Coordination-induced and tunable layered rare-earth hydroxide-complex intercalated nanohybrid phosphorescent photosensitizer and therapy.

Hydrotalcite intercalated nanohybrid has served as a vital phosphorescent photosensitizer owing to remarkable 1O2 quantum yield and high cell mortality performance. However, it is rather difficult for potential large or complex guest phosphors to directly intercalate into the hydrotalcite gallery. Hence, it is necessary to regulate the interlayer microenvironment of hydrotalcites firstly for outstanding photosensitive properties. Herein, two isomers, 5,5'BDA and 4,4'BDA, with distinctive dual coordinative features were selected to modify the layer microenvironment of the LGdH gallery and induce the introduction of prospective Gd(HPhN)3 phosphorescent complexes into hydrotalcite through two different coordination effects successively. A LGdH-BDA-Gd(HPhN)3 intercalated nanohybrid phosphorescent photosensitizer was successfully obtained. The results indicated that the more efficient improvement was observed from 5,5'BDA due to offering a more spacious and stable space. Specifically, LGdH-5,5'BDA-Gd(HPhN)3 showed significantly better room temperature phosphorescence properties than LGdH-4,4'BDA-Gd(HPhN)3, whose lifetime was nearly 15 times longer than the latter. Additionally, the LGdH-5,5'BDA-Gd(HPhN)3 system displayed superior singlet oxygen generation in vitro under 460 nm irradiation (the quantum yield Φ = 0.48) and outstanding photodynamic therapy performance in tumor cells. LGdH presented more remarkable enhancement performance on the RTP properties of the luminescent molecules. This work provides a novel platform for designing a high-performance hydrotalcite intercalated nanohybrid phosphorescent photosensitizer through coordination induction to regulate the layer microenvironment.

CARM1 drives triple-negative breast cancer progression by coordinating with HIF1A.

Coactivator-associated arginine methyltransferase 1 (CARM1) promotes the development and metastasis of estrogen receptor alpha (ERα)-positive breast cancer. The function of CARM1 in triple-negative breast cancer (TNBC) is still unclear and requires further exploration. Here, we report that CARM1 promotes proliferation, epithelial-mesenchymal transition (EMT), and stemness in TNBC. CARM1 is upregulated in multiple cancers and its expression correlates with breast cancer progression. Genome-wide analysis of CARM1 showed that CARM1 is recruited by hypoxia-inducible factor 1 subunit alpha (HIF1A) and occupy the promoters of CDK4, Cyclin D1, ß-catenin, HIF1A, MALAT1, and SIX1 critically involved in cell cycle, HIF-1 signaling pathway, Wnt signaling pathway, VEGF signaling pathway, thereby modulating the proliferation and invasion of TNBC cells. We demonstrated that CARM1 is physically associated with and directly interacts with HIF1A. Moreover, we found that ellagic acid, an inhibitor of CARM1, can suppress the proliferation and metastasis of TNBC by directly inhibiting CDK4 expression. Our research has determined the molecular basis of CARM1 carcinogenesis in TNBC and its effective natural inhibitor, which may provide new ideas and drugs for cancer therapy.

Metabolomic machine learning predictor for diagnosis and prognosis of gastric cancer.

Gastric cancer (GC) represents a significant burden of cancer-related mortality worldwide, underscoring an urgent need for the development of early detection strategies and precise postoperative interventions. However, the identification of non-invasive biomarkers for early diagnosis and patient risk stratification remains underexplored. Here, we conduct a targeted metabolomics analysis of 702 plasma samples from multi-center participants to elucidate the GC metabolic reprogramming. Our machine learning analysis reveals a 10-metabolite GC diagnostic model, which is validated in an external test set with a sensitivity of 0.905, outperforming conventional methods leveraging cancer protein markers (sensitivity < 0.40). Additionally, our machine learning-derived prognostic model demonstrates superior performance to traditional models utilizing clinical parameters and effectively stratifies patients into different risk groups to guide precision interventions. Collectively, our findings reveal the metabolic landscape of GC and identify two distinct biomarker panels that enable early detection and prognosis prediction respectively, thus facilitating precision medicine in GC.

