Tetrahydrocurcumin targets TRIP13 inhibiting the interaction of TRIP13/USP7/c-FLIP to mediate c-FLIP ubiquitination in triple-negative breast cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) has a high mortality rate and limited treatment options. Tetrahydrocurcumin (THC), a major metabolite of curcumin, has potential antitumor activities. However, the antitumor effects and mechanism of THC in TNBC remain elusive. OBJECTIVES: To investigate the mechanism of THC in combating TNBC by targeting TRIP13 to disrupt the interaction of the TRIP13/USP7/c-FLIP complex and mediate c-FLIP ubiquitination both in vitro and in vivo. METHODS: Apoptosis was measured by TUNEL and flow cytometry. Click chemistry-based target fishing, CETSA, DARTS, and SPR were used to identify direct target of THC. Protein interactions was examined using co-immunoprecipitation. The role of USP7 in THC-mediated c-FLIP ubiquitination was evaluated by in vitro deubiquitination assay. Human breast cancer clinical samples were employed to assess the expression of c-FLIP, TRIP13, and USP7. The impact of THC on USP7/TRIP13/c-FLIP was analyzed using co-immunoprecipitation, confocal microscopy, molecular docking and dynamics simulations. RESULTS: THC effectively inhibits TNBC cell proliferation and tumor growth in vitro and in vivo without significant toxicity. Mechanistically, THC induces extrinsic apoptosis in TNBC primarily by promoting degradation of c-FLIP, a key negative regulator in the apoptotic pathway. Furthermore, utilizing click chemistry-based target fishing, we identified TRIP13, a component of the highly conserved AAA ATPase family, as a direct target of THC in combating TNBC. Interestingly, contrary to previous drug-target studies, the knockdown of TRIP13 further amplified the antitumor effects of THC. After in-depth investigation, it was revealed that TRIP13 forms a trimeric complex with USP7 and c-FLIP in TNBC cells. THC specifically targets TRIP13 to disrupt the interaction of TRIP13/USP7/c-FLIP, leading to the ubiquitination of c-FLIP, ultimately inducing extrinsic apoptosis. CONCLUSIONS: These findings offer new insights into the novel molecular mechanisms of anti-TNBC effects of THC and present a promising targeted therapeutic strategy for TNBC.

MAL2 reprograms lipid metabolism in intrahepatic cholangiocarcinoma via EGFR/SREBP-1 pathway based on single-cell RNA sequencing.

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive cancer characterized by a poor prognosis and resistance to chemotherapy. In this study, utilizing scRNA-seq, we discovered that the tetra-transmembrane protein mal, T cell differentiation protein 2 (MAL2), exhibited specific enrichment in ICC cancer cells and was strongly associated with a poor prognosis. The inhibition of MAL2 effectively suppressed cell proliferation, invasion, and migration. Transcriptomics and metabolomics analyses suggested that MAL2 promoted lipid accumulation in ICC by stabilizing EGFR membrane localization and activated the PI3K/AKT/SREBP-1 axis. Molecular docking and Co-IP proved that MAL2 interacted directly with EGFR. Based on constructed ICC organoids, the downregulation of MAL2 enhanced apoptosis and sensitized ICC cells to cisplatin. Lastly, we conducted a virtual screen to identify sarizotan, a small molecule inhibitor of MAL2, and successfully validated its ability to inhibit MAL2 function. Our findings highlight the tumorigenic role of MAL2 and its involvement in cisplatin sensitivity, suggesting the potential for novel combination therapeutic strategies in ICC.

Kill two birds with one stone: simultaneous removal of volatile organic compounds and ozone secondary pollution by a novel photocatalytic process.

Volatile organic compounds (VOCs) originating from diverse sources with complex compositions pose threats to both environmental safety and human health. Photocatalytic treatment of VOCs has garnered attention due to its high efficacy at room temperature. However, the intricate photochemical reaction generates ozone (O3), causing secondary pollution. Herein, our work developed a novel "synergistic effect" system for photocatalytic co-treatment of VOCs and O3 secondary pollution. Under the optimized reactor conditions simulated with computational fluid dynamics (CFD), MgO-loaded g-C3N4 composites (MgO/g-C3N4) were synthesized as efficient catalysts for the photocatalytic synergistic treatment process. Density functional theory (DFT) calculations, characterization, and electron paramagnetic resonance (EPR) tests revealed that the addition of MgO reduced the band gap of g-C3N4, and increased O3 molecule adsorption in the composites, efficiently harnessing the synergistic effect of O3 to generate a significant quantity of reactive oxygen radicals, thereby facilitating the removal of VOCs and O3. This study provides new insights for simultaneous elimination of VOCs and O3 secondary pollution by a photocatalytic process.

