Dysregulation and impaired anti-bacterial potential of mucosal-associated invariant T cells in autoimmune liver diseases.

Autoimmune liver diseases (AILD) encompass a group of conditions in which the immune system mistakenly attacks the liver tissue. Mucosal-associated invariant T (MAIT) cells are enriched in the liver, where they play crucial roles in antibacterial defense and inflammation regulation. Compared to other autoimmune conditions affecting the synovium of the joints, MAIT cells from AILD exhibited a greater deficiency in ratio, elevated activation markers, increased apoptosis, and higher pro-inflammatory cytokines production. However, the frequency of MAIT cells in AILD was negatively correlated with anti-bacterial indexes, and their impaired responsiveness and weakened anti-bacterial potential were evidenced by reduced expansion ability, lower maximal IFN-γ production, and diminished E. coli-induced cytotoxic mediators release. Similar shifts in MAIT cell ratios and phenotypes were observed in both primary biliary cirrhosis and autoimmune hepatitis, linked to upregulation of bile acid components in the affected tissue. Specifically, ursodeoxycholic acid, a metabolic intermediate and traditional anti-primary biliary cirrhosis drug, inhibited TCR-mediated expansion and downregulated pro-inflammatory cytokines and anti-bacterial-related mediators in MAIT cells. These findings underscore the intricate interplay between hepatic pathology and MAIT cells, and highlight the importance of antibacterial monitoring during ursodeoxycholic acid treatment in AILD.

A new strategy for the preparation of polylactic acid composites with UV resistance, light conversion, and antibacterial properties.

A novel rare earth complex, Eu(IAA)2(phen)2 (EuIP), was synthesized by solution-based synthesis method. Then, EuIP and polylactic acid (PLA) were melt-blended at 190 °C to obtain a multifunctional PLA/EuIP composite. The incorporation of EuIP provided PLA/EuIP composites with good light conversion ability. Under UV irradiation, PLA/EuIP composites converted the absorbed UV light into red light. Moreover, the PLA/1.0EuIP composite exhibited excellent light transmittance of 88 % in the visible region and showed strong red emission under UV light. After UV irradiation for 96 h, the molecular weights and mechanical properties of neat PLA decreased dramatically. Interestingly, the molecular weights and mechanical properties of PLA/EuIP composites did not deteriorate after 96 h of UV irradiation. The reason was that EuIP could absorb UV light and utilize the absorbed energy to emit red fluorescence. Furthermore, PLA/EuIP composites showed good antibacterial activities against E. coli and S. aureus. In addition, in vitro cell experiments showed that PLA/EuIP composites was suitable for the growth of murine breast cancer (4 T1) cells. Besides, enzymatic degradation testing also proved that PLA/EuIP composites had good biodegradability. This work provides an ingenious design strategy for the preparation of PLA/EuIP composites possessing light conversion ability, UV resistance, and antibacterial properties.

Bortezomib restrains M2 polarization and reduces CXCL16-associated CXCR6+CD4 T cell chemotaxis in bleomycin-induced pulmonary fibrosis.

BACKGROUND: The development of pulmonary fibrosis involves a cascade of events, in which inflammation mediated by immune cells plays a pivotal role. Chemotherapeutic drugs have been shown to have dual effects on fibrosis, with bleomycin exacerbating pulmonary fibrosis and bortezomib alleviating tissue fibrotic processes. Understanding the intricate interplay between chemotherapeutic drugs, immune responses, and pulmonary fibrosis is likely to serve as the foundation for crafting tailored therapeutic strategies. METHODS: A model of bleomycin-induced pulmonary fibrosis was established, followed by treatment with bortezomib. Tissue samples were collected for analysis of immune cell subsets and functional assessment by flow cytometry and in vitro cell experiments. Additionally, multi-omics analysis was conducted to further elucidate the expression of chemokines and chemokine receptors, as well as the characteristics of cell populations. RESULTS: Here, we observed that the expression of CXCL16 and CXCR6 was elevated in the lung tissue of a pulmonary fibrosis model. In the context of pulmonary fibrosis or TGF-ß1 stimulation in vitro, macrophages exhibited an M2-polarized phenotype and secreted more CXCL16 than those of the control group. Moreover, flow cytometry revealed increased expression levels of CD69 and CXCR6 in pulmonary CD4 T cells during fibrosis progression. The administration of bortezomib alleviated bleomycin-induced pulmonary fibrosis, accompanied by reduced ratio of M2-polarized macrophages and decreased accumulation of CD4 T cells expressing CXCR6. CONCLUSIONS: Our findings provide insights into the key immune players involved in bleomycin-induced pulmonary fibrosis and offer preclinical evidence supporting the repurposing strategy and combination approaches to reduce lung fibrosis.

