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Although various anti-osteoporosis drugs are available, the limitations of these therapies, including drug resistance and collateral responses, require the development of novel anti-osteoporosis agents. Rhizoma Drynariae displays a promising anti-osteoporosis effect, while the effective component and mechanism remain unclear. Here, we revealed the therapeutic potential of Rhizoma Drynariae-derived nanovesicles (RDNVs) for postmenopausal osteoporosis and demonstrated that RDNVs potentiated osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) by targeting estrogen receptor-alpha (ERα). RDNVs, a natural product isolated from fresh Rhizoma Drynariae root juice by differential ultracentrifugation, exhibited potent bone tissue-targeting activity and anti-osteoporosis efficacy in an ovariectomized mouse model. RDNVs, effectively internalized by hBMSCs, enhanced proliferation and ERα expression levels of hBMSC, and promoted osteogenic differentiation and bone formation. Mechanistically, via the ERα signaling pathway, RDNVs facilitated mRNA and protein expression of bone morphogenetic protein 2 and runt-related transcription factor 2 in hBMSCs, which are involved in regulating osteogenic differentiation. Further analysis revealed that naringin, existing in RDNVs, was the active component targeting ERα in the osteogenic effect. Taken together, our study identified that naringin in RDNVs displays exciting bone tissue-targeting activity to reverse osteoporosis by promoting hBMSCs proliferation and osteogenic differentiation through estrogen-like effects.

Abstract Background Cisplatin (CDDP)-based chemotherapy is a standard first-line treatment for metastatic bladder cancer (BCa) patients, and chemoresistance remains a major challenge in clinical practice. Circular RNAs (circRNAs) have emerged as essential regulators in carcinogenesis and cancer progression. However, the role of circRNAs in mediating CDDP chemosensitivity has yet to be well elucidated in BCa. Methods CircSTX6 (hsa_circ_0007905) was identified by mining the public circRNA datasets and verified by Sanger sequencing, agarose gel electrophoresis, RNase R treatment and qRT-PCR assays. Then, function experiments were performed to evaluate the effects of circSTX6 on BCa metastasis. Luciferase reporter assay, RNA pull-down, RNA immunoprecipitation (RIP), RNA stability assay, Fluorescence in situ hybridization (FISH) and Immunofluorescence (IF) were conducted to evaluate the interaction among circSTX6, miR-515-3p, PABPC1 and SUZ12. Animal experiments were performed to explore the function of circSTX6 in tumor metastasis and CDDP sensitivity. Results We identified that circSTX6 was significantly upregulated in clinical samples and cells of BCa. Functionally, circSTX6 promoted cell migration and invasion both in vitro and in vivo. Mechanistically, circSTX6 could act as a miR-515-3p sponge and abolish its effect on SUZ12. Moreover, circSTX6 was confirmed to increase the stability of SUZ12 mRNA by interacting with a mRNA stabilizer PABPC1 and subsequently promote the expression of SUZ12. Importantly, silencing of circSTX6 improved the chemosensitivity of CDDP-resistant bladder cancer cells to CDDP. Furthermore, in vivo analysis supported that knockdown of circSTX6 attenuated CDDP resistance in BCa tumors. Conclusion These studies demonstrate that circSTX6 plays a pivotal role in BCa metastasis and chemoresistance, and has potential to serve as a therapeutic target for treatment of BCa.

Abstract Plant-derived nanovesicles (NVs) and extracellular vesicles (EVs) are the next generation of nanocarrier platforms for biotherapeutics and drug delivery. EVs exist not only in the extracellular space, but also within the cell wall. Due to the limitations of existing isolation methods, the EVs extraction efficiency is low, and a large amount of plant material is wasted, which is of concern for rare and expensive medicinal plants. We proposed and validated a novel method for isolation of plant EVs by enzyme degradation of the plant cell wall to release the EVs. The released EVs can easily be collected. The new method was used for extraction of EVs from the roots of Morinda officinalis (MOEVs). For comparison, nanoparticles from the roots (MONVs) were extracted using the grinding method. The new method yielded a greater amount of MOEVs, and the vesicles had a smaller diameter compared to MONVs. Both MOEVs and MONVs were readily absorbed by endothelial cells without cytotoxic effect and promoted the expression of miR-155. The promotion of miR-155 by MOEVs was dose-dependent. More importantly, we found that MOEVs and MONVs were enriched toward bone tissue. These results support our hypothesis that EVs in plants could be efficiently extracted by enzymatic cell wall digestion and confirm the potential of MOEVs as therapeutic agents and drug carriers.

