Development of prognostic signatures and risk index related to lipid metabolism in ccRCC.

Background: Clear cell renal cell carcinoma (ccRCC) is a metabolic disorder characterized by abnormal lipid accumulation in the cytoplasm. Lipid metabolism-related genes may have important clinical significance for prognosis prediction and individualized treatment. Methods: We collected bulk and single-cell transcriptomic data of ccRCC and normal samples to identify key lipid metabolism-related prognostic signatures. qPCR was used to confirm the expression of signatures in cancer cell lines. Based on the identified signatures, we developed a lipid metabolism risk score (LMRS) as a risk index. We explored the potential application value of prognostic signatures and LMRS in precise treatment from multiple perspectives. Results: Through comprehensive analysis, we identified five lipid metabolism-related prognostic signatures (ACADM, ACAT1, ECHS1, HPGD, DGKZ). We developed a risk index LMRS, which was significantly associated with poor prognosis in patients. There was a significant correlation between LMRS and the infiltration levels of multiple immune cells. Patients with high LMRS may be more likely to respond to immunotherapy. The different LMRS groups were suitable for different anticancer drug treatment regimens. Conclusion: Prognostic signatures and LMRS we developed may be applied to the risk assessment of ccRCC patients, which may have potential guiding significance in the diagnosis and precise treatment of ccRCC patients.

A mesoporous theranostic platform for ultrasound and photoacoustic dual imaging-guided photothermal and enhanced starvation therapy for cancer.

Tumor starvation therapy utilizing glucose oxidase (GOx), has gained traction due to its non-invasive and bio-safe attributes. However, its effectiveness is often hampered by severe hypoxia in the tumor microenvironment (TME), limiting GOx's catalytic activity. To address this issue, a multifunctional nanosystem based on mesoporous polydopamine nanoparticles (MPDA NPs) was developled to alleviate TME hypoxia. This nanosystem integrated GOx modification and oxygenated perfluoropentane (PFP) encapsulation to address hypoxia-related challenges in the TME. Under NIR laser irradiation, the MPDA NPs exhibit significant photothermal conversion efficacy, activating targeted tumor photothermal therapy (PTT), while also serving as proficient photoacoustic (PA) imaging agents. The ensuing temperature rise facilitates oxygen (O2) release and induces liquid-gas conversion of PFP, generating microbubbles for enhanced ultrasound (US) imaging signals. The supplied oxygen alleviates local hypoxia, thereby enhancing GOx-mediated endogenous glucose consumption for tumor starvation. Overall, the integration of ultrasound/photoacoustic dual imaging-guided PTT and starvation therapy within MPDA-GOx@PFP@O2 nanoparticles (MGPO NPs) presents a promising platform for enhancing the efficacay of tumor treatment by overcoming the complexities of the TME. STATEMENT OF SIGNIFICANCE: A multifunctional MPDA-based theranostic nanoagent was developed for US/PAI imaging-guided PTT and starvation therapy against tumor hypoxia by direct O2 delivery. The incorporation of oxygenated perfluoropentane (PFP) within the mesoporous structure of MGPO not only enables efficient US imaging but also helps in alleviating tumor hypoxia. Moreover, the strong near-infrared (NIR) absorption of MGPO NPs promote the generation of PFP microbubbles and release of oxygen, thereby enhancing US imaging and GOx-mediated starvation therapy. Such a multifunctional nanosystem leverages synergistic effects to enhance therapeutic efficacy while incorporating US/PA imaging for precise visualization of the tumor.

SynergyX: a multi-modality mutual attention network for interpretable drug synergy prediction.

Discovering effective anti-tumor drug combinations is crucial for advancing cancer therapy. Taking full account of intricate biological interactions is highly important in accurately predicting drug synergy. However, the extremely limited prior knowledge poses great challenges in developing current computational methods. To address this, we introduce SynergyX, a multi-modality mutual attention network to improve anti-tumor drug synergy prediction. It dynamically captures cross-modal interactions, allowing for the modeling of complex biological networks and drug interactions. A convolution-augmented attention structure is adopted to integrate multi-omic data in this framework effectively. Compared with other state-of-the-art models, SynergyX demonstrates superior predictive accuracy in both the General Test and Blind Test and cross-dataset validation. By exhaustively screening combinations of approved drugs, SynergyX reveals its ability to identify promising drug combination candidates for potential lung cancer treatment. Another notable advantage lies in its multidimensional interpretability. Taking Sorafenib and Vorinostat as an example, SynergyX serves as a powerful tool for uncovering drug-gene interactions and deciphering cell selectivity mechanisms. In summary, SynergyX provides an illuminating and interpretable framework, poised to catalyze the expedition of drug synergy discovery and deepen our comprehension of rational combination therapy.