Loss of macrophage TSC1 exacerbates sterile inflammatory liver injury through inhibiting the AKT/MST1/NRF2 signaling pathway.

Tuberous sclerosis complex 1 (TSC1) plays important roles in regulating innate immunity. However, the precise role of TSC1 in macrophages in the regulation of oxidative stress response and hepatic inflammation in liver ischemia/reperfusion injury (I/R) remains unknown. In a mouse model of liver I/R injury, deletion of myeloid-specific TSC1 inhibited AKT and MST1 phosphorylation, and decreased NRF2 accumulation, whereas activated TLR4/NF-κB pathway, leading to increased hepatic inflammation. Adoptive transfer of AKT- or MST1-overexpressing macrophages, or Keap1 disruption in myeloid-specific TSC1-knockout mice promoted NRF2 activation but reduced TLR4 activity and mitigated I/R-induced liver inflammation. Mechanistically, TSC1 in macrophages promoted AKT and MST1 phosphorylation, and protected NRF2 from Keap1-mediated ubiquitination. Furthermore, overexpression AKT or MST1 in TSC1-knockout macrophages upregulated NRF2 expression, downregulated TLR4/NF-κB, resulting in reduced inflammatory factors, ROS and inflammatory cytokine-mediated hepatocyte apoptosis. Strikingly, TSC1 induction in NRF2-deficient macrophages failed to reverse the TLR4/NF-κB activity and production of pro-inflammatory factors. Conclusions: Macrophage TSC1 promoted the activation of the AKT/MST1 signaling pathway, increased NRF2 levels via reducing Keap1-mediated ubiquitination, and modulated oxidative stress-driven inflammatory responses in liver I/R injury. Our findings underscore the critical role of macrophage TSC1 as a novel regulator of innate immunity and imply the therapeutic potential for the treatment of sterile liver inflammation in transplant recipients. Schematic illustration of macrophage TSC1-mediated AKT/MST1/NRF2 signaling pathway in I/R-triggered liver inflammation. Macrophage TSC1 can be activated in I/R-stressed livers. TSC1 activation promotes phosphorylation of AKT and MST1, which in turn increases NRF2 expression and inhibits ROS production and TLR4/NF-κB activation, resulting in reduced hepatocellular apoptosis in I/R-triggered liver injury.

Integrated analysis of transcriptomic and proteomic data reveals novel regulators of soybean (Glycine max) hypocotyl development.

Hypocotyl elongation directly affects the seedling establishment and soil-breaking after germination. In soybean (Glycine max ), the molecular mechanisms regulating hypocotyl development remain largely elusive. To decipher the regulatory landscape, we conducted proteome and transcriptome analysis of soybean hypocotyl samples at different development stages. Our results showed that during hypocotyl development, many proteins were with extreme high translation efficiency (TE) and may act as regulators. These potential regulators include multiple peroxidases and cell wall reorganisation related enzymes. Peroxidases may produce ROS including H2 O2 . Interestingly, exogenous H2 O2 application promoted hypocotyl elongation, supporting peroxidases as regulators of hypocotyl development. However, a vast variety of proteins were shown to be with dramatically changed TE during hypocotyl development, including multiple phytochromes, plasma membrane intrinsic proteins (PIPs) and aspartic proteases. Their potential roles in hypocotyl development were confirmed by that ectopic expression of GmPHYA1 and GmPIP1-6 in Arabidopsis thaliana affected hypocotyl elongation. In addition, the promoters of these potential regulatory genes contain multiple light/gibberellin/auxin responsive elements, while the expression of some members in hypocotyls was significantly regulated by light and exogenous auxin/gibberellin. Overall, our results revealed multiple novel regulatory factors of soybean hypocotyl elongation. Further research on these regulators may lead to new approvals to improve soybean hypocotyl traits.

The serum lipidomics reveal the action mechanism of Danggui-Yimucao herbal pair in abortion mice.

