The value of preoperative neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and red blood cell distribution width in predicting positive surgical margin after laparoscopic radical prostatectomy.

BACKGROUND: Prostate cancer (PCa) is one of the most common malignant tumors in men, and laparoscopic radical prostatectomy (LRP) is commonly used to treat localized and advanced PCa. Positive surgical margin (PSM) is one of the most frequent problems faced by surgeons. AIMS: This study aimed to explore the value of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and red blood cell distribution width (RDW) in predicting PSM after LRP. METHODS AND RESULTS: Three hundred and twenty patients with PCa were admitted and underwent LRP in Beijing Chaoyang Hospital from January 2017 to June 2023. Patients were randomly divided into a training set (225 cases) and a validation set (95 cases) in a 7:3 ratio. NLR, PLR, and RDW were significantly higher in the PSM group than in the negative surgical margins (NSM) group. In addition, the NLR, PLR, and RDW values correlated with clinical T stage, Gleason score, and seminal vesicle invasion in the PSM group. In training set, ROC curve analysis revealed that the optimal cutoff values of NLR, PLR, and RDW for predicting postoperative PSM in PCa were 2.31, 115.40, and 12.85%, respectively. Multivariate Logistic regression analysis showed NLR and RDW were the clinical independent predictors. The area under the curve (AUC, 0.770, 95% CI 0.709-0.831) for postoperative PSM was the highest when a combination of the three parameters was used, with sensitivity and specificity of 62.5% and 85.2%, respectively. In validation set, the AUC values for NLR, PLR, RDW and the three markers combined were 0.708, 0.675, 0.723, and 0.780, respectively. Correlation analysis showed that in the PSM group, NLR was positively correlated with PLR and RDW, and PLR was positively correlated with RDW. By contrast, in the NSM group, a positive association was only found between NLR and PLR. CONCLUSIONS: Higher preoperative NLR, PLR, and RDW values were associated with postoperative PSM. Additionally, the three markers combined may be useful to predict PSM.

Network Pharmacology and Bioinformatics Analyses Identify the Core Genes and Pyroptosis-Related Mechanisms of Nardostachys Chinensis for Atrial Fibrillation.

BACKGROUND: Nardostachys chinensis is an herbal medicine widely used in the treatment of atrial fibrillation (AF), but the mechanism is unclear. OBJECTIVE: To explore the molecular mechanism of N. chinensis against AF. METHODS: The TCMSP was used to screen the active N. chinensis compounds and their targets. Differentially expressed genes (DEGs) for AF were identified using open-access databases. Using Venn diagrams, the cross-targets of N. chinensis, pyroptosis, and AF were obtained. The genes underwent molecular docking as well as gene set enrichment analysis (GSEA). A nomogram based on candidate genes was constructed and evaluated with the clinical impact curve. After that, the immune infiltration of the dataset was analyzed by single sample GSEA (ssGSEA). Finally, microRNAs (miRNAs) and transcription factors (TFs) were predicted based on candidate genes. RESULTS: Tumor necrosis factor (TNF) and caspase-8 (CASP8) were obtained as candidate genes by taking the intersection of DEGs, targets of N. chinensis, and pyroptosis-related genes. Tolllike receptor (TLR) and peroxisome proliferator-activated receptor (PPAR) signaling pathways were linked to candidate genes. Additionally, immune cell infiltration analysis revealed that CASP8 was associated with natural killer T cells, natural killer cells, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSC), macrophages, CD8 T cells, and CD4 T cells. Finally, miR-34a-5p and several TFs were found to regulate the expression of CASP8 and TNF. CONCLUSION: CASP8 and TNF are potential targets of N. chinensis intervention in pyroptosisrelated AF, and the TLR/NLRP3 signaling pathway may be associated with this process.

Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy.

Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share features with embryonic development, characterized by robust proliferation and differentiation regulated by signaling pathways such as Wnt, Notch, hedgehog, and Hippo signaling. In certain phase, these cells also mimic embryonic diapause and fertilized egg implantation to evade treatments or immune elimination and promote metastasis. Additionally, the upregulation of ATP-binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer-resistant protein (BCRP), in drug-resistant cancer cells, analogous to their role in placental development, may facilitate chemotherapy efflux, further resulting in treatment resistance. In this review, we concentrate on the underlying mechanisms that contribute to tumor development and progression from the perspective of embryonic development, encompassing the dysregulation of developmental signaling pathways, the emergence of dormant cancer cells, immune microenvironment remodeling, and the hyperactivation of ABC transporters. Furthermore, we synthesize and emphasize the connections between cancer hallmarks and embryonic development, offering novel insights for the development of innovative cancer treatment strategies.