LuQi formula attenuates Cardiomyocyte ferroptosis via activating Nrf2/GPX4 signaling axis in heart failure.

BACKGROUND: The terminal stage of all cardiovascular diseases typically culminates in heart failure (HF), with no effective intervention available to halt its progression. LuQi formula (LQF) has been employed in clinical for numerous years to significantly ameliorate cardiac function in HF patients. Nevertheless, the underlying mechanism of LQF's efficacy remains inadequately comprehended. Cardiomyocyte ferroptosis has served as a pathogenic mechanism in HF. The goal of the current experiment was to ascertain whether LQF ameliorates HF by preventing cardiomyocyte ferroptosis and to elucidate the intrinsic mechanism involved. PURPOSE: This research objective is to investigate the impact and underlying mechanism of LQF attenuating cardiomyocyte ferroptosis in heart failure. METHODS: Transverse aortic constriction (TAC) was performed to construct the HF mouse model. Neonatal rat cardiomyocytes (NRCMs) were subjected to in vitro experiments. High-performance liquid chromatography (HPLC) identified the bioactive compounds in LQF. Transcriptomic and quantitative proteomic analyses revealed the potential targets of LQF anti-HF. Specifically, histological staining evaluated cardiac hypertrophy and fibrosis. Transmission electron microscopy (TEM) observed mitochondrial morphology. The content of Fe2+, ROS, MDA, GSH, and GSSH was detected using kits. Molecular docking evaluated the binding activities between essential active ingredients of LQF and critical proteins of cardiomyocyte ferroptosis. Mechanistically, the expression levels of Nrf2, Keap1, HO-1, SLC7A11, and GPX4 were evaluated using qPCR, Western blot (WB), or immunohistochemical staining. RESULTS: The primary nine active ingredients in LQF were detected. Transcriptomic and proteomic analyses demonstrated that LQF may ameliorate HF by preventing cardiomyocyte ferroptosis. Histomorphometric analyses revealed that LQF attenuates myocardial hypertrophy and fibrosis. TEM revealed that LQF diminished mitochondrial shrinkage and increased membrane density in myocardial tissue. Additionally, LQF diminished reactive oxygen species (ROS) generation in cardiomyocytes and suppressed cardiomyocyte ferroptosis. Furthermore, the molecular docking technique revealed that the primary active ingredients of LQF had suitable binding activities with Nrf2, GPX4, and SLC7A11. Western analysis further verified that LQF activated the Nrf2/GPX4 signaling axis. decreased SLC7A11 and HO-1 expression. CONCLUSIONS: These results demonstrated that LQF prevents cardiomyocyte ferroptosis via activating Nrf2/GPX4 signaling axis and suppressing SLC7A11 and HO-1 expression. Concurrently, it contributed to elucidating the intrinsic mechanism of LQF and provided a scientific rationale for its development as a novel cardiovascular therapeutic drug.

The Causal Role of Temporoparietal Junction in Mediating Self-Other Mergence during Mentalizing.

