Background:There is growing evidence that long non-coding RNAs (lncRNAs) play crucial roles in cancer progression and therapy. Our previous study showed that the lncRNA plasmacytoma variant translocation 1 (PVT1) regulates tumor growth and metastasis in breast cancer (BC). As a conventional chemotherapeutic drug, doxorubicin (DOX) resistance continues to be a major challenge in BC treatment. This study aimed to explore the role and underlying mechanism of PVT1 in doxorubicin-resistant BC. Methods:Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting (WB) were carried out to detect gene and protein expression levels. The extent of ferroptosis was measured based on the cellular glutathione (GSH) levels and total or lipid reactive oxygen species (ROS) levels. An in-situ tumor implantation model in nude mice was employed to validate the mechanism in vivo. Transcriptome analysis was conducted to identify downstream target genes. Results:This study found that PVT1 was highly expressed in the plasma of drug-resistant patients and drug-resistant cell lines. Silencing PVT1 reduced cellular glutathione level, increased reactive oxygen species (ROS) and lipid peroxidation (LPO), while ferroptosis inhibition in rescue experiments partially reversed the oxidative stress. In-vivo study confirmed that silencing PVT1 increased the sensitivity of BC cells to doxorubicin treatment. Transcriptomic sequencing revealed that solute carrier family 3 member 2 (SLC3A2) was the most potential target gene of PVT1, which was confirmed in PVT1-silenced cell models. Conclusion:Mechanistically, PVT1 increased SLC3A2 expression, thus inhibiting ferroptosis and promoting doxorubicin resistance in BC, indicating that PVT1 could be a promising therapeutic target for doxorubicin-resistant BC patients.

Type 2 alveolar epithelial cell (AEC2) senescence is crucial to the pathogenesis of pulmonary fibrosis (PF). The nicotinamide adenine dinucleotide (NAD(+))-consuming enzyme cluster of differentiation 38 (CD38) is a marker of senescent cells and is highly expressed in AEC2s of patients with PF, thus rendering it a potential treatment target. Umbilical cord mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) have emerged as a cell-free treatment with clinical application prospects in antiaging and antifibrosis treatments. Herein, we constructed CD38 antigen receptor membrane-modified MSC-EVs (CD38-ARM-MSC-EVs) by transfecting MSCs with a lentivirus loaded with a CD38 antigen receptor-CD8 transmembrane fragment fusion plasmid to target AEC2s and alleviate PF. Compared with MSC-EVs, the CD38-ARM-MSC-EVs engineered in this study showed a higher expression of the CD38 antigen receptor and antifibrotic miRNAs and targeted senescent AEC2s cells highly expressing CD38 in vitro and in naturally aged mouse models after intraperitoneal administration. CD38-ARM-MSC-EVs effectively restored the NAD(+) levels, reversed the epithelial-mesenchymal transition phenotype, and rejuvenated senescent A549 cells in vitro, thereby mitigating multiple age-associated phenotypes and alleviating PF in aged mice. Thus, this study provides a technology to engineer MSC-EVs and support our CD38-ARM-MSC-EVs to be developed as promising agents with high clinical potential against PF. [GRAPHICS]

Background: Neuronal loss occurs early and is recognized as a hallmark of Alzheimer’s disease (AD). Promoting neurogenesis is an effective treatment strategy for neurodegenerative diseases. Traditional Chinese herbal medicines serve as a rich pharmaceutical source for modulating hippocampal neurogenesis. Objective: Gallic acid (GA), a phenolic acid extracted from herbs, possesses anti-inflammatory and antioxidant properties. Therefore, we aimed to explore whether GA can promote neurogenesis and alleviate AD symptoms. Methods: Memory in mice was assessed using the Morris water maze, and protein levels were examined via western blotting and immunohistochemistry. GA’s binding site in the promoter region of transcription regulator nuclear factor erythroid 2-related factor 2 (Nrf2) was calculated using AutoDock Vina and confirmed by a dual luciferase reporter assay. Results: We found that GA improved spatial memory by promoting neurogenesis in the hippocampal dentate gyrus zone. It also improved synaptic plasticity, reduced tau phosphorylation and amyloid-β concentration, and increased levels of synaptic proteins in APP/PS1 mice. Furthermore, GA inhibited the activity of glycogen synthase kinase-3β (GSK-3β). Bioinformatics tools revealed that GA interacts with several amino acid sites on GSK-3β. Overexpression of GSK-3β was observed to block the protective effects of GA against AD-like symptoms, while GA promoted neurogenesis via the GSK-3β-Nrf2 signaling pathway in APP/PS1 mice. Conclusions: Based on our collective findings, we hypothesize that GA is a potential pharmaceutical agent for alleviating the pathological symptoms of AD.

