Treatment with walnut peptide ameliorates memory impairment in zebrafish and rats: promoting the expression of neurotrophic factors and suppressing oxidative stress.

Walnut peptide, a low molecular weight peptide separated from walnuts by enzymatic hydrolysis, is considered as a potential nutraceutical with a variety of biological activities. In this study, we characterized the walnut peptide prepared by alkaline protease hydrolysis and evaluated its neuroprotective effect in zebrafish and rat models of memory disorders. Series of concentrations of the walnut peptide were orally administered to zebrafish and rats to examine its impact on the behavior and biochemical indicators. The results showed that the oral administration of walnut peptide significantly ameliorated the behavioral performance in zebrafish exposed to bisphenol AF (1 µg mL-1) and rats exposed to alcohol (30% ethanol, 10 mL kg-1). Furthermore, the walnut peptide upregulated the expression of neurotrophic-related molecules in zebrafish, such as the brain-derived neurotrophic factor (BDNF) and the glial cell-derived neurotrophic factor (GDNF). In the rat brain, the walnut peptide increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), while dramatically reduced malondialdehyde (MDA) level. Together, these findings elucidated that the walnut peptide might partially offset the declarative memory deficits via regulation of neurotrophic-related molecule expression and promotion of the antioxidant defense ability. Therefore, walnut peptide holds the potential for development into functional foods as a nutritional supplement for the management of certain neurodegenerative disorders.

Surface functionalization of calcium magnesium phosphate cements with alginate sodium for enhanced bone regeneration via TRPM7/PI3K/Akt signaling pathway.

Although calcium­magnesium phosphate cements (CMPCs) have been widely applied to treating critical-size bone defects, their repair efficiency is unsatisfactory owing to their weak surface bioactivity and uncontrolled ion release. In this study, we lyophilized alginate sodium (AS) as a coating onto HAp/K-struvite (H@KSv) to develop AS/HAp/K-struvite (AH@KSv), which promotes bone regeneration. The compressive strength and hydrophilicity of AH@KSv significantly improved, leading to enhanced cell adhesion in vitro. Importantly, the SA coating enables continuous ions release of Mg2+ and Ca2+, finally leading to enhanced osteogenesis in vitro/vivo and different patterns of new bone ingrowth in vivo. Furthermore, these composites increased the expression levels of biomarkers of the TRPM7/PI3K/Akt signaling pathway via an equilibrium effect of Mg2+ to Ca2+. In conclusion, our study provides novel insights into the mechanisms of Mg-based biomaterials for bone regeneration.

Effect of fascia iliaca compartment block combined with ropivacaine on post-operative outcomes in elderly patients undergoing hip fracture repair.

Objective: To explore the effect of fascia iliaca compartment block (FICB) in combination with ropivacaine on post-operative outcomes in elderly patients undergoing hip fracture (HF) repair. Methods: Retrospective analysis included data of 111 elderly patients who underwent HF surgery with FICB in Changxing County People's Hospital from October 2018 to October 2022. Observation group received 0.25% ropivacaine combined with FICB (n=52), and the control group was administered an intravenous injection of parecoxib sodium (n=59). Baseline characteristics of the patients, and indexes such as mean arterial pressure (MAP), heart rate (HR), and visual analogue scale (VAS) pain scores, were collected at one-, six-, 12- and 24-hours past surgery, both at rest and after passive movement. Results: VAS scores, MAP and HR at rest and after a passive movement in both groups were comparable before the surgery. VAS sores were significantly lower in the observation group at one-, six-, 12- and 24-hours after the surgery (P<0.05). Postoperative MAP in the observation group (80.83 ± 8.31) was significantly lower compared to the control group (95.29 ± 8.45 (t = -9.0659, p < 0.0001). Similarly, HR of the observation group was significantly lower one-hour post-surgery both at rest (t = -2.0468, p = 0.0431) and after passive movement (t = -6.0625, p < 0.001), and at all subsequent time intervals after the passive movement (P<0.05). Conclusions: Ropivacaine combined with FICB was associated with improved post-operative outcomes such as lower post-surgery VAS scores, MAP and HR compared to the intravenous injection of parecoxib sodium.

