Diabetic chronic wound, plagued by hyperglycemia-driven oxidative stress, bacterial infection, and impaired angiogenesis, represent a critical biomedical challenge with limited treatment options and dire clinical outcomes. Herein, a glucose-responsive “sense-and-treat” microneedle (MN) patch was designed for on-demand drug release and comprehensive diabetic chronic wound therapy. The multifunctional MN patch (denoted EAG-MNs patch) was fabricated from two functional precursors. Solution A was consisted of phenylboronic acid modified gelatin (PBA-Gel) complexed with epigallocatechin gallate (EGCG) through dynamic boronic ester bonds to provide glucose responsiveness. Solution B contained silver nanoparticle-decorated graphene oxide (AgGO) dispersed in hyaluronic acid (HA) to enable sustained antibacterial action. Upon exposure to hyperglycemic wound microenvironment, the boronic ester bonds undergo dissociation, triggering the rapid release of EGCG to scavenge reactive oxygen species, alleviate inflammation, and promote angiogenesis. Simultaneously, the dissolved AgGO component ensures robust and long-lasting antibacterial activity against prevalent pathogens. In an infected diabetic mouse wound model, the EAG-MNs patch significantly accelerated wound closure, reduced granulation tissue formation, enhanced collagen deposition and vascularization, and effectively eliminated bacterial infection compared to control groups. This intelligent MNs platform exemplifies a novel “sense-and-treat” paradigm for diabetic chronic wound management by actively sensing pathological cues and executing synergistic therapeutic actions, offering a promising versatile strategy for advanced wound care.

BACKGROUND:Osteosarcoma is the malignant bone neoplasm affecting pediatric and adolescent with unsatisfactory five-year survival. Dysregulated phospholipid metabolism is crucial for membrane integrity, signaling, and energy homeostasis, contributinga range of cancers' progression. Nevertheless, itsrolein osteosarcoma persists uncertain. The investigation aims to identify phospholipid metabolism-related signature genes for osteosarcoma and evaluate their prognostic value and therapeutic potential. METHODS:The data curated from the TARGET and GEO databases. Differential expression analysis, LASSO, and SVM-RFE screened feature genes. A Cox regression-based prognostic model was established and validated internally (survival analysis, ROC) and externally, assessing discrimination and calibration. Analyses of the tumor microenvironment composition, immunocyte infiltration, and drug sensitivity and key findings were validatedin vitro. RESULTS:A risk model incorporating seven prognostic genes was constructed and confirmed using univariate Cox regression. High-risk patients showed markedly reduced overall survival(P < 0.001). ROC curves validated the predictive power of risk model (AUCs > 0.81 at 1, 3, and 5 years). Single-cell sequencing uncovered a linkage between genes and immunocyte infiltration. Risk scores covaried with infiltration extent and immune pathway activity. Metabolomic analysis of five phospholipid-related genes revealed tumor-associated metabolite differences. In vitro, Vorinostat strongly induced Osteosarcoma cell apoptosis and upregulated VAC14 protein expression. CONCLUSIONS:The phospholipid metabolism-based risk model aids Osteosarcoma prognosis. The immune microenvironment and drug sensitivity lay the groundwork for future mechanistic investigations. VAC14 is a potential target for neoadjuvant therapy, highlighting phospholipid metabolism as a promising therapeutic avenue.

Exosomes exert a protective effect on motor functional recovery after spinal cord injury (SCI) but are limited by the lack of effective preservation in situ and the indeterminate underlying mechanism. Firstly, we fabricated a versatile and optimized controlled release system for mesenchymal stromal cells-derived exosomes, precise concentration of Laponite dispersion combines with exosomes via electrostatic incorporation to form a 3D porous structure, exhibiting excellent biocompatibility and a sustained release of exosomes. Secondly, we assess multiple therapeutic benefits of the Lap@exo gel, including motor recovery, axonal rehabilitation, scar growth, inflammatory response and remyelination. The comprehensive demonstration a unique synergistic effect of Laponite gel and exosomes. Last, we analysis the functional underlying mechanism of the exosomes. We used ExoRNA sequencing and bioinformatic analysis to find that microtubule polymerization and cytoskeleton organization pathways were related to the axon regeneration. Additionally, the microtubule dynamic regulated by Lap@exo was studied for the axonal regeneration as well as the distribution of mitochondria. The study demonstrated that Lap@exo released exosomes for a sustained period of time and protected its bioactivities, and the combination of exosomes with bioactive multifunctional gel could lead to satisfactory recovery of locomotor function for patients with diseases of the central nervous system.