Synergistically enhancing the selective adsorption of cationic dyes through copper impregnation and amino functionality into iron-based metal-organic frameworks.

Dyes contaminating the sewages have seriously threatened the living beings and their separation from wastewater in terms of potential resource recovery is of high value. Herein, both of metal node doping and ligand group grafting were taken into account to enhance the adsorption selectivity of Fe-MOFs towards cationic dyes. The positive correlation between copper doping amount and selective coefficient (∂MOMB) for methylene blue (MB) over methyl orange (MO) within a certain range was mainly attributed to the increased surface negative charges via partial replacement of Fe(III) with Cu(II). Moreover, the amount of surface negative charges was further increased after amino functionalization and there was a synergism between Cu(II) and -NH2 in selectivity enhancement. As a result, Fe0.6Cu0.4-BDC-NH2 exhibited a 22.5-times increase in ∂MOMB and other cationic dyes including malachite green (MG) and rhodamine B (Rh. B) could also be selectively separated from binary and quaternary mixed dye systems. Moreover, Fe0.6Cu0.4-BDC-NH2 showed many superiorities like a wide pH range of 4.0-8.0, strong anti-interference ability over various inorganic ions, good recyclability, and stability. The adsorption kinetics and isotherm suggested that the MB adsorption process was a homogeneous single-layer chemisorption. Additionally, the thermodynamics manifested that the overall process was exothermic and spontaneous. According to the FT-IR and XPS spectra analysis, the electrostatic interaction and hydrogen bonding were determined as the main driving forces, and π-π interaction also contributed to the adsorption process.

Distinctly altered lipid components in hepatocellular carcinoma relate to impaired T cell-dependent antitumor immunity.

BACKGROUND AND AIMS: T cells are master effectors of anti-tumor immunity in cancer. Recent studies suggest that altered lipid metabolism imposed by the tumor microenvironment constrains anti-tumor immunity. However, the tumor-associated lipid species changes that dampen T cell ability to control tumor progression are not fully understood. Here, we plan to clarify the influences of distinctly altered lipid components in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) on T-cell function, aiming to seek lipid metabolic targets for improving T cell anti-tumor effects. METHODS: Tumor tissues and non-tumor liver from HCC patients were collected for RNA-sequencing, lipid profiling and T cell characterizing, followed by correlation analysis. Additionally, the effects of significantly changed lipid components on anti-tumor potential of T cells were tested by in vitro cell experiments and/or in vivo tumor inoculated model. RESULTS: Altered lipid metabolism coincides with impaired T cell response in HBV-related HCC. Characteristic lipid composition, significantly marked by accumulation of long-chain acylcarnitines (LCACs) and reduction of lysophosphatidylcholines (LPCs), are found in the tumor tissue. Notably, LCACs accumulated are associated with T cells exhaustion and deficient functionality, while LPCs correlate to anti-tumor effects of T cells. In particular, supplement of LPCs, including LPC (20:0) and LPC (22:0), directly promote the activation and IFN-γ secretion of T cells in vitro, and suppress tumor growth in vivo. CONCLUSIONS: Our study highlights the distinctly changed lipid components closely related to T cell dysregulation in HCC, and suggests a promising strategy by decreasing LCACs and increasing LPCs for anti-tumor immunotherapy.

