Hydralazine represses Fpn ubiquitination to rescue injured neurons via competitive binding to UBA52.

A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.

Corydecusines A-H, new phthalideisoquinoline hemicetal alkaloids from the bulbs of Corydalis decumbens inhibit Tau pathology by activating autophagy mediated by AMPK-ULK1 pathway.

Twelve phthalideisoquinoline hemiacetal alkaloids including eight new ones (1-8) and one natural alkaloid characterized by an aziridine moiety with unassigned NMR data (9), were isolated and identified from the bulbs of Corydalis decumbens. Their structures were established by comprehensive analyses of HRESIMS, NMR, X-ray crystallography, and ECD analyses. The unambiguously established structures of the phthalideisoquinoline hemiacetal alkaloids indicated that the absolute configurations of C-1, C-9, and C-7' were confusable only relied on coupling constants. A summary of their ECD spectra was concluded and provided an insight for C-1, C-9, and C-7' absolute configuration assignment. These new compounds were evaluated to induce autophagy flux through flow cytometry analysis. Moreover, compounds 2 and 6 could significantly induce autophagy and inhibit Tau pathology by AMPK-ULK1 pathway activation, which provided an avenue for anti-AD lead compounds discovery.

A Novel Superparamagnetic Multifunctional Nerve Scaffold: A Remote Actuation Strategy to Boost In Situ Extracellular Vesicles Production for Enhanced Peripheral Nerve Repair.

Extracellular vesicles (EVs) have inherent advantages over cell-based therapies in regenerative medicine because of their cargos of abundant bioactive cues. Several strategies are proposed to tune EVs production in vitro. However, it remains a challenge for manipulation of EVs production in vivo, which poses significant difficulties for EVs-based therapies that aim to promote tissue regeneration, particularly for long-term treatment of diseases like peripheral neuropathy. Herein, a superparamagnetic nanocomposite scaffold capable of controlling EVs production on-demand is constructed by incorporating polyethyleneglycol/polyethyleneimine modified superparamagnetic nanoparticles into a polyacrylamide/hyaluronic acid double-network hydrogel (Mag-gel). The Mag-gel is highly sensitive to a rotating magnetic field (RMF), and can act as mechano-stimulative platform to exert micro/nanoscale forces on encapsulated Schwann cells (SCs), an essential glial cell in supporting nerve regeneration. By switching the ON/OFF state of the RMF, the Mag-gel can scale up local production of SCs-derived EVs (SCs-EVs) both in vitro and in vivo. Further transcriptome sequencing indicates an enrichment of transcripts favorable in axon growth, angiogenesis, and inflammatory regulation of SCs-EVs in the Mag-gel with RMF, which ultimately results in optimized nerve repair in vivo. Overall, this research provides a noninvasive and remotely time-scheduled method for fine-tuning EVs-based therapies to accelerate tissue regeneration, including that of peripheral nerves.

A Novel Magnetic Responsive miR-26a@SPIONs-OECs for Spinal Cord Injury: Triggering Neural Regeneration Program and Orienting Axon Guidance in Inhibitory Astrocytic Environment.

Addressing the challenge of promoting directional axonal regeneration in a hostile astrocytic scar, which often impedes recovery following spinal cord injury (SCI), remains a daunting task. Cell transplantation is a promising strategy to facilitate nerve restoration in SCI. In this research, a pro-regeneration system is developed, namely miR-26a@SPIONs-OECs, for olfactory ensheathing cells (OECs), a preferred choice for promoting nerve regeneration in SCI patients. These entities show high responsiveness to external magnetic fields (MF), leading to synergistic multimodal cues to enhance nerve regeneration. First, an MF stimulates miR-26a@SPIONs-OECs to release extracellular vesicles (EVs) rich in miR-26a. This encourages axon growth by inhibiting PTEN and GSK-3ß signaling pathways in neurons. Second, miR-26a@SPIONs-OECs exhibit a tendency to migrate and orientate along the direction of the MF, thereby potentially facilitating neuronal reconnection through directional neurite elongation. Third, miR-26a-enriched EVs from miR-26a@SPIONs-OECs can interact with host astrocytes, thereby diminishing inhibitory cues for neurite growth. In a rat model of SCI, the miR-26a@SPIONs-OECs system led to significantly improved morphological and motor function recovery. In summary, the miR-26a@SPIONS-OECs pro-regeneration system offers innovative insights into engineering exogenous cells with multiple additional cues, augmenting their efficacy for stimulating and guiding nerve regeneration within a hostile astrocytic scar in SCI.