Medical abortion is a common medical procedure that women choose to terminate an unwanted pregnancy, but it often brings post-abortion complications. Danggui (Angelica sinensis Radix)-Yimucao (Leonuri Herba), as a herbal pair (DY) in clinical prescriptions of traditional Chinese medicine, is often used in the treatment of gynecological diseases and has the traditional functions of tonifying the blood, promoting blood circulation, removing blood stasis and regulating menstruation. In this study, serum lipidomics were adopted to dissect the mechanism of DY in promoting recovery after medical abortion. A total of 152 differential metabolites were screened by lipidomics. All metabolites were imported into MetaboAnalyst for analysis, and finally key metabolic pathways such as glycerophospholipid metabolism, linoleic acid metabolism and pentose and glucuronate interconversions were enriched. Our results indicated that metabolic disorders in abortion mice were alleviated by DY through glycerophospholipid metabolism, while prostaglandin and leukotriene metabolites might be the key targets of DY to promote post-abortion recovery.

An immunogenic cell death-related classification predicts response to immunotherapy and prognosis in triple-negative breast cancer.

OBJECTIVE: Immunogenic cell death (ICD) of tumor cells is characterized by the induction of adaptive and innate immune responses, which in turn activates the immune surveillance and improves the efficacy of immunotherapy. In this study, we aimed to investigate the effect of ICD on the prognosis and the efficacy of immunotherapy in patients with triple-negative breast cancer (TNBC). METHODS: TNBC samples from The Cancer Genome Atlas-Breast Cancer (TCGA-BRCA) dataset were divided into two subtypes (ICD-high and ICD-low) based on the ICD status by using the consensus clustering method, and their genomic landscape and immune landscape were delineated. Furthermore, we established an ICD-related prognostic model to predict the efficacy of immunotherapy and the survival of TNBC. RESULTS: Our study showed that a poor prognosis of TNBC was associated with ICD-high subtype, while a favorable outcome was associated with ICD-low subtype. The immune landscape profiling results revealed that ICD-high subtype presented an immune-hot phenotype, whereas ICD-low subtype was associated with an immune-cold phenotype. Furthermore, our prognostic model predicted that the high-risk score group had a poor overall survival (OS), which was consistent with the actual data in the Gene Expression Omnibus (GEO) dataset. We also used tumor immune dysfunction and exclusion (TIDE) to determine the predictive significance of our ICD risk signature in immunotherapy efficacy, and found that ICD high-risk group had the highest response rate to immunotherapy in the immunotherapy response group. CONCLUSION: Our results reveal a correlation between ICD status and alterations in the tumor immune microenvironment in patients with TNBC. This finding might help guide clinicians in immunotherapy application for TNBC patients.

A novel effector RipBT contributes to Ralstonia solanacearum virulence on potato.

Ralstonia solanacearum is one of the most destructive plant-pathogenic bacteria, infecting more than 200 plant species, including potato (Solanum tuberosum) and many other solanaceous crops. R. solanacearum has numerous pathogenicity factors, and type III effectors secreted through type III secretion system (T3SS) are key factors to counteract host immunity. Here, we show that RipBT is a novel T3SS-secreted effector by using a cyaA reporter system. Transient expression of RipBT in Nicotiania benthamiana induced strong cell death in a plasma membrane-localization dependent manner. Notably, mutation of RipBT in R. solanacearum showed attenuated virulence on potato, while RipBT transgenic potato plants exhibited enhanced susceptibility to R. solanacearum. Interestingly, transcriptomic analyses suggest that RipBT may interfere with plant reactive oxygen species (ROS) metabolism during the R. solanacearum infection of potato roots. In addition, the expression of RipBT remarkably suppressed the flg22-induced pathogen-associated molecular pattern-triggered immunity responses, such as the ROS burst. Taken together, RipBT acts as a T3SS effector, promoting R. solanacearum infection on potato and presumably disturbing ROS homeostasis.

Trans-axillary single port insufflation technique-assisted endoscopic surgery for breast diseases: Clinic experience, cosmetic outcome and oncologic result.

