Resveratrol as a cardioprotective adjuvant for 5-fluorouracil in the treatment of gastric cancer cells.

The clinical application of 5-fluorouracil (5-Fu), a potent chemotherapeutic agent, is often hindered by its well-documented cardiotoxic effects. Nevertheless, natural polyphenolic compounds like resveratrol (RES), known for their dual anti-tumor and cardioprotective properties, are potential adjunct therapeutic agents. In this investigation, we examined the combined utilization of RES and 5-Fu for the inhibition of gastric cancer using both in vitro and in vivo models, as well as their combined impact on cardiac cytotoxicity. Our study revealed that the co-administration of RES and 5-Fu effectively suppressed MFC cell viability, migration, and invasion, while also reducing tumor weight and volume. Mechanistically, the combined treatment prompted p53-mediated apoptosis and autophagy, leading to a considerable anti-tumor effect. Notably, RES mitigated the heightened oxidative stress induced by 5-Fu in cardiomyocytes, suppressed p53 and Bax expression, and elevated Bcl-2 levels. This favorable influence enhanced primary cardiomyocyte viability, decreased apoptosis and autophagy, and mitigated 5-Fu-induced cardiotoxicity. In summary, our findings suggested that RES holds promise as an adjunct therapy to enhance the efficacy of gastric cancer treatment in combination with 5-Fu, while simultaneously mitigating cardiotoxicity.

N-Acetylcysteine Inhibits Coxsackievirus B3 Replication by Downregulating Eukaryotic Translation Elongation Factor 1 Alpha 1.

Group B Coxsackieviruses (CVB) are one of the causative pathogens of myocarditis, which may progress to cardiomyopathy. The pathogenesis of CVB is not fully understood, and effective antiviral therapy is not available. N-acetylcysteine (NAC), the classic antioxidant, has been used in clinical practice for several decades to treat various medical conditions. In this study, the anti-CVB effect of NAC was investigated. We show that NAC dramatically suppressed viral replication and alleviated cardiac injury induced by CVB3. To further study the antiviral mechanism of NAC, RNA-sequencing was performed for CVB3-infected cells with NAC treatment. We found that eukaryotic elongation factor 1 alpha 1 (EEF1A1) is one of the most upregulated genes in CVB3-infected cells. However, EEF1A2, the highly homologous isoform of EEF1A1, remains unchanged. EEF1A1 expression was significantly suppressed by NAC treatment in CVB3-infected cells, while EEF1A2 was not affected. eEF1A1 knockdown significantly inhibited CVB3 replication, implicating that eEF1A1 facilitates viral replication. Importantly, we show that eEF1A1, which was not expressed in the myocardia of newborn mice, was significantly upregulated by CVB3 infection. NAC markedly downregulated the expression of eEF1A1 but not eEF1A2 in the myocardia of CVB3-infected mice. Furthermore, NAC accelerated eEF1A1 degradation by promoting autophagy in CVB3-infected cells. We show that p62, one of the critical adaptors of autophagic targets, interacts with eEF1A1 and was downregulated in CVB3-infected cells upon NAC treatment. Taken together, this study demonstrated that NAC shows a potent anti-CVB effect through the downregulation of eEF1A1.

Baicalein suppresses Coxsackievirus B3 replication by inhibiting caspase-1 and viral protease 2A.

Myocarditis is an inflammatory disease of the cardiac muscle and one of the primary causes of dilated cardiomyopathy. Group B coxsackievirus (CVB) is one of the leading causative pathogens of viral myocarditis, which primarily affects children and young adults. Due to the lack of vaccines, the development of antiviral medicines is crucial to controlling CVB infection and the progression of myocarditis. In this study, we investigated the antiviral effect of baicalein, a flavonoid extracted from Scutellaria baicaleinsis. Our results demonstrated that baicalein treatment significantly reduced cytopathic effect and increased cell viability in CVB3-infected cells. In addition, significant reductions in viral protein 3D, viral RNA, and viral particles were observed in CVB3-infected cells treated with baicalein. We found that baicalein exerted its inhibitory effect in the early stages of CVB3 infection. Baicalein also suppressed viral replication in the myocardium and effectively alleviated myocarditis induced by CVB3 infection. Our study revealed that baicalein exerts its antiviral effect by inhibiting the activity of caspase-1 and viral protease 2A. Taken together, our findings demonstrate that baicalein has antiviral activity against CVB3 infection and may serve as a potential therapeutic option for the myocarditis caused by enterovirus infection.