Designing a Hierarchical Porous Carbon with Optimized Nitrogen Doping for Efficient Oxygen Reduction Reaction.

Nitrogen-doped carbon is considered one of the most promising oxygen reduction catalysts due to its low cost and high activity, however, it still falls short of Pt/C. In this study, we report a strategy for the preparation of highly reactive N-doped hierarchical porous carbon by primary pyrolysis using zinc acetate as a stand-alone zinc source and amino-rich reactants as carbon and nitrogen sources to introduce Zn-Nx structures into mesoporous structures generated by the hard template method using the strong coordination of zinc and amino groups. Benefited from the simultaneous optimization of the hierarchical porous structure and nitrogen-doping, the half-wave potential of Zn(OAc)2 -DCD/HPC is as high as 0.909 V vs. RHE, much better than that of commercial Pt/C catalysts (0.872 V vs. RHE). In addition, zinc-air batteries assembled with Zn(OAc)2 -DCD/HPC (Pmax =198 mW cm-2 ) as the cathode exhibit higher peak power density compared to Pt/C (Pmax =168 mW cm-2 ). This strategy might open up new opportunities for designing and developing highly active metal-free catalysts.

Bioinformatics analysis reveals lipid metabolism may play an important role in the SiO2-stimulated rat model.

Silicosis is a progressive and irreversible common occupational disease caused by long-term inhalation of a large amount of free silica dust. Its pathogenesis is complex, and the existing prevention and treatment methods can not effectively improve silicosis injury. To uncover potential differential genes in silicosis, SiO2-stimulated rats and their control original transcriptomic data sets GSE49144, GSE32147 and GSE30178 were downloaded for further bioinformatics analysis. We used R packages to extract and standardize transcriptome profiles, then screened differential genes, and enriched GO and KEGG pathways through clusterProfiler packages. In addition, we investigated the role of lipid metabolism in the progression of silicosis by qRT-PCR validation and transfection with si-CD36. A total of 426 differential genes were identified in this study. Based on GO and KEGG enrichment analysis, it was found that lipid and atherosclerosis were significantly enriched. qRT-PCR was used to detect the relative expression level of differential genes in this signaling pathway of silicosis rat models. mRNA levels of Abcg1, Il1b, Sod2, Cyba, Cd14, Cxcl2, Ccl3, Cxcl1, Ccl2 and CD36 increased, mRNA levels of Ccl5, Cybb and Il18 decreased. In addition, at the cellular level, SiO2-stimulated lead to lipid metabolism disorder in NR8383, and silencing CD36 inhibited SiO2-induced lipid metabolism disorder. These results indicate that lipid metabolism plays an important role in the progression of silicosis, and the genes and pathways reported in this study may provide new ideas for the pathogenesis of silicosis.

Inhibition of Oncogenic Src Ameliorates Silica-Induced Pulmonary Fibrosis via PI3K/AKT Pathway.