ANXA1sp attenuates sepsis-induced myocardial injury by promoting mitochondrial biosynthesis and inhibiting oxidative stress and autophagy via SIRT3 upregulation.

Sepsis-induced myocardial injury is one of the most difficult complications of sepsis in intensive care units. Annexin A1 (ANXA1) short peptide (ANXA1sp) protects organs during the perioperative period. However, the protective effect of ANXA1sp against sepsis-induced myocardial injury remains unclear. We aimed to explore the protective effects and mechanisms of ANXA1sp against sepsis-induced myocardial injury both in vitro and in vivo. Cellular and animal models of myocardial injury in sepsis were established with lipopolysaccharide. The cardiac function of mice was assessed by high-frequency echocardiography. Elisa assay detected changes in inflammatory mediators and markers of myocardial injury. Western blotting detected autophagy and mitochondrial biosynthesis-related proteins. Autophagic flux changes were observed by confocal microscopy, and autophagosomes were evaluated by TEM. ATP, SOD, ROS, and MDA levels were also detected.ANXA1sp pretreatment enhanced the 7-day survival rate, improved cardiac function, and reduced TNF-α, IL-6, IL-1ß, CK-MB, cTnI, and LDH levels. ANXA1sp significantly increased the expression of sirtuin-3 (SIRT3), mitochondrial biosynthesis-related proteins peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), and mitochondrial transcription factor A (TFAM). ANXA1sp increased mitochondrial membrane potential (△Ψm), ATP, and SOD, and decreased ROS, autophagy flux, the production of autophagosomes per unit area, and MDA levels. The protective effect of ANXA1sp decreased significantly after SIRT3 silencing in vitro and in vivo, indicating that the key factor in ANXA1sp's protective role is the upregulation of SIRT3. In summary, ANXA1sp attenuated sepsis-induced myocardial injury by upregulating SIRT3 to promote mitochondrial biosynthesis and inhibit oxidative stress and autophagy.

PLZF protein forms a complex with protein TET1 to target TCF7L2 in undifferentiated spermatogonia.

The transcription factor promyelocytic leukemia zinc finger (PLZF, also known as ZBTB16) is critical for the self-renewal of spermatogonial stem cells (SSCs). However, the function of PLZF in SSCs is not clear. Here, we found that PLZF acted as an epigenetic regulator of stem cell maintenance and self-renewal of germ cells. The PLZF protein interacts with the ten-eleven translocation 1 (TET1) protein and subsequently acts as a modulator to regulate the expression of self-renewal-related genes. Furthermore, Transcription Factor 7-like 2 (TCF7L2) is promoted by the coordination of PLZF and Tri-methylation of lysine 4 on histone H3 (H3K4me3). In addition, testicular single-cell sequencing indicated that TCF7L2 is commonly expressed in the PLZF cluster. We demonstrated that PLZF directly targets TCF7L2 and alters the landscape of histone methylation in the SSCs nucleus. Meanwhile, the RD domain and Zn finger domain of PLZF synergize with H3K4me3 and directly upregulate TCF7L2 expression at the transcriptional level. Additionally, we identified a new association between PLZF and the histone methyltransferase EZH2 at the genomic level. Our study identified a new association between PLZF and H3K4me3, established the novel PLZF&TET1-H3K4me3-TCF7L2 axis at the genomic level which regulates undifferentiated spermatogonia, and provided a platform for studying germ cell development in male domestic animals.

The exceptional form and function of the giant bacterium Ca. Epulopiscium viviparus revolves around its sodium motive force.