Purpose: With an increasing demand for postoperative cosmetic effects in breast diseases, the single port by trans-axillary incision and air-inflation system, which provided better space and spared the assistant the effort of retraction, is widely used in clinic surgical treatment for multiple breast diseases. Methods: According to inclusion and exclusion criteria, patients who underwent trans-axillary single-incision surgery at Tianjin Medical University Cancer Hospital between December 2020 and July 2022 were included in the study. We collected and analyzed data on age, fertility history, ultrasound grade, clinical stage, pathological results, oncological prognosis, patient-centered cosmetic outcome, etc. Results: A total of 115 cases were included, of which 33 patients with benign disease underwent mass resection, 68 patients with malignant tumors underwent mastectomy. 10 patients had a special type of breast lesion. A mastectomy was performed in 4 patients with male mammary gland development. Of the 115 cases, the maximum mass diameter was 3.00 ± 1.644 (0.6-8.5) cm. Blood loss during surgery was 85.77 ± 50.342 (10-200) ml. The surgery took 131.84 ± 59.332 (30-280) minutes to complete. The patient spent a total of 5.05 ± 2.305 (2-18) days in the hospital. And the length of surgical incision in all patients was 3.83 ± 0.884 (3-8) cm. All patients were very satisfied with the appearance of their breasts after dressing. 94.78% of patients were satisfied with the position of the incision. Conclusion: Through this study, we believe that in benign breast diseases and malignant breast tumors, trans-axillary single port insufflation technique-assisted endoscopic surgery has oncological safety and an aesthetic effect for most people with breast diseases.

Breast microbiome associations with breast tumor characteristics and neoadjuvant chemotherapy: A case-control study.

Background: Commensal microbiota have been proven to colonize the mammary gland, but whether their composition is altered in patients with breast cancer (BC) remains elusive. This study intends to explore the breast microbiome differences between benign and malignant diseases and to investigate the impact of neoadjuvant chemotherapy (NAC) on the breast microbiota in patients with BC. Methods: Breast normal adipose tissues (NATs) were collected from 79 patients with BC and 15 controls between July 2019 and November 2021. The BC group consisted of 29 patients who had received NAC and 50 who were non-NAC patients. Participants diagnosed with benign breast disease were recruited as controls. 16S rRNA gene sequencing was used to analyze the bacterial diversity of NATs. Results: The community structure of the NAT microbiome was significantly different between the BC and control groups. Proteobacteria decreased (47.40% versus 39.74%), whereas Firmicutes increased (15.71% versus 25.33%) in patients with BC when compared with that in control tissues. Nine genera were enriched in BC NATs, and four genera levels increased in the control group. The associations between differential bacterial genera and breast tumor grade were calculated by Spearman's correlation. The results showed that tumor grade was positively associated with the relative abundance of Streptococcus and negatively related to Vibrio, Pseudoalteromonas, RB41, and Photobacterium. Moreover, menopause was associated with the microbiota composition change of non-NAC BC patients and related to the significant reduction in the abundance level of Pseudoalteromonas, Veillonella, and Alcaligenes. In addition, NAC was related to the beta diversity of patients with BC and associated with the decrease of Clostridium_sensu_stricto_7 and Clostridium_sensu_stricto_2 in postmenopausal patients. Of note, Tax4Fun functional prediction analysis revealed that the metabolic state was more exuberant in the BC group with upregulating of multiple metabolism-related pathways. Conclusion: Our results offer new insight into the relationship between NAC and breast microbiota and help to better characterize the breast microbial dysbiosis that occurs in patients with BC. Further epidemiological studies with larger sample size and well-designed animal experiments are required to elucidate the role of breast microbiota in the therapeutic outcome of BC.