Silicosis is a refractory disease. Previous studies indicate that damaged alveolar epithelial cells act as a driver in pulmonary fibrosis. Our results show that epithelial cells that acquire the mesenchymal phenotype are associated with the pathogenesis of silicosis. c-Src kinase, a non-receptor tyrosine kinase, has been shown to be a positive regulator of organ fibrosis, but specific mechanisms remain unclear and rarely researched in silicosis. The activated Phosphatidylinositol-3 kinases/AKT(PI3K/AKT) pathway promotes fibrosis. We aimed to determine whether c-Src regulates fibrosis via the PI3K/AKT signaling pathway in the development of silicosis. C57/BL mice were intratracheally perfused with 10 mg silica suspension to establish a model of silicosis. In vivo, silica particles induced lung fibrosis. The profibrotic cytokine transforming growth factor-ß1 (TGF-ß1) exhibited a high expression in pulmonary fibrosis. The phosphorylated c-Src protein was increased and the PI3K/AKT pathway was activated in model lung tissue. In vitro, silica increased the expression of TGF-ß1- and TGF-ß1-induced mesenchymal phenotype and fibrosis in a mouse epithelial cells line. siRNA-Src inhibited the c-Src, the phosphorylation of the PI3K/AKT pathway, and the mesenchymal phenotype induced by TGF-ß1. LY294002, a specific inhibitor of PI3K, suppressed the phosphorylation of PI3K/AKT but did not affect Src activation. SU6656, a selective Src inhibitor, attenuated fibrosis in silicosis model. In summary, c-Src promotes fibrosis via the PI3K/AKT pathway in silica-induced lung fibrosis, and Src kinase inhibitors are potentially effective for silicosis treatment.

Core-shell oxygen-releasing fibers for annulus fibrosus repair in the intervertebral disc of rats.

The repair of annulus fibrosus (AF) defect after discectomy in the intervertebral disc (IVD) has presented a challenge over the past decade. Hostile microenvironments in the IVD, including, compression and hypoxia, are critical issues that require special attention. Till date, little information is available on potential strategies to cope with the hypoxia dilemma in AF defect sites. In this study, perfluorotributylamine (PFTBA) core-shell fibers were fabricated by coaxial electrospinning to construct oxygen-releasing scaffold for promoting endogenous repair in the AF after discectomy. We demonstrated that PFTBA fibers (10% chitosan, chitosan: PCL, 1:6) could release oxygen for up to 144 â€‹h. The oxygen released from PFTBA fibers was found to protect annulus fibrosus stem cells (AFSCs) from hypoxia-induced apoptosis. In addition, the PFTBA fibers were able to promote proliferation, migration and extracellular matrix (ECM) production in AFSCs under hypoxia, highlighting their therapeutic potential in AF defect repair. Subsequent in vivo studies demonstrated that oxygen-supplying fibers were capable of ameliorating disc degeneration after discectomy, which was evidenced by improved disc height and morphological integrity in rats with the oxygen-releasing scaffolds. Further transcriptome analysis indicated that differential expression genes (DEGs) were enriched in "oxygen transport" and "angiogenesis", which likely contributed to their beneficial effect on endogenous AF regeneration. In summary, the oxygen-releasing scaffold provides novel insights into the oxygen regulation by bioactive materials and raises the therapeutic possibility of oxygen supply strategies for defect repair in AF, as well as other aerobic tissues.

New Monoterpenoid Indole Alkaloids from Tabernaemontana crassa Inhibit ß-Amyloid42 Production and Phospho-Tau (Thr217).

Eleven monoterpenoid indole alkaloids, including three new ones, tabercrassines A-C (1-3), were isolated from the seeds of Tabernaemontana crassa. Tabercrassine A (1) is an ibogan-ibogan-type bisindole alkaloid which is formed by the polymerization of two classic ibogan-type monomers through a C3 unit aliphatic chain. Their structures were established by extensive analysis of HRESIMS, NMR, and ECD spectra. Cellular assays showed that alkaloids 1-3 all reduce Aß42 production and inhibit phospho-tau (Thr217), a new biomarker of Alzheimer's disease [AD] associated with BACE1-, NCSTN-, GSK3ß-, and CDK5-mediated pathways, suggesting these alkaloids' potential against AD.

One stage reconstruction of mid-face fistulous defects after maxillary sinus carcinoma resection with chimeric perforator free flaps.