Epulopiscium spp. are the largest known heterotrophic bacteria; a large cigar-shaped individual is a million times the volume of Escherichia coli. To better understand the metabolic potential and relationship of Epulopiscium sp. type B with its host Naso tonganus, we generated a high-quality draft genome from a population of cells taken from a single fish. We propose the name Candidatus Epulopiscium viviparus to describe populations of this best-characterized Epulopiscium species. Metabolic reconstruction reveals more than 5% of the genome codes for carbohydrate active enzymes, which likely degrade recalcitrant host-diet algal polysaccharides into substrates that may be fermented to acetate, the most abundant short-chain fatty acid in the intestinal tract. Moreover, transcriptome analyses and the concentration of sodium ions in the host intestinal tract suggest that the use of a sodium motive force (SMF) to drive ATP synthesis and flagellar rotation is integral to symbiont metabolism and cellular biology. In natural populations, genes encoding both F-type and V-type ATPases and SMF generation via oxaloacetate decarboxylation are among the most highly expressed, suggesting that ATPases synthesize ATP and balance ion concentrations across the cell membrane. High expression of these and other integral membrane proteins may allow for the growth of its extensive intracellular membrane system. Further, complementary metabolism between microbe and host is implied with the potential provision of nitrogen and B vitamins to reinforce this nutritional symbiosis. The few features shared by all bacterial behemoths include extreme polyploidy, polyphosphate synthesis, and thus far, they have all resisted cultivation in the lab.

Prediction models for post-thrombectomy brain edema in patients with acute ischemic stroke: a systematic review and meta-analysis.

Objective: The objective of this study is to systematically evaluate prediction models for post-thrombectomy brain edema in acute ischemic stroke (AIS) patients. This analysis aims to equip clinicians with evidence-based guidance for the selection of appropriate prediction models, thereby facilitating the early identification of patients at risk of developing brain edema post-surgery. Methods: A comprehensive literature search was conducted across multiple databases, including PubMed, Web of Science, Embase, The Cochrane Library, CNKI, Wanfang, and Vip, aiming to identify studies on prediction models for post-thrombectomy brain edema in AIS patients up to January 2023. Reference lists of relevant articles were also inspected. Two reviewers independently screened the literature and extracted data. The Prediction Model Risk of Bias Assessment Tool (PROBAST) and the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) guidelines were employed to assess study bias and literature quality, respectively. We then used random-effects bivariate meta-analysis models to summarize the studies. Results: The review included five articles, yielding 10 models. These models exhibited a relatively high risk of bias. Random effects model demonstrated that the AUC was 0.858 (95% CI 0.817-0.899). Conclusion: Despite the promising discriminative ability shown by studies on prediction models for post-thrombectomy brain edema in AIS patients, concerns related to a high risk of bias and limited external validation remain. Future research should prioritize the external validation and optimization of these models. There is an urgent need for large-scale, multicenter studies to develop robust, user-friendly models for real-world clinical application. Systematic review registration: https://www.crd.york.ac.uk, unique Identifier: CRD42022382790.

Effect of postoperative radiotherapy on survival in patients with completely resected and pathologically confirmed stage N2 non-small-cell lung cancer: a systematic review and meta-analysis.

Background: The role of postoperative radiotherapy (PORT) for patients with completely resected stage N2 non-small-cell lung cancer (NSCLC) has been controversial. This study aimed to investigate the efficacy of PORT and prognosis in these patients. Objectives: An updated meta-analysis was conducted in this study to investigate the efficacy of PORT and prognosis in patients with completely resected and pathologically confirmed stage N2 NSCLC. Design: This study is a systematic review and meta-analysis. Data source and methods: Databases were searched up to 2 March 2022. All trials on patients with completely resected and pathologically confirmed stage N2 NSCLC undergoing PORT were screened, and data indicators in the PORT and non-PORT groups were extracted, respectively. The effect of PORT on overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) was estimated. Subgroup and sensitivity analyses were performed. Results: In all, 20 studies involving 6340 patients were finally included. The PORT significantly increased OS [hazard ratio (HR) = 0.77, 95% CI: 0.71-0.84, p < 0.001), LRFS (HR = 0.63, 95% CI: 0.52-0.76, p < 0.001), and DFS (HR = 0.72, 95% CI: 0.63-0.82, p < 0.001) while it showed no significant difference in improving DMFS (HR = 0.86, 95% CI: 0.71-1.05, p = 0.14). Conclusion: Our results suggest that in the postoperative treatment of patients with completely resected and pathologically confirmed stage N2 NSCLC, the addition of PORT provides better local recurrence control and survival benefit, but no benefit for distant metastases. The PORT may be incorporated into the postoperative treatment options for some patients with high-risk factors. However, it needs to be validated by more prospective studies in the future. Trail registration: CRD42022314095.