Background: Atherosclerosis, a chronic inflammatory disease, poses a significant risk for cardiovascular disorders. Meanwhile, emerging evidence suggests that long noncoding RNAs (lncRNAs) play pivotal roles in diverse cardiovascular conditions. Nonetheless, the functional implications of lncRNAs in atherosclerosis remain largely unexplored. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to assess lncRNA HOTAIR and miR-19a-3p expression levels in patients with atherosclerosis and macrophage-derived foam cells. The release of inflammatory factors was evaluated using enzyme-linked immunosorbent assay (ELISA), while lipid uptake by foam cells was assessed through Oil Red O staining. Additionally, the targeting relationship between lncRNA HOTAIR and miR-19a-3p was validated via a Luciferase reporter assay. Results: LncRNA HOTAIR exhibited downregulation in the plasma of atherosclerosis patients and was found to be inhibited by ox-LDL in human macrophage-derived foam cells. Overexpression of HOTAIR effectively reduced lipid uptake and suppressed the inflammatory response by downregulating the expression of TNF-α and IL-6 during foam cell formation. Mechanistically, HOTAIR mitigated foam cell formation by repressing the expression of miR-19a-3p. Conclusions: In conclusion, our findings, in conjunction with previous studies, elucidate the role of HOTAIR in atherosclerosis. Specifically, we demonstrate that HOTAIR plays a role in alleviating foam cell formation and suppressing the inflammatory response by inhibiting miR-19a-3p in the context of atherosclerosis. Our results suggest the involvement of the TNF-α/miR-19a/HBP1/MIF pathway in mediating these effects. These findings contribute to a better understanding of atherosclerosis's molecular mechanisms and highlight the potential therapeutic implications of targeting HOTAIR and its associated pathways.

Accumulating studies suggest that Huaier exerts anti-tumor effects through intricate mechanisms. Despite extensive research on its efficacy in lung cancer, further investigation is required to elucidate the molecular mechanism of Huaier. The involvement of long noncoding RNAs (lncRNAs) in the anti-lung cancer effects of Huaier remains unknown. In this study, we found Huaier suppressed cell viability, migration and invasion in non-small cell lung cancer (NSCLC) cells. LncRNA sequencing analysis revealed Deleted in lymphocytic leukemia 2 (DLEU2) to be significantly downregulated in Huaier-treated NSCLC cells. Furthermore, DLEU2 silencing was observed to suppress NSCLC progression, while DLEU2 overexpression attenuated the anti-tumor effects of Huaier in NSCLC, thereby promoting cell viability, migration and invasion of NSCLC. The ceRNA role of DLEU2 had been demonstrated in NSCLC, which directly interacted with miR-212-5p to rescue the repression of E74 Like ETS Transcription Factor 3 (ELF3) by this microRNA. Additionally, Huaier was found to regulate the expression of miR-212-5p and ELF3. Functionally, miR-212-5p inhibitor or ELF3 overexpression reversed the effects of DLEU2 silencing or Huaier treatment, resulting in increased colony formation, migration and invasion in NSCLC. Taken together, these results illuminate the mechanism underlying Huaier's anti-tumor effects via the DLEU2/miR-212-5p/ELF3 signaling pathway, which offers novel insights into the anti-tumor effects of Huaier and constitutes a promising therapeutic target for the treatment in NSCLC.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13046-022-02588-8.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13046-022-02588-8.

Breast cancer is a highly lethal disease due to cancer metastasis. Harmine (HM), a β-carboline alkaloid, is present in various medicinal plants. Our previous study demonstrated that HM suppresses cell proliferation and migration by regulating TAZ in breast cancer cells and accelerates apoptosis. Epithelial-mesenchymal transition (EMT) plays an important role in the development of breast cancer by inducing the characteristics of cancer stem cells, cancer metastasis and recurrence. Overexpression of TAZ was shown to mediate EMT in breast cancer cells. We aimed to investigate whether HM inhibits EMT and metastasis of breast cancer cells by targeting TAZ. In this study, the cells treated with HM or with downregulated expression of TAZ showed an increase in epithelial markers and decrease in mesenchymal markers in breast cancer cells. Consistently, the breast cancer cells treated with HM or with downregulated expression of TAZ showed suppressed migration and proliferation. Moreover, TAZ overexpression reversed EMT and metastasis induced by HM in breast cancer cells. Thus, HM suppresses EMT and metastasis and invasion by targeting TAZ in breast cancer cells. HM can be used as an anticancer drug for breast cancer treatment and chemoprevention.