Roles of lncRNA in the diagnosis and prognosis of triple-negative breast cancer. / LncRNAåœ¨ä¸‰é˜´æ€§ä¹³è ºç™Œè¯Šæ–­å’Œé¢„åŽä¸­çš„ä½œç”¨.

Breast cancer is a malignant tumor that seriously endangers women's lives. The prognosis of breast cancer patients differs among molecular types. Compared with other subtypes, triple-negative breast cancer (TNBC) has been a research hotspot in recent years because of its high degree of malignancy, strong invasiveness, rapid progression, easy of recurrence, distant metastasis, poor prognosis, and high mortality. Many studies have found that long non-coding RNA (lncRNA) plays an important role in the occurrence, proliferation, migration, recurrence, chemotherapy resistance, and other characteristics of TNBC. Some lncRNAs are expected to become biomarkers in the diagnosis and prognosis of TNBC, and even new targets for its treatment. Based on a PubMed literature search, this review summarizes the progress in research on lncRNAs in TNBC and discusses their roles in TNBC diagnosis, prognosis, and chemotherapy with the hope of providing help for future research.

Advantages of contrast-enhanced ultrasound in the localization and diagnostics of sentinel lymph nodes in breast cancer. / è¶ å£°é€ å½±åœ¨ä¹³è ºç™Œå‰å“¨æ·‹å·´ç»“å®šä½å’Œè¯Šæ–­ä¸­çš„ä¼˜åŠ¿.

Sentinel lymph nodes (SLNs) are the first station of lymph nodes that extend from the breast tumor to the axillary lymphatic drainage. The pathological status of these LNs can predict that of the entire axillary lymph node. Therefore, the accurate identification of SLNs is necessary for sentinel lymph node biopsy (SLNB) to replace axillary lymph node dissection (ALND). The quality of life and prognosis of breast cancer patients are related to proper surgical treatment after the precise identification of SLNs. Some of the SLN tracers that have been identified include radioisotope, nano-carbon, indocyanine green (ICG), and methylene blue (MB). However, these tracers have certain limitations, such as pigmentation, radiation dangers, and the requirement for costly detection equipment. Ultrasound contrast agents (UCAs) have good specificity and sensitivity, and thus can compensate for some shortcomings of the mentioned tracers. This technique is also being applied to SLNB in patients with breast cancer, and can even provide an initial judgment on SLN status. Contrast-enhanced ultrasound (CEUS) has the advantages of high distinguishability, simple operation, no radiation harm, low cost, and accurate localization; therefore, it is expected to replace the traditional biopsy methods. In addition, it can significantly enhance the accuracy of SLN localization and shorten the operation time.

Identification and evaluation of a risk model predicting the prognosis of breast cancer based on characteristic signatures.

Background: Breast cancer (BC) is one of the most common fatal cancers in women. Identifying new biomarkers is thus of great significance for the diagnosis and prognosis of BC. Methods: In this study, 1,030 BC cases from The Cancer Genome Atlas (TCGA) were obtained for differential expression analysis and Short Time-series Expression Miner (STEM) analysis to identify characteristic BC development genes, which were further divided into upregulated and downregulated genes. Two predictive prognosis models were both defined by Least Absolute Shrinkage and Selection Operator (LASSO). Survival analysis and receiver operating characteristic (ROC) curve analysis were used to determine the diagnostic and prognostic capabilities of the two gene set model scores, respectively. Results: Our findings from this study suggested that both the unfavorable (BC1) and favorable (BC2) gene sets are reliable biomarkers for the diagnosis and prognosis of BC, although the BC1 model presents better diagnostic and prognostic value. Associations between the models and M2 macrophages and sensitivity to Bortezomib were also found, indicating that unfavorable BC genes are significantly involved in the tumor immune microenvironment. Conclusions: We successfully established one predictive prognosis model (BC1) based on characteristic gene sets of BC to diagnose and predict the survival time of BC patients using a cluster of 12 differentially expressed genes (DEGs).