Comprehensive Analysis to Reveal Amino Acid Metabolism-Associated Genes as a Prognostic Index in Gastric Cancer.

Background: Amino acid metabolism (AAM) is related to tumor growth, prognosis, and therapeutic response. Tumor cells use more amino acids with less synthetic energy than normal cells for rapid proliferation. However, the possible significance of AAM-related genes in the tumor microenvironment (TME) is poorly understood. Methods: Gastric cancer (GC) patients were classified into molecular subtypes by consensus clustering analysis using AAMs genes. AAM pattern, transcriptional patterns, prognosis, and TME in distinct molecular subtypes were systematically investigated. AAM gene score was built by least absolute shrinkage and selection operator (Lasso) regression. Results: The study revealed that copy number variation (CNV) changes were prevalent in selected AAM-related genes, and most of these genes exhibited a high frequency of CNV deletion. Three molecular subtypes (clusters A, B, and C) were developed based on 99 AAM genes, which cluster B had better prognosis outcome. We developed a scoring system (AAM score) based on 4 AAM gene expressions to measure the AAM patterns of each patient. Importantly, we constructed a survival probability prediction nomogram. The AAM score was substantially associated with the index of cancer stem cells and sensitivity to chemotherapy intervention. Conclusion: Overall, we detected prognostic AAM features in GC patients, which may help define TME characteristics and explore more effective treatment approaches.

Gossypium mustelinum genome and an introgression population enrich interspecific genetics and breeding in cotton.

KEY MESSAGE: Genomic and genetic resources of G. mustelinum were effective for identifying genes for qualitative and quantitative traits. Gossypium mustelinum represents the earliest diverging evolutionary lineage of polyploid Gossypium, representing a rich gene pool for numerous desirable traits lost in cotton cultivars. Accurate information of the genomic features and the genetic architecture of objective traits are essential for the discovery and utilization of G. mustelinum genes. Here, we presented a chromosome-level genome assembly of G. mustelinum and developed an introgression population of the G. mustelinum in the background of G. hirsutum that contained 264 lines. We precisely delimited the boundaries of the 1,662 introgression segments with the help of G. mustelinum genome assembly, and 87% of crossover regions (COs) were less than 5 Kb. Genes for fuzzless and green fuzz were discovered, and a total of 14 stable QTLs were identified with 12 novel QTLs across four independent environments. A new fiber length QTL, qUHML/SFC-A11, was confined to a 177-Kb region, and GmOPB4 and GmGUAT11 were considered as the putative candidate genes as potential negative regulator for fiber length. We presented a genomic and genetic resource of G. mustelinum, which we demonstrated that it was efficient for identifying genes for qualitative and quantitative traits. Our study built a valuable foundation for cotton genetics and breeding.

Enzyme/inorganic nanoparticle dual-loaded animal protein/plant protein composite nanospheres and their synergistic effect in cancer therapy.

