Extracellular Matrix-Trapped Bioinspired Lipoprotein Prolongs Tumor Retention to Potentiate Antitumor Immunity.

The immunomodulatory effects of many therapeutic agents are significantly challenged by their insufficient delivery efficiency and short retention time in tumors. Regarding the distinctively upregulated fibronectin (FN1) and tenascin C (TNC) in tumor stroma, herein a protease-activated FN1 and/or TNC binding peptide (FTF) is designed and an extracellular matrix (ECM)-trapped bioinspired lipoprotein (BL) (FTF-BL-CP) is proposed that can be preferentially captured by the TNC and/or FN1 for tumor retention, and then be responsively dissociated from the matrix to potentiate the antitumor immunity. The FTF-BL-CP treatment produces a 6.96-, 9.24-, 6.72-, 7.32-, and 6.73-fold increase of CD3+CD8+ T cells and their interferon-γ-, granzyme B-, perforin-, and Ki67-expressing subtypes versus the negative control, thereby profoundly eliciting the antitumor immunity. In orthotopic and lung metastatic breast cancer models, FTF-BL-CP produces notable therapeutic benefits of retarding tumor growth, extending survivals, and inhibiting lung metastasis. Therefore, this ECM-trapping strategy provides an encouraging possibility of prolonging tumor retention to potentiate the antitumor immunity for anticancer immunotherapy.

Integrated Multi-omics Analyses Identify CDCA5 as a Novel Biomarker Associated with Alternative Splicing, Tumor Microenvironment, and Cell Proliferation in Colon Cancer Via Pan-cancer Analysis.

Background: CDCA5 has been reported as a gene involved in the cell cycle, however current research provides little details. Our goal was to figure out its functions and probable mechanisms in pan-cancer. Methods: Pan-cancer bulk sequencing data and web-based analysis tools were applied to analyze CDCA5's correlations with the gene expression, clinical prognosis, genetic alterations, promoter methylation, alternative splicing, immune checkpoints, tumor microenvironment and enrichment. Real­time PCR, cell clone formation assay, CCK-8 assay, cell proliferation assay, migration assay, invasion assay and apoptosis assay were used to evaluate the effect of CDCA5 silencing on colon cancer cell lines. Results: CDCA5 is highly expressed in most tumors, which has been linked to a poor prognosis. Immune checkpoints analysis revealed that CDCA5 was associated with the immune gene CD276 in various tumors. Single-cell analysis showed that CDCA5 correlated with proliferating T cell infiltration in COAD. Enrichment analysis demonstrated that CDCA5 may modify cell cycle genes to influence p53 signaling. The examination of DLD1 cells revealed that CDCA5 increased the proliferation and blocked cell apoptosis. Conclusion: This study contributes to the knowledge of the role of CDCA5 in carcinogenesis, highlighting the prognostic potential and carcinogenic involvement of CDCA5 in pan-cancer.

Mapping of cytosol-facing organelle outer membrane proximity proteome by proximity-dependent biotinylation in living Arabidopsis cells.

The cytosol-facing outer membrane (OM) of organelles communicates with other cellular compartments to exchange proteins, metabolites, and signaling molecules. Cellular surveillance systems also target OM-resident proteins to control organellar homeostasis and ensure cell survival under stress. However, the OM proximity proteomes have never been mapped in plant cells since using traditional approaches to discover OM proteins and identify their dynamically interacting partners remains challenging. In this study, we developed an OM proximity labeling (OMPL) system using biotin ligase-mediated proximity biotinylation to identify the proximity proteins of the OMs of mitochondria, chloroplasts, and peroxisomes in living Arabidopsis (Arabidopsis thaliana) cells. Using this approach, we mapped the OM proximity proteome of these three organelles under normal conditions and examined the effects of the ultraviolet-B (UV-B) or high light (HL) stress on the abundances of OM proximity proteins. We demonstrate the power of this system with the discovery of cytosolic factors and OM receptor candidates potentially involved in local protein translation and translocation. The candidate proteins that are involved in mitochondrion-peroxisome, mitochondrion-chloroplast, or peroxisome-chloroplast contacts, and in the organellar quality control system are also proposed based on OMPL analysis. OMPL-generated OM proximity proteomes are valuable sources of candidates for functional validation and suggest directions for further investigation of important questions in cell biology.