Endothelial progenitor cells (EPCs) derived extracellular vesicles (EVs) are involved in maintaining vascular homeostasis, while effects of hypoxic preconditioned EPCs-derived EVs (Hy-EVs) on atherosclerosis (AS) remain unclear. Hy-EVs and normal oxygen EVs (N-EVs) were pretreated for ApoE-/- mice and ox-LDL treated macrophages. N-EVs administration attenuated atherosclerosis progression, Hy-EVs further decreased the plaque area, increased collagen content, reduced lipid deposition and improved inflammatory response. Proteomics and in vitro data suggested that Hy-EVs inhibited macrophages ferroptosis and improved oxidative stress via increasing GPX4 and xCT level. Hy-EVs proteomics revealed that argininosuccinate synthetase1 (ASS1) levels were significantly higher in Hy-EVs than N-EVs, ASS1 knockdown in EPCs blocked the protective effects of Hy-EVs on macrophage ferroptosis and AS progression, whereas ASS1 supplementation restored the effect. Mechanistically, increased ASS1 in Hy-EVs suppressed GCN2 activation by enhancing arginine generation in macrophages. GCN2 agonist or arginine consumption significantly attenuated the protective effect of Hy-EVs on macrophage ferroptosis and AS progression. Furthermore, LC/MS indicated that GCN2 bonded to NRF2, while arginine generated by ASS1 enhanced NRF2 nuclear translocation and increased levels of its downstream target gene GPX4/xCT by reducing GCN2/NRF2 interaction. Our study suggested that Hy-EVs further attenuated atherosclerosis progression by inhibiting macrophage ferroptosis via enhancing arginine generation and inhibiting GCN2/NRF2 interaction. The data provides strong evidence for the translational application of EPCs derived Hy-EVs as atherosclerotic plaques.

Smoking is considered as the major risk factor for the progression of atherosclerosis (AS), whereas the underlying immunological mechanism remains unclear. ApoEKO mice were treated with cigarette tar via inhalation in vivo, mouse arterial endothelial cells (MAECs) and human coronary artery endothelial cells (HCAECs) were treated with cigarette tar in vitro. Single cell RNA sequencing (scRNA-seq) was utilized to explore the molecular mechanism of CD4+ Granzyme A (Gzma+) T cells activation in smoke-related atherosclerotic progression. Cigarette tar significantly aggravated the development of atherosclerotic lesion in ApoEKO mice. Results of scRNA-seq and validation experiments further indicated that cigarette tar inhalation significantly increased the proportion of CD4+Gzma+ T cells, a T cell subset which could lead to endothelial cells (ECs) damage. Concurrently, a significant reduction in the proportion of ECs was observed. Of note, cigarette tar enhanced interaction of ECs and CD4+Gzma+ T cells via mediating major histocompatibility complex II (MHC II) signaling pathway activation rather than other antigen-presenting cell types. Mechanistically, class II major histocompatibility complex transactivator (CIITA), a key transcriptional regulator of MHC II genes expression, was identified to connect with protein arginine methyltransferases-5 (PRMT5), scoring highest via utilizing mass spectrometry analysis, which triggered symmetrical dimethylation modification of H3R2 and promoted MHC II expression. Meanwhile, CIITA knockout/knockdown, and PRMT5 inhibition/knockdown inhibited the infiltration of CD4+Gzma+ T cells and MHC II expression of ECs, alleviating the atherosclerotic lesion severity. Additionally, findings from the in vitro co-culture experiment provided additional confirmation that activated CD4+Gzma+ T cells possessed the capability to induce cytotoxicity in ECs. Cigarette tar augments the expression of MHC II in ECs via promoting CIITA nuclear translocation and PRMT5-mediated methylation modification. This process activates CD4+Gzma+ T cells, which subsequently mediate ECs injury in turn, thereby contributing to the progression of AS. Therefore, CIITA and PRMT5 represent potential therapeutic targets for interventions aimed at mitigating smoke-related AS.

