Modulatory Effects of XIAOPI Formula on CXCL1 and Selected Outcomes in Triple-Negative Breast Cancer: A Randomized Controlled Clinical Trial.

Background: Triple-negative breast cancer (TNBC) is the most aggressive malignancy. Psychological distress and elevated CXCL1 level have been reported to be closely associated with the poor prognosis and quality of life of patients with TNBC. In preclinical studies using xenograft mouse models, XIAOPI formula, a nationally approved drug prescribed to patients at high risk for breast cancer, inhibited CXCL1 expression and improved survival. Traditional Chinese medicine has unique advantages in improving patients' emotional disorders and quality of life. However, the impact of XIAOPI formula on the serum level of CXCL1, psychological distress, and quality of life among patients with TNBC is currently unknown. Methods: In this study, we designed a randomized, double-blind, placebo-controlled trial. Patients with TNBC were randomly assigned to receive either the XIAOPI formula or a placebo for three months. The primary outcomes include serum CXCL1 expression, Self-Rating Anxiety Scale (SAS), and the Self-Rating Depression Scale (SDS). Secondary outcomes included the Pittsburgh Sleep Quality Index (PSQI) and the Functional Assessment of Cancer Therapy-Breast (FACT-B). Results: A total of 60 patients with TNBC were enrolled in the investigation. The results showed that the XIAOPI formula significantly decreased CXCL1 expression compared with the control group. Moreover, in comparison to the placebo, the XIAOPI formula increased FACT-B scores while decreasing SDS, SAS, and PSQI scores. Conclusion: In patients with TNBC, XIAOPI formula may be effective in reducing CXCL1 levels, enhancing psychological well-being, and quality of life. While our research offers a natural alternative therapy that may enhance the prognosis of TNBC, future validation of its therapeutic effects will require large-scale, long-term clinical trials. Clinical Registration Number: Registration website: www.chictr.org.cn, Registration date: 2018-1-19, Registration number: ChiCTR1800014535.

ATIP/ATIP1 regulates prostate cancer metastasis through mitochondrial dynamic-dependent signaling.

Mitochondria play a fundamental role in cell survival and motility. Abnormalities in mitochondria are associated with carcinogenesis, especially with tumor metastasis. In this study, we explore the biological function of ATIP1, which is a mitochondrial-located isoform of angiotensin II AT2 receptor interacting proteins (ATIPs) in prostate cancer cells. The results showed that ATIP is downregulated in prostate cancer tissues and is negatively correlated with the disease-free survival rate of prostate cancer patients. Silencing of ATIP promotes mitochondrial fission and enhances tumor cell migration and invasion. Reconstitution of ATIP1 in ATIP-deficient cells significantly attenuates mitochondrial trafficking and tumor cell movement. Therefore, ATIP1 is a negative regulator of mitochondrial dynamics and tumor cell motility and is also a potential biomarker for predicting prostate cancer malignancy.

Prevalence and genotype distribution of HPV6/11/16/18 infections among 180,276 outpatient females from a Women's and Children's Central Hospital, 2015-2021, Chengdu, China.

The aims of this study on human papilloma virus (HPV) 6/11/16/18 infection among females in Chengdu were to provide more targeted strategies for the prevention and treatment of cervical cancer and genital warts. In this study, the infection status of 20 genotypes was analysed by gene chip technology. The prevalence rates of HPV-6, -11, -16, and -18 infection among 180,276 cases were 0.94%, 0.57%, 3.22%, and 1.28%, respectively. The prevalence of HPV 6/11/16/18 showed a bimodal U-shaped curve with age; the first and second peak occurred among females < 20 and ≥ 60 years old, respectively. As the multiplicity of infections involving HPV6/11/16/18 increases, the infection rate decreases. The ratios of HPV16 single infection showed a yearly increase. The top five genotypes with HPV-16, -18, -6, and -11 in coinfection were HPV52/58/53/51/33, HPV 52/16/53/58/51, HPV52/16/58/51/53 and HPV16/52/58/59/18, respectively, HPV16/18/6/11 were mainly coinfected with HR-HPV. In sum, among the five vaccines available, nonavalent vaccine is more suitable for Chengdu females. For young females prioritizing vaccination is essential in the current context, while HPV screening remains an effective approach for older females. Additionally, in patients with genital warts, it is necessary to assess the presence of high-risk HPV infection and manage it appropriately in patients with genital warts.