Nitric Oxide-Loaded Bioinspired Lipoprotein Normalizes Tumor Vessels To Improve Intratumor Delivery and Chemotherapy of Albumin-Bound Paclitaxel Nanoparticles.

The disorganized vasculatures in tumors represent a substantial challenge of intratumor nanomedicine delivery to exert the anticancer effects. Herein, we rationally designed a glutathione (GSH)-activated nitric oxide (NO) donor loaded bioinspired lipoprotein system (NO-BLP) to normalize tumor vessels and then promote the delivery efficiency of sequential albumin-bound paclitaxel nanoparticles (PAN) in tumors. NO-BLP exhibited higher tumor accumulation and deeper penetration versus the counterpart liposomal formulation (NO-Lipo) in 4T1 breast cancer tumors, thus producing notable vascular normalization efficacy and causing a 2.33-fold increase of PAN accumulation. The sequential strategy of NO-BLP plus PAN resulted in an 81.03% inhibition of tumor growth in 4T1 tumors, which was better than the NO-BLP monotherapy, PAN monotherapy, and the counterpart NO-Lipo plus PAN treatment. Therefore, the bioinspired lipoprotein of NO-BLP provides an encouraging platform to normalize tumor vessels and promote intratumor delivery of nanomedicines for effective cancer treatment.

Assessment of Diagnosis, Prognosis and Immune Infiltration Response to the Expression of the Ferroptosis-Related Molecule HAMP in Clear Cell Renal Cell Carcinoma.

BACKGROUND: Hepcidin antimicrobial peptide (HAMP) is a key factor in maintaining iron metabolism, which may induce ferroptosis when upregulated. However, its prognostic value and relation to immune infiltrating cells remains unclear. METHODS: This study analyzed the expression levels of HAMP in the Oncomine, Timer and Ualcan databases, and examined its prognostic potential in KIRC with R programming. The Timer and GEPIA databases were used to estimate the correlations between HAMP and immune infiltration and the markers of immune cells. The intersection genes and the co-expression PPI network were constructed via STRING, R programming and GeneMANIA, and the hub genes were selected with Cytoscape. In addition, we analyzed the gene set enrichment and GO/KEGG pathways by GSEA. RESULTS: Our study revealed higher HAMP expression levels in tumor tissues including KIRC, which were related to poor prognosis in terms of OS, DSS and PFI. The expression of HAMP was positively related to the immune infiltration level of macrophages, Tregs, etc., corresponding with the immune biomarkers. Based on the intersection genes, we constructed the PPI network and used the 10 top hub genes. Further, we performed a pathway enrichment analysis of the gene sets, including Huntington's disease, the JAK-STAT signaling pathway, ammonium ion metabolic process, and so on. CONCLUSION: In summary, our study gave an insight into the potential prognosis of HAMP, which may act as a diagnostic biomarker and therapeutic target related to immune infiltration in KIRC.

[Effects of aerobic exercise combined with chlorella pyrenoidos of disintegrated cell wall on some indicators of lipid metabolism in rats with high-fat diet].