Pan-Cancer Identification of Prognostic-Associated Metabolic Pathways.

Metabolic dysregulation has been reported involving in the clinical outcomes of multiple cancers. However, systematical identification of the impact of metabolic pathways on cancer prognosis is still lacking. Here, we performed a pan-cancer analysis of popular metabolic checkpoint genes and pathways with cancer prognosis by integrating information of clinical survival with gene expression and pathway activity in multiple cancer patients. By discarding the effects of age and sex, we revealed extensive and significant associations between the survival of cancer patients and the expression of metabolic checkpoint genes, as well as the activities of three primary metabolic pathways: amino acid metabolism, carbohydrate metabolism, lipid metabolism, and eight nonprimary metabolic pathways. Among multiple cancers, we found the survival of kidney renal clear cell carcinoma and low-grade glioma exhibit high metabolic dependence. Our work systematically assesses the impact of metabolic checkpoint genes and pathways on cancer prognosis, providing clues for further study of cancer diagnosis and therapy.

Bile acids promote the development of HCC by activating inflammasome.

BACKGROUND: Hepatocellular carcinoma (HCC) is associated with chronic inflammation caused by different factors; especially, the interaction of inflammatory pathways and bile acids (BAs) can affect hepatocyte proliferation, death, and regeneration, but whether BAs promote HCC progression through inflammatory pathways and the mechanisms is still unclear. METHODS AND RESULTS: By examining cancer and tumor-adjacent tissue BA levels and genes associated with BA homeostasis in 37 HCC patients, we found that total bile acids (TBAs) were decreased by 36% and varying degrees of changes in factors regulating BA homeostasis (p < 0.05). In addition, we found that BA homeostasis was disturbed in diethylnitrosamine-induced HCC mouse models, and TBA was correlated with inflammasome activation during HCC progression (6-24 W) (p < 0.05). Similarly, the inflammasome and chenodeoxycholic acid (CDCA) content were suppressed in cholestasis model mice (Mrp2-deficient mice) (p < 0.05). In vitro, CDCA significantly promoted the malignant transformation of hepatocytes (p < 0.001), activated the inflammasome by triggering the release of mitochondrial reactive oxygen species and mitochondrial DNA, and ultimately induced pyroptosis. Furthermore, we found that CDCA has a targeted binding effect with HO-1 through molecular docking and Cellular Thermal Shift Assay experiments. CONCLUSIONS: In conclusion, we found that CDCA can trigger the excessive accumulation of mitochondrial reactive oxygen species by targeting HO-1 to promote the activation of the inflammasome and ultimately promote the progression of HCC. Our study provides a novel mechanism by which BAs promote HCC by activating the inflammasome and establishes the important role of BA homeostasis imbalance in the progression of HCC from the aspect of inflammation.

Eif2s3y alleviated LPS-induced damage to mouse testis and maintained spermatogenesis by negatively regulating Adamts5.

Eif2s3y (eukaryotic translation initiation factor 2, subunit 3, structural gene Y-linked, Eif2s3y) is an essential gene for spermatogenesis. Early studies have shown that Eif2s3y can promote the proliferation of spermatogonial stem cells (SSCs) and can replace the Y chromosome together with sex-determining region Y (Sry) to transform SSCs into round spermatozoa. We injected lentiviral particles into the seminiferous tubules of mouse testes by sterile surgery surgically to establish overexpressing Eif2s3y testes. And then the mice were intraperitoneally injected with LPS to established the model of testis inflammation. Through RNA sequencing, qRT-PCR analysis, Western blot, co-culture etc., we found that Eif2s3y alleviated LPS-induced damage in mouse testes and maintained spermatogenesis. In testes with Eif2s3y overexpression, the seminiferous tubules were more regularly organized after exposure to LPS compared with the control. Eif2s3y performs its function by negatively regulating Adamts5 (a disintegrin and metalloproteinase containing a thrombospondin-1 motif), an extracellular matrix-degrading enzyme. ADAMTS5 shows a disruptive effect when the testis is exposed to LPS. Overexpression of Eif2s3y inhibited the TLR4/NFκB signaling pathway in the testis in response to LPS. Generally, our research shows that Eif2s3y protects the testis from LPS and maintains spermatogenesis by negatively regulating Adamts5.