Epithelial responses and Candida albicans pathogenicity are enhanced in the presence of oral streptococci

Abstract Experimental models that consider host-pathogen interactions are relevant for improving knowledge about oral candidiasis. The aim of this study was to assess the epithelial immune responses, Candida penetration of cell monolayers, and virulence during mixed species culture infections. Single species cultures of Candida albicans and mixed cultures (C. albicans, Streptococcus mutans, and Streptococcus sanguinis) were used to infect monolayers of HaCaT and FaDu ATCC HTB-43 cells for 12 h. After infection, IL-18 and IL-34 gene expression was measured to assess epithelial cell immune responses, and lactate dehydrogenase (LDH) activity was measured as an indicator of cell damage. Microscopy determined C. albicans morphology and penetration of fungal cells through the keratinocyte monolayer. Monolayers devoid of infection served as controls. Data were analyzed by an ANOVA one-way test followed by Tukey's post-hoc test (α = 0.05). The results found that IL-18 and IL-34 gene expression and LDH activity were significantly (p < 0.05) upregulated for both cell lines exposed to mixed species cultures compared with C. albicans alone. Candida albicans yeast and hyphae were evident in C. albicans only infections. In contrast, monolayers infected by C. albicans, S. mutans, and S. sanguinis exhibited higher microbial invasion with several hyphal aggregates detected. The presence of streptococci in C. albicans infection enhances the virulence and pathogenicity of the fungus with associated increased immune responses and tissue damage. Extrapolation of these findings to oral infection would indicate the added potential benefit of managing bacterial components of biofilms during treatment.

Resumo O objetivo deste estudo foi avaliar a resposta epithelial imune, a colonização da Candida albicans em monocamadas celulares e sua virulência em resposta a infecções de culturas de biofilme multiespécie. Culturas de biofilme monoespécie de C. albicans e culturas mistas (C. albicans, Streptococcus mutans e Streptococcus sanguinis) foram utilizadas para infectar monocamadas de células HaCaT e FaDu por 12 h. Após a infecção, a expressão dos genes IL-18 e IL-34 foi medida para avaliar as respostas imunes das células epiteliais. A atividade da lactato desidrogenase (LDH) foi medida como um indicador de dano celular. A microscopia determinou a morfologia de C. albicans e a penetração das células fúngicas através da monocamada de queratinócitos. Monocamadas em que não houve infecção serviram como controles. Os dados foram analisados por um teste ANOVA one-way seguido pelo teste post-hoc de Tukey (α = 0,05). Os resultados demonstraram que a expressão gênica de IL-18 e IL-34 e a atividade de LDH foram (p < 0,05) reguladas positivamente para ambas as linhagens de células expostas a culturas de espécies mistas em comparação com C. albicans isoladamente. Leveduras de C.albicans e hifas foram evidentes em infecções apenas por C. albicans. Entretanto, monocamadas infectadas por C. albicans, S. mutans e S. sanguinis exibiram maior invasão microbiana com vários agregados de hifas detectados. Dessa maneira, a presença de estreptococos na infecção por C. albicans aumentou a virulência e a patogenicidade do fungo com respostas imunes aumentadas associadas a danos nos tecidos. A extrapolação desses achados para a infecção oral indicaria o potencial benéfico do controle dos componentes bacterianos em biofilmes durante a terapia da candidíase

TNFR2+ regulatory T cells protect against bacteremic pneumococcal pneumonia by suppressing IL-17A-producing γδ T cells in the lung.