Background Mounting evidence supports that long noncoding RNAs (lncRNAs) have critical roles during cancer initiation and progression. In this study, we report that the plasmacytoma variant translocation 1 (PVT1) lncRNA is involved in breast cancer progression. Methods qRT-PCR and western blot were performed to detect the gene and protein expression. Colony formation would healing and transwell assays were used to detect cell function. Dual-luciferase reporter assay and RNA pull-down experiments were used to examine the mechanisms interaction between molecules. Orthotopic mouse models were established to evaluate the influence of PVT1 on tumor growth and metastasis in vivo. Results PVT1 is significant upregulated in breast cancer patients' plasma and cell lines. PVT1 promotes breast cancer cell proliferation and metastasis both in vitro and in vivo. Mechanistically, PVT1 upregulates FOXQ1 via miR-128-3p and promotes epithelial-mesenchymal transition. In addition, PVT1 binds to the UPF1 protein, thereby inducing epithelial-mesenchymal transition, proliferation and metastasis in breast cancer cells. Conclusion PVT1 may act as an oncogene in breast cancer through binding miR-128-3p and UPF1 and represents a potential target for BC therapeutic development.

Macrophages exhibit distinct phenotypes in response to environmental signals. The polarization of M1 macrophages plays an essential role in the inflammatory response. However, the specific molecular mechanisms regulating the inflammatory response during M1 macrophage polarization remain to be further understood. Here, we found that the histone acetyltransferase P300/CBP-associated factor (PCAF) was a potential negative regulator of the M1 macrophage inflammatory response. During M1 macrophage polarization, the inflammatory response gradually reduced, but PCAF expression increased. Furthermore, the overexpression of PCAF significantly inhibited the expression of the M1 macrophage-related pro-inflammatory genes TNF-α, IL-6 and CXCL10, while PCAF deficiency enhanced the expression of these genes. Furthermore, we found that PCAF overexpression suppressed the NF-κB signaling pathway and promoted the expression of the Krüppel-like factors (KLF) KLF2 and KLF4 through regulating their transcriptional levels. In addition, KLF2 and KLF4 deficiency reversed the PCAF-induced inhibition of the expression of pro-inflammatory genes in M1 macrophages. Collectively, the present results demonstrate a potential negative regulatory mechanism of the inflammatory response during M1 macrophage polarization and propose a novel mechanism of inflammation resolution for maintaining homeostasis.

Macrophages exhibit distinct phenotypes in response to environmental signals. The polarization of M1 macrophages plays an essential role in the inflammatory response. However, the specific molecular mechanisms regulating the inflammatory response during M1 macrophage polarization remain to be further understood. Here, we found that the histone acetyltransferase P300/CBP‐associated factor (PCAF) was a potential negative regulator of the M1 macrophage inflammatory response. During M1 macrophage polarization, the inflammatory response gradually reduced, but PCAF expression increased. Furthermore, the overexpression of PCAF significantly inhibited the expression of the M1 macrophage‐related pro‐inflammatory genes TNF‐α, IL‐6 and CXCL10, while PCAF deficiency enhanced the expression of these genes. Furthermore, we found that PCAF overexpression suppressed the NF‐κB signaling pathway and promoted the expression of the Krüppel‐like factors (KLF) KLF2 and KLF4 through regulating their transcriptional levels. In addition, KLF2 and KLF4 deficiency reversed the PCAF‐induced inhibition of the expression of pro‐inflammatory genes in M1 macrophages. Collectively, the present results demonstrate a potential negative regulatory mechanism of the inflammatory response during M1 macrophage polarization and propose a novel mechanism of inflammation resolution for maintaining homeostasis.