Exploring Shared Biomarkers of Myocardial Infarction and Alzheimer's Disease via Single-Cell/Nucleus Sequencing and Bioinformatics Analysis.

BACKGROUND: Patients are at increased risk of dementia, including Alzheimer's disease (AD), after myocardial infarction (MI), but the biological link between MI and AD is unclear. OBJECTIVE: To understand the association between the pathogenesis of MI and AD and identify common biomarkers of both diseases. METHODS: Using public databases, we identified common biomarkers of MI and AD. Least absolute shrinkage and selection operator (LASSO) regression and protein-protein interaction (PPI) network were performed to further screen hub biomarkers. Functional enrichment analyses were performed on the hub biomarkers. Single-cell/nucleus analysis was utilized to further analyze the hub biomarkers at the cellular level in carotid atherosclerosis and AD datasets. Motif enrichment analysis was used to screen key transcription factors. RESULTS: 26 common differentially expressed genes were screened between MI and AD. Function enrichment analyses showed that these differentially expressed genes were mainly associated with inflammatory pathways. A key gene, Regulator of G-protein Signaling 1 (RGS1), was obtained by LASSO regression and PPI network. RGS1 was confirmed to mainly express in macrophages and microglia according to single-cell/nucleus analysis. The difference in expression of RGS1 in macrophages and microglia between disease groups and controls was statistically significant (p < 0.0001). The expression of RGS1 in the disease groups was upregulated with the differentiation of macrophages and microglia. RelA was a key transcription factor regulating RGS1. CONCLUSION: Macrophages and microglia are involved in the inflammatory response of MI and AD. RGS1 may be a key biomarker in this process.

Drug Repurposing-Based Brain-Targeting Self-Assembly Nanoplatform Using Enhanced Ferroptosis against Glioblastoma.

Glioblastoma (GBM), the most aggressive and lethal form of malignant brain tumor, is a therapeutic challenge due to the drug filtration capabilities of the blood-brain barrier (BBB). Interestingly, glioblastoma tends to resist apoptosis during chemotherapy, but is susceptible to ferroptosis. Developing therapies that can effectively target glioblastoma by crossing the BBB and evoke ferroptosis are, therefore, crucial for improving treatment outcomes. Herein, a versatile biomimetic nanoplatform, L-D-I/NPs, is designed that self-assembled by loading the antimalarial drug dihydroartemisinin (DHA) and the photosensitizer indocyanine green (ICG) onto lactoferrin (LF). This nanoplatform can selectively target glioblastoma by binding to low-density lipoprotein receptor-related protein-1 (LRP1) and crossing the BBB, thus inducing glioblastoma cell ferroptosis by boosting intracellular reactive oxygen species (ROS) accumulation and iron overload. In addition, L-D-I/NPs have demonstrated the ability to effectively suppress the progression of orthotopic glioblastoma and significantly prolong survival in a mouse glioblastoma model. This nanoplatform has facilitated the application of non-chemotherapeutic drugs in tumor treatment with minimal adverse effects, paving the way for highly efficient ferroptosis-based therapies for glioblastoma.

Development and external validation of a novel nomogram to predict intravesical recurrence after radical nephroureterectomy: a multicenter study.

OBJECTIVE: This study aimed to establish and validate nomograms to predict the probability of intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper urinary tract epithelial carcinoma (UTUC). METHODS: Clinical data of 528 patients with UTUC after RNU were collected from two medical centers between 2009 and 2020. We used the least absolute shrinkage and selection operator (LASSO) regression to select variables for multivariable Cox regression analysis in the training cohort and included independent risk factors into nomogram models predicting IVR-free survival (IVRFS). Another center was applied as the external cohort to validate the predictive accuracy and discriminative ability of the nomogram by performing area under the receiver operating curve (AUC), consistency index (C-index), and calibration curve. RESULTS: History of bladder cancer, tumor size, preoperative urine cytology, postoperative instillation, Ki-67, and platelet-to-lymphocyte ratio (PLR) were identified as independent risk factors for IVR. The prognosis model including these predictors demonstrated excellent discriminatory performance in both the training cohort (C-index, 0.814) and external validation cohort (C-index, 0.748). The calibration plots of the nomogram revealed good consistency in both cohorts. Finally, patients could be classified into two risk groups based on scores obtained from the nomogram, with significant differences in IVRFS. CONCLUSION: Our study provided a reliable nomogram for predicting the probability of IVR in patients with UTUC after RNU. Risk stratification based on this model may assist urologists make optimal clinical decisions on the management of UTUC.