Mentalizing is a core faculty of human social behaviors that involves inferring the cognitive states of others. This process necessitates adopting an allocentric perspective and suppressing one's egocentric perspective, referred to as self-other distinction (SOD). Meanwhile, individuals may project their own cognitive states onto others in prosocial behaviors, a process known as self-other mergence (SOM). It remains unclear how the two opposing processes coexist during mentalizing. We here combined functional magnetic resonance imaging (fMRI) and repetitive transcranial magnetic stimulation (rTMS) techniques with intranasal oxytocin (OTint) as a probe to examine the SOM effect in healthy male human participants, during which they attributed the cognitive states of decision confidence to an anonymous partner. Our results showed that OTint facilitated SOM via the left temporoparietal junction (lTPJ), but did not affect neural representations of internal information about others' confidence in the dorsomedial prefrontal cortex, which might be dedicated to SOD, although the two brain regions, importantly, have been suggested to be involved in mentalizing. Further, the SOM effect induced by OTint was fully mediated by the lTPJ activities and became weakened when the lTPJ activities were suppressed by rTMS. These findings suggest that the lTPJ might play a vital role in mediating SOM during mentalizing.SIGNIFICANCE STATEMENT Every human mind is unique. It is critical to distinguish the minds of others from the self. On the contrary, we often project the current mental states of the self onto others; that is to say, self-other mergence (SOM). The neural mechanism underlying SOM remains unclear. We here used intranasal oxytocin (OTint) as a probe to leverage SOM, which is typically suppressed during mentalizing. We revealed that OTint specifically modulated the left temporoparietal junction (lTPJ) neural activities to fully mediate the SOM effect, while suppressing the lTPJ neural activities by transcranial magnetic stimulations causally attenuated the SOM effect. Our results demonstrate that the lTPJ might mediate SOM during social interactions.

What can we do to optimize mitochondrial transplantation therapy for myocardial ischemia-reperfusion injury?

Mitochondrial transplantation is a promising solution for the heart following ischemia-reperfusion injury due to its capacity to replace damaged mitochondria and restore cardiac function. However, many barriers (such as inadequate mitochondrial internalization, poor survival of transplanted mitochondria, few mitochondria colocalized with cardiac cells) compromise the replacement of injured mitochondria with transplanted mitochondria. Therefore, it is necessary to optimize mitochondrial transplantation therapy to improve clinical effectiveness. By analogy, myocardial ischemia-reperfusion injury is like a withered flower, it needs to absorb enough nutrients to recover and bloom. In this review, we present a comprehensive overview of "nutrients" (source of exogenous mitochondria and different techniques for mitochondrial isolation), "absorption" (mitochondrial transplantation approaches, mitochondrial transplantation dose and internalization mechanism), and "flowering" (the mechanism of mitochondrial transplantation in cardioprotection) for myocardial ischemia-reperfusion injury.

Generalization of the modulatory effect of social interaction on personal space.

Introduction: Personal space (PS) is a safe area around an individual's body that affects spatial distance when socially interacting with others. Previous studies have shown that social interaction may modulate PS. However, these findings are often confounded by the effects of familiarization. Furthermore, whether the potential regulatory effects of social interaction on PS can be generalized from interacting confederates to strangers remains unclear. Methods: To answer these questions, we enrolled 115 participants in a carefully designed experiment. Results: We found that prosocial interaction in the form of a cooperative task effectively reduced PS, and this regulatory effect could be generalized from interacting confederates to non-interacting confederates. Discussion: These findings deepen our understanding of PS regulation and may be aid in the diagnosis and rehabilitation of dysfunctional social behaviors.

Prognostic analysis of patients with breast cancer based on tumor mutational burden and DNA damage repair genes.

Background: Breast cancer has a high tumor-specific death rate and poor prognosis. In this study, we aimed to provide a basis for the prognostic risk in patients with breast cancer using significant gene sets selected by analyzing tumor mutational burden (TMB) and DNA damage repair (DDR). Methods: Breast cancer genomic and transcriptomic data were obtained from The Cancer Genome Atlas (TCGA). Breast cancer samples were dichotomized into high- and low-TMB groups according to TMB values. Differentially expressed DDR genes between high- and low-TMB groups were incorporated into univariate and multivariate cox regression model to build prognosis model. Performance of the prognosis model was validated in an independently new GEO dataset and evaluated by time-dependent ROC curves. Results: Between high- and low-TMB groups, there were 6,424 differentially expressed genes, including 67 DDR genes. Ten genes associated with prognosis were selected by univariate cox regression analysis, among which seven genes constituted a panel to predict breast cancer prognosis. The seven-gene prognostic model, as well as the gene copy numbers are closely associated with tumor-infiltrating immune cells. Conclusion: We established a seven-gene prognostic model comprising MDC1, PARP3, PSMB1, PSMB9, PSMD2, PSMD7, and PSMD14 genes, which provides a basis for further exploration of a population-based prediction of prognosis and immunotherapy response in patients with breast cancer.