Prevention of the nuclear translocation of ANXA1 with Tat-NTS was recently reported to alleviate neuronal injury and protect against cerebral stroke. However, the role that Tat-NTS plays in the occurrence and development of gliomas still needs to be elucidated. Therefore, human glioblastoma (GB) cells were treated with various concentrations of Tat-NTS for 24 h, and cell proliferation, migration and invasion were assessed with CCK-8 and Transwell assays. The nuclear translocation of ANXA1 was evaluated by subcellular extraction and immunofluorescence, and protein expression levels were detected by Western blot analysis. In addition, the activity of MMP-2/9 was measured by gelatin zymography. The results revealed that Tat-NTS significantly inhibited the nuclear translocation of ANXA1 in U87 cells and inhibited the proliferation, migration and invasion of GB cells. Tat-NTS also suppressed cell cycle regulatory proteins and MMP-2/-9 activity and expression. Moreover, Tat-NTS reduced the level of p-p65 NF-κB in U87 cells. These results suggest that the Tat-NTS-induced inhibition of GB cell proliferation, migration and invasion is closely associated with the induction of cell cycle arrest, downregulation of MMP-2/-9 expression and activity and suppression of the NF-κB signaling pathway. Thus, Tat-NTS may be a potential chemotherapeutic agent for the treatment of GB.

Background: Recent studies have considered the obesity-related lipid environment as the potential cause for M1 macrophage polarization in type 2 diabetes. However, the specific regulatory mechanism is still unclear. Here, we investigated the role and molecular mechanism of histone methyltransferases G9a in lipids-induced M1 macrophage polarization in type 2 diabetes. Methods: We used saturated fatty acid palmitate to induce macrophage polarization, and performed real-time PCR, western blot, flow cytometry and CHIP assay to study the function and molecular mechanism of G9a. Additionally, we isolated the peripheral blood mononuclear cells (PBMCs) from 187 patients with type 2 diabetes and 68 healthy individuals, and analyzed the expression level of G9a. Results: The palmitate treatment induced the macrophage M1 polarization, and decreased the expression of G9a. The deficiency of G9a could promote the palmitate-induced M1 macrophage polarization, whereas, overexpressing G9a notably suppressed this process. Meanwhile, we observed the regulatory role of G9a on the ER stress which could contribute to M1 macrophage. Furthermore, we identified the fatty acid transport protein CD36 as the potential target of G9a. Dependent on the methyltransferase activity, G9a could negatively regulate the expression of CD36 induced by palmitate. The CD36 inhibitor SSO could significantly attenuate the regulatory effect of G9a on M1 macrophage polarization and ER stress. Importantly, G9a was decreased, and suppressed CD36 and M1 macrophage genes in the PBMCs from individuals with type 2 diabetes. Conclusions: Our studies demonstrate that G9a plays critical roles in lipid-induced M1 macrophage polarization via negatively regulating CD36. (C) 2020 Elsevier Inc. All rights reserved.

Stem cell senescence increases alongside the progressive functional declines that characterize aging. The effects of extracellular vesicles (EVs) are now attracting intense interest in the context of aging and age-related diseases. Here, we demonstrate that neonatal umbilical cord (UC) is a source of EVs derived from mesenchymal stem cells (MSC-EVs). These UC-produced MSC-EVs (UC-EVs) contain abundant anti-aging signals and rejuvenate senescing adult bone marrow-derived MSCs (AB-MSCs). UC-EV-rejuvenated AB-MSCs exhibited alleviated aging phenotypes and increased self-renewal capacity and telomere length. Mechanistically, UC-EVs rejuvenate AB-MSCs at least partially by transferring proliferating cell nuclear antigen (PCNA) into recipient AB-MSCs. When tested in therapeutic context, UC-EV-triggered rejuvenation enhanced the regenerative capacities of AB-MSCs in bone formation, wound healing, and angiogenesis. Intravenously injected UC-EVs conferred anti-aging phenotypes including decreased bone and kidney degeneration in aged mice. Our findings reveal that UC-EVs are of high translational value in anti-aging intervention.

Objectives: The post-imaging, mathematical predictive model was established by combining demographic and imaging characteristics with a pulmonary nodule risk score. The prediction model provides directions for the treatment of pulmonary nodules. Many studies have established predictive models for pulmonary nodules in different populations. However, the predictive factors contained in each model were significantly different. We hypothesized that applying different models to local research groups will make a difference in predicting the benign and malignant lung nodules, distinguishing between early and late lung cancers, and between adenocarcinoma and squamous cell carcinoma. In the present study, we compared four widely used and well-known mathematical prediction models. Materials and methods: We performed a retrospective study of 496 patients from January 2017 to October 2019, they were diagnosed with nodules by pathological. We evaluate models’ performance by viewing 425 malignant and 71 benign patients’ computed tomography results. At the same time, we use the calibration curve and the area under the receiver operating characteristic curve whose abbreviation is AUC to assess one model’s predictive performance. Results: We find that in distinguishing the Benign and the Malignancy, Peking University People’s Hospital model possessed excellent performance (AUC = 0.63), as well as differentiating between early and late lung cancers (AUC = 0.67) and identifying lung adenocarcinoma (AUC = 0.61). While in the identification of lung squamous cell carcinoma, the Veterans Affairs model performed the best (AUC = 0.69). Conclusions: Geographic disparities are an extremely important influence factors, and which clinical features contained in the mathematical prediction model are the key to affect the precision and accuracy.