Do patients with metastatic renal cell carcinoma obtain survival benefits from cytoreductive nephrectomy? A population-based study.

PURPOSE: This study aimed to explore the value of cytoreductive nephrectomy (CN) and develop nomograms to predict the prognosis of metastatic renal cell carcinoma (mRCC) patients with receiving radiology therapy or/and chemotherapy (RT/&CT). METHODS: Clinical data of patients with mRCC between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Prognostic nomograms were constructed to predict the overall survival (OS) and cancer-specific survival (CSS) probability for 1-, 3-, and 5- years in patients with mRCC. A series of validation methods were used to validate the accuracy and reliability of the model, including area under the receiver operating curve (AUC), consistency index (C-index), calibration curve, and decision curve analysis (DCA). RESULTS: 1394 patients were enrolled in this study. All patients were randomly divided into the training cohort (n = 976) and the validation cohort (n = 418). In the training cohort, multivariate Cox regression analysis suggested that pathology grade, histology type, T stage, N stage, surgery, and distant metastasis were independent risk factors for OS and CSS. The AUC and C-index were both over 0.65 in both cohorts, indicating that the nomograms for OS and CSS had satisfactory discriminative power. The calibration curves revealed that the predictive nomograms had a good consistency between the observed and the predicted survival. CONCLUSION: This study provided evidence that mRCC patients underwent RT/&CT could gain survival benefits from CN. The prognostic nomogram constructed in our study is reliable and practical, may help guide clinical strategies in the treatment of mRCC.

Protein persulfidation: Rewiring the hydrogen sulfide signaling in cell stress response.

The past few decades have witnessed significant progress in the discovery of hydrogen sulfide (H2S) as a ubiquitous gaseous signaling molecule in mammalian physiology, akin to nitric oxide and carbon monoxide. As the third gasotransmitter, H2S is now known to exert a wide range of physiological and cytoprotective functions in the biological systems. However, endogenous H2S concentrations are usually low, and its potential biologic mechanisms responsible have not yet been fully clarified. Recently, a growing body of evidence has demonstrated that protein persulfidation, a posttranslational modification of cysteine residues (RSH) to persulfides (RSSH) elicited by H2S, is a fundamental mechanism of H2S-mediated signaling pathways. Persulfidation, as a biological switch for protein function, plays an important role in the maintenance of cell homeostasis in response to various internal and external stress stimuli and is also implicated in numerous diseases, such as cardiovascular and neurodegenerative diseases and cancer. In this review, the biological significance of protein persulfidation by H2S in cell stress response is reviewed providing a framework for understanding the multifaceted roles of H2S. A mechanism-guided perspective can help open novel avenues for the exploitation of therapeutics based on H2S-induced persulfidation in the context of diseases.

EVA1A regulates hematopoietic stem cell regeneration via ER-mitochondria mediated apoptosis.

Excessive protein synthesis upon enhanced cell proliferation frequently results in an increase of unfolded or misfolded proteins. During hematopoietic regeneration, to replenish the hematopoietic system, hematopoietic stem cells (HSCs) are activated and undergo a rapid proliferation. But how the activated HSCs respond to the proliferation pressure is still ambiguous; The proper control of the functional reservoir in the activated HSCs remains poorly understood. Here, we show a significant upregulation of EVA1A protein associated with the increase of ER stress during hematopoietic regeneration. Deletion of Eva1a significantly enhances the regeneration capacity of HSCs by inhibiting the ER stress-induced apoptosis. Mechanistically, the expression of EVA1A protein was upregulated by CHOP, and thereby promoted the ER-mitochondria interlinking via MCL1, which resulted in mitochondria-mediated apoptosis. These findings reveal a pathway for ER stress responses of HSCs by the EVA1A mediated apoptosis, which play an important role in HSCs regeneration.

Protein degradation: expanding the toolbox to restrain cancer drug resistance.

Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies.

P311 Promotes IL-4 Receptor‒Mediated M2 Polarization of Macrophages to Enhance Angiogenesis for Efficient Skin Wound Healing.