Isorhamnetin induces cell cycle arrest and apoptosis by triggering DNA damage and regulating the AMPK/mTOR/p70S6K signaling pathway in doxorubicin-resistant breast cancer.

BACKGROUND: Acquired resistance to doxorubicin (DOX) inevitably limits its clinical use against breast cancer (BC). Isorhamnetin (IS), a native flavonoid which extensively available in vegetables, fruits, and phytomedicine, has been deemed to the probable cancer chemopreventive agent in preceding explorations since it exhibits satisfied antitumor activity. So far, the strategy for alleviating DOX resistance by using IS as a sensitizer against resistant BC has not yet been covered. PURPOSE: To investigate the effect of IS on potentiating the chemoreceptivity of drug-resistant BC cells to DOX in vitro and in vivo and elucidate the possible molecular mechanisms. METHODS: MTS assays, colony formation assays, three-dimensional (3D) tumor spheroid model, and migration assay were deployed to verify the inhibiting action of IS in the presence or absence of DOX on resistant BC cells in vitro. Apoptosis, cell cycle regulation, and endocellular reactive oxygen species (ROS) were determined by flow cytometry. Protein levels were monitored by western blotting. Nuclear staining and EdU proliferation were photographed with a confocal laser scanning microscope. The effects of the IS and DOX combination on the tumorigenesis in the xenograft experiments were evaluated for further confirming the in vitro cytotoxicity. RESULTS: IS significantly inhibited cell proliferation and migration and enhanced the antitumor competence of DOX against resistant BC cells both in vitro and in vivo. Adjuvant IS (50 µM) effectively enhanced the proapoptotic impacts of DOX in resistant BC cells (35.38 ± 3.18%, vs. 5.83 ± 0.68% in the DOX group) by suppressing the expression of bcl 2 in addition to enhancing cleaved caspase 3, ultimately leading to DNA condensation and fragmentation. IS (20, 30, and 50 µM) treatments induced significant increases in the G2/M populations (41.60 ± 1.28%, 44.60 ± 1.14%, and 50.64 ± 0.67%, vs. 35.84 ± 1.56% in the untreated control in MCF7/ADR cells, p < 0.01) via regulating CDK1/Cyclin B1 complex expression, subsequently triggering the inhibition of BC proliferation. In addition, IS (10, 20, 30, and 50 µM) stimulated the production of interstitial ROS in MCF7/ADR cells, by 3.99-, 4.20-, 6.29-, and 6.78-fold, respectively, versus the untreated group (p < 0.001), which were involved in DNA damage and AMPK-caused intercept of the mTOR/p70S6K signaling. CONCLUSION: Our study suggested the anti-breast cancer actions of IS as a DOX sensitizer and expounded the underlying molecular mechanisms, showing that IS could be deemed to a capable alternative for resistant BC cure.

Targeting regulatory T cells for cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide. The CVDs are accompanied by inflammatory progression, resulting in innate and adaptive immune responses. Regulatory T cells (Tregs) have an immunosuppressive function and are one of the subsets of CD4+T cells that play a crucial role in inflammatory diseases. Whether using Tregs as a biomarker for CVDs or targeting Tregs to exert cardioprotective functions by regulating immune balance, suppressing inflammation, suppressing cardiac and vascular remodeling, mediating immune tolerance, and promoting cardiac regeneration in the treatment of CVDs has become an emerging research focus. However, Tregs have plasticity, and this plastic Tregs lose immunosuppressive function and produce toxic effects on target organs in some diseases. This review aims to provide an overview of Tregs' role and related mechanisms in CVDs, and reports on the research of plasticity Tregs in CVDs, to lay a foundation for further studies targeting Tregs in the prevention and treatment of CVDs.

