Application of Nanoparticles in the Diagnosis and Treatment of Colorectal Cancer.

Colorectal cancer is a common malignant tumor with high morbidity and mortality rates, imposing a huge burden on both patients and the healthcare system. Traditional treatments such as surgery, chemotherapy and radiotherapy have limitations, so finding more effective diagnostic and therapeutic tools is critical to improving the survival and quality of life of colorectal cancer patients. While current tumor targeting research mainly focuses on exploring the function and mechanism of molecular targets and screening for excellent drug targets, it is crucial to test the efficacy and mechanism of tumor cell therapy that targets these molecular targets. Selecting the appropriate drug carrier is a key step in effectively targeting tumor cells. In recent years, nanoparticles have gained significant interest as gene carriers in the field of colorectal cancer diagnosis and treatment due to their low toxicity and high protective properties. Nanoparticles, synthesized from natural or polymeric materials, are NM-sized particles that offer advantages such as low toxicity, slow release, and protection of target genes during delivery. By modifying nanoparticles, they can be targeted towards specific cells for efficient and safe targeting of tumor cells. Numerous studies have demonstrated the safety, efficiency, and specificity of nanoparticles in targeting tumor cells, making them a promising gene carrier for experimental and clinical studies. This paper aims to review the current application of nanoparticles in colorectal cancer diagnosis and treatment to provide insights for targeted therapy for colorectal cancer while also highlighting future prospects for nanoparticle development.

Baohuoside I chemosensitises breast cancer to paclitaxel by suppressing extracellular vesicle/CXCL1 signal released from apoptotic cells.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and chemotherapy is the cornerstone treatment for TNBC. Regrettably, emerging findings suggest that chemotherapy facilitates pro-metastatic changes in the tumour microenvironment. Extracellular vesicles (EVs) have been highly implicated in cancer drug resistance and metastasis. However, the effects of the EVs released from dying cancer cells on TNBC prognosis and corresponding therapeutic strategies have been poorly investigated. This study demonstrated that paclitaxel chemotherapy elicited CXCL1-enriched EVs from apoptotic TNBC cells (EV-Apo). EV-Apo promoted the chemoresistance and invasion of co-cultured TNBC cells by polarizing M2 macrophages through activating PD-L1 signalling. However, baohuoside I (BHS) remarkably sensitized the co-cultured TNBC cells to paclitaxel chemotherapy via modulating EV-Apo signalling. Mechanistically, BHS remarkably decreased C-X-C motif chemokine ligand 1 (CXCL1) cargo within EV-Apo and therefore attenuated macrophage M2 polarization by suppressing PD-L1 activation. Additionally, BHS decreased EV-Apo release by diminishing the biogenesis of intraluminal vesicles (ILVs) within multivesicular bodies (MVBs) of TNBC cells. Furthermore, BHS bound to the LEU104 residue of flotillin 2 (FLOT2) and interrupted its interaction with RAS oncogene family member 31 (RAB31), leading to the blockage of RAB31-FLOT2 complex-driven ILV biogenesis. Importantly, BHS remarkably chemosensitised paclitaxel to inhibit TNBC metastasis in vivo by suppressing EV-ApoCXCL1-induced PD-L1 activation and M2 polarization of tumour-associated macrophages (TAMs). This pioneering study sheds light on EV-ApoCXCL1 as a novel therapeutic target to chemosensitise TNBC, and presents BHS as a promising chemotherapy adjuvant to improve TNBC chemosensitivity and prognosis by disturbing EV-ApoCXCL1 biogenesis.

Mapping alternative splicing events in colorectal cancer.

Although aberrant splicing events of genes are closely related to the development and progression of colorectal cancer (CRC), the mapping of abnormal splicing events, especially alternative splicing (AS) event types and the underlying effects, remain investigational. In the present study, we analyzed a public RNA-seq database (GSE138202) and identified 14,314 significant AS events in CRC patients compared to healthy individuals. Most of the key genes such as oncogenes involved in the development of CRC have different AS event types. Moreover, the results demonstrate that certain AS events may play a significant role in the functioning of key genes involved in splicing factors and microRNAs. Furthermore, we observed that the oncogene CDK4 in CRC tends to undergo exon 2 skipping AS events, resulting in a stronger tendency for protein expression to form complexes with CCND1, thereby inhibiting the cell cycle and weakening cell proliferation, while enhancing cell migration capability. These findings not only provide new insights into the mechanism of AS in regulating CRC, but also offers a theoretical basis for targeted splicing therapy in CRC.