OBJECTIVE: To study the effects of aerobic exercise combined with chlorella pyrenoidos of disintegrated cell wall on the lipid metabolism in rats with high-fat diet. METHODS: Fifty-five male Wistar rats were subjected to adaptive feeding for 4 days and weight-free swimming training for 3 days, 20 min/d. After eliminating 5 rats that were not suitable for swimming training, the other rats were randomly divided into 5 groups according to their body weight:control group (C group), high fat diet group (H group), high-fat diet + chlorella group(HC group), high fat diet + aerobic exercise group (HM group), high fat diet + chlorella + aerobic exercise group (HMC group), 10 in each group. The HM and HMC group were subjected to 60 min/d swimming training for 6 weeks with non-weight-bearing. Group C were fed regular diet. The other groups were fed with high-fat diet, the rats in group HC and HMC were intragastrically treated with chlorella pyrenoidos of disintegrated cell wall at the dose of 3.9 g/(kg·d), the volume was 5 ml/kg, and the other groups are given equivalent saline. The Lee's index and biochemical indexes of blood and liver were measured after 6 weeks. RESULTS: Compared with group C, Lee's index, serum levels of free fatty acids(FFA), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-c), liver FFA and interleukin-10 (IL-10) were increased significantly (P<0.01), the serum level of high-density lipoprotein cholesterol (HDL-c) was decreased significantly (P<0.01) in group H. Compared with group H, Lee's index, serum FFA, IL-6, TNF-α, TC, TG, LDL-c, liver FFA and IL-10 were decreased significantly (P<0.05 or P<0.01), serum level of HDL-c was increased significantly (P<0.05 or P<0.01) in group HC, HM and HMC. Compared with group HC and HM, Lee's index, serum FFA, IL-6, TNF-α, TC, TG, LDL-c, liver FFA and IL-10 were decreased significantly (P<0.05), serum level of HDL-c was increased significantly (P<0.05) in group HMC. CONCLUSIONS: Aerobic exercise and chlorella pyrenoidos of disintegrated cell wall can improve lipid metabolism in rats with high-fat diet and reduce the lipid toxicity caused by obesity. Joint intervention is more effective than single intervention.

[Regulatory effect of curcumin on renal apoptosis and its mechanism in overtraining rats].

OBJECTIVE: To study the effects and mechanisms of curcumin alleviating oxidative stress induced by overtraining and inhibiting renal apoptosis in rats. METHODS: Male Wistar rats of 7 weeks old were divided into control group (C group, 12), overtraining group (OM group, 11), curcumin + overtraining group (COM group, 14). Group C did not undergo any exercise intervention. Rats in OM group and COM group underwent 8-week incremental load swimming training. During the training, the COM group was treated with curcumin at the dose of 200 mg/(kg·d) in the volume as 5 ml/kg by intragastric administration, and the other groups was treated with an equal volume of 0.5% carboxymethylcellulose. Twenty-four hours after the last training, renal histopathological changes were observed by light microscopy, related biochemical indicators in blood and renal tissue were detected. RESULTS: The results showed that after 8 weeks of incremental load swimming training, the renal tissue structure of group C was normal under light microscope; histopathological changes were observed in OM group; COM group was significantly relieved compared with OM group. Compared with group C, serum levels of corticosterone (Cor), creatinine (Cr) and blood urea nitrogen (BUN) in OM group were increased (P<0.01), serum level of testosterone (T) was lower (P<0.01); the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was not changed significantly (P>0.05), while the expression of heme oxygenase-1 (HO-1) was decreased (P<0.05), total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) activity were decreased (P<0.01), malondialdehyde (MDA) concentration was increased (P<0.01); the renal apoptosis was increased (P<0.01), the expression of anti-apoptotic B cell lymphoma-2 protein (Bcl-2) was decreased (P<0.01), and the expression of proapoptotic Bcl-2 associated X protein (Bax) was increased (P<0.01). Compared with the OM group, Cor level was decreased (P<0.01) in the COM group, T level was increased (P<0.01), Cr and BUN levels were lower (P<0.05); the expression of Nrf2 and HO-1 were increased (P<0.05), T-AOC and SOD activity were increased (P<0.01), MDA concentration was decreased (P<0.05); the renal apoptosis was decreased (P<0.05), the expression of Bcl-2 was increased (P<0.05), and the expression of Bax was decreased (P<0.01). The trend of testosterone/corticosterone ratio between groups was consistent with testosterone change, and the change trend of Bcl-2/Bax ratio was consistent with the change of Bcl-2. CONCLUSIONS: The 8-week incremental load swimming training triggered excessive training in rats, aggravated oxidative stress and accelerated renal apoptosis, leading to pathological changes and dysfunction of kidney. Curcumin can up-regulate expression of Nrf2 and HO-1, effectively alleviates oxidative stress induced by overtraining, thereby increasing Bcl-2 expression, decreasing Bax expression, inhibiting renal apoptosis and protecting renal tissue structure and function properly.