Priming behavior: A meta-analysis of the effects of behavioral and nonbehavioral primes on overt behavioral outcomes.

Past meta-analyses of the effects of priming on overt behavior have not examined whether the effects and processes of priming behavioral or nonbehavioral concepts (e.g., priming action through the word go and priming religion through the word church) differ, even though these possibilities are important to our understanding of concept accessibility and behavior. Hence, we meta-analyzed 351 studies (224 reports and 862 effect sizes) involving incidental presentation of behavioral or nonbehavioral primes, a neutral control group, and at least one behavioral outcome. Our random-effects analyses, which used the correlated and hierarchical effects model with robust variance estimation (Pustejovsky & Tipton, 2021; Tanner-Smith et al., 2016), revealed a moderate priming effect (d = 0.37) that remained stable across behavioral and nonbehavioral primes and across different methodological procedures and adjustments for possible inclusion/publication biases (e.g., sensitivity analyses from Mathur & VanderWeele, 2020; sensitivity analyses from Vevea & Woods, 2005). Although the findings suggest that associative processes explain both the effects of behavioral and nonbehavioral primes, lowering the value of a behavior weakened the effect only when the primes were behavioral. These findings support the possibility that even though both types of primes activate associations that promote behavior, behavioral (vs. nonbehavioral) primes may provide a greater opportunity for goals to control the effect of the primes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The PRMT6/PARP1/CRL4B Complex Regulates the Circadian Clock and Promotes Breast Tumorigenesis.

Circadian rhythms, as physiological systems with self-regulatory functions in living organisms, are controlled by core clock genes and are involved in tumor development. The protein arginine methyltransferase 6 (PRMT6) serves as an oncogene in a myriad of solid tumors, including breast cancer. Hence, the primary aim of the current study is to investigate the molecular mechanisms by which the PRMT6 complex promotes breast cancer progression. The results show that PRMT6, poly(ADP-ribose) polymerase 1 (PARP1), and the cullin 4 B (CUL4B)-Ring E3 ligase (CRL4B) complex interact to form a transcription-repressive complex that co-occupies the core clock gene PER3 promoter. Moreover, genome-wide analysis of PRMT6/PARP1/CUL4B targets identifies a cohort of genes that is principally involved in circadian rhythms. This transcriptional-repression complex promotes the proliferation and metastasis of breast cancer by interfering with circadian rhythm oscillation. Meanwhile, the PARP1 inhibitor Olaparib enhances clock gene expression, thus, reducing breast carcinogenesis, indicating that PARP1 inhibitors have potential antitumor effects in high-PRMT6 expression breast cancer.

Ehm2 transcript variant 1 inhibits breast cancer progression and increases E-cadherin stability.

Ehm2/1, an Ehm2 transcript variant, regulates the cytoskeleton by binding to plasma membrane proteins. However, the role of Ehm2/1 in breast cancer development remains poorly understood. This study shows that, the expression of Ehm2/1 was decreased in breast cancer and that patients with low Ehm2/1 expression had a significantly poorer prognosis than those with high expression of Ehm2/1. Overexpression of Ehm2/1 in MCF-7 breast cancer cells inhibited cell migration and invasion. Ehm2/1 markedly increased the stability and half-life of E-cadherin. Moreover, Ehm2/1 was collocated with E-cadherin in the plasma membrane of MCF-7 cells. Furthermore, downregulation of Ehm2/1 promoted ubiquitination of E-cadherin, whereas overexpression of Ehm2/1 inhibited ubiquitination of E-cadherin. These results suggest that Ehm2/1 could suppress the migration and invasion of breast cancer cells by increasing E-cadherin stability.