Successful Undergoing Esophagogastric Anastomosis with Right Gastroepiploic Vessels Congenital Absence: A Case Report.

A 60-year-old male farmer was admitted to the hospital with dysphagia for 2 months, and minimally invasive McKeown esophagectomy with lymphadenectomy was initially planned. However, congenital absence of the right gastroepiploic vessels (RGEVs) was blocked surgical procedure. Fortunately, we successfully performed esophagectomy and unconventional gastric remnant reconstruction without RGEVs, and intraoperative cervical venous superdrainage.

Fu-Zheng-Yi-Liu Formula inhibits the stem cells and metastasis of prostate cancer via tumor-associated macrophages/C-C motif chemokine ligand 5 pathway in tumor microenvironment.

Prostate cancer (PCa) is the second most common malignancy among men globally. The Fu-Zheng-Yi-Liu (FZYL) Formula has been widely utilized in the treatment of PCa. This study investigates whether the FZYL Formula can inhibit PCa by targeting the TAMs/CCL5 pathway. We conducted in vitro co-cultures and in vivo co-injections of PCa cells and TAMs to mimic their interaction. Results showed that the FZYL Formula significantly reduced the proliferation, colony formation, subpopulations of PCSCs, and sphere-formation efficacy of PCa cells, even in the presence of TAM co-culture. Additionally, the Formula markedly decreased the migration, invasion, and epithelial-mesenchymal transition (EMT) of PCa cells induced by TAMs. The FZYL Formula also reversed M2 phenotype polarization in TAMs and dose-dependently reduced their CCL5 expression and secretion, with minimal cytotoxicity observed. Mechanistic studies confirmed that the TAMs/CCL5 axis is a critical target of the FZYL Formula, as the addition of exogenous CCL5 partially reversed the formula's inhibitory effects on PCSCs self-renewal in the co-culture system. Importantly, the Formula also significantly inhibited the growth of PCa xenografts, bone metastasis, and PCSCs activity in vivo by targeting the TAMs/CCL5 pathway. Overall, this study not only elucidates the immunomodulatory mechanism of the FZYL Formula in PCa therapy but also highlights the TAMs/CCL5 axis as a promising therapeutic target.

Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. METHODS: Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. RESULTS: It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-L1+ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that CXCL1EV-dead enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. CONCLUSIONS: Our results highlight CXCL1EV-dead as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis.

Axl as a potential therapeutic target for adamantinomatous craniopharyngiomas: Based on single nucleus RNA-seq and spatial transcriptome profiling.

Craniopharyngiomas (CPs), particularly Adamantinomatous Craniopharyngiomas (ACPs), often exhibit a heightened risk of postoperative recurrence and severe complications of the endocrine and hypothalamic function. The primary objective of this study is to investigate potential novel targeted therapies within the microenvironment of ACP tumors. Cancer-Associated Fibroblasts (CAFs) were identified in the craniopharyngioma microenvironment, notably in regions characterized by cholesterol clefts, wet keratin, ghost cells, and fibrous stroma in ACPs. CAFs, alongside ghost cells, basaloid-like epithelium cells and calcifications, were found to secrete PROS1 and GAS6, which can activate AXL receptors on the surface of tumor epithelium cells, promoting immune suppression and tumor progression in ACPs. Additionally, the AXL inhibitor Bemcentinib effectively inhibited the proliferation organoids and enhanced the immunotherapeutic efficacy of Atezolizumab. Furthermore, neural crest-like cells were observed in the glial reactive tissue surrounding finger-like protrusions. Overall, our results revealed that the AXL might be a potentially effective therapeutic target for ACPs.

Integrative dissection of 5-hydroxytryptamine receptors-related signature in the prognosis and immune microenvironment of breast cancer.