BACKGROUND: The reconstruction of large fistulous defects following the radical ablation of maxillary sinus carcinoma remains challenging. The procedure requires not only the coverage of both intra-nasal lining and cheek skin but also sufficient obliteration of dead space between the two surfaces. In this report, we present our experience on the reconstruction of through-and-through defects in the mid-face with poly-foliated chimeric perforator flaps. METHODS: Nine patients (five males and four females) who received a two-skin paddled and one muscle segment chimeric perforator flap reconstruction after maxillary sinus carcinoma ablation between March 2015 and December 2019 were retrospectively reviewed in authors' hospital. The mean age of the patients was 59.11. Six patients were diagnosed as squamous cell carcinoma, two as adenoid cystic carcinoma, and one as adenocarcinoma. Brown class IIIa defects were found in eight patients, and one patient had a Brown class IVa defect. The mean size of intra-nasal defect was 5.67 × 4.06 cm2 , and the mean size of facial skin defect was 8.94 × 6.56 cm2 . ALT flaps were used in five patients, LD flaps in four patients. The minor skin paddle was firstly inset to the mucosal defect site as the lining. Then, the muscle segment was inset to eliminate the dead cavity. Finally, the major skin paddle was inset to recover the cutaneous defect. RESULTS: In ALT group, the mean size of the minor skin paddle was 5.7 × 4.7 cm2 , and the mean size of the major skin paddle was 8.7 × 6.6 cm2 . In LD group, the mean size of the minor skin paddle was 6.88 × 4.38 cm2 , and the mean size of the major skin paddle was 11 × 7.75 cm2 .All donor sites were closed primarily. All flaps survived and no partial flap loss was encountered. The mean follow-up time was 14.67 months, and there were no major postoperative complications. CONCLUSION: The use of poly-foliated chimeric perforator free flaps can provide functional and aesthetic coverage for extensive through-and-through mid-face defects without significant donor-site morbidities.

Lipid nanoparticle-encapsulated VEGFa siRNA facilitates cartilage formation by suppressing angiogenesis.

Cartilage is an important tissue that is widely found in joints, ears, nose and other organs. The limited capacity to regenerate makes cartilage reconstruction an urgent clinical demand. Due to the avascular nature of cartilage, we hypothesized that inhibition of vascularization contributes to cartilage formation. Here, we used VEGFa siRNA to inhibit the infiltration of the local vascular system. Optimized lipid nanoparticles were prepared by microfluidics for the delivery of siRNA. Then, we constructed a tissue engineering scaffold. Both seed cells and VEGFa siRNA-LNPs were loaded in a GELMA hydrogel. Subcutaneous implantation experiments in nude mice indicate that this is a promising strategy for cartilage reconstruction. The regenerated cartilage was superior, with significant upregulation of SOX9, COL-II and ACAN. This is attributed to an environment deficient in oxygen and nutrients, which facilitates cartilage formation by upregulating HIF-1α and FOXO transcription factors. In conclusion, a GelMA/Cells+VEGFa siRNA-LNPs scaffold was constructed to achieve superior cartilage regeneration.

Effects of dual-gene modification on biological characteristics of vascular endothelial cells and their significance as reserving cells for chronic wound repair.

bFGF is a commonly used and reliable factor for improving chronic wound healing, and hSulf-1 expression is abundant in surrounding cells of chronic wound tissue and vascular endothelial cells, which can reverse the effect of bFGF and inhibit the signalling activity of cell proliferation. In this study, an adenovirus, Ad5F35ET1-bFGF-shSulf1, was designed for establishing the dual-gene modified vascular endothelial cells, which were used as the repair cells for skin chronic wound. Ad5F35ET1-bFGF-shSulf1 infected ECV304 cells in vitro and mediated the overexpression of bFGF and the knockdown of hSulf-1, which effectively activated the AKT and ERK signal transduction pathways, facilitate cell proliferation and migration, with the cell viability to 128.29% at 72 h after infection, compared to 66.65%, 73.74%, 87.63%, 103.14% in the blank control, Ad5F35ET1-EGFP-shNC, Ad5F35ET1-shSulf1, Ad5F35ET1-bFGF groups, respectively. In the rat ear skin injury model, the wound healing was significantly accelerated in the Ad5F35ET1-rbFGF-shrSulf1 group compared to the blank control group (p = 0.0046), Ad5F35ET1-EGFP-shNC group (p = 0.0245), Ad5F35ET1-shrSulf group (p = 0.0426), and Ad5F35ET1-rbFGF group (p = 0.2853). The results demonstrated that this strategy may be a candidate therapy for chronic injury repair.