Streptococcus pneumoniae is a pathogen of global morbidity and mortality. Pneumococcal pneumonia can lead to systemic infections associated with high rates of mortality. We find that, upon pneumococcal infection, pulmonary Treg cells are activated and have upregulated TNFR2 expression. TNFR2-deficient mice have compromised Treg cell responses and highly activated IL-17A-producing γδ T cell (γδT17) responses, resulting in significantly enhanced neutrophil infiltration, tissue damage, and rapid development of bacteremia, mirroring responses in Treg cell-depleted mice. Deletion of total Treg cells predominantly activate IFNγ-T cell responses, whereas adoptive transfer of TNFR2+ Treg cells specifically suppress the γδT17 response, suggesting a targeted control of γδT17 activation by TNFR2+ Treg cells. Blocking IL-17A at early stage of infection significantly reduces bacterial blood dissemination and improves survival in TNFR2-deficient mice. Our results demonstrate that TNFR2 is critical for Treg cell-mediated regulation of pulmonary γδT17-neutrophil axis, with impaired TNFR2+ Treg cell responses increasing susceptibility to disease.

A hybrid bacterium with tumor-associated macrophage polarization for enhanced photothermal-immunotherapy.

Remodeling the tumor microenvironment through reprogramming tumor-associated macrophages (TAMs) and increasing the immunogenicity of tumors via immunogenic cell death (ICD) have been emerging as promising anticancer immunotherapy strategies. However, the heterogeneous distribution of TAMs in tumor tissues and the heterogeneity of the tumor cells make the immune activation challenging. To overcome these dilemmas, a hybrid bacterium with tumor targeting and penetration, TAM polarization, and photothermal conversion capabilities is developed for improving antitumor immunotherapy in vivo. The hybrid bacteria (B.b@QDs) are prepared by loading Ag2S quantum dots (QDs) on the Bifidobacterium bifidum (B.b) through electrostatic interactions. The hybrid bacteria with hypoxia targeting ability can effectively accumulate and penetrate the tumor tissues, enabling the B.b to fully contact with the TAMs and mediate their polarization toward M1 phenotype to reverse the immunosuppressive tumor microenvironment. It also enables to overcome the intratumoral heterogeneity and obtain abundant tumor-associated antigens by coupling tumor penetration of the B.b with photothermal effect of the QDs, resulting in an enhanced immune effect. This strategy that combines B.b-triggered TAM polarization and QD-induced ICD achieved a remarkable inhibition of tumor growth in orthotopic breast cancer.

Coronary Atherosclerotic Disease and Cancer: Risk Factors and Interrelation.

Background: In our clinical work, we found that cancer patients were susceptible to coronary atherosclerotic heart disease (CAD). However, less is known about the relationship between CAD and cancer. The present study aimed to identify the risk factors for CAD and cancer, as well as the relationship between CAD and cancer. Methods: In this retrospective study, 1600 patients between January 2012 and June 2019 were enrolled and divided into groups according to whether they had CAD or cancer. Single-factor and multivariate analysis methods were applied to examine the risk factors for CAD and cancer. Results: (1) Cancer prevalence was significantly higher in patients with CAD than in patients without CAD (47.2 vs. 20.9%). The prevalence of CAD in cancer and non-cancer patients was 78.9 and 52.4%, respectively. (2) Multivariable logistic regression showed that patients with cancer had a higher risk of developing CAD than non-cancer patients (OR: 2.024, 95% CI: 1.475 to 2.778, p < 0.001). Respiratory (OR: 1.981, 95% CI: 1.236-3.175, p = 0.005), digestive (OR: 1.899, 95% CI: 1.177-3.064, p = 0.009) and urogenital (OR: 3.595, 95% CI: 1.696-7.620, p = 0.001) cancers were significantly associated with a higher risk of CAD compared with no cancer. (3) Patients with CAD also had a higher risk of developing cancer than non-CAD patients (OR = 2.157, 95% CI: 1.603 to 2.902, p < 0.001). Patients in the Alanine aminotransferase (ALT) level ≥ 40 U/L group had a lower risk of cancer than patients in the ALT level < 20 U/L group (OR: 0.490, 95% CI: 0.333-0.722, p < 0.001). (4) An integrated variable (Y = 0.205 × 10-1 age - 0.595 × 10-2 HGB - 0.116 × 10-1 ALT + 0.135 FIB) was identified for monitoring the occurrence of cancer among CAD patients, with an AUC of 0.720 and clinical sensitivity/specificity of 0.617/0.711. Conclusion: (1) We discovered that CAD was an independent risk factor for cancer and vice versa. (2) Digestive, respiratory and urogenital cancers were independent risk factors for CAD. (3) We created a formula for the prediction of cancer among CAD patients. (4) ALT, usually considered a risk factor, was proven to be a protective factor for cancer in this study.