Background: Depression increases the risk of breast cancer recurrence and metastasis. However, there lacks potential biomarkers for predicting prognosis in breast cancer. 5-hydroxytryptamine (5-HT) plays a key role in the pathogenesis and treatment of depression. In this study, we developed a prognostic signature based on 5-HT receptors (5-HTRs) and elucidated its potential immune regulatory mechanisms for breast cancer prognosis. Methods: Oncomine, GEPIA, UALCAN, cBioPortal, Kaplan-Meier plotter, and TIMER were used to analyze differential expression, prognostic value, genetic alteration, and immune cell infiltration of HTRs in breast cancer patients. The model training and validation assays were based on the analyses of GSE1456 and GSE86166. A risk signature was established by univariate and multivariate Cox regression analyses. The transwell assay was utilized to verify the effect of the 5-HTRs expression on breast cancer invasion. Effects of HTR2A/2B inhibitor on CD8+ T cell proliferation and infiltration as well as apoptosis of 4T1 cells in the tumor microenvironment were detected by flow cytometry and TUNEL assay. Zebrafish and mouse breast cancer xenografts were used to determine the effect of HTR2A/2B inhibitor on breast cancer metastasis. Results: The expression levels of HTR1A, HTR1B, HTR2A, HTR2B, HTR2C, HTR4, and HTR7 were significantly downregulated in highly malignant breast cancer types. 5-HTRs were significantly associated with recurrence-free survival (RFS) in breast cancer patients. The genetic alteration of HTR1D, HTR3A, HTR3B, and HTR6 in breast cancer patients was significantly associated with shorter overall survival (OS). Finally, HTR2A and HTR2B were determined to construct the risk signature. The expression of HTR2A/2B was positively correlated with the infiltration of immune cells such as CD8+ T cells and macrophages. Furthermore, inhibition of HTR2A expression could suppress CD8+ T cell proliferation and enhance invasion and metastasis of breast cancer cells in both zebrafish and mice model. Conclusions: The HTR2A/2B risk signature not only highlights the significance of HTRs in breast cancer prognosis by modulating cancer immune microenvironment, but also provides a novel gene-testing tool for early prevention of depression in breast cancer patients and lead to an improved prognosis and quality of life.

Icariin inhibits prostate cancer bone metastasis and destruction via suppressing TAM/CCL5-mediated osteoclastogenesis.

BACKGROUND: Bone metastasis occurs in nearly 70% of patients with metastatic prostate cancer (PCa), and represents the leading cause of death in patients with PCa. Emerging evidence has demonstrated the potential activities of icariin in modulating bone metabolism and remodelling the tumor microenvironment (TME). However, whether icariin could inhibit PCa bone metastasis and destruction by modulating the TME as well as the underlying mechanisms remains unclear. PURPOSE: This study investigated whether icariin could inhibit PCa bone metastasis and destruction by modulating the bone TME as well as the underlying mechanisms. METHODS: Osteoclasts were induced from mouse bone marrow-derived macrophages (BMMs) or Raw264.7 cells. PCa cells were cultured in the conditional medium (CM) of macrophages in vitro or co-injected with macrophages in vivo to simulate their coexistence in the TME. Multiple molecular biology experiments and the mouse RM1-Luc PCa bone metastasis model were used to explore the inhibitory activity and mechanism of icariin on PCa metastasis and bone destruction. RESULTS: Icariin treatment significantly suppressed PCa growth, bone metastasis and destruction as well as osteoclastogenesis in vivo. Furthermore, icariin remarkably inhibited osteoclast differentiation, even in the presence of the CM of tumor-associated macrophages (TAMs), while exhibiting no obvious effect on osteoblasts. Moreover, icariin suppressed the M2 phenotype polarization of Raw264.7-derived TAMs and transcriptionally attenuated their CC motif chemokine ligand 5 (CCL5) expression and secretion via inhibiting SPI1. Additionally, CCL5 induced the differentiation and chemotaxis of osteoclast precursor cells by binding with its receptor CCR5. The clinicopathological analysis further verified the positive correlation between the TAM/CCL5/CCR5 axis and osteoclastogenesis within the TME of PCa patients. More importantly, icariin remarkably suppressed PCa metastasis-induced bone destruction in vivo by inhibiting osteoclastogenesis via downregulating the TAM/CCL5 pathway. CONCLUSION: Altogether, these results not only implicate icariin as a promising candidate immunomodulator for PCa bone metastasis and destruction but also shed novel insight into targeting TAM/CCL5-mediated osteoclastogenesis as a potential treatment strategy for osteolytic bone metastasis. This study helps to advance the understanding of the crosstalk between bone TME and bone homeostasis.

Targeted splicing therapy: new strategies for colorectal cancer.