Bone marrow mesenchymal stem cell-derived exosomal microRNAs target PI3K/Akt signaling pathway to promote the activation of fibroblasts.

BACKGROUND: Fibroblast plays a major role in tendon-bone healing. Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) can activate fibroblasts and promote tendon-bone healing via the contained microRNAs (miRNAs). However, the underlying mechanism is not comprehensively understood. Herein, this study aimed to identify overlapped BMSC-derived exosomal miRNAs in three GSE datasets, and to verify their effects as well as mechanisms on fibroblasts. AIM: To identify overlapped BMSC-derived exosomal miRNAs in three GSE datasets and verify their effects as well as mechanisms on fibroblasts. METHODS: BMSC-derived exosomal miRNAs data (GSE71241, GSE153752, and GSE85341) were downloaded from the Gene Expression Omnibus (GEO) database. The candidate miRNAs were obtained by the intersection of three data sets. TargetScan was used to predict potential target genes for the candidate miRNAs. Functional and pathway analyses were conducted using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, respectively, by processing data with the Metascape. Highly interconnected genes in the protein-protein interaction (PPI) network were analyzed using Cytoscape software. Bromodeoxyuridine, wound healing assay, collagen contraction assay and the expression of COL I and α-smooth muscle actin positive were applied to investigate the cell proliferation, migration and collagen synthesis. Quantitative real-time reverse transcription polymerase chain reaction was applied to determine the cell fibroblastic, tenogenic, and chondrogenic potential. RESULTS: Bioinformatics analyses found two BMSC-derived exosomal miRNAs, has-miR-144-3p and has-miR-23b-3p, were overlapped in three GSE datasets. PPI network analysis and functional enrichment analyses in the GO and KEGG databases indicated that both miRNAs regulated the PI3K/Akt signaling pathway by targeting phosphatase and tensin homolog (PTEN). In vitro experiments confirmed that miR-144-3p and miR-23b-3p stimulated proliferation, migration and collagen synthesis of NIH3T3 fibroblasts. Interfering with PTEN affected the phosphorylation of Akt and thus activated fibroblasts. Inhibition of PTEN also promoted the fibroblastic, tenogenic, and chondrogenic potential of NIH3T3 fibroblasts. CONCLUSION: BMSC-derived exosomes promote fibroblast activation possibly through the PTEN and PI3K/Akt signaling pathways, which may serve as potential targets to further promote tendon-bone healing.

Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway. / åŒç¡«ä»‘é€šè¿‡æŠ‘åˆ¶èŒƒå¯å°¼è´«è¡€ä¿®å¤é€”å¾„å¢žåŠ é¡ºé“‚çš„æŠ—è‚¿ç˜¤æ´»æ€§.

A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.

Horizontally transferred genes as RNA interference targets for aphid and whitefly control.

RNA interference (RNAi)-based technologies are starting to be commercialized as a new approach for agricultural pest control. Horizontally transferred genes (HTGs), which have been transferred into insect genomes from viruses, bacteria, fungi or plants, are attractive targets for RNAi-mediated pest control. HTGs are often unique to a specific insect family or even genus, making it unlikely that RNAi constructs targeting such genes will have negative effects on ladybugs, lacewings and other beneficial predatory insect species. In this study, we sequenced the genome of a red, tobacco-adapted isolate of Myzus persicae (green peach aphid) and bioinformatically identified 30 HTGs. We then used plant-mediated virus-induced gene silencing (VIGS) to show that several HTGs of bacterial and plant origin are important for aphid growth and/or survival. Silencing the expression of fungal-origin HTGs did not affect aphid survivorship but decreased aphid reproduction. Importantly, although there was uptake of plant-expressed RNA by Coccinella septempunctata (seven-spotted ladybugs) via the aphids that they consumed, we did not observe negative effects on ladybugs from aphid-targeted VIGS constructs. To demonstrate that this approach is more broadly applicable, we also targeted five Bemisia tabaci (whitefly) HTGs using VIGS and demonstrated that knockdown of some of these genes affected whitefly survival. As functional HTGs have been identified in the genomes of numerous pest species, we propose that these HTGs should be explored further as efficient and safe targets for control of insect pests using plant-mediated RNA interference.