[Retrospective Study of Bronchoscopic Intervention Therapy for Bronchopleural Fistula Induced by Pulmonary Surgery].

BACKGROUND: As a new technique developed in recent years, bronchoscopic intervention therapy has the advantages of minimal invasion, high safety and repeatability. The aim of this study is to investigate the clinical characteristics of bronchopleural fistula (BPF) induced by surgeries for lung malignancies or benign diseases and the effect of bronchoscopic intervention therapy for BPF, so as to provide support for prevention and treatment of BPF. METHODS: Data 64 patients with BPF who were treated by bronchoscopic intervention in Respiratory Disease Center of Dongzhimen Hospital, Beijing University of Chinese Medicine from June 2020 to September 2023 were collected. Patients with fistula diameter ≤5 mm were underwent submucous injection of macrogol, combined with blocking therapy with N-butyl cyanoacrylate, medical bioprotein glue or silicone prosthesis. Patients with fistula diameter >5 mm were implanted with different stents and cardiac occluders. Locations and characteristics of fistulas were summarized, meanwhile, data including Karnofsky performance status (KPS), shortbreath scale (SS), body temperature, pleural drainage volume and white blood cell count before and after operation were observed. RESULTS: For all 64 patients, 96 anatomic lung resections including pneumonectomy, lobectomy and segmentectomy were executed and 74 fistulas occurred in 65 fistula locations. The proportion of fistula in the right lung (63.5%) was significantly higher than that in the left (36.5%). Besides, the right inferior lobar bronchial fistula was the most common (40.5%). After operation, KPS was significantly increased, while SS, body temperature, pleural drainage volume and white blood cell count were significantly decreased compared to the preoperative values (P<0.05). By telephone follow-up or readmission during 1 month to 38 months after treament, median survival time was 21 months. 33 patients (51.6%) showed complete response, 7 patients (10.9%) showed complete clinical response, 18 patients (28.1%) showed partial response, and 6 patients (9.4%) showed no response. As a whole, the total effective rate of bronchoscopic intervention for BPF was 90.6%. CONCLUSIONS: BPF induced by pulmonary surgery can lead to severe symptoms and it is usually life-threating. Bronchoscopic intervention therapy is one of the fast and effective therapeutic methods for BPF.

[A Case of Multidomain Integrated Treatment Strategy 
for Complex Primary Pulmonary Sarcomatoid Carcinoma].

Pulmonary sarcomatoid carcinoma (PSC) is a rare and highly malignant tumor, which includes the following five pathologic types: pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and pulmonary blastoma. The onset of PSC is occult with non-specific clinical symptoms and signs. The clinical manifestations include irritating cough, bloody sputum, dyspnea, chest pain and so on, which are closely related to the growth and invasion site of the tumor. PSC tends to metastasize early, so most patients are already in local advanced stage or advanced stage with a median survival of 9 months at the time of hospital visit. A patient with primary PSC which led to 90% stenosis in central airway was treated by combined method of vascular and tracheoscopic intervention in our respiratory center. This treatment prolonged the patient's survival time and got a satisfactory effect at 19-month follow-up after surgery. Herein we report the case for clinical reference.
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Co-delivery of siBcl-2 and PTX with mitochondria-targeted functions to overcoming multidrug resistance.