Dendritic Cell Vaccine Loaded with MG-7 Antigen Induces Cytotoxic T Lymphocyte Responses against Gastric Cancer.

Dendritic cells (DCs) are antigen-presenting cells that can activate T cells and initiate a primary immune response. Personalized DC vaccines have demonstrated a modest antitumor potential in some clinical pilot studies. However, those vaccines are difficult to manufacture and have a limited antitumor response. In this study, a lentiviral vector-programmed DC vaccine with high antitumor responses is developed. By transfecting with a lentiviral vector, the DC vaccine is loaded with MG-7 antigen (MG-7Ag). Three representative gastric cancer cell lines, such as KATO-3, MKN45, and SNU16, are used to estimate the in vitro cytotoxic effect of the MG-7Ag DC vaccine. Furthermore, we examine the in vivo antitumor efficacy of specific cytotoxic T lymphocytes (CTLs) induced by the MG-7Ag DC vaccine in patient-derived xenograft (PDX) mice models. The current data demonstrate that the MG-7Ag DC vaccine induced a potent CTL activity. Those CTLs have a significant cytotoxic effect on both KATO-3 and MKN45 with high level of MG-7 expression. In addition, MG-7Ag DC vaccine-mediated CTLs significantly inhibit the growth of tumor xenografts in nude mice. The MG-7Ag DC vaccine activate the cytotoxic effect of lymphocytes and can be employed as a vaccine in gastric cancer immunotherapy.

PGK1 represses autophagy-mediated cell death to promote the proliferation of liver cancer cells by phosphorylating PRAS40.

Autophagy predominantly promotes cell survival by recycling cell components, while it kills cells in specific contexts. Cell death related to autophagy plays important roles in multiple physiological and pathological situations including tumorigenesis, and the mechanism needs to be defined further. PRAS40 was found to be crucial in various cancers, and phosphorylation was reported to be involved in autophagy inhibition in monocytes. However, the detailed role of PRAS40 in autophagy and the relationship to tumorigenesis remain largely unknown. Herein we screened the binding partners of PRAS40, and found that PRAS40 interacted with Phosphoglycerate kinase 1 (PGK1). PGK1 phosphorylated PRAS40 at Threonine 246, which could be inhibited by blocking the interaction. Both in vitro and in vivo results revealed that PRAS40 mediated PGK1-induced cell growth. By tracing the mechanism, we found that PGK1 suppressed autophagy-mediated cell death, in which PRAS40 was crucial. Thus PGK1 phosphorylates PRAS40 to repress autophagy-mediated cell death under normoxia, promoting cellular proliferation. The binding of PGK1 to PRAS40 was transferred to Beclin1 under hypoxia, resulting in the increase of Beclin1 phosphorylation. These results suggest a novel model of tumorigenesis, in which PGK1 switches between repressing autophagy-mediated cell death via PRAS40 and inducing autophagy through Beclin1 according to the environmental oxygen level. Our study is anticipated to be able to offer novel insights in understanding PGK1/PRAS40 signaling hyperactivated cancers.