It is a viable strategy to develop a safer and tumor-specific method by considering the tumor microenvironment to optimize the curative effect and reduce the side effects in cancer treatment. In this study, glucose oxidase (GOx) and Fe3O4 nanoparticles were successfully loaded inside regenerated silk fibroin/zein (RSF/zein) nanospheres to obtain dual-loaded Fe3O4/GOx@RSF/zein nanospheres. The unique structure of the RSF/zein nanospheres reported in our previous work was favorable to loading sufficient amounts of GOx and Fe3O4 nanoparticles in the nanospheres. For Fe3O4/GOx@RSF/zein nanospheres, GOx depletes endogenous glucose via an enzyme-catalyzed bioreaction, simultaneously generating plenty of H2O2in situ. It was further catalyzed through a Fe3O4-mediated Fenton reaction to form highly toxic hydroxyl free radicals (˙OH) in the acidic tumor microenvironment. These two successive reactions made up the combination of starvation therapy and chemodynamic therapy during cancer treatment. The catalytic activity of GOx loaded in the RSF/zein nanospheres is similar to that of the pristine enzyme. It was maintained for more than one month due to the protection of the RSF/zein nanospheres. The methylene blue degradation results confirmed the sequential reaction by GOx and Fe3O4 from Fe3O4/GOx@RSF/zein nanospheres. The in vitro experiments demonstrated that the Fe3O4/GOx@RSF/zein nanospheres entered MCF-7 cells and generated ˙OH free radicals. Therefore, these Fe3O4/GOx@RSF/zein nanospheres exhibited a considerable synergistic therapeutic effect. They showed more efficient suppression in cancer cell growth than either single-loaded GOx@RSF/zein or Fe3O4@RSF/zein nanospheres, achieving the design goal for the nanospheres. Therefore, the Fe3O4/GOx@RSF/zein nanospheres cut off the nutrient supply due to the strong glucose dependence of tumor cells and generated highly toxic ˙OH free radicals in tumor cells, effectively enhancing the anticancer effect and minimizing side effects. Therefore, in future clinical applications, the Fe3O4/GOx@RSF/zein nanospheres developed in this study have significant potential for combining starvation and chemodynamic therapy.

IKZF3 is a novel prognostic biomarker for head and neck squamous cell carcinoma: A study based on bioinformatics analysis.

In the past few years, immunotherapy of tumors has become an extensive research hotspot, and the value of IKZF family genes in the tumor microenvironment has also been increasingly recognized. However, the expression of the IKAROS family zinc finger 3 (IKZF3) gene in human head and neck squamous cell carcinoma (HNSCC) and its prognostic value were not reported for the main subset until now. In the present study, we analyzed the relationship between IKZF3 gene expression and the survival of HNSCC patients. To evaluate the potential of IKZF3 as a prognostic biomarker for HNSCC comprehensively, multiple online analysis tools, including UALCAN, cBioPortal, GEPIA, WebGestalt, String, Genomic Data Commons, and TIMER databases were utilized in our study. We observed that the HNSCC patients with higher IKZF3 expression tended to exhibit longer overall survival. Univariate and multivariate Cox regression analyses indicated that age and grade were independent prognostic indicators in HNSCC. Moreover, Gene Ontology and KEGG function enrichment analyses showed that several pathways in HNSCC might be pivotal pathways regulated by IKZF3, which revealed that IKZF3 was probably participating in the occurrence and development of HNSCC. Furthermore, the hypomethylation of the IKZF3 gene was closely associated with genes that observed mutation in HNSCC. IKZF3 was significantly correlated with several immune cells in HNSCC (e.g., CD8+ T cell, CD4+ cell, and dendritic cell). We explored the potential prognostic values and roles of the IKZF3 in HNSCC, revealing that IKZF3 was probably a novel and reliable prognostic biomarker for patients with HNSCC.

Long-Chain Acylcarnitines Induce Senescence of Invariant Natural Killer T Cells in Hepatocellular Carcinoma.

CD1d-restricted invariant natural killer T (iNKT) cells actively patrol the liver and possess valuable antitumor potential. However, clinical trials evaluating administration of iNKT cell-specific agonist α-galactosylceramide (α-GalCer) have failed to achieve obvious tumor regression. Improving the efficacy of iNKT cell-based immunotherapy requires a better understanding of the factors restraining the clinical benefits. In the context of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we found circulating and hepatic iNKT cells were hyperactivated but demonstrated imbalances in ratio and defective α-GalCer responsiveness. Exogenous IL2 helped to expand residual α-GalCer-responsive clones with reduced T-cell receptor diversity. However, transcriptome-wide analysis revealed activation of the senescence-associated secretory phenotype and dampened cytotoxicity in iNKT cells, weakening their immune surveillance capacity. The senescent status of iNKT cells from the patients was further illustrated by cell-cycle arrest, impaired telomere maintenance, perturbed calcium transport-related biological processes, and altered metabolism. Lipidomic profiling revealed the accumulation of long-chain acylcarnitines (LCAC) and aberrant lipid metabolism in HCC tissue. Exogenous LCACs, especially palmitoyl-carnitine and stearoyl-carnitine, inhibited iNKT cell expansion and promoted senescence. Collectively, our results provide deeper insights into iNKT cell dysregulation and identify a cell senescence-associated challenge for iNKT cell-based immunotherapy in HBV-related HCC. The mechanistic links between iNKT cell senescence and accumulated LCACs suggest new targets for anti-HCC immunotherapies. SIGNIFICANCE: Patients with HBV-related HCC exhibit a cell senescence-associated dysregulation of invariant natural killer cells that is related to altered lipid metabolism and accumulated LCACs in tumor tissue.