Research on the Gut Microbiota of Hainan Black Goat.

The intestine of animals is a complex micro-ecosystem containing a large number of microbiomes, which is essential for the host's health development. The Hainan black goat with good resistance and adaptability is a unique species in Hainan, China. These unique physiological characteristics are inseparable from their intestinal microbiota. In this study, high-throughput sequencing was used to investigate bacterial communities in different segments of the intestinal tract of Hainan black goat. The results showed that the indices of Chao1 and ACE in the cecum and colon were significantly greater than those in the ileum (p = 0.007, 0.018). According to PCoA, the intestinal flora composition of the cecum and colon is almost equivalent. In contexts of the phylum, Firmicutes, Bacteroidota, and Pseudomonadota were the dominant phyla in the gut of the Hainan black goat. While in context of the genus, the dominant groups in the gut of black goats mainly include Ruminococcaceae_UCG-005, Bacteroides, Paeniclostridium, Christensenellaceae_R-7_group, Rikenellaceae_RC9_gut_group, and Eubacterium coprostanoligenes _group, Prevotella_1, they have different proportions in different intestinal segments. The gut microbiota of Hainan black goat is mainly Firmicutes, Bacteroidota, and Pseudomonadota. Influenced by the intestinal location where they colonize, the large intestine has a more complex intestinal flora than the small intestine. In contrast, there are only minor differences between the caecum and the colon in the large intestine.

Antioxidative properties analysis of gastrointestinal lactic acid bacteria in Hainan black goat and its effect on the aerobic stability of total mixed ration.

In this study, lactic acid bacteria strains (HCS-01, HCS-05, HCS-07, HCW-08, and HCW-09) derived from the gastrointestinal tract of Hainan black goat were evaluated for their antioxidant capacity in vitro, and the lactic acid bacteria with strong antioxidant capacity were screened for application to improve the aerobic stability of total mixed ration (TMR). The results showed that all the tested lactic acid bacteria had a certain tolerance to hydrogen peroxide. By comprehensively comparing the scavenging abilities of fermentation supernatants, whole cell bacterial suspensions and cell contents of five lactic acid bacteria strains to 2,2-diphenyl-1-picrylhydrazine (DPPH), hydroxyl radicals and superoxide anions, and their antioxidant enzyme activity, it was found that Lactobacillus fermentum HCS-05 and Lactobacillus plantarum HCW-08 have the strongest comprehensive antioxidant capacity, and their scavenging capacity for various free radicals has reached more than 60%. Using strains HCS-05, HCW-08 and laboratory-preserved Lactobacillus plantarum HDX1 fermented TMR, the fermentation quality and aerobic stability of the feed after 60 days of fermentation were significantly higher than those of the blank treatment group. The effect of mixed strains HCS-05 and HCS-08 for TMR fermentation was the best (P < 0.05). At the same time, the fermentation effect of Lactobacillus plantarum HDX1 on TMR was significantly lower than that of the selected lactic acid bacteria from the gastrointestinal tract of Hainan black goats (P < 0.05). The results show that the test strain can significantly improve the aerobic stability of the fermented feeds.

Ginsenoside Rd Promotes Cardiac Repair After Myocardial Infarction by Modulating Monocytes/Macrophages Subsets Conversion.