T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments, severely compromising the effectiveness of antitumor and antiviral immunity. In recent years, there has been significant progress in understanding the underlying mechanisms of T cell exhaustion, including external factors and intrinsic cellular changes that drive this dysfunctional state. Key external factors such as persistent antigen exposure, immune checkpoint signaling, and the cytokine milieu, as well as intrinsic changes such as altered metabolic processes, epigenetic modifications, and transcriptional reprogramming, contribute to T cell dysfunction. Emerging therapies targeting T cell exhaustion aim to restore immune function and enhance antitumor and antiviral immunity. These therapeutic strategies include immune checkpoint inhibition, cytokine therapies, metabolic reprogramming, and cell-based therapies. Despite these advancements, reversing T cell exhaustion presents several challenges, such as individual variability, resistance, and potential side effects. Furthermore, accurately assessing markers of T cell functional recovery and the long-term impacts of these therapeutic approaches remain challenging research areas. This review provides an overview of the history and milestones in T cell exhaustion research; summarizes the mechanisms of T cell exhaustion and its implications in cancer, chronic infections, and autoimmune diseases; discusses advancements and challenges in emerging therapies; and explores future research directions aimed at improving T cell function and enhancing immune responses.

Background Dimethylglycine (DMG) has been shown to be highly correlated with coronary heart disease (CHD), whose pathological basic is atherosclerosis (AS). Macrophage ferroptosis is the crucial pathological events in AS progression, but the underlying mechanism is unclear. Hence, we conducted a series of studies to elucidate the specific effects and mechanism of DMG on macrophages in the progression of AS. Method A case-control study was conducted on patients with CHD to evaluate the levels of DMG. Additionally, a prospective cohort study was performed to assess the association between baseline serum DMG levels and the incidence of major adverse cardiovascular events (MACE). Single-cell RNA sequencing (scRNA-seq) and proteomics analyses were conducted on the aortas of high-fat diet-fed ApoE knockout (ApoEKO) mice administered with or without DMG. THP-1 were exposed to DMG in vitro to investigate potential underlying mechanisms. Results High level DMG level was associated with higher MACE rate in patients with ST-segment elevation myocardial infarction (STEMI). DMG administration significantly decreased the glutathione Peroxidase 4 (GPX4)/solute carrier family 7 member 11 (xCT) expression of macrophages of aortas in ApoEKO mice. Mechanically, Mechanistically, DMG bound to the Ile559 (I559) site of NRF2 (identified by molecular docking and validated by site-directed mutagenesis), inhibited NRF2 nuclear translocation and its promoter enrichment on GPX4/xCT, which was reversed by TBHQ. and mutation of the I559 site (I559S) significantly inhibited the DMG-induced ferroptosis of macrophages. In vivo study demonstrated that the administration of DMG via gavage markedly exacerbated atherosclerotic lesion severity, exhibiting elevated the extent of aortic lipid peroxidation, and increased ferroptosis levels in macrophages, which were ameliorated by TBHQ administration. Conclusions DMG inhibits NRF2 nuclear translocation mainly by binding to the I559 site of NRF2 (identified by molecular docking and validated by site-directed mutagenesis), thereby reducing GPX4/xCT expression and promoting macrophage ferroptosis to accelerate AS. Targeting macrophages ferroptosis may serve as a potential intervention strategy for CHD patients with high DMG.

Patients with sepsis commonly endure severe renal dysfunction and damage, hastening to end-stage renal failure with high mortality, and effective treatment options are currently lacking. Growth differentiation factor 11 (GDF11), belonging to the transforming growth factor beta (TGF-β) superfamily, has shown therapeutic potential for numerous acute and chronic inflammatory conditions. Nevertheless, its function in sepsis-associated acute kidney injury (SAKI) remains unclear. This study sought to explore GDF11’s role in SAKI and determine the signaling pathways it modulates. Alterations in GDF11 expression in the kidneys of mice with SAKI were analyzed. The influence of GDF11 knockdown and recombinant GDF11 (rGDF11) supplementation on cecal ligation and puncture (CLP)-induced SAKI in mice was determined. RNA sequencing, Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and kit assays were performed to explore the underlying mechanisms. Tubular epithelial cells and macrophages in the kidneys of CLP-induced SAKI mice exhibited high levels of GDF11 expression. Moreover, gene silencing of GDF11 using adeno-associated virus (AAV) aggravated renal dysfunction, increased tubular damage, and augmented renal apoptosis in CLP-induced SAKI mice. In contrast, replenishment of rGDF11 significantly mitigated these adverse effects. Further studies indicated that GDF11 stimulated the nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated antioxidative pathways, primarily by inducing the expression of Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which subsequently decreased excessive inflammation and coagulation. Additionally, these beneficial effects of GDF11 were largely diminished by AAV-mediated PGC-1α knockdown and depletion of Nrf2 in CLP-induced SAKI mice. In summary, these findings indicate that GDF11 is a potential therapeutic approach for SAKI and highlight the crucial role of PGC-1α/Nrf2 signaling in GDF11-mediated renal protection during SAKI.