Regulating Lewis acidity and local electron density of iron-based metal organic frameworks via cerium doping for efficient photo-Fenton process.

The photo-Fenton performance of Fe-based metal organic frameworks (Fe-MOFs) largely depends on the amount and the local electron density of metal coordinately unsaturated sites (M CUSs). However, a majority of Fe active sites are fully bound by organic ligands leading to decreased Fe CUSs. Additionally, the symmetrical electronic distribution of iron-oxo (Fe-O) clusters and the fast electron-hole recombination are unbeneficial for the directional electron transfer and the following electron accumulation on Fe CUSs. Herein, the structure of Fe-O clusters onto the framework of MIL-88B was controllably regulated via change of Ce doping amount, among which Fe0.8Ce0.2-MIL-88B exhibited highest removal efficiency of tetracycline (TC). That was mainly ascribed to the following two points: for one, the induced ligand missing defects ameliorated the pore structures and generated more M CUSs; for another, the lower electronegativity of Ce than Fe and the role of ligand missing defects as electron trap state collectively increased the local electron density at Fe CUSs. As a result, the increased M CUSs provided more active sites for H2O2 coordination and the highly concentrated electrons density at Fe CUSs afforded the substantial electron donation towards robust H2O2 dissociation into ∙OH. Furthermore, the increased mesoporous size favored highly-efficient utilization of ∙OH. This work provides a facile strategy to improve photo-Fenton performance of Fe-MOFs.

Mucosal-associated invariant T cells reduce and display tissue-resident phenotype with elevated IL-17 producing capacity in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the important causes of cancer-related mortality worldwide. Previous studies have demonstrated the crucial roles of mucosal-associated invariant T (MAIT) cells in regulating tumor immunity, while their roles in NSCLC remain largely unknown. The aim of this study is to evaluate clinical relevance of MAIT cells in blood and tumor tissues of patients with NSCLC. Here, we find that there is no significant difference in the frequency of circulating MAIT cells between NSCLC patients and healthy donors. However, the MAIT-frequency is significantly declined in lung tumor tissues compared to their peri-tumor counterparts, which relates to Tumor-Node-Metastasis (TNM) stage. The MAIT-frequency in lung tumor tissues is higher in node-negative patients compared to node-positive patients. Furthermore, tumor-infiltrating MAIT cells display a tissue-resident effector-memory phenotype and exhibit upregulated levels of exhaustion markers. The percentage of tissue-resident cells in MAIT tends to be higher in tumor tissues than in peri-tumor tissues. In addition, the percentage of IL-17A+ MAIT cells is significantly higher in lung tumor tissues than that in peri-tumor tissues. In summary, our results indicate the possible detrimental role of MAIT cells in the development and progression of NSCLC.