Ferroptosis-related lncRNA signature predicts prognosis and immunotherapy efficacy in cutaneous melanoma.

Purpose: Ferroptosis-related lncRNAs are promising biomarkers for predicting the prognosis of many cancers. However, a ferroptosis-related signature to predict the prognosis of cutaneous melanoma (CM) has not been identified. The purpose of this study was to construct a ferroptosis-related lncRNA signature to predict prognosis and immunotherapy efficacy in CM. Methods: Ferroptosis-related differentially expressed genes (FDEGs) and lncRNAs (FDELs) were identified using TCGA, GTEx, and FerrDb datasets. We performed Cox and LASSO regressions to identify key FDELs, and constructed a risk score to stratify patients into high- and low-risk groups. The lncRNA signature was evaluated using the areas under the receiver operating characteristic curves (AUCs) and Kaplan-Meier analyses in the training, testing, and entire cohorts. Multivariate Cox regression analyses including the lncRNA signature and common clinicopathological characteristics were performed to identify independent predictors of overall survival (OS). A nomogram was developed for clinical use. We performed gene set enrichment analyses (GSEA) to identify significantly enriched pathways. Differences in the tumor microenvironment (TME) between the 2 groups were assessed using 7 algorithms. To predict the efficacy of immune checkpoint inhibitors (ICI), we analyzed the association between PD1 and CTLA4 expression and the risk score. Finally, differences in Tumor Mutational Burden (TMB) and molecular drugs Sensitivity between the 2 groups were performed. Results: We identified 5 lncRNAs (AATBC, AC145423.2, LINC01871, AC125807.2, and AC245041.1) to construct the risk score. The AUC of the lncRNA signature was 0.743 in the training cohort and was validated in the testing and entire cohorts. Kaplan-Meier analyses revealed that the high-risk group had poorer prognosis. Multivariate Cox regression showed that the lncRNA signature was an independent predictor of OS with higher accuracy than traditional clinicopathological features. The 1-, 3-, and 5-year survival probabilities for CM patients were 92.7%, 57.2%, and 40.2% with an AUC of 0.804, indicating a good accuracy and reliability of the nomogram. GSEA showed that the high-risk group had lower ferroptosis and immune response. TME analyses confirmed that the high-risk group had lower immune cell infiltration (e.g., CD8+ T cells, CD4+ memory-activated T cells, and M1 macrophages) and lower immune functions (e.g., immune checkpoint activation). Low-risk patients whose disease expressed PD1 or CTLA4 were likely to respond better to ICIs. The analysis demonstrated that the TMB had significantly difference between low- and high- risk groups. Chemotherapy drugs, such as sorafenib, Imatinib, ABT.888 (Veliparib), Docetaxel, and Paclitaxel showed Significant differences in the estimated IC50 between the two risk groups. Conclusion: Our novel ferroptosis-related lncRNA signature was able to accurately predict the prognosis and ICI outcomes of CM patients. These ferroptosis-related lncRNAs might be potential biomarkers and therapeutic targets for CM.

Monoterpenoid indole alkaloid dimers from Kopsia arborea inhibit cyclin-dependent kinase 5 and tau phosphorylation.

Three undescribed monoterpenoid indole alkaloid dimers (kopoffines A-C, which are connected via a methylene unit) and with nine known alkaloids were isolated and identified from the fruits of Kopsia arborea Blume. Their structures, including their absolute configurations, were established by HRESIMS, NMR, single-crystal X-ray diffraction, and ECD analyses. Kopoffines A-C showed significant inhibition against cyclin-dependent kinase 5 (IC50: 0.34-2.18 µM). Western blotting analyses showed that kopoffines A-C significantly decreased the protein levels of CDK5 and phospho-CDK5 (Tyr15) (pCDK5) at concentrations of 2.5 and 10 µM. The levels of phospho-Tau (Thr217) (pTau217, a new biomarker of AD), and phospho-Tau (Ser396) (pTau396), which play major roles in the formation of neurofibrillary tangles , were decreased by the kopoffines A-C treatment. Molecular docking studies indicated that kopoffines A-C could form stable interactions with CDK5.