RNA splicing is the process of forming mature mRNA, which is an essential phase necessary for gene expression and controls many aspects of cell proliferation, survival, and differentiation. Abnormal gene-splicing events are closely related to the development of tumors, and the generation of oncogenic isoform in splicing can promote tumor progression. As a main process of tumor-specific splicing variants, alternative splicing (AS) can promote tumor progression by increasing the production of oncogenic splicing isoforms and/or reducing the production of normal splicing isoforms. This is the focus of current research on the regulation of aberrant tumor splicing. So far, AS has been found to be associated with various aspects of tumor biology, including cell proliferation and invasion, resistance to apoptosis, and sensitivity to different chemotherapeutic drugs. This article will review the abnormal splicing events in colorectal cancer (CRC), especially the tumor-associated splicing variants arising from AS, aiming to offer an insight into CRC-targeted splicing therapy.

Exon Junction Complex Mediates the Cap-Independent Translation of Circular RNA.

Evidence that circular RNAs (circRNA) serve as protein template is accumulating. However, how the cap-independent translation is controlled remains largely uncharacterized. Here, we show that the presence of intron and thus splicing promote cap-independent translation. By acquiring the exon junction complex (EJC) after splicing, the interaction between circRNA and ribosomes was promoted, thereby facilitating translation. Prevention of splicing by treatment with spliceosome inhibitor or mutating splicing signal hindered cap-independent translation of circRNA. Moreover, EJC-tethering using Cas13 technology reconstituted EJC-dependent circRNA translation. Finally, the level of a coding circRNA from succinate dehydrogenase assembly factor 2 (circSDHAF2) was found to be elevated in the tumorous tissues from patients with colorectal cancer, and shown to be critical in tumorigenesis of colorectal cancer in both cell and murine models. These findings reveal that EJC-dependent control of circSDHAF2 translation is involved in the regulation of oncogenic pathways. IMPLICATIONS: EJC-mediated cap-independent translation of circRNA is implicated in the tumorigenesis of colorectal cancer.

Chronic psychological stress promotes breast cancer pre-metastatic niche formation by mobilizing splenic MDSCs via TAM/CXCL1 signaling.

BACKGROUND: Emerging studies have identified chronic psychological stress as an independent risk factor influencing breast cancer growth and metastasis. However, the effects of chronic psychological stress on pre-metastatic niche (PMN) formation and the underlying immunological mechanisms remain largely unknown. METHODS: The effects and molecular mechanisms of chronic unpredictable mild stress (CUMS) on modulating tumor-associated macrophages (TAMs) and PMN formation were clarified by multiplex immunofluorescence technique, cytokine array, chromatin immunoprecipitation, the dual-luciferase reporter assay, and breast cancer xenografts. Transwell and CD8+ T cytotoxicity detection were used to analyze the mobilization and function of myeloid-derived suppressor cells (MDSCs). mCherry-labeled tracing strategy and bone marrow transplantation were applied to explore the crucial role of splenic CXCR2+/+ MDSCs facilitating PMN formation under CUMS. RESULTS: CUMS significantly promoted breast cancer growth and metastasis, accompanied by TAMs accumulation in the microenvironment. CXCL1 was identified as a crucial chemokine in TAMs facilitating PMN formation in a glucocorticoid receptor (GR)-dependent manner. Interestingly, the spleen index was significantly reduced under CUMS, and splenic MDSCs were validated as a key factor mediating CXCL1-induced PMN formation. The molecular mechanism study revealed that TAM-derived CXCL1 enhanced the proliferation, migration, and anti-CD8+ T cell functions of MDSCs via CXCR2. Moreover, CXCR2 knockout and CXCR2-/-MDSCs transplantation significantly impaired CUMS-mediated MDSC elevation, PMN formation, and breast cancer metastasis. CONCLUSION: Our findings shed new light on the association between chronic psychological stress and splenic MDSC mobilization, and suggest that stress-related glucocorticoid elevation can enhance TAM/CXCL1 signaling and subsequently recruit splenic MDSCs to promote PMN formation via CXCR2.

Quercetin Ameliorates Diabetic Kidney Injury by Inhibiting Ferroptosis via Activating Nrf2/HO-1 Signaling Pathway.