Targeting FAM134B-mediated reticulophagy activates sorafenib-induced ferroptosis in hepatocellular carcinoma.

Ferroptosis is a kind of cell death closely related to selective autophagy, such as ferritinophagy, lipophagy, clockophagy and chaperone-mediated autophagy. However, the role of reticulophagy, which specifically degrades endoplasmic reticulum (ER) fragments (also known as ER-phagy), in ferroptosis regulation is still unclear. In this study, we found that sorafenib (ferroptosis inducer) can effectively activate the receptor protein FAM134B-mediated ER-phagy, and FAM134B knockdown not only blocked ER-phagy but also significantly strengthened cellular sensitivity to ferroptosis without affecting macroautophagy. In vivo experiments also yielded similar results. These evidences provided new clues for ferroptosis regulation. Subsequently, bioinformatic analysis combined with RNA binding protein immunoprecipitation and polyribosome fractionation preliminarily indicated that PABPC1 can interact with FAM134B mRNA and promote its translation. Taken together, this study revealed the role of the PABPC1-FAM134B-ER-phagy pathway on ferroptosis, providing important evidence for novel anti-cancer strategies.

Radially Aligned Porous Silk Fibroin Scaffolds as Functional Templates for Engineering Human Biomimetic Hepatic Lobules.

Bioengineering functional hepatic tissue constructs that physiologically replicate the human native liver tissue in vitro is sought for clinical research and drug discovery. However, the intricate architecture and specific biofunctionality possessed by the native liver tissue remain challenging to mimic in vitro. In the present study, a versatile strategy to fabricate lobular-like silk protein scaffolds with radially aligned lamellar sheets, interconnected channels, and a converging central cavity was designed and implemented. A proof-of-concept study to bioengineer biomimetic hepatic lobules was conducted through coculturing human hepatocytes and primary endothelial cells on these lobular-like scaffolds. Relatively long-term viability of hepatocyte/endothelial cells was found along with cell alignment and organization in vitro. The hepatocytes showed special epithelial polarity and bile duct formation, similar to the liver plate, while the aligned endothelial cells generated endothelial networks, similar to natural hepatic sinuses. This endowed the three-dimensional (3D) tissue constructs with the capability to recapitulate hepatic-like parenchymal-mesenchymal growth patterns in vitro. More importantly, the cocultured hepatocytes outperformed monocultures or monolayer cultures, displaying significantly enhanced hepatocyte functions, including functional gene expression, albumin (ALB) secretion, urea synthesis, and metabolic activity. Thus, this functional unit with a biomimetic phenotype provides a novel technology for bioengineering biomimetic hepatic lobules in vitro, with potential utility as a building block for bioartificial liver (BAL) engineering or as a robust tool for drug metabolism investigation.

A pH-triggered fluorescence-switchable extracellular vesicle for tracing drug release and improving drug delivery.

Extracellular vesicles have shown great potential in drug delivery for clinical applications. However, some obstacles still need to be overcome before their clinical translation, including on demand release of drugs to improve the efficacy and monitoring of the drug release process to ascertain drug dosage. Herein, a pH-triggered fluorescence-switchable extracellular vesicle as a smart nanocarrier is fabricated by loading zwitterionic fluorescent carbon dots (CDs) into macrophage cell-secreted vesicles to achieve improved drug delivery and real-time monitoring of drug release. When circulating in the blood, the zwitterionic CDs loaded in the vesicles can tightly bind the chemotherapeutic drug DOX through electrostatic interactions to avoid premature drug unload. The nanocarriers have a long blood circulation half-life of 15.12 h and a high tumor accumulation of 9.88% ID/g. Meanwhile, the fluorescence of the CDs is in the "off" state due to the fluorescence inner filter effect (IFE) between the DOX and the CDs. When the nanocarriers enter the tumor cells, the low pH of the lysosome leads to charge reversal of the CDs. DOX can be quickly released through electrostatic repulsion and the fluorescence of the CDs turns "on" after the release of the drugs, thus enabling an improved drug delivery and real-time tracking of the drug release process.