New progress in the role of microRNAs in the diagnosis and prognosis of triple negative breast cancer.

Triple negative breast cancer is distinguished by its high malignancy, aggressive invasion, rapid progression, easy recurrence, and distant metastases. Additionally, it has a poor prognosis, a high mortality, and is unresponsive to conventional endocrine and targeted therapy, making it a challenging problem for breast cancer treatment and a hotspot for scientific research. Recent research has revealed that certain miRNA can directly or indirectly affect the occurrence, progress and recurrence of TNBC. Their expression levels have a significant impact on TNBC diagnosis, treatment and prognosis. Some miRNAs can serve as biomarkers for TNBC diagnosis and prognosis. This article summarizes the progress of miRNA research in TNBC, discusses their roles in the occurrence, invasion, metastasis, prognosis, and chemotherapy of TNBC, and proposes a treatment strategy for TNBC by interfering with miRNA expression levels.

Synergistic anti-cancer and attenuation effects of thymosin on chemotherapeutic drug vinorelbine in tumor-bearing zebrafish.

Vinorelbine, the standard chemotherapy drug on advanced lung cancer, causes adverse events such as immunosuppression and bone marrow suppression. Thus, it is necessary to find drugs that could improve immune function and synergistically enhance the anti-tumor effect of vinorelbine. Thymosin is reported to inhibit tumor growth as an immunomodulator. Herein, to study the synergistic anti-cancer and attenuation effects of thymosin on vinorelbine, human lung cancer A549 cells that were labeled with CM-DiI were transplanted into zebrafish to establish the lung cancer xenotransplanted model. After treatment of vinorelbine and different concentrations of thymosin, the fluorescence intensity of CM-DiI-labeled A549 cells and the number of apoptotic muscle cells in the tumor-bearing zebrafish were detected. Besides, effects of thymosin on vinorelbine-reduced macrophages and T cells were identified in the transgenic zebrafish (Tg:zlyz-EGFP and Tg:rag2-DsRed). Then, the qRT-PCR was used to determine the alterations of the immune-related factors at the transcription level. Thymosin showed a marked synergistic anti-cancer effect with vinorelbine for the xenograft human lung cancer A549 cells, and the synergistic effect enhanced in a dose-dependent manner. Moreover, thymosin alleviated vinorelbine-induced muscle cell apoptosis, macrophage reduction, and T cell suppression. Compared with the vinorelbine group, co-administration with thymosin raised the mRNA levels of TNF-α, TNF-ß, INF-γ, and GM-CSF. Thus, thymosin possesses synergistic anti-cancer effect on vinorelbine, and has protective effect on vinorelbine-induced immunosuppression. Thymosin, as an adjuvant immunomodulatory therapy, has great potential in enhancing the clinical application of vinorelbine.

Total neoadjuvant therapy versus standard therapy in locally advanced rectal cancer: A systematic review and meta-analysis of 15 trials.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) before total mesorectal excision (TME) and followed systemic chemotherapy is widely accepted as the standard therapy for locally advanced rectal cancer (LARC). This meta-analysis was to evaluate the current evidence regarding nCRT in combination with induction or consolidation chemotherapy for rectal cancer in terms of oncological outcomes. METHODS: A systematic search of medical databases (PubMed, EMBASE and Cochrane Library) was conducted up to the end of July 1, 2021. This meta-analysis was performed to evaluate the efficacy of TNT in terms of pathological complete remission (pCR), nCRT or surgical complications, R0 resection, local recurrence, distant metastasis, disease-free survival (DFS) and overall survival (OS) in LARC. RESULTS: Eight nRCTs and 7 RCTs, including 3579 patients were included in the meta-analysis. The rate of pCR was significantly higher in the TNT group than in the nCRT group, (OR 1.85, 95% CI 1.39-2.46, p < 0.0001), DFS (HR 0.80, 95% CI 0.69-0.92, p = 0.001), OS (HR 0.75, 95% CI 0.62-0.89, p = 0.002), nCRT complications (OR 1.05, 95% CI 0.77-1.44, p = 0.75), surgical complications (OR 1.02, 95% CI 0.83-1.26, p = 0.83), local recurrence (OR 1.82, 95% CI 0.95-3.49, p = 0.07), distant metastasis (OR 0.77, 95% CI 0.58-1.03, p = 0.08) did not differ significantly between the TNT and nCRT groups. CONCLUSION: TNT appears to have advantages over standard therapy for LARC in terms of pCR, R0 resection, DFS, and OS, with comparable nCRT and postoperative complications, and no increase in local recurrence and distant metastasis.

TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma.

To identify drivers of sensitivity and resistance to Protein Arginine Methyltransferase 5 (PRMT5) inhibition, we perform a genome-wide CRISPR/Cas9 screen. We identify TP53 and RNA-binding protein MUSASHI2 (MSI2) as the top-ranked sensitizer and driver of resistance to specific PRMT5i, GSK-591, respectively. TP53 deletion and TP53R248W mutation are biomarkers of resistance to GSK-591. PRMT5 expression correlates with MSI2 expression in lymphoma patients. MSI2 depletion and pharmacological inhibition using Ro 08-2750 (Ro) both synergize with GSK-591 to reduce cell growth. Ro reduces MSI2 binding to its global targets and dual treatment of Ro and PRMT5 inhibitors result in synergistic gene expression changes including cell cycle, P53 and MYC signatures. Dual MSI2 and PRMT5 inhibition further blocks c-MYC and BCL-2 translation. BCL-2 depletion or inhibition with venetoclax synergizes with a PRMT5 inhibitor by inducing reduced cell growth and apoptosis. Thus, we propose a therapeutic strategy in lymphoma that combines PRMT5 with MSI2 or BCL-2 inhibition.

Effects of Oral Administration of Bamboo (Dendrocalamus membranaceus) Leaf Flavonoids on the Antioxidant Capacity, Caecal Microbiota, and Serum Metabolome of Gallus gallus domesticus.

The consumption of bamboo leaf flavonoids (BLFs) as novel dietary antioxidants has increased owing to their beneficial biological and pharmacological functions. This study assessed the in vivo effects of BLFs on antioxidant capacity, as well as caecal microbiota, serum metabolome, and health status. The Gallus gallus domesticus model and the oral administration approach were used with four treatment groups (basal diet, basal diet with 20 mg bacitracin/kg, basal diet with 50 mg BLF/kg, and basal diet with 250 mg BLF/kg). Ultra-high-performance liquid chromatography triple-quadrupole mass spectrometry analysis indicated that vitexin, fumaric acid, orientin, isoorientin, and p-coumaric acid were the predominant BLF components. From days 1 to 21, BLF increased the average daily gain and decreased the feed:gain of broilers. Moreover, BLF enhanced the serum antioxidant capacity and immune responses. Further, 16S rRNA sequencing showed that BLF modulated the caecal microbial community structure, which was dominated by Betaproteobacteriales, Erysipelatoclostridium, Parasutterella, Lewinella, Lactobacillus, and Candidatus Stoquefichus in BLF broilers. Among the 22 identified serum metabolites in BLF broilers, sphinganine, indole-3-acetaldehyde retinol, choline, 4-methylthio-2-oxobutanoic acid, and L-phenylalanine were recognised as biomarkers. In summary, BLFs appeared to modulate the caecal microbiome, alter the serum metabolome, and indirectly improve antioxidant capacity and health status.

Multiomics analysis reveals that peach gum colouring reflects plant defense responses against pathogenic fungi.