Diabetic nephropathy (DN) is thought to be the major cause of end-stage renal disease. Due to its complicated pathogenesis and the low efficacy of DN treatment, a deep understanding of new etiological factors may be useful. Ferroptosis, a nonapoptotic form of cell death, is characterized by the accumulation of iron-dependent lipid peroxides to lethal levels. Ferroptosis-triggered renal tubular injury is reported to participate in the development of DN, and blocking ferroptosis might be an effective strategy to prevent the development of DN. Quercetin (QCT), a natural flavonoid that is present in a variety of fruits and vegetables, has been reported to ameliorate DN. However, its underlying nephroprotective mechanism is unclear. Herein, we explored the antiferroptosic effect of QCT and verified its nephroprotective effect using DN mice and high glucose (HG)-incubated renal tubular epithelial cell models. We found HG-induced abnormal activation of ferroptosis of renal tubular epithelial cells, and QCT treatment inhibited ferroptosis by downregulating the expression of transferrin receptor 1 (TFR-1) and upregulating the expression of glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH-1), and the cystine/glutamate reverse antiporter solute carrier family 7 member (SLC7A11) in DN mice and HG-incubated HK-2 cells. Subsequently, both in vitro and in vivo results confirmed that QCT activated the NFE2-related factor 2 (Nrf2)/Heme oxygenase-1(HO-1) signaling pathway by increasing the levels of Nrf2 and HO-1. Therefore, this study supports that QCT inhibits the ferroptosis of renal tubular epithelial cells by regulating the Nrf2/HO-1 signaling pathway, providing a novel insight into the protective mechanism of QCT in DN treatment.

Correlation between neutrophil/lymphocyte ratio, platelet/lymphocyte ratio and postoperative cognitive dysfunction in elderly patients with esophageal cancer.

The present study intends to investigate the correlation between neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and postoperative cognitive dysfunction (POCD) in elderly patients with esophageal cancer. Elderly patients >65 years old with esophageal cancer in our department from October 2017 to June 2021 were included in the study. The cognitive function of the patients was assessed by the mini-mental state examination (MMSE) Scale at 1day, 3 days, and 7days after surgery. POCD was considered when the scores were <27 points, and the remaining patients were included in the control group. A total of 104 elderly patients with esophageal cancer were included in this study, and 24 patients developed POCD, with an incidence of 23.1%. The expression of NLR and PLR in both 2 groups was increased on the 1st postoperative day compared with that before surgery. There was no significant difference in the expression of NLR and PLR between the 2 groups before operation, but the expression of both in the POCD group was significantly higher than that in the control group after operation (P < .05). Logistic regression analysis showed that smoking, postoperative NLR and postoperative PLR were independent risk factors for POCD. Spearman test showed that NLR was negatively correlated with MMSE scores at postoperative 1 day and 3 days (P < .05), while PLR was negatively correlated with MMSE scores at postoperative 1 day, 3 days and 7 days (P < .05). The Area Under receiver operating characteristic curve (AUC) of postoperative NLR for predicting POCD in elderly patients with esophageal cancer was 0.656, and the AUC of postoperative PLR was 0.722. After combination of NLR and PLR, the AUC increased to 0.803 with the sensitivity of 66.7% and specificity of 82.5%. The expression level of postoperative NLR and PLR in elderly patients with esophageal cancer combined with POCD is significantly increased, which is associated with postoperative cognitive impairment. Moreover, the combination of NLR and PLR has a good predictive ability for POCD, which could be used as a potential biomarker for early diagnosis of POCD.

CircIFNGR2 enhances proliferation and migration of CRC and induces cetuximab resistance by indirectly targeting KRAS via sponging to MiR-30b.

Currently the clinical efficacy of colorectal cancer (CRC) which is the most common malignant tumors over the world has not reached an ideal level. Cetuximab, the monoclonal antibody targeting the extracellular domain of EGFR, has shown its great efficacy in the promotion of apoptosis and the inhibition of tumor cells-like characteristics in numerous cancers. However certain KRAS wild-type CRC patients unexpectedly show cetuximab resistance and the specific mechanism remains unclear. Circular RNAs (circRNAs) as the promising novel type of biomarkers in the cancer diagnosis and therapy, have been reported to be related with the drug resistance. In this study, with wondering the mechanism of cetuximab resistance in KRAS wild-type CRC patients, we evaluate the impact of circIFNGR2 on CRC and detect the association among circIFNGR2, miR-30b and KRAS via various experiments such as RT-qPCR, immunohistochemistry, luciferase assays, cell functional experiments and xenograft model. We conclude that circIFNGR2 induces cetuximab resistance in colorectal cancer cells by indirectly regulating target gene KRAS by sponging miR-30b at the post-transcriptional level. It is thus suggested that inhibition of circIFNGR2 can be a promising therapeutic strategy for malignant CRC patients with cetuximab resistance.