Purpose: This study aimed to elucidate the potential molecular mechanisms by which GSRd improves cardiac inflammation and immune environment after MI. Materials and Methods: The potential target genes of GSRd were predicted using the STITCH database. In vivo, MI mice models were established by left anterior descending ligation and were divided into the sham group, MI + Vehicle group, and MI + GSRd group. DMSO, DMSO, and GSRd 50 µL/day were intraperitoneally injected, respectively. After 28 days, echocardiography, Masson staining, immunofluorescence staining, flow cytometry, RT-PCR, and Western blot were performed. Mice peritoneal macrophages were extracted in vitro, and Western blot was performed after GSRd and/or Akt inhibitor MK2206 intervention. Results: GSRd significantly improved mouse myocardial function, attenuated cardiac fibrosis, and inhibited inflammation and apoptosis in myocardial tissues after myocardial infarction. Meanwhile, GSRd increased non-classical Ly6Clow Mos/Mps while reduced of classical Ly6Chigh Mos/Mps at the same time in myocardial tissues. In addition, GSRd significantly reversed the activity of p-Akt and p-mTOR in the heart Mos/Mps after MI. In vitro studies showed that the activity of p-Akt and p-mTOR in peritoneal macrophages were significantly increased in a dose-dependent manner after GSRd treatment. Furthermore, the AKT inhibitor MK2206 was found to block the enhanced activity of p-Akt and p-mTOR induced by GSRd in peritoneal macrophages. Conclusion: GSRd can enhance the transformation of Ly6Chigh Mos/Mps to Ly6Clow Mos/Mps in mice after MI by activating the Akt/mTOR signaling pathway, inhibiting cardiac dysfunction and promoting cardiac repair.

RUNX2 recruits the NuRD(MTA1)/CRL4B complex to promote breast cancer progression and bone metastasis.

Runt-related transcription factor 2 (RUNX2) is an osteogenesis-related transcription factor that has emerged as a prominent transcription repressing factor in carcinogenesis. However, the role of RUNX2 in breast cancer metastasis remains poorly understood. Here, we show that RUNX2 recruits the metastasis-associated 1 (MTA1)/NuRD and the Cullin 4B (CUL4B)-Ring E3 ligase (CRL4B) complex to form a transcriptional-repressive complex, which catalyzes the histone deacetylation and ubiquitylation. Genome-wide analysis of the RUNX2/NuRD(MTA1)/CRL4B complex targets identified a cohort of genes including peroxisome proliferator-activated receptor alpha (PPARα) and superoxide dismutase 2 (SOD2), which are critically involved in cell growth, epithelial-to-mesenchymal transition (EMT) and invasion. We demonstrate that the RUNX2/NuRD(MTA1)/CRL4B complex promotes the proliferation, invasion, tumorigenesis, bone metastasis, cancer stemness of breast cancer in vitro and in vivo. Strikingly, RUNX2 expression is upregulated in multiple human carcinomas, including breast cancer. Our study suggests that RUNX2 is a promising potential target for the future treatment strategies of breast cancer.

A Nanosized Codelivery System Based on Intracellular Stimuli-Triggered Dual-Drug Release for Multilevel Chemotherapy Amplification in Drug-Resistant Breast Cancer.

Lacking nano-systems for precisely codelivering the chemotherapeutics paclitaxel (PTX) and the natural P-glycoprotein (P-gp) inhibitor, quercetin (QU), into cancer cells and controlling their intracellular release extremely decreased the anticancer effects in multidrug resistant (MDR) tumors. To overcome this hurdle, we constructed hybrid polymeric nanoparticles (PNPs) which consist of redox-sensitive PTX/polyethyleneimine-tocopherol hydrogen succinate-dithioglycollic acid PNPs and pH-sensitive hyaluronic acid-QU conjugates. The obtained hybrid PNPs can be internalized into drug-resistant breast cancer cells by the hyaluronic acid/CD44-mediated endocytosis pathway and escape from the lysosome through the "proton sponge effect". Under the trigger of intracellular stimuli, the nanoplatform used the pH/glutathione dual-sensitive disassembly to release QU and PTX. The PTX diffused into microtubules to induce tumor cell apoptosis, while QU promoted PTX retention by down-regulating P-gp expression. Moreover, tocopherol hydrogen succinate and QU disturbed mitochondrial functions by generating excessive reactive oxygen species, decreasing the mitochondrial membrane potential, and releasing cytochrome c into the cytosol which consequently achieved intracellular multilevel chemotherapy amplification in MDR cancers. Importantly, the PNPs substantially suppressed tumors growth with an average volume 2.54-fold lower than that of the control group in the MCF-7/ADR tumor-bearing nude mice model. These presented PNPs would provide a valuable reference for the coadministration of natural compounds and anticarcinogens for satisfactory combination therapy in MDR cancers.