In the present study, the differences in the antioxidant capability, metabolite composition and fungal diversity in peach gum with various colours were investigated. Metabolomics revealed that peach gum comprised many small-molecule metabolites (including primary and secondary metabolites), and most polyphenols (such as flavonoids and phenolic acids) showed a significantly positive relationship with the colour deepening, total phenol content and antioxidant capability. Using fungal diversity analysis, the abundance of five fungi at the genus level increased with peach gum colour deepening, and these fungi demonstrated a significantly positive relationship with two defense hormones (salicylic acid and abscisic acid) and most polyphenols (particularly flavonoids). The gummosis pathogenic fungus Botryosphaeria was among the five fungi, suggesting that peach gum colouring may reflect plant defense responses against pathogenic fungi. Additionally, the concentrations of 12 flavonoids in peach gum samples were detected based on LC-QQQ/MS, among which hesperetin, naringenin and eriodictyol were the most abundant.

Sea Cucumber Intestinal Peptide Induces the Apoptosis of MCF-7 Cells by Inhibiting PI3K/AKT Pathway.

Sea cucumbers are one of many marine echinoderm animals that contain valuable nutrients and medicinal compounds. The bioactive substances in sea cucumbers make them have promising biological and pharmacological properties, including antioxidant, anti-bacterial, and anti-tumor effects. In this study, sea cucumber intestinal peptide (SCIP) is a small molecular oligopeptide (<1,000 Da) extracted from sea cucumber intestines hydrolyzed by alkaline protease. The analysis of amino acid composition showed that hydrophobic amino acids and branched-chain amino acids were rich in SCIP. Nowadays, although increasing studies have revealed the biological functions of the sea cucumber active substances, there are few studies on the function of SCIP. Furthermore, due to the anti-cancer activity being an essential characteristic of sea cucumber active substances, we also investigated the anti-cancer potential and the underlying mechanism of SCIP in vivo and in vitro. The results indicate that SCIP inhibits the growth of MCF-7 tumor cells in zebrafish and increases the apoptosis of human breast cancer MCF-7 cells. Further mechanism studies confirm that SCIP promotes the expression of apoptosis-related proteins and thus promotes the breast cancer cells (MCF-7) apoptosis via inhibition of PI3K/AKT signal transduction pathway.

Curcuma zedoaria petroleum ether extract reverses the resistance of triple-negative breast cancer to docetaxel via pregnane X receptor.

BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by its aggressiveness and poor prognosis. Docetaxel is the common chemotherapeutic drug used in the treatment of TNBC. However, resistance to docetaxel has limited the effectiveness of TNBC treatment. Petroleum ether extracts of Curcuma zedoaria (PECZ) can inhibit the proliferation of MDA-MB-231 cells. However, the effect of PECZ on docetaxel resistance is not clear. METHODS: A docetaxel-resistant MDA-MB-231 (MDA-MB-231/docetaxel) cell line was established, and Cell Counting Kit-8 (CCK-8), quantitative real-time PCR (qRT-PCR), and western blotting assays were used to evaluate the effect of docetaxel resistance in MDA-MB-231 cells. Next, CCK-8 was also performed to detect the effect of docetaxel or the combination treatment of docetaxel and PECZ on the proliferation of MDA-MB-231/docetaxel cells. Thereafter, MDA-MB-231/docetaxel cells were subcutaneously injected into nude mice to induce a TNBC xenograft model, and the mice were divided into a model group, docetaxel group, PECZ group, and combination of docetaxel and PECZ group. Subsequently, hematoxylin and eosin (HE) staining, immunohistochemical, qRT-PCR, and western blotting were used to estimate the effect of pre-treatment with PECZ on docetaxel tolerance reversal. RESULTS: PECZ significantly inhibited the expression of pregnane X receptor (PXR), multidrug resistance 1 (MDR1), breast cancer resistance protein (BCRP), and cytochrome P-450 (CYP3A4) in MDA-MB-231/docetaxel cells. Only higher concentrations of docetaxel could inhibit the viability of MDA-MB-231/docetaxel cells. When pre-treated with PECZ, lower concentrations of docetaxel could significantly inhibit cell viability. Meanwhile, combination treatment also reduced the tumor volume, ameliorated the pathological change of tumor tissues, and down-regulated the expressions of PXR, MDR1, BCRP, and CYP3A4 (according to HE staining, immunohistochemical, qRT-PCR and western blotting results in vivo). CONCLUSIONS: Our research showed that PECZ reversed docetaxel resistance in TNBC by PXR both in vitro and in vivo, which provides the basis for further investigations into the potential therapeutic impact of docetaxel resistance in TNBC.