The transition from the proinflammatory phase to the prohealing phase in wound healing is essential for effective skin wound repair, which involves the balance of M1 and M2 polarization of wound-infiltrating macrophages. P311 plays an essential role in promoting wound closure by enhancing the biological function of epidermal stem cells, endothelial cells, and fibroblasts. Nevertheless, whether and how P311 regulates macrophage polarization remains unclear. In this study, we showed that P311 deficiency reduced the M2 polarization of macrophages, thereby attenuating the secretion of M2-like cytokines. The P311 deficiency prolonged the transition from the proinflammatory phase to the prohealing phase, accompanied by weakened angiogenesis and retarded granulation tissue formation, both of which coordinately hinder the healing of skin wounds. Mechanistically, P311 deficiency downregulated the expression of IL-4 receptor on macrophages, followed by less activation of the IL-4 receptor‒signal transducer and activator of transcription 6 signaling pathway, resulting in impaired M2 macrophage polarization. We further revealed that the mTOR signaling pathway was associated with the regulation of P311 on the expression of IL-4 receptor in macrophages. Thus, our study has highlighted the pivotal role of P311 in promoting the M2 polarization of macrophages for effective skin wound healing.

Qingre Huoxue Decoction regulates macrophage polarisation to attenuate atherosclerosis through the inhibition of NF-κB signalling-mediated inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Atherosclerosis (AS) is a common pathogenesis of cardiovascular diseases. Qingre Huoxue Decoction (QRHX) is an herbal formula used for the prevention and treatment of AS. However, the potential mechanism of QRHX is not clear. AIM OF THE STUDY: In our study, RNA sequencing combined with preclinical models were used to analyse the effect and mechanism of QRHX for the treatment of AS. MATERIALS AND METHODS: For in vivo studies, ApoE-/- mice were fed with a high-fat diet to induce AS. We measured weight, blood lipid, inflammatory cytokines, lipid deposition, plaque, and the M1/M2 macrophage. For in vitro studies, RAW264.7 were induced by lipopolysaccharides and treated with different concentrations of QRHX. We focusd on the relationship between QRHX, the NF-κB pathway, and macrophage polarisation, and performed simultaneous RNA sequencing both in vivo and in vitro. RESULTS: In vivo, QRHX decreased weight, improved blood lipid, relieved the degree of lipid deposition, reduced plaque area, decreased the levels of inflammatory cytokines (MCP-1, NLRP3, and TNFα), down-regulated the expression of iNOS, and up-regulated the expression of Arg-1. In vitro, QRHX down-regulated M1 markers, iNOS and CCR7, with lower concentrations of IL-1ß; furthermore, QRHX up-regulated M2 markers, Arg-1, CD163, Ym-1, and Fizz-1, with higher concentrations of IL-4 and IL-10. RNA sequencing of both samples in vivo and in vitro suggested that NF-κB was the target pathway of QRHX to regulate macrophage polarisation; this result was validated at the gene and protein levels. CONCLUSIONS: QRHX induced M2 polarisation, reduced an inflammatory response, and played a role in stabilising plaque by mediating the NF-κB signalling pathway.

Autophagy in health and disease: From molecular mechanisms to therapeutic target.

Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over the past two decades, autophagy has been extensively studied, from the molecular mechanisms, biological functions, implications in various human diseases, to development of autophagy-related therapeutics. This review will focus on the latest development of autophagy research, covering molecular mechanisms in control of autophagosome biogenesis and autophagosome-lysosome fusion, and the upstream regulatory pathways including the AMPK and MTORC1 pathways. We will also provide a systematic discussion on the implication of autophagy in various human diseases, including cancer, neurodegenerative disorders (Alzheimer disease, Parkinson disease, Huntington's disease, and Amyotrophic lateral sclerosis), metabolic diseases (obesity and diabetes), viral infection especially SARS-Cov-2 and COVID-19, cardiovascular diseases (cardiac ischemia/reperfusion and cardiomyopathy), and aging. Finally, we will also summarize the development of pharmacological agents that have therapeutic potential for clinical applications via targeting the autophagy pathway. It is believed that decades of hard work on autophagy research is eventually to bring real and tangible benefits for improvement of human health and control of human diseases.

A minimalist and robust chemo-photothermal nanoplatform capable of augmenting autophagy-modulated immune response against breast cancer.