[Application of two-stage operation on free latissimus dorsi myocutaneous flap transplantation and skull contour reconstruction in treatment of head titanium mesh exposure with soft tissue infection].

Objective: To explore the effectiveness of two-stage operation on free latissimus dorsi myocutaneous flap transplantation and skull contour reconstruction in the treatment of head titanium mesh exposure complicated with soft tissue infection. Methods: Between January 2015 and December 2021, 13 patients with head titanium mesh exposure complicated with soft tissue infection were admitted. There were 9 males and 4 females with a mean age of 42.9 years (range, 23-64 years). The duration of titanium mesh exposure was 22-609 days (median, 102 days). The wound site located at the frontal part in 3 cases, the parietal part in 1 case, the occipital part in 2 cases, the frontal-parietal part in 1 case, the temporal-parietal part in 4 cases, and the frontotemporal part in 2 cases. The titanium mesh had been taken out in 5 patients before admission, leaving skull defect and shape collapse, with signs of infection. The bacterial culture was positive in 7 cases and negative in 6 cases. The imaging examination revealed that the size of the skull defect ranged from 6 cm×5 cm to 21 cm×17 cm and the scalp defect ranged from 1 cm×1 cm to 15 cm×10 cm. The soft tissue infection did not reach dura in 5 cases, reached dura in 6 cases, and reached frontal sinus in 2 cases. The two-stage surgical protocol was used in all patients. In the first-stage operation, the latissimus dorsi myocutaneous flap was designed to repair the skull and scalp defects after removing the titanium mesh and thorough debridement. The size of muscle flap ranged from 13.5 cm×4.0 cm to 21.0 cm×17.0 cm, and the skin flap ranged from 7.0 cm×4.0 cm to 15.0 cm×10.0 cm. After the flap survived and stabilized, the second-stage operation was performed. The titanium mesh was implanted to reconstruct the skull contour. The size of titanium mesh ranged from 7.0 cm×6.0 cm to 21.5 cm×17.5 cm. The interval between the first- and second-stage operations was 3.7-17.8 months, with an average of 11.4 months. The survival of the skin flap, the appearance of the head, and the presence of re-exposed titanium mesh and infection were observed after operation. Results: At the first-stage operation, venous embolism occurred in 1 case, and no obvious abnormality was observed after treatment. All the flaps survived and the incisions healed by first intention. Besides, the incisions of the second-stage operation healed by first intention. All patients were followed up 1-96 months (median, 14 months). During follow-up, no exposure to titanium mesh, infection, or other complications occurred. The appearance satisfaction rate of the patients was 92.31% (11/13). There was no significant difference in the skull contour between the affected side and the healthy side in all patients. Conclusion: For the head titanium mesh exposure with soft tissue infection, the application of two-stage operation on free latissimus dorsi myocutaneous flap transplantation and skull contour reconstruction can reduce the risks of implant exposure and infection again by increasing the thickness of the scalp and blood supply, filling the wound cavity, and obtain good effectiveness.

The Multi-Omics Landscape and Clinical Relevance of the Immunological Signature of Phagocytosis Regulators: Implications for Risk Classification and Frontline Therapies in Skin Cutaneous Melanoma.