We studied admission and dynamic demographic, hematological and biochemical co-variates in 1449 hospitalized subjects with coronavirus infectious disease-2019 (COVID-19) in five hospitals in Wuhan, Hubei province, China. We identified two admission co-variates: age (Odds Ratio [OR] = 1.18, 95% Confidence Interval [CI] [1.02, 1.36]; P = 0.026) and baseline D-dimer (OR = 3.18 [1.48, 6.82]; P = 0.003) correlated with an increased risk of death in persons with COVID-19. We also found dynamic changes in four co-variates, Δ fibrinogen (OR = 6.45 [1.31, 31.69]; P = 0.022), Δ platelets (OR = 0.95 [0.90–0.99]; P = 0.029), Δ C-reactive protein (CRP) (OR = 1.09 [1.01, 1.18]; P = 0.037), and Δ lactate dehydrogenase (LDH) (OR = 1.03 [1.01, 1.06]; P = 0.007) correlated with an increased risk of death. The potential risk factors of old age, high baseline D-dimer, and dynamic co-variates of fibrinogen, platelets, CRP, and LDH could help clinicians to identify and treat subjects with poor prognosis.

Colorectal cancer (CRC) is one of the most common malignant tumors in the digestive tract in humans. The development of colorectal cancer is composed of multiple stages, starting with benign adenomatous polyps in the inner wall of the large intestine and rectum, and then gradually developing. Then it developed into advanced adenomas carcinoma in situ and invasive carcinoma. Represents the distant metastasis of the most advanced development. The purpose of this review is to novel routine screening and diagnostic methods (e.g., Endoscopy and CT colonoscopy, SEPT9 methylation assay, Fecal test) and find reliable molecular markers for early diagnosis of CRC.

Breast cancer, one of the most common diseases among women, is regarded as a heterogeneous and complicated disease that remains a major public health concern. Recently, owing to the development of next-generation sequencing technologies, long non-coding RNAs have received extensive attention. Numerous studies reveal that long non-coding RNAs are playing important roles in tumor development. Although the biological function and molecular mechanisms of long non-coding RNAs remain enigmatic, recent researchers have demonstrated that an array of long non-coding RNAs express abnormally in cancers, including breast cancer. Herein, we summarized the latest literature about long non-coding RNAs in breast cancer, with a particular focus on the multiple molecular roles of regulatory long non-coding RNAs that regulate cell proliferation, invasion, metastasis, and apoptosis.

Abdominal Aortic Aneurysm (AAA) is a severe cardiovascular disease, with high mortality rate after acute rupture of blood vessels. However, the underlying pathogenesis of different morbidity between men and women remains unclear. In the present study, we first selected four datasets including 68 AAA and 32 control samples from published data on GEO database, and analyzed them by data mining. The integrative analysis found a total of 368 differentially expressed genes in E2-related AAA. Next, regulatory mechanism networks among these target genes were predicted, and four genes were identified as key nodes in the network, which play a major role in the immune system. We focused on the role of monocytes/macrophages in the development of cardiovascular diseases to further explore the role of estrogen in the polarization of monocytes/macrophage, the mRNA level of the four genes was validated by RT-PCR in RAW264.7 cells treated with β-estradiol (E2), diarylpropionitrile (DPN), 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), fulvestrant or vehicle. The results showed that the mRNA level and protein level of TROVE2 was significantly increased in estrogen or estrogen receptor agonist-treated groups. Moreover, estrogen affected the transformation of macrophages to M2 phenotype by detecting M1- and M2-related indicator genes at the mRNA level. Flow cytometry demonstrated that the TROVE2 deficiency led to a notable decrease in the level of M2 phenotype marker protein CD206. In conclusion, our results suggest that E2 can promote the expression of TROVE2, which is closely related to the M2-phenotype transformation of macrophages.