Rapid detection of adulteration of olive oil with soybean oil combined with chemometrics by Fourier transform infrared, visible-near-infrared and excitation-emission matrix fluorescence spectroscopy: A comparative study.

Several spectroscopic techniques have been used to detect olive oil adulteration. To evaluate the performance of these spectral techniques on this issue, this work performed a comparative study on identifying adulterated olive oil with different concentrations of soybean oil based on Fourier-transform infrared (FTIR), visible-near-infrared (Vis-NIR) and excitation-emission matrix fluorescence spectroscopy (EEMs) combined with chemometrics. Principal component analysis (PCA)/ multi-way-PCA analysis showed the feasibility of the three spectral methods for the identification of olive oil adulteration. The accuracy of FTIR and Vis-NIR based on partial least squares discriminant analysis (PLS-DA) for adulterated olive oil was 100%, while the accuracy of EEMs based on unfold-PLS-DA was only 73%. The accuracy of EEMs combined with back-propagation artificial neural network based on self-weighted alternating trilinear decomposition is 100%. In comparison, FTIR and Vis-NIR are superior for the detection of olive oil adulteration due to the convenience of instrument operation and modeling.

SRC-3 deficiency prevents atherosclerosis development by decreasing endothelial ICAM-1 expression to attenuate macrophage recruitment.

Steroid receptor coactivator 3 (SRC-3) is a member of the p160 SRC family. This factor can interact with multiple nuclear hormone receptors and transcription factors to regulate the expression of their target genes. Although many physiological roles of SRC-3 have been revealed, its role in atherosclerosis is not clear. In this study, we found that SRC-3-/-ApoE-/- mice have reduced atherosclerotic lesions and necrotic areas in their aortas and aortic roots compared with SRC-3+/+ApoE-/- mice after Western diet (WD) feeding for 12 weeks. RNA-Seq and Western blot analyses of the aorta revealed that SRC-3 was required for maintaining the expression of ICAM-1, which was required for macrophage recruitment and atherosclerosis development. siRNA-mediated knockdown of SRC-3 in endothelial cells significantly reduced WD-induced atherosclerotic plaque formation. Additionally, treatment of ApoE-/- mice with SRC-3 inhibitor bufalin prevented atherosclerotic plaque development. SRC-3 deficiency reduced aortic macrophage recruitment. Accordingly, ICAM-1 expression was markedly decreased in the aortas of SRC-3-/-ApoE-/- mice and ApoE-/- mice with endothelial SRC-3 knockdown mediated by AAV9-shSRC-3 virus. Mechanistically, SRC-3 coactivated NF-κB p65 to increase ICAM-1 transcription in endothelial cells. Collectively, these findings demonstrate that inhibiting SRC-3 ameliorates atherosclerosis development, at least in part through suppressing endothelial activation by decreasing endothelial ICAM-1 expression via reducing NF-κB signaling.

Identification and Validation of Two Heterogeneous Molecular Subtypes and a Prognosis Predictive Model for Hepatocellular Carcinoma Based on Pyroptosis.