Efficacy and Safety of Lianhua Qingwen for Patients with COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND: Corona virus disease 2019 (COVID-19) has spread around the world since its outbreak, and there is no ascertained effective drug up to now. Lianhua Qingwen (LHQW) has been widely used in China and overseas Chinese, which had some advantages in the treatment of COVID-19. OBJECTIVE: To evaluate the efficacy and safety of LHQW for COVID-19 by conducting a systematic review with meta-analysis. METHODS: A comprehensive literature search was conducted in 12 electronic databases from their establishment to October 30, 2021. Note Express 3.2.0 was used for screening of trials, and the data was independently extracted in duplicate by 2 researchers. The risk of bias of randomized controlled trials (RCTs) and retrospective studies were assessed by using the Cochrane collaboration tool and Newcastle Ottawa Scale, respectively, followed by data analysis using RevMan 5.3. The RCTs or retrospective studies to treat COVID-19 using LHQW were included. The intervention measures in the experimental group were LHQW alone or combined with chemical drugs (LCWC), and that in the control group were chemical drugs (CDs). Outcome measures included computed tomography (CT) recovery rate, disappearance rates of primary (fever, cough, fatigue), respiratory, gastrointestinal and other symptoms, exacerbation rate and adverse reaction. Subgroup analysis was conducted according to whether LHQW was combined with CDs and the different treatment methods in the control group. RESULTS: Nine trials with 1,152 participants with COVID-19 were included. The CT recovery rates of LHQW and LCWC were 1.36 and 1.32 times of CDs, respectively (P<0.05). Compared with CDs, LCWC remarkably increased the disappearance rates of fever, cough, fatigue, expectoration, shortness of breath, and muscle soreness (P<0.05). LHQW also obviously decreased the exacerbation rate, which was 0.45 times of CDs alone (P<0.05). There was no obvious difference between LCWC and CDs in adverse reaction (P>0.05). CONCLUSIONS: LHQW was more suitable for treating COVID-19 patients with obvious expectoration, shortness of breath and muscle soreness. LHQW had advantages in treating COVID-19 with no obvious exacerbation. (PROSPERO No. CRD42021235937).

Spent LiFePO4: An old but vigorous peroxymonosulfate activator for degradation of organic pollutants in water.

Iron-based catalysts have been demonstrated to activate peroxymonosulfate (PMS) to generate reactive radicals, which is however limited by their complex preparation process, high costs and inefficiency for practical applications. Herein we obtain spent LiFePO4 (SLFP), with powerful catalytic capacity by a simple one-step treatment of the retired LiFePO4 cathode material, for PMS activation to decontaminate organic pollutants. Lithium defects and oxygen vacancies in SLFP play critical roles for PMS utilization, further confirmed by density functional theory (DFT) calculations. SLFP materials rapidly adsorb PMS, and the surface PMS is activated by Fe(II) to generate radicals, with •OH playing a major role for the degradation of organics after multi-step reactions. The SLFP/PMS process is finally validated for ability to remove organic contaminants and potential environmental application.

Benefits of Prophylactic Cranial Irradiation in the MRI Era for Patients With Limited Stage Small Cell Lung Cancer.

Purpose: Previous studies have shown that prophylactic cranial irradiation (PCI) can improve the survival of patients with limited-stage small cell lung cancer (LS-SCLC). PCI is recommended for patients who respond well to chemoradiotherapy. However, whether PCI could be extrapolated to the LS-SCLC patients in the modern era of MRI is unknown. This study aimed to explore the value of PCI in patients with LS-SCLC in the era of brain MRI. Methods: This study included 306 patients with LS-SCLC at the Cancer Hospital of China Medical University. All patients received brain MRI at diagnosis and after radiochemotherapy to exclude brain metastases. A propensity score matching was performed to reduce the influence of potential confounders. Overall survival (OS), progression-free survival (PFS), and recurrence failure types were compared between PCI and non-PCI groups. Results: Among the 306 eligible patients, 81 underwent PCI, and 225 did not. After propensity score matching, there was no statistical difference in baseline data between the two groups, with 75 patients in each group. PCI did not achieve OS (median OS: 35 vs. 28 months, p = 0.128) or PFS (median PFS: 15 vs. 10 months, p = 0.186) benefits. During follow-up, 30 patients (20.0%) developed brain metastases, including 13 patients (17.3%) in the PCI group and 17 patients (22.7%) in the non-PCI group. Regarding death as a competitive risk, patients who received PCI had a lower cumulative incidence of brain metastasis than those who did not (3 years: 14.7% vs. 22.7%; Gray's test, p = 0.007). Conclusions: When brain MRI was performed at diagnosis and pre-PCI, PCI could reduce the cumulative rate of brain metastases, but it did not achieve survival benefits for LS-SCLC patients.

Molecular Mechanism of Expression Changes of Immunological Indexes of PD-1/sPD-L1 after Radiotherapy in Nonsmall Cell Lung Cancer.