Multidrug resistance (MDR) poses a significant impediment to the efficacy of chemotherapy in clinical settings. Despite Paclitaxel (PTX) being designated as the primary pharmaceutical agent for treating recurrent and metastatic breast cancer, the emergence of PTX resistance frequently results in therapeutic shortcomings, representing a substantial obstacle in clinical breast cancer management. In response, we developed a delivery system exhibiting dual specificity for both tumors and mitochondria. This system facilitated the sequential administration of small interfering B-cell lymphoma-2 (siBcl-2) and PTX to the tumor cytoplasm and mitochondria, respectively, with the aim of surmounting PTX resistance in tumor cells through the activation of the mitochondrial apoptosis pathway. Notably, we employed genetic engineering techniques to fabricate a recombinant ferritin containing the H-subunit (HFn), known for its tumor-targeting capabilities, for loading siBcl-2. This HFn-siBcl-2 complex was then combined with positively charged Triphenylphosphine-Liposome@PTX (TL@PTX) nanoparticles (NPs) to formulate HFn/siBcl-2@TL/PTX. Guided by HFn, these nanoparticles efficiently entered cells and released siBcl-2 through the action of triphenylphosphine (TPP)-mediated "proton sponge," thereby precisely modulating the expression of Bcl-2 protein. Simultaneously, PTX was directed to the mitochondria through the accurate targeting of TL@PTX, synergistically initiating the mitochondrial apoptosis pathway and effectively suppressing PTX resistance both in vitro and in vivo. In conclusion, the development of this dual-targeting delivery system presents a promising therapeutic strategy for overcoming PTX resistance in the clinical treatment of breast cancer.

Modified cotton fabric based on thiolene click reaction and its oil/water separation application.

A cotton fabric with special wettability was prepared in two simple steps. The surface of the fabric was grafted with silicon-oxygen group using 3-(methacryloyloxy) propyl trimethoxysilane (MSPMA) as the reagent, and then (3-mercaptopropyl)triethoxysilane (MPTES) was used to react with the grafted fabric under ultraviolet light according to the principle of thiolene reaction. Meanwhile, the modified cotton fabrics with various pore sizes were obtained via modifying the cotton fabric with different pore size under the same experimental conditions. The as-prepared fabric had a better hydrophobic and lipophilic effect, whose water contact angle could be up to 146.7° and the separation efficiency for different kinds of oil/water mixtures was better than 94%. In addition, the pore sizes of cotton fabrics had a great effect on the rate of oil/water separation, which increased with the increase of the pore size.

Can virtual touch tissue imaging quantification be a reliable method to detect anterior talofibular ligament type I injury at the acute, subacute, and chronic stages?

BACKGROUND: Anterior talofibular ligament (ATFL) injury affects ankle joint stability. To date, very few studies have examined tissue stiffness changes inside injured ligaments. Virtual touch tissue imaging quantification (VTIQ) allows for the non-invasive quantitative measurement of tissue stiffness. The present study aimed to examine the efficacy of VTIQ as a method for detecting ligament injury. METHODS: A total of 206 patients diagnosed with unilateral ATFL type I injury (81 acute cases, 69 subacute cases, and 56 chronic cases) were reviewed retrospectively. Shear wave velocity (SWV) values were collected from both the injured and non-affected sides of the ATFL using a virtual touch tissue imaging quantification technique (ACUSON Oxana 2, Siemens Medical Solutions USA, Inc.). RESULTS: The average SWV of injured ATFL was 4.09±1.15 m/s in the acute group, 5.60±1.39 m/s in the subacute group, and 7.74±1.44 m/s in the chronic group (P<0.001). The SWV values of the ATFL on the non-affected side were almost identical (acute 7.50±1.12 m/s, subacute 7.53±1.06 m/s, and chronic 7.61±1.30 m/s; P>0.05). The injured ATFL had a significantly lower SWV value than the non-affected ATFL in the acute and subacute groups (P<0.001); however, there was no significant difference in the chronic group (P>0.05). Concerning the validity of SWV as a predictor of acute and subacute ATFL injury, the receiver operator characteristics curve analysis showed that the best cut-off point for SWV was 6.165 m/s, with 84.3% sensitivity, 88.5% specificity, and an area under the curve of 0.93 (95% CI, 0.90-0.95). CONCLUSIONS: VTIQ is a reliable sonographic method for detecting acute and subacute ATFL type I injury.