GSK137, a potent small-molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice.

B-cell lymphoma 6 (BCL6) is a zinc finger transcriptional repressor possessing a BTB-POZ (BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain, which is required for homodimerization and association with corepressors. BCL6 has multiple roles in normal immunity, autoimmunity, and some types of lymphoma. Mice bearing disrupted BCL6 loci demonstrate suppressed high-affinity antibody responses to T-dependent antigens. The corepressor binding groove in the BTB-POZ domain is a potential target for small compound-mediated therapy. Several inhibitors targeting this binding groove have been described, but these compounds have limited or absent in vivo activity. Biophysical studies of a novel compound, GSK137, showed an in vitro pIC50 of 8 and a cellular pIC50 of 7.3 for blocking binding of a peptide derived from the corepressor silencing mediator for retinoid or thyroid hormone receptors to the BCL6 BTB-POZ domain. The compound has good solubility (128 µg/ml) and permeability (86 nM/s). GSK137 caused little change in cell viability or proliferation in four BCL6-expressing B-cell lymphoma lines, although there was modest dose-dependent accumulation of G1 phase cells. Pharmacokinetic studies in mice showed a profile compatible with achieving good levels of target engagement. GSK137, administered orally, suppressed immunoglobulin G responses and reduced numbers of germinal centers and germinal center B cells following immunization of mice with the hapten trinitrophenol. Overall, we report a novel small-molecule BCL6 inhibitor with in vivo activity that inhibits the T-dependent antigen immune response.

Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors.

The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6. We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.

Microglial Annexin A3 promoted the development of melanoma via activation of hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway.

BACKGROUND: Melanoma, a relatively common malignancy, has become one of the tumors with the fastest rising incidence in recent years. The purpose of this study was to investigate the effect of Microglial Annexin A3 (ANXA3) on melanoma. METHODS: Serum samples were obtained from 20 patients with melanoma or 20 healthy controls. Kaplan-Meier survival analysis was performed. Transcriptome were used to analyze the correlation between ANXA3 expression and overall survival in patients with melanoma. Human melanoma cell lines WM-115 cells were transfected with ANXA3, si-ANXA3, ANXA3 + si-hypoxia inducible factor-1α (HIF-1α), si-ANXA3 + HIF-1α, and negative plasmids. Cell proliferation assay, cell invasion assay, and wound healing assay were performed on WM-115 cells. Lactate dehydrogenase (LDH) and caspase-3/9 activities were detected by commercial kits. Western blot and RT-PCR were used to detect the protein and mRNA expression of relation factors. RESULTS: ANXA3 expression was up-regulated in patients with melanoma in comparison with healthy controls. Over-expression of ANXA3 promoted cell growth and migration, and reduced cytotoxicity of WM-115 cells. Overall survival (OS) and disease-free survival (DFS) of patients with high ANXA3 expression were both lower than those of patients with low ANXA3 expression. Down-regulation of ANXA3 reduced cell growth and migration, and promoted cytotoxicity of WM-115 cells. ANXA3 induced vascular endothelial growth factor (VEGF) signaling pathway by activation of HIF-1α. CONCLUSION: In conclusion, our results indicated that ANXA3 promoted cell growth and migration of melanoma via activation of HIF-1α/VEGF signaling pathway.

Quercetin induced NUPR1-dependent autophagic cell death by disturbing reactive oxygen species homeostasis in osteosarcoma cells.