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, and the prognosis is poor due to distant metastasis. Thus, there is an urgent need to discover novel therapeutic targets and strategies to overcome metastasis. A series of in vitro and in vivo phenotype experiments were performed to investigate the role of phosphodiesterase 1A (PDE1A) in NSCLC. The RNA binding protein immunoprecipitation (RIP) assay, messenger RNA (mRNA) stability assay, and LC-MS/MS were performed to investigate the molecular mechanisms of PDE1A in NSCLC progression. PDE1A has been shown to promote metastasis and epithelial-mesenchymal transition (EMT) progression of NSCLC. In addition, NSCLC cells overexpressing PDE1A promoted angiogenesis by regulating exosome release. IL-6/JAK/STAT3 signaling pathway was highly enriched in PDE1A-coexpressed genes, and PDE1A promoted NSCLC metastasis by activating the STAT3 pathway. GO enrichment analysis of PDE1A-interacting genes showed that PDE1A might interact with YTHDF2 and participate in m6A-containing RNA binding. The binding between PDE1A and YTHDF2 was verified, and PDE1A regulated the STAT3 pathway by interacting with YTHDF2. The mechanism of the YTHDF2/PDE1A complex in regulating the STAT3 pathway was predicted by overlapping YTHDF2-interacting RNAs and genes coexpressed with YTHDF2 and STAT3. The interactions between YTHDF2 and target mRNAs were predicted, and there were three predicted targets of YTHDF2 with high scores: NRF2, SOCS2, and MET. Indeed, PDE1A interacted with YTHDF2, destabilized SOCS2, and activated the STAT3 pathway. Mechanistic data uncover a novel PDE1A/YTHDF2/STAT3 axis driving NSCLC metastasis and suggest potential therapeutic strategies for metastatic disease.

Background Cardiac issues following radiotherapy are increasingly prevalent among patients with thoracic cancer and coronary disease. However, the mechanisms underlying radiotherapy-induced plaque instability and changes in plaque characteristics on imaging remain unclear. This study used single-cell RNA sequencing to identify key features of vulnerable plaques following radiotherapy.Methods We applied dual-mode synchronized optical coherence tomography-intravascular ultrasound imaging in a rabbit model to reveal the characteristics of vulnerable plaques at various time points postradiotherapy. We then conducted single-cell RNA sequencing on atherosclerotic lesions from ApoE-/- (apolipoprotein E-/-) mice across 3 stages: nonirradiated, early irradiation, and advanced irradiation. Bioinformatics was used to analyze cell populations, trajectories, and interaction differences among the groups. This was followed by pathological staining, flow cytometry, gene knockout, and antibody depletion.Results In vivo optical coherence tomography-intravascular ultrasound imaging at the initial stage accurately evaluated radiation exposure's effect on the stability of rabbit carotid plaques. High-throughput single-cell transcriptomics mapped the radiotherapy-induced immune system remodeling in atherosclerotic lesions, and identified a granzyme K+ CD8+ (cluster of differentiation 8+) T-cell subpopulation. The infiltrating cells highly expressed the cytotoxic molecule GZMB (granzyme B) in the plaques. The absence of CD8+ T cells or GZMB ameliorated radiotherapy-exacerbated atherosclerotic lesions. This demonstrates the pathogenic function of GZMK+ (granzyme K+) CD8+ cytotoxic T cells in promoting radiotherapy-induced atherosclerotic lesion progression.Conclusions We identified characteristic arterial imaging changes resulting from radiation injury, accurately and dynamically assessing the effects of radiation exposure on plaque stability. Radiation exposure affected plaque stability by modulating GZMK+ CD8+ T-cell activation and GZMB function, suggesting GZMB as a mediator of radio-cardiovascular injury and a potential therapeutic target.