Review on experimental study and clinical application of low-intensity pulsed ultrasound in inflammation.

Low-intensity pulsed ultrasound (LIPUS), as physical therapy, is widely used in both research and clinical settings. It induces multiple bioeffects, such as alleviating pain, promoting tissue repair, and shortening disease duration. LIPUS can also mediate inflammation. This paper reviews the application of LIPUS in inflammation and discusses the underlying mechanism. In basic experiments, LIPUS can regulate inflammatory responses at the cellular level by affecting some signaling pathways. In a clinical trial, LIPUS has been shown to alleviate inflammatory responses efficiently. As a cheap, safe, and convenient physical method, LIPUS is promising as anti-inflammatory therapy.

Preparation and modification of cellulose sponge and application of oil/water separation.

This work presents a facile preparation and modification of cellulose sponge with hydrophobic/oleophilic surface wetting properties. The modification method included several steps: sodium hydroxide (NaOH) and urea were introduced to dissolve cellulose, after which calcium carbonate (CaCO3) and epichlorohydrin were added into the solution for formation of a hydrogel. Finally, the cellulose sponge was obtained through hydrochloric acid (HCl) etching of CaCO3, and octadecyl trichlorosilane (OTS) self-assembly modification. The prepared cellulose sponge exhibited hydrophobicity with a water contact angle of 153.5°, and oleophilicity with an oil contact angle of 0°. The prepared cellulose sponge demonstrated a separation efficiency as high as 92% for various types of oil/water mixtures. The prepared cellulose sponge could achieve continuous separation with the assistance of a peristaltic pump. The material will be a promising candidate to be used in oil/water separation.

N-Acetyl cysteine effectively alleviates Coxsackievirus B-Induced myocarditis through suppressing viral replication and inflammatory response.

Viral myocarditis caused by Coxsackievirus B (CVB) infection is a severe inflammatory disease of the myocardium, which may develop to cardiomyopathy and heart failure. No effective specific treatment is available. Our previous study demonstrated that suppression of proinflammatory caspase-1 activation effectively inhibited CVB replication. N-acetyl cysteine (NAC) is a widely used antioxidant. In this study, we found that NAC significantly alleviated the myocardial injury caused by CVB type 3 (CVB3) under in vivo condition. Importantly, NAC treatment simultaneously suppressed viral replication and inflammatory response in both myocardium and cell culture. The antiviral and anti-inflammation mechanism of NAC, while independent of its antioxidant property, relies on its inhibition on caspase-1 activation. Moreover, NAC promotes procaspase-1 degradation via ubiquitin proteasome system, which further contributes to caspase-1 down-regulation. NAC also inhibits the activity of viral proteases. Taken together, this study shows that NAC exerts potent anti-CVB and anti-inflammation effect through targeting caspase-1. Given that NAC is a clinically approved medicine, we recommend NAC as a valuable therapeutic agent for viral myocarditis caused by CVB.

Modification of Polyurethane Sponge Based on the Thiol-Ene Click Reaction and Its Application for Oil/Water Separation.

A polyurethane (PU) sponge with hydrophobic/oleophilic property was prepared based on the thiol-ene click reaction, which was a simple method with only one step. Photopolymerization was induced through UV light on the sponge surface in a homogeneous solution containing polyethylene glycol diacrylate, pentaerythritol (mercaptoacetic acid) ester, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, and octadecyl methacrylate. The as-prepared sponge possessed excellent selective for oil from various types of oil/water mixtures. It also had a high absorption capacity for toluene, >21 times its self-weight, and it had about 20 times its self-weight for vegetable oil, even after five extrusion-adsorption cycles, presenting a good recyclability. It created a new method to prepare oil/water separation sponge.

Methane-Rich Saline: A Potential Resuscitation Fluid for Hemorrhagic Shock.