Identification of Core Regulatory Genes and Metabolic Pathways for the n-Propanol Synthesis in Saccharomyces cerevisiae.

The n-propanol produced by Saccharomyces cerevisiae has a remarkable effect on the taste and flavor of Chinese Baijiu. The n-propanol metabolism-related genes were deleted to evaluate the role in the synthesis of n-propanol to ascertain the key genes and pathways for the production of n-propanol by S. cerevisiae. The results showed that CYS3, GLY1, ALD6, PDC1, ADH5, and YML082W were the key genes affecting the n-propanol metabolism in yeast. The n-propanol concentrations of α5ΔGLY1, α5ΔCYS3, and α5ΔALD6 increased by 121.75, 22.75, and 17.78%, respectively, compared with α5. The n-propanol content of α5ΔPDC1, α5ΔADH5, and α5ΔYML082W decreased by 24.98, 8.35, and 8.44%, respectively, compared with α5. The contents of intermediate metabolites were measured, and results showed that the mutual transformation of glycine and threonine in the threonine pathway and the formation of propanal from 2-ketobutyrate were the core pathways for the formation of n-propanol. Additionally, YML082W played important role in the synthesis of n-propanol by directly producing 2-ketobutyric acid through l-homoserine. This study provided valuable insights into the n-propanol synthesis in S. cerevisiae and the theoretical basis for future optimization of yeast strains in Baijiu making.

Circ-NOLC1 promotes epithelial ovarian cancer tumorigenesis and progression by binding ESRP1 and modulating CDK1 and RhoA expression.

Circular RNAs (circRNAs) play important roles in cancer tumorigenesis and progression, representing prognostic biomarkers and therapeutic targets. In this case, we demonstrated the role of circ-NOLC1 in epithelial ovarian cancer (EOC). Our results have shown that Circ-NOLC1 expression was higher in EOC tissues than in normal tissues, and was positively associated with FIGO stage, differentiation. Among ovarian cancer cell lines, circ-NOLC1 expression was the highest in A2780, and lowest in CAOV3. Overexpression of circ-NOLC1 in CAOV3 cells increased cell proliferation, migration, and invasion ability, whereas silencing of circ-NOLC1 in A2780 cells had the opposite effect: however, neither circ-NOLC1 downregulation nor overexpression influenced NOLC1 mRNA expression. In nude mice with subcutaneous tumors, circ-NOLC1 downregulation decreased tumor growth. Bioinformatic analysis and RNA-binding protein immunoprecipitation showed that circ-NOLC1 could bind to ESRP1. In addition, the overexpression of circ-NOLC1 significantly increased ESRP1, RhoA, and CDK1 protein and mRNA expression level; circ-NOLC1 downregulation had the opposite effects. The tumor-promoting effect of circ-NOLC1 was inhibited by knockdown of ESRP1, CDK1, or RhoA expression in circ-NOLC1-overexpressing cells, which might act by modulating RhoA and CDK1 expression. In conclusion, our study demonstrated that Circ-NOLC1 might promote EOC tumorigenesis and development by binding ESRP1 and modulating CDK1 and RhoA expression.

A near-infrared light-responsive extracellular vesicle as a "Trojan horse" for tumor deep penetration and imaging-guided therapy.