Spinal cord injury (SCI) is a potentially fatal condition that often results in loss of motor and sensory functions, thereby significantly burdening global health initiatives. Urolithin A (UA), an intestinal microbial metabolite of ellagic acid, is known for its potent anti-inflammatory properties in chronic inflammation contexts. UA treatment in humans induces a molecular signature of improved mitochondrial and cellular health. Yet, its effects on acute inflammation following SCI remain unclear. In this study, we developed an impact-induced mouse model for SCI and treated the injured mice with UA (50 mg/kg/d, till 8 weeks) via intragastric administration. Furthermore, we subjected BV2 cells to lipopolysaccharide and adenosine 5 '-triphosphate to simulate the post-injury inflammatory response. Our results demonstrated that pre-treatment with UA (10 mu M) effectively inhibited NLRP3 inflammasome activation in LPS-primed BV2 cells. This inhibition was evidenced by reduced cleaved Caspase-1 and mature IL-1 beta release, diminished ASC speck formation, and decreased gasdermin D (GSDMD)-mediated pyroptosis. Additionally, UA treatment restored mitochondrial activity and ROS production attenuated by NLRP3 activation, increased LC3-II expression, and enhanced LC3 co-localization with mitochondria. 3-Methyladenine (3-MA), an autophagy inhibitor, can partially reverse the stimulatory effect of UA on mitophagy, as well as the inhibitory effect of UA on pyroptosis. This study highlighted the protective role of UA against SCI through its promotion of mitophagy, which in turn inhibits NLRP3 inflammasome activation and pyroptosis.

Objectives:COTI-2, an innovative oral homocysteine, has shown promising antitumor results on multiple types of cancer. However, its effects in treating bladder cancer (BCa) and the underlying molecular mechanisms have not been elucidated. The present study aimed to explore the antitumor effects of COTI-2 on BCa and the potential mechanisms. Materials and Methods:BCa cell lines, including the 5637 and T24 cell lines, were treated with COTI-2 at concentrations of 0.5 and 1 μM, respectively. Cell Counting Kit (CCK)-8 assay, colony formation assay, apoptosis assay, and transwell migration and invasion assay were conducted to evaluate the antitumor effects of COTI-2 on BCa cells. Western blotting, H&E, immunohistochemical staining, and immunofluorescence analysis were performed to investigate the underlying mechanisms. Moreover, a xenograft model in nude mice using T24 cells was generated to determine the antitumor activities of COTI-2 in vivo. Results:COTI-2 highly inhibited the proliferation of BCa cell lines, including 5637 and T24 cells, and induced their apoptosis. Moreover, it efficiently suppressed the migration and invasion of BCa cells. Additionally, the subcutaneous xenograft model in nude mice showed that COTI-2 treatment inhibited the tumor growth of BCa by inducing its apoptosis in vivo. We also found that COTI-2 promoted apoptosis in BCa cells, presumably through activating the AMPK/mTOR pathway. Conclusion:Our data suggest that COTI-2 effectively reduces the malignancy of BCa, probably by inducing apoptosis via the AMPK/mTOR signaling pathway. These data highlight the potential of COTI-2 as a therapeutic agent for the treatment of BCa.

BACKGROUND:Nowadays, emerging evidence have suggested that the ferroptosis of macrophages could contribute to the progression of atherosclerosis (AS). Meanwhile, Spermine (Sp) could serve as an endogenous small molecule exhibiting a wide range of cardiovascular protective effects. METHODS:Zeolitic imidazolate framework-90 (ZIF90) nanoparticles were synthesized and utilized to create a novel delivery nanosystem encapsulated with Sp (CD16/32-ZIF90@Sp). The efficacy of CD16/32-ZIF90@Sp in protecting against AS and ferroptosis was evaluated in ApoE-/- mice and macrophages, with a focus on assessing potential adverse effects in vivo. RESULTS:CD16/32-ZIF90@Sp exhibited reliable and stable delivery of Sp within acidic environments and ATP sensitivity. CD16/32-ZIF90@Sp effectively reduced the cytotoxicity of Sp. As is evidenced by in vitro and vivo experiments, CD16/32-ZIF90@Sp showed precise targeting of macrophages within atherosclerotic plaques and ox-LDL-activated macrophages. Furthermore, treatment with CD16/32-ZIF90@Sp effectively attenuated the progression of AS and the ferroptosis of macrophage within plaque in ApoE-/- mice without causing significant side effects. Mechanistically, we found that CD16/32-ZIF90@Sp inhibited ferroptosis via improving mitochondrial function and upregulating the expression level of GPX4/xCT. CONCLUSION:Our study demonstrated that CD16/32-modified ZIF90 nanoparticles could effectively target macrophages within atherosclerotic plaques, leading to the inhibition of atherosclerotic plaque progression in ApoE-/- mice. These effects were attributed to the enhancement of mitochondrial function and the inhibition of macrophage ferroptosis, with limited side effects.