Hexokinase 2 Is a Pivot for Lovastatin-induced Glycolysis-to-Autophagy Reprogramming in Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited therapeutic options available. We have recently demonstrated that lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, suppresses TNBC cell proliferation and stemness properties in vitro and in vivo. However, the mechanisms through which lovastatin inhibits TNBC cells are not fully understood. Here, we used 1H NMR-based metabolomic profiling to investigate lovastatin-induced metabolic changes in TNBC cell line MDA-MB-231. Among the 46 metabolites identified, lactate demonstrated the highest variable importance in projection (VIP) score. Glycolysis stress test revealed that lovastatin significantly decreased the extracellular acidification rate (ECAR) in MDA-MB-231 cells. Furthermore, lovastatin treatment down-regulated the levels of glycolysis-related proteins including GLUT1, PFK1, and PKM2 in MDA-MB-231 but not non-TNBC MDA-MB-453 cells. In addition, lovastatin induced autophagy as evidenced by increased LC3 puncta formation and LC3-II/I ratio, increased AMPK phosphorylation, and decreased Akt phosphorylation. We also revealed the interaction between the glycolytic enzyme hexokinase 2 (HK2) and the mitochondrial membrane protein voltage-dependent anion channel 1 (VDAC1), an important regulator of autophagy. Further bioinformatics analysis revealed that VDAC1 was expressed at a higher level in breast cancer than normal tissues and higher level of VDAC1 predicted poorer survival outcomes in breast cancer patients. The present study suggests that lovastatin might exert anti-tumor activity by reprogramming glycolysis toward autophagy in TNBC cells through HK2-VDAC1 interaction.

Transcriptome analysis of Micrococcus luteus in response to treatment with protocatechuic acid.

AIM: To reveal the antibacterial mechanism of protocatechuic acid (PCA) against Micrococcus luteus. METHODS AND RESULTS: M. luteus was exposed to PCA, and the antibacterial mechanism was revealed by measuring membrane potential, intracellular ATP and pH levels and transcriptome analysis. PCA induced the membrane potential depolarization of M. luteus, significantly decreased the intracellular ATP and pH levels of M. luteus and disrupted the integrity of the M. luteus cell membrane. Transcriptome analysis showed that PCA induced 782 differentially expressed genes (DEGs) of M. luteus. GO enrichment analysis revealed that the majority of DEGs are involved in pathways of metabolic process, cellular process, biological regulation and transport activity. In addition, PCA inhibited the growth of M. luteus in skimmed milk and extended the shelf life of skimmed milk. CONCLUSION: PCA had good bactericidal activity against M. luteus through the mechanism of cell membrane disruption and metabolic process disorder. SIGNIFICANCE AND IMPACT OF THE STUDY: PCA inhibits the growth of M. luteus in skimmed milk, suggesting that PCA is promising to be used as a novel preservative in food storage.

Application of adipose mesenchymal stem cell-derived exosomes-loaded ß-chitin nanofiber hydrogel for wound healing.

INTRODUCTION: Clarifying the role and mechanism of exosome gel in wound repair can provide a new effective strategy for wound treatment. MATERIALS AND METHODS: The cellular responses of adipose mesenchymal stem cell-derived exosomes (AMSC-exos) and the wound healing ability of AMSC-exos-loaded ß-chitin nanofiber (ß-ChNF) hydrogel were studied in vitro in mouse fibroblasts cells (L929) and in vivo in rat skin injury model. The transcriptome and proteome of rat skin were studied with the use of sequenator and LC-MS/MS, respectively. RESULTS: 80 and 160 µg/mL AMSC-exos could promote the proliferation and migration of mouse fibroblastic cells. Furthermore, AMSC-exos-loaded ß-ChNF hydrogel resulted in a significant acceleration rate of wound closure, notably, acceleration of re-epithelialization, and increased collagen expression based on the rat full-thickness skin injury model. The transcriptomics and proteomics studies revealed the changes of the expression of 18 genes, 516 transcripts and 250 proteins. The metabolic pathways, tight junction, NF-κB signaling pathways were enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway. Complement factor D (CFD) and downstream Aldolase A (Aldoa) and Actn2 proteins in rats treated with AMSC-exos-loaded ß-ChNF hydrogel were noticed and further confirmed by ELISA and Western blot. CONCLUSION: These findings suggested that AMSC-exos-loaded ß-ChNF hydrogel could promote wound healing with the mechanism which is related to the effect of AMSC-exos on CFD and downstream proteins.