How to make the nanoparticles evade immune surveillance and deeply penetrate the tumor tissues is of great importance to maximize the therapeutic efficacy of nanomedicines. Here, a near-infrared (NIR) light-responsive extracellular vesicle as a nanoplatform is developed to realize long circulation in blood, deep penetration in tumor tissues and rapid body elimination after the treatment. Like a "Trojan horse", the nanoplatform is obtained by hiding the anti-tumor soldiers (DOX and 4.2 nm Ag2S quantum dots (QDs)) into the macrophage cell-secreted vesicle through electroporation. The natural composition and tumor targeting activity of the extracellular vesicles enable the nanoplatform to achieve a high accumulation in tumor and the in vivo biodistribution can be monitored by NIR fluorescence imaging of the Ag2S QDs. After the nanomedicines accumulate at the tumor sites, the soldiers will be released from the "Trojan horse" by utilizing the NIR photothermal effect of the Ag2S QDs. The released ultrasmall QDs and DOX can penetrate the whole tumor with a diameter of about 9 mm and effectively kill the tumor cells. Moreover, the inorganic QDs can be rapidly excreted from the body through renal clearance after the treatment to avoid the potential toxicity.

MicroRNA-520c-3p suppresses vascular endothelium dysfunction by targeting RELA and regulating the AKT and NF-κB signaling pathways.

Endothelial injury, which can cause endothelial inflammation and dysfunction, is an important mechanism for the development of atherosclerotic plaque. This study aims to investigate the functional role of miR-520c-3p in vascular endothelium during inflammatory diseases such as atherosclerosis. Quantitative real-time PCR was used to detect miR-520c-3p expression in in human umbilical vein endothelial cells (HUVECs) after treatment with platelet-derived growth factor (PDGF). Furthermore, the effects of miR-520c-3p overexpression and silencing on cell proliferation, adhesion, and apoptosis were assessed. Bioinformatics analysis and Biotin-labeled miRNA pull-down assay were used to confirm the targets of miR-520-3p. Then, the effects of miR-520c-3p on AKT and NF-κB signaling pathways were detected by western blot. Herein, we observed that the expression level of miR-520c-3p was downregulated in HUVECs under PDGF stimulation. Overexpression of miR-520c-3p not only decreased cell adhesion but also promoted proliferation and inhibited apoptosis to protect the viability of endothelial cells. It was confirmed that RELA is the target of miR-520c-3p. MiR-520c-3p inhibited the protein phosphorylation of AKT and RELA, and si-RELA reversed the promotion of AKT and RELA protein phosphorylation by anti-miR-520c-3p. In summary, our study suggested that miRNA-520c-3p targeting RELA through AKT and NF-κB signaling pathways regulated the proliferation, apoptosis, and adhesion of vascular endothelial cells. We conclude that miR-520c-3p may play an important role in the suppression of endothelial injury, which could serve as a biomarker and therapeutic target for atherosclerosis.

MicroRNA-520c-3p targeting of RelA/p65 suppresses atherosclerotic plaque formation.

Atherosclerosis is a chronic inflammatory disease, and it's the leading cause of death worldwide. Dysregulation of microRNAs (miRNAs) has been found to be associated with atherosclerosis. miR-520c-3p has been implicated in several types of cancer. However, little is known about the role of miR-520c-3p in atherosclerosis. In this study, we found that miR-520c-3p agomir decreased atherosclerotic plaque size, collagen content, the quantity of PCNA-positive cell and RelA/p65 expression of vascular smooth muscle cells (VSMCs) in the aortic valve of apoE-/- mice in vivo. The possible mechanisms of the protective effects of miR-520c-3p on atherosclerotic mice were then investigated in VSMCs. in vitro experiments showed that miR-520c-3p expressions were significantly reduced in human aortic vascular smooth muscle cell (HASMCs) treated with platelet-derived growth factor (PDGF-BB). miR-520c-3p mimics repress PDGF-BB-mediated the proliferation, migration and decrease in the percentage of cells in G2/M phase, which was associated with downregulation of RelA/p65. Mechanistically, miRNA pull-down, luciferase reporter and mRNA stability assays confirmed miR-520c-3p mimics was able to directly target 3'-UTR of RelA/p65 mRNA and decreased half-life of RelA/p65 mRNA in HASMCs. Overexpression of RelA/p65 reversed the inhibition of cell proliferation induced by miR-520c-3p mimics in HASMCs. In conclusion, our findings suggest that miR-520c-3p inhibits PDGF-BB-mediated the proliferation and migration of HASMCs by targeting RelA/p65, which may provide potential therapeutic strategies in atherosclerosis treatment.

