflammatory cytokine levels. Nevertheless, its role in the treatment of OA has not been elucidated to date. In vitro experiments, the inflammatory response in chondrocytes was realized by stimulation with IL-1 ss. The outcome indicated that SA suppressed the secretion of NO, iNOS, TNF-alpha, COX-2, and PGE2. Moreover, SA reduced the massive IL-1 ss-induced phosphorylation of the PTEN/AKT/NF-kB pathway. Furthermore, SA alleviated the degeneration of cartilage in the OA mice model in vivo. This study also illustrates that SA relieved the inflammation and cartilaginous degradation in OA, which suggests that SA might be an underlying candidate to be exploited for the treatment of OA.

Background: Increasing evidence suggests that acute traumatic spinal cord injury (SCI)-induced defects in autophagy and autophagy-lysosomal pathway (ALP) may contribute to endothelial barrier disruption following injury. Recently, Kruppel-like factor 2 (KLF2) was reported as a key molecular switch on regulating autophagy. Whether KLF2 coordinates endothelial endothelial ALP in SCI is not known. Methods: Genetic manipulations of KLF2 were performed in bEnd.3 cells and SCI model. Western blot, qRT-PCR, immunofluorescence staining and Lyso-Tracker Red staining, Evans blue dye extravasation, behavioral assessment via Basso mouse scale (BMS), electrophysiology and footprint analysis were performed. Results: In SCI, autophagy flux disruption in endothelial cells contributes to TJ proteins degradation, leading to blood-spinal cord barrier (BSCB) impairment. Furthermore, the KLF2 level was decreased in SCI, overexpression of which alleviated TJ proteins loss and BSCB damage, which improve motor function recovery in SCI mice, while knockdown of KLF2 displayed the opposite effects. At the molecular level, KLF2 overexpression alleviated the TJ proteins degradation and the endothelial permeability by tuning the ALP dysfunction caused by SCI and oxygen glucose deprivation (OGD). Conclusions: Endothelial KLF2 as one of the key contributors to SCI-mediated ALP dysfunction and BSCB disruption. KLF2 could be a promising pharmacological target for the management and treatment of SCI.