Abstract Background Inflammation is considered to be one of the driving factors of cancer, and chronic inflammation plays a crucial role in tumor growth and metastasis. The aim of this study was to examine the predictive value of preoperative inflammatory biomarkers for overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC), including preoperative neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and aspartate aminotransferase-to-lymphocyte ratio (ALR), a novel inflammatory biomarker. Method This study included 198 patients with mRCC from a single center from 2006 to 2022. The optimal cut-off levels for the three biomarkers were derived using the receiver operating characteristic curve (ROC). Cox univariate and multivariate analyses were used to assess independent prognostic inflammatory biomarkers. Finally, independent prognostic inflammatory biomarkers were incorporated into the prognostic model to establish a nomogram to predict the postoperative survival of patients with mRCC. Result The area under the ROC curve for NLR, LMR, and ALR, respectively, is 0.71 (CI: 0.635–0.784), 0.68 (CI: 0.604–0.755), and 0.75 (CI: 0.680–0.819). The optimal LMR, NLR, and ALR cut-off levels as evaluated by the ROC curve were 3.836, 3.106, and 68.056, respectively. Patients with NLR and ALR higher than the cut-off level and LMR lower than the cut-off level had a significant relationship with OS. Multivariate analysis revealed that tumor necrosis, lower LMR, and higher ALR were independent risk factors for OS. In addition, a nomogram that includes independent prognostic inflammatory biomarkers can accurately predict the OS in patients with mRCC. Conclusion ALR and LMR are independent risk factors for the prognosis of individuals with mRCC. By monitoring ALR and LMR postoperatively, the prognosis of patients with mRCC can be better evaluated.

Abstract Background Spi-1 proto-oncogene (SPI1), which encodes an ETS-domain transcription factor, can activate gene expression in myeloid and lymphoid lineages. The role of SPI1 in the tumor immune microenvironment in clear cell renal cell carcinoma (ccRCC) remains unknown. In this study, we investigated the possible role of SPI1 in ccRCC using an independent cohort and a comprehensive bioinformatics analysis. Materials and methods Quantitative real-time PCR, western blot and immunohistochemistry assays were used to compare the SPI1 expression levels between ccRCC tissues and normal tissues, analyze the relationships between SPI1 and CD68, CD8, CD4 expression levels, and explore the link between SPI1 and the efficacy of immunotherapy in our cohort. Tumor Immune Estimation Resource, UALCAN, cBioPortal, TISIDB database, and LinkedOmics database were used in our study. Results SPI1 expression level was higher in ccRCC bulk tissues than in normal bulk tissues. SPI1 was an independent prognostic factor for poor overall survival and progression-free survival in patients with ccRCC. SPI1 expression was strongly related to the infiltration of immune cells and immune-related molecules. SPI1 was more highly expressed in tumor-infiltrating immune cells rather than in cancer cells. Non-responders to immunotherapy against ccRCC were more likely to express higher SPI1 levels than responders. Genes co-expressed with SPI1 primarily correlated with immune-related pathways. Conclusions SPI1 expression in tumor bulk tissues is associated with disease progression and poor prognosis, as well as high expression levels of immune markers and infiltration of immune cells. SPI1 can be used as a prognostic biomarker to monitor and evaluate immunotherapy efficacy.

Polyploid plants often exhibit enhanced stress tolerance. Switchgrass is a perennial rhizomatous bunchgrass that is considered ideal for cultivation in marginal lands, including sites with saline soil. In this study, we investigated the physiological responses and transcriptome changes in the octoploid and tetraploid of switchgrass (Panicum virgatum L. ‘Alamo’) under salt stress. We found that autoploid 8× switchgrass had enhanced salt tolerance compared with the amphidiploid 4× precursor, as indicated by physiological and phenotypic traits. Octoploids had increased salt tolerance by significant changes to the osmoregulatory and antioxidant systems. The salt-treated 8× Alamo plants showed greater potassium (K+) accumulation and an increase in the K+/Na+ ratio. Root transcriptome analysis for octoploid and tetraploid plants with or without salt stress revealed that 302 upregulated and 546 downregulated differentially expressed genes were enriched in genes involved in plant hormone signal transduction pathways and were specifically associated with the auxin, cytokinin, abscisic acid, and ethylene pathways. Weighted gene co-expression network analysis (WGCNA) detected four significant salt stress-related modules. This study explored the changes in the osmoregulatory system, inorganic ions, antioxidant enzyme system, and the root transcriptome in response to salt stress in 8× and 4× Alamo switchgrass. The results enhance knowledge of the salt tolerance of artificially induced homologous polyploid plants and provide experimental and sequencing data to aid research on the short-term adaptability and breeding of salt-tolerant biofuel plants.

Ferredoxin 1 (FDX1), an iron-sulphur protein, is responsible for electron transfer in a range of metabolic redox reactions. Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer characterised by metabolic reprogramming, and FDX1 is a critical regulator of cuproptosis. However, the expression profile and prognostic value of FDX1 associated with clinicopathological features in ccRCC remain largely unelucidated. In this study, we integrated a series of public bioinformatic analysis to explore the mRNA and protein profiles of FDX1 across human cancers and cell lines and validated its expression and prognostic value, especially in ccRCC. In this study, FDX1 mRNA and protein expression were aberrantly downregulated and associated with ccRCC grade, stage, and nodal metastasis, whereas in adjacent non-tumour kidney tissue, it was abundantly expressed and cytoplasmically localised in renal tubular epithelial cells. Multivariate analysis indicated that low FDX1 expression contributed to unfavourable overall and disease-free survival. The functional enrichment of FDX1 co-expressed genes in ccRCC involved mainly mitochondrial dysfunction in various metabolic processes and biological oxidation, besides iron-sulphur cluster biogenesis. Furthermore, FDX1 modulates immunological infiltration to affect prognosis. Thus, FDX1 downregulation is mechanistically because of ccRCC tumourigenesis and is a promising prognostic biomarker to stratify patients with ccRCC.