The hub ten gene-based risk score system using RNA m6A methylation regulator features and tumor immune microenvironment in breast cancer.

BACKGROUND: RNA N6-methyladenosine (m6A) modification is primarily regulated by m6A regulators, which play significant epigenetic regulatory roles in tumorigenesis, tumor development, and tumor immune microenvironment. However, the correlation between m6A regulators and immune cell infiltration in breast cancer remains unclear. METHODS: In this study, m6A modification patterns were evaluated based on 31 m6A modification regulators. m6A clusters were determined by consensus clustering. Immune landscape and immune cell infiltration subgroups were characterized by m6A clusters. Key module and hub genes related to m6A regulators and immune infiltration cells were identified by WGCNA. LASSO algorithm was applied to select prognostic signatures. Multivariate Cox regression analysis was applied to assess the prognostic value of gene signatures. RESULTS: Two distinct m6A clusters were determined based on the expression of 31 m6A modification regulators and characterized by two tumor immune microenvironment (TIME) immune cell infiltration subgroups. Further, a total of 1971 differentially expressed genes between breast cancer patients and healthy controls were screened, nine modules associated with clinical characteristics of breast cancer patients were identified. Later, one key module and 13 hub genes correlated with m6A regulators and immune infiltration cells were identified. LASSO Cox regression analysis selected and constructed a ten-gene prognostic model to build a risk score system for individual breast cancer patient prognosis. The performance of the ten-gene-based risk score system was further validated in an independent dataset with an AUC of 0.659. CONCLUSIONS: This study revealed that m6A modification regulators played a significant role in the TIME regulation of breast cancer. The hub ten gene-based risk score system is valuable in predicting the prognosis of breast cancer patients, which may provide potential significance for breast cancer diagnosis, prognosis, and immunotherapy in the future.

BCAS3 exhibits oncogenic properties by promoting CRL4A-mediated ubiquitination of p53 in breast cancer.

OBJECTIVES: Breast cancer-amplified sequence 3 (BCAS3) was initially found to be amplified in human breast cancer (BRCA); however, there has been little consensus on the functions of BCAS3 in breast tumours. MATERIALS AND METHODS: We analysed BCAS3 expression in BRCA using bio-information tools. Affinity purification and mass spectrometry were employed to identify BCAS3-associated proteins. GST pull-down and ubiquitination assays were performed to analyse the interaction mechanism between BCAS3/p53 and CUL4A-RING E3 ubiquitin ligase (CRL4A) complex. BCAS3 was knocked down individually or in combination with p53 in MCF-7 cells to further explore the biological functions of the BCAS3/p53 axis. The clinical values of BCAS3 for BRCA progression were evaluated via semiquantitative immunohistochemistry (IHC) analysis and Cox regression. RESULTS: We reported that the expression level of BCAS3 in BRCA was higher than that in adjacent normal tissues. High BCAS3 expression promoted growth, inhibited apoptosis and conferred chemoresistance in breast cancer cells. Mechanistically, BCAS3 overexpression fostered BRCA cell growth by interacting with the CRL4A complex and promoting ubiquitination and proteasomal degradation of p53. Furthermore, BCAS3 could regulate cell growth, apoptosis and chemoresistance through a p53-mediated mechanism. Clinically, BCAS3 overexpression was significantly correlated with a malignant phenotype. Moreover, higher expression of BCAS3 correlates with shorter overall survival (OS) in BRCA. CONCLUSIONS: The functional characterization of BCAS3 offers new insights into the oncogenic properties and chemotherapy resistance in breast cancer.