It is aimed at investigating the changes of serum soluble programmed death-ligand 1 (sPD-L1) expression level in nonsmall cell lung cancer (NSCLC) before and after radiotherapy, the correlation of PD-L1, PD-1, and proteins of Akt (protein kinase B), mTOR, and HIF-1α, and the molecular mechanism of the PD-1/PD-L1 pathway in the development of NSCLS. A total of 126 NSCLC patients receiving radiotherapy in Liaoning Cancer Hospital from September 2018 to September 2019 were selected as the observation group, and another 58 healthy volunteers were selected as the control group. NSCLC patients were divided into group A (stage I-II, stereotactic radiotherapy) and group B (stage III, intensity-modulated radiation therapy) according to the cancer stage. The efficacy of radiotherapy was evaluated, and sPD-L1 expression was detected by ELISA. The immunohistochemical staining was adopted to detect protein expressions of Akt, mTOR, and HIF-1α in NSCLC tissues. The correlation between their expression and expression of PD-L1 and PD-1 was analyzed. The results showed that the overall response rate (ORR) of group A was 89.29%, the clinical benefit response (CBR) was 96.43%, the median survival time (MST) was 25 months, and the survival rate within three years was 72.56%. In group B, the ORR was 70.41%, the CBR was 97.96%, the MST was 18 months, and the survival rate within three years was 34.67%. Comparison of overall serum sPD-L1 expression in the control group, group A, and group B and between groups before radiotherapy was statistically significant (P < 0.01). After radiotherapy, serum sPD-L1 expression in group A and group B decreased compared with that before radiotherapy (P < 0.01). Among NSCLC patients, the positive expression rate of Akt, mTOR, and HIF-1α was 71.32%, 41.26%, and 80.65%, respectively. PD-L1 expression and Akt, mTOR, and HIF-1α expression showed a significant correlation. PD1 expression and Akt, mTOR, and HIF-1α expression also showed a significant correlation. It indicated that the expression level of sPD-L1 in NSCLC patients was higher than that in normal subjects, but the expression level of sPD-L1 was decreased after radiotherapy. PD-1/PD-L1 may play important roles in NSCLC procession through the Akt/mTOR and HIF-1α pathway.

Association Between Head and Neck Cancers and Polymorphisms 869T/C, 509C/T, and 915G/C of the Transforming Growth Factor-ß1 Gene: A Meta-Analysis of Case-Control Studies.

BACKGROUND Worldwide, head and neck cancers are the eighth most common malignancy. Single nucleotide polymorphisms (SNPs) are associated with susceptibility to cancer and sensitivity to radiotherapy and chemotherapy. The inflammatory cytokine, transforming growth factor-ß1 (TGF-ß1), is involved in the progression of malignancy. This study aimed to systematically review the literature and undertake a meta-analysis of case-control studies on the association between 869T/C, 509C/T, and 915G/C polymorphisms of the TGF-ß1 gene and head and neck cancers. MATERIAL AND METHODS The published literature in the English and Chinese languages were searched to identify relevant studies reporting TGF-ß1 gene polymorphisms and head and neck cancer. The PubMed, Embase, Wanfang Data, and CNKI databases were searched. Data were extracted from eligible studies, and meta-analysis was performed using Stata version 12.0 software. RESULTS Ten case-control studies were identified. There was a significant association between the 869T/C polymorphism of the TGF-ß1 gene and susceptibility to head and neck cancer. Subgroup analysis showed that the 869T/C polymorphism was not significantly associated with the histological type of head and neck cancer, but was significantly associated with susceptibility to head and neck cancer in the Asian population. The 509C/T polymorphism of the TGF-ß1 gene was not significantly associated with susceptibility to nasopharyngeal cancer (NPC), but the 915G/C polymorphism was associated with susceptibility to oral cancer. CONCLUSIONS Data from this meta-analysis showed that the 869T/C and 915G/C polymorphisms of the TGF-ß1 gene might be associated with susceptibility to head and neck cancer.

Oroxylin A Suppresses the Cell Proliferation, Migration, and EMT via NF-κB Signaling Pathway in Human Breast Cancer Cells.