TL1A/TNFR2 Axis Enhances Immunoregulatory Effects of Bone Marrow Derived Mesenchymal Stem Cell by Indian Hedgehog Signaling Pathway.

BACKGROUND AND OBJECTIVES: The immunomodulatory potential of mesenchymal stem cells (MSCs) can be regulated by a variety of molecules, especially cytokines. The inflammatory cytokine, TNF-like ligand 1A (TL1A), has been reported as an inflammation stimulator in-multiple autoimmune diseases. Here, we studied the effects of TL1A/TNF-receptor 2 (TNFR2) pathway on the therapeutic potency of bone marrow-derived MSCs (BMSCs). METHODS AND RESULTS: BMSCs, fibroblast-like synoviocytes (FLSs), and H9 and jurkat human T lymphocytes were used in this study. BMSCs paracrine activities, differentiation, proliferation, and migration were investigated after stimulation with TL1A, and intervened with anti-TNFR2. Additionally, the effects of TL1A on BMSCs therapeutic potency were evaluated by treating RA-FLSs, and H9 and jurkat T cells with TL1A-stimulated BMSCs conditioned medium (CM). Indian hedgehog (IHH) involvement was determined by gene silencing and treatment by recombinant IHH (rIHH). TL1A induced BMSCs stemness-related genes, COX-2, IL-6, IDO, TGF-ß and HGF through TNFR2. Also, TL1A corrected biased differentiation and increased proliferation, and migration through TNFR2. Meanwhile, CM of TL1A-stimulated BMSCs decreased the inflammatory markers of RA-FLSs and T cells. Moreover, TL1A-stimulated BMSCs experienced IHH up-regulation coupled with NF-κB and STAT3 signaling up-regulation, while p53 and oxidative stress were down-regulated. Furthermore, treatment of BMSCs by rIHH increased their anti-inflammatory effects. More importantly, knockdown of IHH decreased the ability of TL1A-stimulated BMSCs to alleviating the inflammation in RA-FLSs and T cells. CONCLUSIONS: This study reports the effects of TL1A/TNFR2 pathway on the biological behaviors and therapeutic potency of BMSCs through IHH. These findings could introduce novel procedures to increase the stemness of MSCs in cellular therapy.

Circular RNA cIARS regulates ferroptosis in HCC cells through interacting with RNA binding protein ALKBH5.

Circular RNAs (circRNAs) are a novel and unique class of noncoding RNAs that are back-spliced from pre-mRNAs. It has been confirmed that circRNAs are involved in various malignant behaviors of hepatocellular carcinoma (HCC). However, the role of circRNA in the regulation of ferroptosis and the underlying mechanism remain unknown. Here, cIARS (hsa_circ_0008367) was found to be the most highly expressed circRNA after sorafenib (SF) treatment in HCC cells. Small interfering RNA against cIARS (si-cIARS) significantly suppressed the cellular sensitivity to SF or Erastin through inactivating ferroptosis, which may be partially attributed to the inhibition of autophagy and ferritinophagy. Prediction analysis and mechanistic identification revealed that cIARS physically interacted with RNA binding protein (RBP) ALKBH5, which was a negative regulator of autophagic flux in HCC. The dissociation of BCL-2/BECN1 complex, mediated by ALKBH5 silencing was effectively blocked by si-cIARS. Furthermore, the inhibition of ferroptotic events, autophagic flux and ferritinophagy resulted from si-cIARS, were significantly rescued by ALKBH5 downregulation. Overall, cIARS may be an important circRNA, positively regulating SF-induced ferroptosis through suppressing the ALKBH5-mediated autophagy inhibition.