Tumor-associated macrophages (TAMs) have gained considerable attention as therapeutic targets. Monoclonal antibody treatments directed against tumor antigens contribute significantly to cancer cell clearance by activating macrophages to phagocytose tumor cells. Due to its complicated genetic and molecular pathways, skin cutaneous melanoma (SKCM) has not yet attained the expected clinical efficacy and prognosis when compared to other skin cancers. Therefore, we chose TAMs as an entrance point. This study aimed to thoroughly assess the dysregulation and regulatory role of phagocytosis regulators in SKCM, as well as to understand their regulatory patterns in SKCM. This study subtyped prognosis-related phagocytosis regulators to investigate prognostic differences between subtypes. Then, we screened prognostic factors and constructed phagocytosis-related scoring models for survival prediction using differentially expressed genes (DEGs) between subtypes. Additionally, we investigated alternative treatment options using chemotherapeutic drug response data and clinical cohort treatment data. We first characterized and generalized phagocytosis regulators in SKCM and extensively examined the tumor immune cell infiltration. We created two phagocytosis regulator-related system (PRRS) phenotypes and derived PRRS scores using a principal component analysis (PCA) technique. We discovered that subtypes with low PRRS scores had a poor prognosis and decreased immune checkpoint-associated gene expression levels. We observed significant therapeutic and clinical improvements in patients with higher PRRS scores. Our findings imply that the PRRS scoring system can be employed as an independent and robust prognostic biomarker, serving as a critical reference point for developing novel immunotherapeutic methods.

The regulatory effect of pulmonary lymphatic drainage on silicosis fibrosis.

Silicosis is a fibrotic disease caused by long-term inhalation of SiO2 particles that currently has no effective treatment. Earlier studies have suggested that pulmonary lymphatic vessels play a key role in the transport of silica but have not address the long-term effects of altered pulmonary lymphatic drainage on silicosis. Here, we investigated the impact of impaired pulmonary lymphatic drainage on silicosis. In the past, lymphatic drainage disorders were established mainly through the use of VEGF inhibitors. For the first time, we established a model of pulmonary lymphatic drainage disorder by ligating the thoracic duct in rats. Impaired pulmonary lymphatic drainage was found to aggravate inflammation and oxidative damage in silicosis rats and accelerate silicosis progression. Next, we investigated the effect of pulmonary lymphatic drainage on silicosis. We have demonstrated the effect of sodium tanshinone IIA sulfonate(STS) on lymphangiogenesis, which revealed that STS promotes lymphangiogenesis and can delay inflammation, oxidative damage, and fibrosis progression in silicosis rats by promoting the pulmonary lymphatic drainage response, and this effect is mediated by the VEGFR-3/PI3K/AKT signaling pathway. These findings suggest that pulmonary lymphogenesis plays an important role in silicosis pathogenesis, and targeted intervention in pulmonary lymphangiogenesis may be a potential strategy for treating of silicosis in the future.

A Novel Pyroptotic and Inflammatory Gene Signature Predicts the Prognosis of Cutaneous Melanoma and the Effect of Anticancer Therapies.

Purpose: The purpose of this study was to construct a gene signature comprising genes related to both inflammation and pyroptosis (GRIPs) to predict the prognosis of patients with cutaneous melanoma patients and the efficacy of immunotherapy, chemotherapy, and targeted therapy in these patients. Methods: Gene expression profiles were collected from The Cancer Genome Atlas. Weighted gene co-expression network analysis was performed to identify GRIPs. Univariable Cox regression and Lasso regression further selected key prognostic genes. Multivariable Cox regression was used to construct a risk score, which stratified patients into high- and low-risk groups. Areas under the ROC curves (AUCs) were calculated, and Kaplan-Meier analyses were performed for the two groups, following validation in an external cohort from Gene Expression Omnibus (GEO). A nomogram including the GRIP signature and clinicopathological characteristics was developed for clinical use. Gene set enrichment analysis illustrated differentially enriched pathways. Differences in the tumor microenvironment (TME) between the two groups were assessed. The efficacies of immune checkpoint inhibitors (ICIs), chemotherapeutic agents, and targeted agents were predicted for both groups. Immunohistochemical analyses of the GRIPs between the normal and CM tissues were performed using the Human Protein Atlas data. The qRT-PCR experiments validated the expression of genes in CM cell lines, Hacat, and PIG1 cell lines. Results: A total of 185 GRIPs were identified. A novel gene signature comprising eight GRIPs (TLR1, CCL8, EMP3, IFNGR2, CCL25, IL15, RTP4, and NLRP6) was constructed. The signature had AUCs of 0.714 and 0.659 for predicting 3-year overall survival (OS) in the TCGA entire and GEO validation cohorts, respectively. Kaplan-Meier analyses revealed that the high-risk group had a poorer prognosis. Multivariable Cox regression showed that the GRIP signature was an independent predictor of OS with higher accuracy than traditional clinicopathological features. The nomogram showed good accuracy and reliability in predicting 3-year OS (AUC = 0.810). GSEA and TME analyses showed that the high-risk group had lower levels of pyroptosis, inflammation, and immune response, such as lower levels of CD8+ T-cell infiltration, CD4+ memory-activated T-cell infiltration, and ICI. In addition, low-risk patients whose disease expressed PD-1 or CTLA-4 were likely to respond better to ICIs, and several chemotherapeutic and targeted agents. Immunohistochemical analysis confirmed the distinct expression of five out of the eight GRIPs between normal and CM tissues. Conclusion: Our novel 8-GRIP signature can accurately predict the prognosis of patients with CM and the efficacies of multiple anticancer therapies. These GRIPs might be potential prognostic biomarkers and therapeutic targets for CM.