Oroxylin A is a natural extract and has been reported to have a remarkable anticancer function. However, the mechanism of its anticancer activity remains not quite clear. In this study, we examined the inhibiting effects of Oroxylin A on breast cancer cell proliferation, migration, and epithelial-mesenchymal transition (EMT) and its possible molecular mechanism. The cytoactive and inflammatory factors were analyzed via Cell Counting Kit-8 assay and ELISA assay, respectively. Flow cytometry and western blotting were used to assess the cell proliferation. In addition, a wound healing assay and transwell assay were used to detect cell invasion and migration. qRT-PCR and western blot were employed to determine the effect of Oroxylin A on the EMT formation. Moreover, expression level of protein related to NF-κB signaling pathway was determined by western blot. The results revealed that Oroxylin A attenuated the cytoactivity of MDA-MB-231 cells in a dose- and a time-dependent manner. Moreover, cell proliferation, invasion, and migration of breast cancer cells were inhibited by Oroxylin A compared to the control. The mRNA and protein expression levels of E-cadherin were remarkably increased while N-cadherin and Vimentin remarkably decreased. Besides, Oroxylin A suppressed the expression of inflammatory factors and NF-κB activation. Furthermore, we also found that supplement of TNF-α reversed the effects of Oroxylin A on the cell proliferation, invasion, migration, and EMT in breast cancer cells. Taken together, our results suggested that Oroxylin A inhibited the cell proliferation, invasion, migration, and EMT through inactivating NF-κB signaling pathway in human breast cancer cells. These findings strongly suggest that Oroxylin A could be a therapeutic potential candidate for the treatment of breast cancer.

miR-142-3p inhibits cancer cell proliferation by targeting CDC25C.

OBJECTIVES: MicroRNAs (miRNAs) contribute to control of cell cycle progression and are frequently deregulated in cancer. The focus of this study was to determine effects of miR-142-3p on the cell cycle progression and cancer cell proliferation. MATERIALS AND METHODS: RT-qPCR was performed to determine expression of miR-142-3p in a range of cancer cell lines and in clinical cancer specimens. To further understand its role, we restored its expression in cancer cell lines by transfection with miR-142-3p mimics or inhibitors. Effects of miR-142-3p on cell cycle progression and cell proliferation were also determined. RESULTS: miR-142-3p was down-regulated in both cancer cell lines and cancer specimens. Its overexpression suppressed proliferation, whereas its depletion promoted it. In addition, miR-142-3p lead to cell cycle arrest in G2/M. Moreover, CDC25C was identified as being a target of miR-142-3p, ectopic expression of which reversed suppression of cell proliferation. CONCLUSIONS: Our observations suggest that miR-142-3p functioned as a tumor suppressor by targeting CDC25C.

Down-regulation of miR-129-5p via the Twist1-Snail feedback loop stimulates the epithelial-mesenchymal transition and is associated with poor prognosis in breast cancer.

The epithelial to mesenchymal transition (EMT) plays a pivotal role in breast cancer progression. We found that overexpression of miR-129-5p reversed EMT, whereas depletion of miR-129-5p induced EMT in breast cancer cells. We demonstrated that Twist1 is a direct target of miR-129-5p. Both Twist1 and Snail transcriptionally suppressed miR-129-5p expression. Levels of miR-129-5p were low in breast cancer tissues. miR-129-5p down-regulation correlated with advanced clinical stage and poor prognosis in patients with breast cancer. miR-129-5p expression negatively correlated with Twist1 and Snail expression. Thus, miR-129-5p down-regulation fosters EMT in breast cancer by increasing Twist1-Snail and activating a negative feedback loop.

Synthesis of novel core-shell structured dual-mesoporous silica nanospheres and their application for enhancing the dissolution rate of poorly water-soluble drugs.

Novel core-shell dual-mesoporous silica nanospheres (DMSS) with a tunable pore size were synthesized successfully using a styrene monomer as a channel template for the core and cetyltrimethyl ammonium bromide (CTAB) as a channel template for the shell in order to improve the dissolution rate of poorly water-soluble drugs. Simvastatin was used as a model drug and loaded into DMSS and the mesoporous core without the shell (MSC) by the solvent evaporation method. The drug loading efficiency of DMSS and MSC were determined by thermogravimetric analysis (TGA) and ultraviolet spectroscopy (UV). Characterization, using scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR) showed that simvastatin adsorbed in DMSS and MSC was in an amorphous state, and in vitro release test results demonstrated that both DMSS and MSC increased the water solubility and dissolution rate of simvastatin. The shell structure of DMSS was able to regulate the release of simvastatin compared with MSC. It is worth noting that DMSS has significant potential as a carrier for improving the dissolution of poorly water-soluble drugs and reducing the rapid release.