Animal protein-plant protein composite nanospheres for dual-drug loading and synergistic cancer therapy.

The co-delivery of multiple drugs using one drug carrier is a viable strategy to optimize drug dosage and reduce the side effects in chemotherapy. Herein, a hydrophilic animal protein (silk fibroin) and a hydrophobic plant protein (zein) were selected for preparing a composite drug carrier. Adapting our previously developed method for the preparation of regenerated silk fibroin (RSF) nanospheres, we prepared RSF/zein nanospheres that displayed an interesting structure including a single central hole. The particle size of the RSF/zein nanospheres was regulated from 150 to 460 nm by varying the preparation conditions, implying that such a drug carrier is suitable for both intravenous administration and lymphatic chemotherapy. Two anti-cancer drugs with different target sites, paclitaxel (PTX) and curcumin (CUR), were selected for the preparation of dual-drug-loaded CUR/PTX@RSF/zein nanospheres. Both drugs achieved a high loading capacity in the RSF/zein nanospheres, i.e., 8.2% for PTX and 12.1% for CUR. Subsequently, the encapsulated PTX and CUR were released from the RSF/zein nanospheres in a sustained manner for at least 7 days. Importantly, these dual-drug-loaded RSF/zein nanospheres exhibited a considerable synergistic therapeutic effect, showing more efficient suppression of in vitro cancer cell growth than free PTX or CUR, a combination of free PTX and CUR, or single-drug-loaded nanospheres. Therefore, the CUR/PTX@RSF/zein nanospheres developed in this study hold great potential for combination chemotherapy in future clinical applications.

Nucleolar and Coiled-Body Phosphoprotein 1 Is Associated With Stemness and Represents a Potential Therapeutic Target in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lacks approved specific targeted therapies. One of the major reasons why TNBC is difficult to treat is the high proportion of cancer stem cells within the tumor tissue. Nucleolus is the location of ribosome biogenesis which is frequently overactivated in cancer cells and overactivation of ribosome biogenesis frequently drives the malignant transformation of cancer. Nucleolar and coiled-body phosphoprotein 1 (NOLC1) is a nucleolar protein responsible for nucleolus organization and rRNA synthesis and plays an important role in ribosome biogenesis. However, the correlation of NOLC1 expression with patient prognosis and its value as a therapeutic target have not been evaluated in TNBC. In the current study, based on bioinformatics analysis of the online databases, we found that the expression of NOLC1 was higher in breast cancer tissues than normal tissues, and NOLC1 was expressed at a higher level in TNBC than other subtypes of breast cancer. GSEA analysis revealed that stemness-related pathways were significantly enriched in breast cancer with high NOLC1 gene expression. Further analyses using gene expression profiling interactive analysis 2 (GEPIA2), tumor immune estimation resource (TIMER) and search tool for retrieval of interacting genes/proteins (STRING) demonstrated that NOLC1 was significantly associated with stemness in both all breast cancer and basal-like breast cancer/TNBC patients at both gene and protein levels. Knockdown of NOLC1 by siRNA decreased the protein level of the key stemness regulators MYC and ALDH and inhibited the sphere-forming capacity in TNBC cell line MDA-MB-231. Univariate and multivariate Cox regression analyses demonstrated that NOLC1 was an independent risk factor for overall survival in breast cancer. PrognoScan and Kaplan-Meier plotter analyses revealed that high expression of NOLC1 was associated with poor prognosis in both all breast cancer and TNBC patients. Further immunohistochemical analysis of breast cancer patient samples revealed that TNBC cells had a lower level of NOLC1 in the nucleus compared with non-TNBC cells. These findings suggest that NOLC1 is closely associated with the stemness properties of TNBC and represents a potential therapeutic target for TNBC.

Adipose-derived mesenchymal stem cell-loaded ß-chitin nanofiber hydrogel promote wound healing in rats.