Hepatocellular carcinoma (HCC) is a worldwide malignant cancer with high incidence and mortality. Considering the high heterogeneity of HCC, clarifying molecular characteristics associated with HCC development could help improve patients' outcomes. Pyroptosis is a novel form of cell death and is noted to be implicated in HCC pathogenesis whereas its molecular feature in HCC is unclear. Thus, we intended to clarify the molecular characteristic as well as the clinical significance of pyroptosis for HCC. A systematic bioinformatics analysis was conducted among 40 pyroptosis-related genes based on The Cancer Genome Atlas, the International Cancer Genome Consortium, and the Gene Expression Omnibus databases. A total of 12 HCC-associated pyroptosis-related genes (HPRGs) were identified to be overexpressed in HCC tissues and significantly connected to patients' poor survival. Through consensus clustering based on the HPRGs' expression, we found patients could be stratified into two distinctive pyroptosis subtypes, PyLow and PyHigh. The PyHigh group owned a notable lower survival rate and a higher high-grade proportion compared with the PyLow subtype. Besides, patients' sensitivities to chemotherapeutic drugs also presented distinctive differences between the two subtypes. Indicated by pathway enrichment analysis and immune characteristic difference analysis, the distinctions between the pyroptosis subtypes may be related to tumor immunity. Further, a five-gene risk model composed of BAK1, CHMP4A, CHMP4B, DHX9, and GSDME was established. Subsequent analyses demonstrated that the model could credibly classify patients as low or high risk and was an independent prognostic indicator for HCC. Abnormal expressions of the five genes were validated by biological experiments and new bioinformatics analysis. In conclusion, this study recognized and verified two heterogeneous pyroptosis subtypes and a predictable prognosis model for HCC. Our work may help facilitate the clinical management and treatment of HCC and understand the functions of pyroptosis in oncology.

Nanoparticle functionalization with genetically-engineered mesenchymal stem cell membrane for targeted drug delivery and enhanced cartilage protection.

Articular cartilage encounters structural damage and tissue degeneration during osteoarthritis. It is of great significance to effectively deliver the therapeutic drug to the location of the cartilage lesion. Nanoparticle-based biomimetic systems provide an important solution for drug delivery, but they still lack the active targeting capability. Although some physical and chemical modifications could decrease non-specific interactions to some extent, a specific bio-interaction for active targeting is still required for many biomedical purposes. In this study, we proposed genetically-engineered mesenchymal stem cell membrane-derived nanoparticles with the active targeting capability. BMSCs were engineered for the high expression of CXCR4 to actively migrate to the injured locations, and cell membrane of the engineered BMSCs was isolated and camouflaged to fluorescent nanoparticles. The modified nanoparticles that loaded with the therapeutic drug were incubated with IL-1ß-induced injured articular chondrocytes and cartilage. The results invisibly demonstrated that these engineered nanoparticles could increase both cellular uptake and penetration depth in the target cells and tissues under inflammatory microenvironments to protect the injured cartilage. Therefore, this genetically-modified nanoparticle functionalization strategy is expected to provide evidence for active targeting in the tissue injury treatment.

c-Myc-PD-L1 Axis Sustained Gemcitabine-Resistance in Pancreatic Cancer.

Pancreatic cancer ranks fourth among cancer-related deaths, with a 5-years overall survival rate being below 10%. Gemcitabine (dFdC) has been considered the first-line drug for patients with pancreatic cancer. However, the clinical effectiveness is less than 20% due to drug resistance. Most importantly, overwhelming evidence suggested c-Myc and PD-L1 were generally highly expressed in pancreatic cancer patients. However, whether dFdC-resistant pancreatic cancer is associated with c-Myc and PD-L1 has not been elucidated. In our present study, we found that the expression of c-Myc and PD-L1 was markedly increased in pancreatic tumor tissues compared with adjacent tissues. Similarly, c-Myc and PD-L1 expression were also remarkably elevated in dFdC-resistant Panc-1 cells compared with parental cells. In addition, dFdC sensitivity was enhanced by the combination of dFdC and c-Myc inhibitors in Panc-1 cells. Interestingly, its sensitivity was reduced when c-Myc was overexpressed. Moreover, PD-L1 protein expression was dramatically down-regulated when treated with c-Myc inhibitors. Furthermore, artesunate (ARTS) screened from 18 compounds could reverse dFdC resistance in combination with dFdC in dFdC-resistant Panc-1 cells in vitro and suppressed DMBA-induced pancreatic cancer in vivo. In summary, our data revealed that the mechanism of dFdC resistance may be that c-Myc overexpression contributed to increased PD-L1 expression, and ARTS could overcome dFdC-resistant pancreatic cancer by inhibiting c-Myc and PD-L1. Our findings not only suggest c-Myc and PD-L1 as novel prognostic biomarkers in dFdC-resistant pancreatic cancer, but also provide ARTS as a promising candidate for overcoming dFdC resistance.