Hemorrhagic shock is caused by massive blood loss. If the patient is not fully resuscitated in time, this may eventually lead to multiple organ failure and even death. Previous studies on methane-rich saline in animal models showed that it confers resistance against many diseases. In this study, we explored the protective effect of methane-rich saline, used as a resuscitation fluid, in hemorrhagic shock. Hemorrhagic shock was induced in SD rats by bloodletting via intubation of the right femoral artery. The rats were divided into three groups: a sham control group (sham control), a shock group resuscitated by an infusion of autologous blood and an equivalent volume of normal saline (Shock+NS), and a shock group resuscitated by an infusion of autologous blood and an equivalent volume of methane-rich saline (Shock+MRS). Assessment of blood pressure and levels of plasma lactate showed that resuscitation using methane-rich saline (MRS) restored systemic blood pressure and reduced the levels of lactate in the plasma. Meanwhile, lower levels of serum IL-6 and TNF-α were also observed in the group resuscitated with MRS. In the heart, liver, and kidney, MRS reduced inflammation and oxidative stress levels. Analysis of organ function via levels of biochemical indicators revealed that the group resuscitated with MRS had reduced serum levels of AST and CK, indicating a potential cardioprotective effect. The expression levels of apoptosis-related proteins, including those of Bcl-2/Bax, and the results of TUNEL-labeling assay indicated that MRS significantly reduced apoptosis in the heart. Methane also had a positive effect on the expression of the PGC-1α/SIRT3/SOD2 signaling pathway. Our results showed that MRS can potentially serve as a novel resuscitation fluid because of its anti-inflammatory, antioxidative, and antiapoptotic properties.

Determination of Anlotinib, a Tyrosine Kinase Inhibitor, in Rat Plasma by UHPLC-MS/MS and Its Application to a Pharmacokinetic Study.

Anlotinib is a novel inhibitor of receptor kinase tyrosine with multitargets and has a broad spectrum of inhibitory action on tumor angiogenesis and growth. A simple and rapid UHPLC-MS/MS bioanalytical method was validated for the determination of anlotinib in rat plasma, using imatinib as an internal standard. An Acquity BEH C18 column was used to separate analytes. The eluents consisted of formic acid/water (0.1 : 100, v/v) and acetonitrile with a mobile phase. A triple quadrupole mass spectrometer was operated for the quantification with multiple reaction monitoring (MRM) to determine transitions: 408.2 ⟶ 339.1 for anlotinib, and 494.3 ⟶ 394.1 for imatinib. The validated range was 0.1-50 ng/mL for anlotinib. Mean recovery rate of anlotinib in plasma was ≥99.32% and reproducible. Also, the intra- and interday precisions were both below 15%. This robust method was successfully applied to support the pharmacokinetic study of anlotinib in rats.

Effect of HIFU on endometrial receptivity and sex hormone level in uterine fibroid patients and analysis of influencing factors for its treatment rate.

Effect of high intensity focused ultrasound (HIFU) uterine fibroid ablation on the endometrial receptivity and sex hormone level in uterine fibroid patients and the influencing factors for treatment rate were investigated. A retrospective analysis of 266 uterine fibroid patients admitted to the Department of Gynaecology in the Jining Maternity and Child Care Hospital from October 2013 to October 2016 was performed. Among them, observation group was treated with HIFU ablation (n=143), control group with myomectomy (n=123). The pulsatility index (PI) and the resistance index (RI) of the uterine arterial blood flow were measured during the luteal phase of menstruation by transvaginal ultrasonography. The serum luteinizing hormone (LH), follicle stimulating hormone (FSH) and estradiol (E2) were detected by chemical immunofluorescence. The relationship between HIFU treatment rate and clinical pathology of uterine fibroid patients was analyzed, and univariate/multivariate regression analysis was used to analyze the influencing factors for HIFU treatment rate. There was no significant difference in preoperative and postoperative PI and RI between the two groups (P>0.05); no significant difference between preoperative and postoperative PI/RI in the same group (P>0.05). There was no significant difference in preoperative and postoperative LH, FSH and E2 between the two groups (P>0.05); no significant difference between preoperative LH and postoperative LH in the same group (P>0.05), neither FSH or E2 (P>0.05). Results of multivariate analysis showed that fibroid location and ultrasound contrast intensity were independent influencing factors for HIFU treatment rate (P<0.05). Treatment of uterine fibroid with HIFU has no effect on the patient's endometrial receptivity and sex hormone level. Fibroid location and ultrasound contrast intensity are independent risk factors for HIFU treatment rate. This study provides guidance for the clinical optimization of treatment methods and is more conducive to the promotion of HIFU ablation therapy.