Because of stem cells are limited by the low efficiency of their cell homing and survival in vivo, cell delivery systems and scaffolds have attracted a great deal of attention for stem cells' successful clinical practice. ß-chitin nanofibers (ß-ChNF) were prepared from squid pens in this study. Fourier transform infrared spectroscopy, X-ray diffraction and scanning electron microscopy proved that ß-ChNFs with the diameter of 5 to 10 nm were prepared. ß-ChNF dispersion became gelled upon the addition of cell culture medium. Cell culture experiments showed that ß-ChNFs exhibited negligible cytotoxicity towards ADSCs and L929 cells, and it was found that more exosomes were secreted by the globular ADSCs grown in the ß-ChNF hydrogel. The vivo experiments of rats showed that the ADSCs-loaded ß-ChNF hydrogel could directly cover the wound surface and significantly accelerate the wound healing and promote the generation of epithelization, granulation tissue and collagen. In addition, the ADSCs-loaded ß-ChNF hydrogel clearly regulated the expressions of VEGFR, α-SMA, collagen I and collagen III. Finally, we showed that ADSCs-loaded ß-ChNF hydrogel activated the TGFß/smad signaling. The neutralization of TGFß markedly reduced Smad phosphorylation and the expressions of TIMP1, VEGFR and α-SMA. Taken together, these findings suggest that ADSCs-loaded ß-ChNF hydrogel promises for treating wounds that are challenge to heal via conventional methods. Graphical abstract.

Natural products inducing nucleolar stress: implications in cancer therapy.

The nucleolus is the site of ribosome biogenesis and is found to play an important role in stress sensing. For over 100 years, the increase in the size and number of nucleoli has been considered as a marker of aggressive tumors. Despite this, the contribution of the nucleolus and the biologic processes mediated by it to cancer pathogenesis has been largely overlooked. This state has been changed over the recent decades with the demonstration that the nucleolus controls numerous cellular functions associated with cancer development. Induction of nucleolar stress has recently been regarded as being superior to conventional cytotoxic/cytostatic strategy in that it is more selective to neoplastic cells while sparing normal cells. Natural products represent an excellent source of bioactive molecules and some of them have been found to be able to induce nucleolar stress. The demonstration of these nucleolar stress-inducing natural products has paved the way for a new therapeutic approach to more delicate tumor cell-killing. This review provides a contemporary summary of the role of the nucleolus as a novel promising target for cancer therapy, with particular emphasis on natural products as an exciting new class of anti-cancer drugs with nucleolar stress-inducing properties.

Evaluation of the Membrane Damage Mechanism of Chlorogenic Acid against Yersinia enterocolitica and Enterobacter sakazakii and Its Application in the Preservation of Raw Pork and Skim Milk.

Plant-derived antimicrobial agents have adequate antimicrobial effects on food-borne pathogens, which can be used as food preservatives. The purpose of this study was to evaluate the antibacterial mechanism of chlorogenic acid (CA) against Yersinia enterocolitica and Enterobacter sakazakii. The minimum inhibitory concentration (MIC) of CA was determined by employing the broth microdilution method. Then, the cell function and morphological changes of Y. enterocolitica and E. sakazakii treated with CA were characterized. Finally, the growth inhibition models of Y. enterocolitica in raw pork and E. sakazakii in skim milk were constructed through the response surface methodology. The results demonstrated that CA has a satisfactory inhibitory effect against Y. enterocolitica and E. sakazakii with a MIC of 2.5 mg/mL. In addition, CA inhibited the growth of Y. enterocolitica and E. sakazakii via cell membrane damage, such as depolarization of the cell membrane, reduction in intracellular adenosine triphosphate (ATP) and pH levels, and destruction of cell morphology. Moreover, CA reduced two log cycles of Y. enterocolitica in raw pork and E. sakazakii in skim milk at a certain temperature. According to the corresponding findings, CA has the potential to be developed as an effective preservative to control Y. enterocolitica and E. sakazakii-associated foodborne diseases.