Previously used in anti-fungal therapy, itraconazole has now been shown to be successful in treating advanced breast cancer (NCT00798135). However, its poor solubility still restricts its application in clinical treatment. There is therefore an urgent need for combined methods to enhance the therapeutic effect of itraconazole (IC) in breast cancer treatment. With this goal, co-assembled IC/IR820 NPs with synergistic photonic hyperthermia and itraconazole payloads have been constructed to overcome these shortcomings. The IC/IR820 NPs show an enhanced therapeutic effect on breast cancer by inducing reactive oxygen species (ROS)-mediated apoptosis and autophagic death. Further evaluation in a mouse model has shown impressive effects of the IC/IR820 NPs on both inhibiting tumor metastasis and activating immunity to prevent tumor recurrence. Mechanistically, itraconazole may promote both tumor cell antigen presentation through autophagy and the activation of dendritic cells to induce an immune response, which displays a synergistic effect with the immune response generated by photothermal therapy to inhibit tumor recurrence. This strategy of combining itraconazole and IR820 into one minimalist and robust nanoplatform through co-assembly results in excellent therapeutic efficacy, suggesting its potential application as an alternative method for the clinical treatment of breast cancer.

CircCRIM1 promotes nasopharyngeal carcinoma progression via the miR-34c-5p/FOSL1 axis.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a rare malignancy with multiple risk factors (Epstein-Barr virus, etc.) that seriously threatens the health of people. CircRNAs are known to regulate the tumorigenesis of malignant tumours, including NPC. Moreover, circCRIM1 expression is reported to be upregulated in NPC. Nevertheless, the impact of circCRIM1 on NPC progression is not clear. METHODS: An MTT assay was performed to assess cell viability. In addition, cell invasion and migration were assessed by the transwell assay. Dual luciferase assays were performed to assess the association among circCRIM1, miR-34c-5p and FOSL1. Moreover, RT-qPCR was applied to assess mRNA levels, and protein levels were determined by Western blot. RESULTS: CircCRIM1 and FOSL1 were upregulated in NPC cells, while miR-34c-5p was downregulated. Knockdown of circCRIM1 significantly decreased the invasion, viability and migration of NPC cells. The miR-34c-5p inhibitor notably promoted the malignant behaviour of NPC cells, while miR-34c-5p mimics exerted the opposite effect. Moreover, circCRIM1 could bind with miR-34c-5p, and FOSL1 was identified to be downstream of miR-34c-5p. Furthermore, circCRIM1 downregulation notably inhibited the proliferation and invasion of NPC cells, while this phenomenon was significantly reversed by FOSL1 overexpression. CONCLUSION: Silencing circCRIM1 inhibited the tumorigenesis of NPC. Thus, circCRIM1 might be a novel target for NPC.

Effects of ALA-PDT on the macrophages in wound healing and its related mechanisms in vivo and in vitro.

BACKGROUND: Several studies have suggested the effectiveness of photodynamic therapy (PDT) for wound healing. Macrophages are critical immune cells necessary for regulated inflammation during wound repair. However, the available information regarding the effects of PDT on macrophages during cutaneous wound healing remains insufficient. This study aimed to further investigate these aspects in vivo and in vitro. METHODS: Mouse full-thickness wound models were used as the study samples to investigate the therapeutic effects and mechanisms of 5-aminolevulinic acid (ALA) PDT. Wound healing rate, granulation tissue formation, local inflammation, M1/M2 macrophages differentiation, were measured at different time points treated by ALA-PDT. The polarization of macrophages induced by ALA-PDT was further evaluated in vitro using PCR and western blot analysis. RESULTS: ALA-PDT could promote formation of granulation tissue, increase inflammatory infiltration and activate M1 macrophages in the early stage of injury. While, ALA-PDT could also facilitate absorption of granulation tissue, inhibit inflammatory infiltration and enhance M2 macrophages polarization in the later stage of wound repair. In vitro, ALA-PDT could modulate the ratio of M2 polarization to M1 polarization via NF-κB signaling pathway. CONCLUSIONS: ALA-PDT topical application stimulates wound healing by regulating formation of granulation tissue, inflammatory process and M1/M2 macrophages differentiation. The study places a preliminary theoretical basis for topical ALA-PDT to be administered clinically in cutaneous wounds healing.

Telomerase RNA TERC and the PI3K-AKT pathway form a positive feedback loop to regulate cell proliferation independent of telomerase activity.