Prognostic predictors for patients with hepatocellular carcinoma receiving adjuvant transcatheter arterial chemoembolization.

OBJECTIVES: We aimed to confirm the clinical effectiveness of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) in patients with hepatocellular carcinoma after liver resection, and further identify the patients who could benefit most from PA-TACE. PATIENTS AND METHODS: Propensity score matching at a ratio of 1 : 2 was used between hepatectomy patients with and without receiving PA-TACE. Kaplan-Meier analysis was performed to compare overall survival and recurrence-free survival between two groups. Univariate COX regression and stratified analyses were performed to screen and identify survival predictors for PA-TACE patients. The identified predictive markers were validated in an external cohort. RESULTS: The propensity analysis matched 116 patients in PA-TACE group to 232 in the control group. Visible protective effect of PA-TACE was shown by survival curves in matched series (log-rank P=0.009 and 0.008), with hazard ratio of being 0.599 (95% confidence interval: 0.420-0.855) and 0.623 (95% confidence interval: 0.449-0.866), respectively, for overall survival and recurrence-free survival. The identified prognostic predictors for PA-TACE included TNM stage, tumor size and number, hepatitis B infection, spleen diameter, preoperative serum α-fetoprotein, alkaline phosphatase, γ-glutamyl transpeptidase and monocyte, and three risk signatures (aspartate aminotransferase-to-alanine aminotransferase ratio, neutrophil-to-lymphocyte ratio, and systemic immune-inflammation index). CONCLUSION: The treatment effectiveness of adjuvant transcatheter arterial chemoembolization for patients with hepatocellular carcinoma after surgery was validated in this study, and the best candidates for PA-TACE were identified as well, including patients with late-stage tumor, portal hypertension, and high preoperative serum levels of α-fetoprotein, alkaline phosphatase, γ-glutamyl transpeptidase, and monocytes.

Self-assembly modification of polyurethane sponge for application in oil/water separation.

A polyurethane (PU) sponge with excellent oil/water separation property has been successfully prepared by modifying with octadecyltrichlorosilane (OTS) self-assemblies. The chemical structure, surface topography, and surface wettability of the sponge were characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy, and contact angle experiments, respectively. The prepared sponge could completely absorb oil within a few seconds. In addition, it also possessed excellent selectivity for oil, high absorption capacity (25 times the self-weight), high oil retention (92.6%), and good recyclability. The sponge was synthesized by a facile, mild and inexpensive method, and has excellent potential for use in practical applications because of its desirable property of oil/water separation.

Methane-Rich Saline Ameliorates Sepsis-Induced Acute Kidney Injury through Anti-Inflammation, Antioxidative, and Antiapoptosis Effects by Regulating Endoplasmic Reticulum Stress.