Osteosarcoma is a primary bone aggressive cancer, affecting adolescents worldwide. Quercetin (a natural polyphenolic compound) is a polyphenolic flavonoid compound found in a variety of plants. It has been demonstrated to exert cytostatic activity against a variety of human cancer, including the human osteosarcoma. However, its efficacy in the treatment of osteosarcoma and the underlying antitumor mechanism has not been fully elucidated yet. In this study, we exposed MG-63 cells to different concentrations of quercetin (50, 100 and 200 µM) for 24 h. Here, we show that quercetin increased autophagic flux in the MG-63 cells, as evidenced by the upregulation of LC3B-II/LC3B-I and downregulation of P62/SQSTM1. Moreover, the autophagy inhibitor Bafilomycin A1 or genetic blocking autophagy with ATG5 knockdown decreased quercetin-induced cell death, indicating quercetin triggered autophagic cell death in MG-63 cells. Specifically, quercetin increased NUPR1 expression and activated of NUPR1 reporter activity, which contributed to the expression of autophagy-related genes and subsequent initiated autophagic cell death in osteosarcoma cells. Importantly, the increased expression NUPR1 were tightly related to the disturbance of reactive oxygen species (ROS) homeostasis, which could be prevented by inhibiting intracellular ROS with NAC. Finally, NAC also abolished quercetin-induced autophagic cell death in vivo. Taken together, these data demonstrate that quercetin induces osteosarcoma cell death via inducing excessive autophagy, which is mediated through the ROS-NUPR1 pathway. Quercetin application may be a promising and practical strategy for osteosarcoma treatment in clinical practice.

Screening of miRNAs associated with lymph node metastasis in Her-2-positive breast cancer and their relationship with prognosis.

The aim of this study was to identify some biomarkers for predicting lymph node metastasis and prognosis of human epidermal growth factor receptor 2 (Her-2)-positive breast cancer (BC). We analyzed correlations between microRNAs (miRNAs) and the prognosis of patients with BC based on data collected from The Cancer Genome Atlas (TCGA) database. The expression levels of miR-455, miR-143, and miR-99a were measured in clinical samples of Her-2-positive BC patients with different degrees of lymph node metastasis. We investigated the impacts of overexpressed miR-455 on the proliferation and invasiveness of MDA-MB-453 cells and measured its effects on the expression of long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of miR-455 was significantly and positively correlated to the prognosis and overall survival (OS) of the BC (P=0.028), according to TCGA information. The expression level of miR-455 was positively correlated with OS and relapse-free survival (RFS) of patients with Her-2-positive BC, and was negatively correlated with the number of metastatic lymph nodes (P<0.05). Transwell assay suggested that MDA-MB-453 cells became much less invasive (P<0.01) after being transfected with miR-455 mimics. During the qRT-PCR, the expression level of MALAT1 declined significantly after transfection (P<0.01). Overexpressed miR-455 significantly inhibited the proliferation and migration of MDA-MB-453 cells and the expression of MALAT1. We conclude that miR-455 may be a useful potential biomarker for forecasting lymph node metastasis and the prognosis of Her-2-positive BC patients. miR-455 may play an important role in lymph node metastasis of BC by interacting with MALAT1.

Research Progress on Long Non-coding RNAs and Drug Resistance of Breast Cancer.

Breast cancer, as the foremost cause of women's death in the world, is highly metastatic and mutable. Resistance to drugs for chemotherapies, endocrine therapies, and targeted therapies is an important factor that impacts the prognosis of breast cancer. Long non-coding ribonucleic acids (LncRNAs) are crucial regulators of intracellular gene expressions. Some researchers have suggested that expression level of several types of LncRNAs were closely related to the prognosis of patients with breast cancer. LncRNAs significantly impact biological processes such as drug transport, detoxication, apoptosis, epithelial to mesenchymal transition (EMT), and autophagy by regulating intracellular signaling pathways such as multi-drug resistance gene 1 (MDR1), nuclear factor erythroid 2-related factor 2 (NRF2), phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), transforming growth factor-ß (TGF-ß), BRCA1/2, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). This paper will summarize research progress on correlations between LncRNA and drug resistance of breast cancer. It will particularly expound molecular mechanisms through which LncRNAs regulate drug resistance of breast cancer. It will further discuss the feasibility as molecular markers for forecasting drug resistance of breast cancer and may be becoming new targets for treating breast cancer in the future.