Osteoarthritis (OA) is a prevalent degenerative disease that lacks effective therapy. Oxidative stress is one of the major factors contributing to OA; however, treatments targeting oxidative stress are still lacking. In the current study, we established an oxidative stress-induced cell death model in chondrocytes in vitro and screened drugs that may suppress oxidative stress-induced cell death. Ethyl gallate (EG) was identified as the most potent drug against oxidative stress-induced cell death out of more than 600 drugs in the natural product library. Application of drugs without an appropriate delivery system for OA therapy may have drawbacks such as low bioavailability, short action time, and poor efficacy. Herein, poly-His6-zinc assembly (PZA), a pH-responsive metal-organic framework (MOF) loaded with EG (EG@PZA) was designed for OA therapy. It was demonstrated that EG@PZA may have the lysosome escape property, which dramatically increases the utilization of EG. Furthermore, EG@PZA showed enhanced release capability of EG in the acidic microenvironment. In vitro and in vivo studies demonstrated that EG@PZA effectively suppresses oxidative stress-induced extracellular matrix degradation, ferroptosis, and senescence in chondrocytes and also ameliorates OA in the destabilization of the medial meniscus (DMM) mouse model in vivo. Together, the current study showed that EG@PZA may become a potential controlled-release nanomaterial for effective OA therapy.

BACKGROUND AND PURPOSE:Lysosomal membrane permeabilization (LMP) is exacerbated following spinal cord injury (SCI), leading to increased neuronal cell death. Ubiquitination may affect LMP by regulating the stability and functionality of lysosomal membranes. Semax, a synthetic heptapeptide, comprising the ACTH (4-7) fragment and a C-terminal Pro-Gly-Pro tripeptide, exhibits neuroprotective properties and improves cognitive function. Given the key roles of LMP and ubiquitination in SCI pathophysiology, this study investigated how Semax could modulate these pathways to affect functional recovery following SCI. EXPERIMENTAL APPROACH:An SCI mouse model was generated by impacting the spinal cord of female C57BL/6 mice at T9-T10. Functional recovery in SCI mice was evaluated using histochemical methods, along with footprint analysis, Basso scores and inclined plane tests. Marker levels and distributions in the SCI model and in the PC12 cell neuroinflammation model were analysed using immunofluorescence, Western blot, RT-qPCR and transmission electron microscopy. RNA sequencing, network pharmacology and molecular docking were used to identify possible molecular targets of Semax. KEY RESULTS:Semax improved SCI functional recovery and inhibited LMP-related pyroptosis in SCI mice and neuroinflammation models, by decreasing oxidative stress. RNA-seq and other analyses found that Semax regulated the ubiquitin specific protease USP18. USP18 knockdown confirmed Semax's role in SCI recovery. Network pharmacology and docking revealed the μ-opioid receptor as a Semax target. CONCLUSION AND IMPLICATIONS:Semax promoted SCI functional recovery by targeting μ-opioid receptors, which regulated USP18 and, subsequently, deubiquitination of the fat mass and obesity-associated protein (FTO), suggesting its potential for SCI treatment.

After spinal cord injury (SCI), microglia polarization plays an important role in spinal cord recovery and axon regeneration. In this study, we conducted mRNA microarrays to identify genes associated with different microglial phenotypes. The results showed a correlation between microglial polarization and the PI3K/AKT signaling pathway, a key regulator of inflammatory responses. In addition, we found that Pectolinarin (PTR) could effectively inhibit lipopolysaccharide (LPS)-induced M1 polarization of microglia and facilitate their transition to the M2 phenotype by directly suppressing the PI3K/AKT signaling pathway. In our established animal model of SCI, it was confirmed that PTR treatment induced microglial polarization towards the M2 phenotype, resulting in reduced fibrous scar formation, enhanced myelin reconstitution, and improved axonal regeneration. In conclusion, targeting the PI3K/AKT signaling pathway with PTR presents a promising new direction for SCI treatment.

Smoking is the only cardiovascular risk factor for plaque erosion. We found cigarette tar resulted in erosion-like lesion development in apolipoprotein E-/- mice, with mural thrombosis, discontinuous endothelium, platelet activation, smooth muscle cell proliferation, and hyaluronic acid accumulation in the aorta. Single-cell transcriptomics revealed that genes relating to pyroptosis, platelet activation, and leukocytes adhesion were significantly increased in an endothelial cell subset. Rescue assays indicated cigarette tar caused human coronary artery endothelial cell pyroptosis by enhanced calcium-calmodulin-dependent protein kinase II / dynamin-related protein 1-mediated mitochondrial fission and mitochondrial DNA release via activating Ca2+ signaling. Inhibition of endothelial cell pyroptosis may be a novel therapeutic strategy to reduce plaque erosion.