Sepsis-induced acute kidney injury (AKI) is a severe complication of sepsis and an important cause of mortality in septic patients. Previous investigations showed that methane had protective properties against different diseases in animal models. This study is aimed at investigating whether methane-rich saline (MRS) has a protective effect against sepsis-induced AKI. Sepsis was induced in wild-type C57BL/6 mice by cecal ligation and puncture (CLP), and the mice were divided into three groups: a sham control group (sham), a surgery group with saline intraperitoneal injection (i.p.) treatment (CLP + NS), and a surgery group with MRS i.p. treatment (CLP + MRS). 24 h after the establishment of the sepsis, the blood and kidney tissues of mice in all groups were collected. According to the serum levels of blood urea nitrogen (BUN) and creatinine (CRE) and a histologic analysis, which included hematoxylin-eosin (H&E) staining and periodic acid-Schiff (PAS) staining, MRS treatment protected renal function and tissues from acute injury. Additionally, MRS treatment significantly ameliorated apoptosis, based on the levels of apoptosis-related protein makers, including cleaved caspase-3 and cleaved PARP, and the levels of Bcl-2/Bax expression and TUNEL staining. In addition, the endoplasmic reticulum (ER) stress-related glucose-regulated protein 78 (GRP78)/activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP)/caspase-12 apoptosis signaling pathway was significantly suppressed in the CLP + MRS group. The levels of inflammation and oxidative stress were also reduced after MRS treatment. These results showed that MRS has the potential to ameliorate sepsis-induced acute kidney injury through its anti-inflammatory, antioxidative, and antiapoptosis properties.

TRIM59 overexpression correlates with poor prognosis and contributes to breast cancer progression through AKT signaling pathway.

TRIM59 has been recently implicated in the carcinogenesis of several cancers such as lung cancer, gastric cancer, and bladder cancer. However, its expression pattern and clinical significance has not been investigated in human breast cancer. In the present study, we examined TRIM59 protein expression in 95 cases of breast cancer tissues using immunohistochemistry. We found that TRIM59 was upregulated in 42 out of 95 cases and correlated with TNM stage (P = 0.0056), lymph node metastasis (P = 0.0088) and poor prognosis (P = 0.0092). Importantly, TRIM59 level was higher in triple-negative breast cancer (TNBC) (P = 0.0157). Expression of TRIM59 protein was also upregulated in breast cancer cell lines compared to normal MCF-10A cell line. TRIM59 plasmid and shRNA transfection was performed in MCF-7 and SK-BR-3 cells respectively. TRIM59 overexpression promoted cell proliferation, invasion, migration, cell cycle transition, and paclitaxel resistance, whereas TRIM59 depletion showed the opposite results. Further analysis showed that TRIM59 overexpression upregulated expression of cyclinA, cyclinE, Bcl-xl, Bcl-2, p-AKT, and downregulated expression of p21, p27, p53. AKT inhibitor treatment abolished the effect of TRIM59 on Bcl-2 expression. TRIM59 overexpression also upregulated the level of p53 ubiquitination. In conclusion, TRIM59 overexpression correlates with poor prognosis and promotes malignant behavior through regulation of AKT pathway in human breast cancer.

Circular RNA­MTO1 suppresses breast cancer cell viability and reverses monastrol resistance through regulating the TRAF4/Eg5 axis.

Circular RNAs (circRNAs), a class of endogenous RNAs, have emerged as an enigmatic class of genes. However, little is known about their value in the progression and chemoresistance of cancers. The present study sought to determine the expression profiles and potential modulatory role of circRNAs on breast cancer cell viability and monastrol resistance. Monastrol-resistant cell lines were established by exposing breast cancer cells to increasing concentrations of monastrol. A human circRNA microarray was used to search for dysregulated circRNAs in monastrol-resistant cells, then circRNA­MTO1 (hsa­circRNA-007874) was validated as a circRNA that exhibited elevated expression levels in monastrol-resistant cells. Mechanistic investigations suggested that upregulation of circRNA­MTO1 suppressed cell viability, promoted monastrol-induced cell cytotoxicity and reversed monastrol resistance. Subsequently, Eg5 was identified as the functional target of circRNA­MTO1, and MTO1 inhibited Eg5 protein level but not mRNA level. By treating with protein synthesis inhibitor cycloheximide (CHX), it was revealed that MTO1 did not affect the protein stability of Eg5. RNA-pull down experiments followed by mass spectrometry revealed that MTO1 interacted with tumor necrosis factor receptor associated factor 4 (TRAF4), and sequester TRAF4 from activating Eg5 translation, thereby inhibiting the Eg5 protein level. Taken together, the data reveal a regulatory mechanism by circRNA­MTO1 to control cell viability and monastrol resistance in breast cancer cells.