The identification of soy sauce adulterated with bean species and the origin using headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry.

Soy sauce is one of the significant seasonings in Asia but is often mislabeled in ingredients or substituted with geographical information. With no adequate methods to distinguish the bean sources and the origins of soy sauce, our study designed a seamless headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry (HS-SPME/GC-MS) for analyzing unique volatile components of different soy sauces. Over 400 volatile flavor compounds were identified and the assistance of chemometric analysis successfully discriminated different bean sources (black bean and soybean) and producing regions (Taiwan and Japan). The chemometric models can also perfectly evaluate real samples together with adulterated samples. In brief, these soy sauce volatile signatures can solve the problem of authentication and assist the whole industry in preventing adulteration and producing countries' counterfeit.

Naringenin in Si-Ni-San formula inhibits chronic psychological stress-induced breast cancer growth and metastasis by modulating estrogen metabolism through FXR/EST pathway.

INTRODUCTION: Chronic psychological stress is a well-established risk factor for breast cancer development. Si-Ni-San (SNS) is a classical traditional Chinese medicine formula prescribed to psychological disorder patients. However, its action effects, molecular mechanisms, and bioactive phytochemicals against breast cancer are not yet clear. OBJECTIVES: This study aimed to explore the modulatory mechanism and bioactive compound of SNS in regulating estrogen metabolism during breast cancer development induced by chronic psychological stress. METHODS: Mouse breast cancer xenograft was used to determine the effect of SNS on breast cancer growth and metastasis. Metabolomics analysis was conducted to discover the impact of SNS on metabolic profile changes in vivo. Multiple molecular biology experiments and breast cancer xenografts were applied to verify the anti-metastatic potentials of the screened bioactive compound. RESULTS: SNS remarkably inhibited chronic psychological stress-induced breast cancer growth and metastasis in the mouse breast cancer xenograft. Meanwhile, chronic psychological stress increased the level of cholic acid, accompanied by the elevation of estradiol. Mechanistic investigation demonstrated that cholic acid activated farnesoid X receptor (FXR) expression, which inhibited hepatocyte nuclear factor 4α (HNF4α)-mediated estrogen sulfotransferase (EST) transcription in hepatocytes, and finally resulting in estradiol elevation. Notably, SNS inhibited breast cancer growth by suppressing estradiol level via modulating FXR/EST signaling. Furthermore, luciferase-reporting gene assay screened naringenin as the most bioactive compound in SNS for triggering EST activity in hepatocytes. Interestingly, pharmacokinetic study revealed that naringenin had the highest absorption in the liver tissue. Following in vivo and in vitro studies demonstrated that naringenin inhibited stress-induced breast cancer growth and metastasis by promoting estradiol metabolism via FXR/EST signaling. CONCLUSION: This study not only highlights FXR/EST signaling as a crucial target in mediating stress-induced breast cancer development, but also provides naringenin as a potential candidate for breast cancer endocrine therapy via promoting estradiol metabolism.

Experimental Study on the Durability of Steel Anchors for Prestressed CFRP Laminates under Accelerated Galvanostatic Corrosion.

The novelty of the present study is to address the durability of corroded anchors for prestressing CFRP laminates. Two types of steel anchors, clamp anchors and wedge anchors, were used to prestress CFRP laminates and then subjected to steel corrosion through a galvanostatic acceleration approach, which was followed by tensile tests. Compared to clamp anchors, wedge anchors showed a superior durability performance in terms of their prestress retention, anchor efficiency, and resistance to the slippage of the CFRP laminate. After accelerated corrosion for 144 h, the clamp anchor exhibited a prestress retention of 79.1% and an anchorage efficiency of 55%, and the percentages became 9.0% and 100% for the wedge anchor. The slippage rates of the clamp anchor and the wedge anchor were 0.036 mm/kN and 0.026 mm/kN, respectively. Therefore, the wedge anchor, which exhibited higher prestress tension and anchorage efficiency, performed better than the clamp anchor. The present work provides an apparatus for exploring the corrosion-induced durability of steel anchors and experimental evidence that helps refine the provision in the guidelines for addressing anchor durability.