The core catalytic unit of telomerase comprises telomerase reverse transcriptase (TERT) and telomerase RNA (TERC). Unlike TERT, which is predominantly expressed in cancer and stem cells, TERC is ubiquitously expressed in normal somatic cells without telomerase activity. However, the functions of TERC in these telomerase-negative cells remain elusive. Here, we reported positive feedback regulation between TERC and the PI3K-AKT pathway that controlled cell proliferation independent of telomerase activity in human fibroblasts. Mechanistically, we revealed that TERC activated the transcription of target genes from the PI3K-AKT pathway, such as PDPK1, by targeting their promoters. Overexpression of PDPK1 partially rescued the deficiency of AKT activation caused by TERC depletion. Furthermore, we found that FOXO1, a transcription factor negatively regulated by the PI3K-AKT pathway, bound to TERC promoter and suppressed its expression. Intriguingly, TERC-induced activation of the PI3K-AKT pathway also played a critical role in the proliferation of activated CD4+ T cells. Collectively, our findings identify a novel function of TERC that regulates the PI3K-AKT pathway via positive feedback to elevate cell proliferation independent of telomerase activity and provide a potential strategy to promote CD4+ T cells expansion that is responsible for enhancing adaptive immune reactions to defend against pathogens and tumor cells.

P311 Facilitates the Angiogenesis and Wound Healing Function of MSCs by Increasing VEGF Production.

As a potential clinical therapeutic cell for injured tissue repair, mesenchymal stem cells (MSCs) have attracted increasing attention. Enhancing the pro-healing function of MSCs has gradually become an essential topic in improving the clinical efficacy of MSCs. Recently, studies have shown that neuronal protein 3.1 (P311) plays a crucial role in promoting skin wound healing, suggesting P311 gene modification may improve the pro-healing function of MSCs. In this study, we demonstrated that increasing the in vivo expression of P311 could significantly enhance the ability of MSCs to lessen the number of inflammatory cells, increase the expression of IL10, reduce the levels of TNF-α and IFN-γ, increase collagen deposition, promote angiogenesis, and ultimately accelerate skin wound closure and improve the quality of wound healing. Importantly, we uncovered that P311 enhanced the pro-angiogenesis function of MSCs by increasing the production of vascular endothelial growth factor (VEGF) in vitro and in vivo. Mechanistically, we revealed that the mTOR signalling pathway was closely related to the regulation of P311 on VEGF production in MSCs. Together, our data displayed that P311 gene modification in MSCs augments their capabilities to promote skin wound closure, which might bring the dawn for its clinical application in the future.

A cascaded copper-based nanocatalyst by modulating glutathione and cyclooxygenase-2 for hepatocellular carcinoma therapy.

Sorafenib-mediated chemotherapy is currently the first choice for hepatocellular carcinoma (HCC) that cannot be surgically excised, and can significantly improve the survival of patients. However, its poor water solubility restricts its bioavailability, and long-term single use of it does not achieve satisfactory HCC therapy effects. Herein, we report a novel cascaded copper-based metal-organic framework (MOF) therapeutic nanocatalyst using HKUST-1 by integrating cyclooxygenase-2 (COX-2) inhibitor meloxicam (Mel) and chemotherapeutic agent sorafenib (Sol) to amplify HCC therapy. This HKUST-1 nanocatalyst can be degraded by glutathione (GSH) into a Fenton-like agent to trigger chemodynamic therapy (CDT). CDT-mediated cytotoxic reactive oxygen species (ROS) can activate ferroptosis by accumulating lipid peroxides (LPO). Alternatively, GSH depletion not only deactivates glutathione peroxidase 4 (GPX4) to trigger ferroptosis, but also leads to oxidative stress amplification. Moreover, Sol can also activate ferroptosis by inhibiting system XC-, resulting in cascade-amplified ferroptosis mediated HCC therapy. Furthermore, the down-regulation of COX-2 can induce PINK1/Parkin-mediated mitophagy to further act synergistically with Sol-mediated chemotherapy. Therefore, this HKUST-1 nanocatalyst provides a novel strategy to regulate GSH and COX-2 levels for amplified chemo/chemodynamic and ferroptosis-mediated HCC therapy.

Dietary serine supplementation: Friend or foe?

Serine lies at a critical node in biological processes involved in supplying intermediates for redox homeostasis, nucleotide, or lipid biosynthesis and one-carbon metabolism-coupled methyl donor production. Recently, dietary serine supplementation has been reported to modulate cellular serine levels and ameliorate neurological abnormalities induced by serine deficiency. Moreover, growing evidence showed that serine supplementation also alleviates fatty liver, encephalopathy, diabetes mellitus, and related complications, indicating the possibility of serine supplementation as a complementary therapeutic option. However, considering the serine addiction observed in tumorigenesis and tumor development, limitations may exist regarding the application of dietary serine supplementation in patients with cancer. Here, we assess recent research toward the mechanistic understanding of serine supplementation in various diseases to improve our cognition on modulating serine levels in different patients.