Accelerating O-Redox Kinetics with Carbon Nanotubes for Stable Lithium-Rich Cathodes.

Lithium-rich cathodes (LRCs) show great potential to improve the energy density of commercial lithium-ion batteries owing to their cationic and anionic redox characteristics. Herein, a complete conductive network using carbon nanotubes (CNTs) additives to improve the poor kinetics of LRCs is fabricated. Ex situ X-ray photoelectron spectroscopy first demonstrates that the slope at a low potential and the following long platform can be assigned to the transition metal and oxygen redox, respectively. The combination of galvanostatic intermittent titration technique and electrochemical impedance spectroscopy further reveal that a battery with CNTs exhibited accelerated kinetics, especially for the O-redox process. Consequently, LRCs with CNTs exhibit a much better rate and cycling performance (≈89% capacity retention at 2 C for over 200 cycles) than the Super P case. Eventually, TEM results imply that the improved electrochemical performance of the CNTs case also benefits from its more stable bulk and surface structures. Such a facile conductive additive modification strategy also provides a universal approach for the enhancement of the electron diffusion properties of other electrode materials.

The significance of serum S100 calcium-binding protein A4 in silicosis.

BACKGROUND: Silicosis is a chronic occupational pulmonary disease characterized by persistent inflammation and irreversible fibrosis. Considerable evidences now indicate that S100 calcium-binding protein A4 (S100A4) has been associated with fibrotic diseases. However, the role of S100A4 in silicosis is still unclear. METHODS: In this study, serum levels of S100A4, transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor (CTGF), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) in patients with silicosis (n = 42) and control group (CG, n = 12) were measured by ELISA. S100A4 expression in lung tissues and primary alveolar macrophages (AMs) of mice with and without silicosis was detected by immunohistochemistry (IHC)/real-time PCR. The correlations between S100A4 and cytokines or lung function were assessed by Spearman's rank correlation analyses. RESULTS: Compared with CG, the levels of S100A4 were significantly increased in silicosis patients (70.84 (46.22, 102.46) ng/ml vs (49.84 (42.86, 60.02) ng/ml). The secretions of TGF-ß1, CTGF, IL-6 and TNF-α in silicosis group were significantly higher than that in control group (p < 0.05). Serum S100A4 levels were positively correlated with TGF-ß1 and IL-6, while were negatively correlated with lung function parameters including percentage of predicted forced vital capacity (FVC%pre), maximum vital capacity (Vcmax), deep inspiratory capacity (IC) and peak expiratory flow at 75% of vital capacity (PEF75). In receiver operating characteristic (ROC) analyses, S100A4 > 61.7 ng/ml had 63.4% sensitivity and 83.3% specificity for silicosis, and the area under the curve (AUC) was 0.707. Furthermore, immunostaining of lung tissues showed the accumulation of S100A4-positive cells in the areas of nodules of silicotic mice. The mRNA expression of S100A4 in the lung tissues and AMs of silicotic mice were significantly higher than controls. CONCLUSION: These data suggested that increased S100A4 might contribute to the pathogenesis of silicosis.