Comprehensive multi-omics analysis and experimental verification reveal PFDN5 is a novel prognostic and therapeutic biomarker for gastric cancer.

Prefoldin Subunit 5 (PFDN5) plays a critical role as a member of the prefoldins (PFDNs) in maintaining a finely tuned equilibrium between protein production and degradation. However, there has been no comprehensive analysis specifically focused on PFDN5 thus far. Here, a comprehensive multi-omics (transcriptomics, genomics, and proteomics) analysis, systematic molecular biology experiments (in vitro and in vivo), transcriptome sequencing and PCR Array were performed for identifying the value of PFDN5 in pan-cancer, especially in Gastric Cancer (GC). We found PFDN5 had the potential to serve as a prognostic and therapeutic biomarker in GC. And PFDN5 could promote the proliferation of GC cells, primarily by affecting the cell cycle, cell death and immune process etc. These findings provide novel insights into the molecular mechanisms and precise treatments of in GC.

CT-guided radioactive 125I seeds brachytherapy for lung oligometastases from colorectal cancer: initial results.

OBJECTIVES: To evaluate the safety and effectiveness of computed tomography (CT)-guided radioactive 125I seeds brachytherapy (RISB) for lung oligometastases (LO) from colorectal cancer (CRC). METHODS: Data for 144 LOs from 70 CRC patients who underwent CT-guided RISB were retrospectively analyzed. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoints were technical success, local control rate (LCR), and complications. Kaplan-Meier method was used for survival analysis. Cox model was used to identify the independent predictors of poor prognosis. RESULTS: The RISB procedures were successfully performed in all patients, and the success rate was 100%. The median follow-up was 27.8 months. The median PFS was 10.0 months (95% CI: 8.9-11.1) and the 1- and 2-year PFS rates were 32.9% and 5.9%, respectively. On multivariate analysis, serum carcinoembryonic antigen (CEA) ≤ 15 ng/ml (P = 0.048), middle-high differentiated pathological classification (P = 0.015), primary TNM stages I-III (P = 0.001), LO number ≤ 2 (P < 0.001) and cumulative gross tumor volume (GTV) ≤ 40 cm3 (P < 0.001) showed superior PFS. The median OS was 30.8 months (95% CI: 27.1-34.4) and the 1-, 2-, and 3-year OS rates were 95.7%, 67.4%, and 42.5%, respectively. On multivariate analysis, serum CEA ≤ 15 ng/ml (P = 0.004), middle-high differentiated pathological classification (P < 0.001), primary TNM stages I-III (P < 0.001), LO number ≤ 2 (P < 0.001), cumulative GTV ≤ 40 cm3 (P < 0.001) and system treatments combined with chemotherapy and target therapy (P < 0.001) showed superior OS. The LCR for 3, 6, and 12 months was 97.9%, 91.0%, and 83.6%, respectively. There were 4 cases of pneumothorax at 5.7% that required drainage. CONCLUSIONS: RISB for LO from CRC is safe and effective, and serum CEA, TNM stage, LO number, cumulative GTV, and system treatments should be emphasized for long OS.

Polyamine metabolism patterns characterized tumor microenvironment, prognosis, and response to immunotherapy in colorectal cancer.

BACKGROUND: Changes in Polyamine metabolism (PAM) have been shown to establish a suppressive tumor microenvironment (TME) and substantially influence the progression of cancer in the recent studies. However, newly emerging data have still been unable to fully illuminate the specific effects of PAM in human cancers. Here, we analyzed the expression profiles and clinical relevance of PAM genes in colorectal cancer (CRC). METHODS: Based on unsupervised consensus clustering and principal component analysis (PCA) algorithm, we designed a scoring model to evaluate the prognosis of CRC patients and characterize the TME immune profiles, with related independent immunohistochemical validation cohort. Through comparative profiling of cell communities defined by single cell sequencing data, we identified the distinct characteristics of polyamine metabolism in the TME of CRC. RESULTS: Three PAM patterns with distinct prognosis and TME features were recognized from 1224 CRC samples. Moreover, CRC patients could be divided into high- and low-PAMscore subgroups by PCA-based scoring system. High PAMscore subgroup were associated to more advanced stage, higher infiltration level of immunosuppressive cells, and unfavorable prognosis. These results were also validated in CRC samples from other public CRC datasets and our own cohort, which suggested PAM genes were ideal biomarkers for predicting CRC prognosis. Notably, PAMscore also corelated with microsatellite instability-high (MSI-H) status, higher tumor mutational burden (TMB), and increased immune checkpoint gene expression, implying a potential role of PAM genes in regulating response to immunotherapy. To further confirm above results, we demonstrated a high-resolution landscape of TME and cell-cell communication network in different PAM patterns using single cell sequencing data and found that polyamine metabolism affected the communication between cancer cells and several immune cells such as T cells, B cells and myeloid cells. CONCLUSION: In total, our findings highlighted the significance of polyamine metabolism in shaping the TME and predicting the prognosis of CRC patients, providing novel strategies for immunotherapy and the targeting polyamine metabolites.

TACE sequential MWA guided by cone-beam computed tomography in the treatment of small hepatocellular carcinoma under the hepatic dome.

PURPOSE: An assessment is being conducted to determine the safety and effectiveness of using Cone-beam computed tomography (CBCT)-guided transcatheter arterial chemoembolization (TACE) and microwave ablation (MWA) sequentially to treat small hepatocellular carcinomas (HCCs) located in the hepatic dome. MATERIALS AND METHODS: Fifty-three patients with small HCCs in the hepatic dome who underwent TACE combined with simultaneous CBCT-guided MWA were studied. Inclusion criteria were a single HCCs ≤ 5.0 cm or a maximum of three. The safety and interventional-related complications were monitored, and local tumor progression (LTP), overall survival (OS), and prognostic factors for LTP/OS were evaluated. RESULTS: The procedures were successfully accomplished in all patients. According to Common Terminology Criteria for Adverse Events (CTCAE), adverse reactions and complications are mainly Grade 1 or 2 (mild symptoms, no or local/noninvasive intervention indicated). Liver and kidney function and alpha-fetoprotein (AFP) levels remained within a reasonable range after 4 weeks of treatment (both p < 0.001). The mean LTP was 44.406 months (95% CI: 39.429, 49.383) and the mean OS rate was 55.157 months (95% CI: 52.559, 57.754). The combination treatment achieved 1-, 3-, and 5-year LTP rates of 92.5%, 69.6%, and 34.5%, respectively; and 1-, 3-, and 5-year OS rates of 100.0%, 88.4%, and 70.2%, respectively. Results from both univariate and multivariate Cox regression analyses showed that the tumor diameter (< 3 cm) and the distance to the hepatic dome (≥ 5 mm, < 10 mm) had a significant impact on the patient's LTP and OS, and were related to better survival. CONCLUSION: CBCT-guided TACE combined with simultaneous MWA was a safe and successful treatment of HCCs located under the hepatic dome.

Curcumin activates Nrf2/HO-1 signaling to relieve diabetic cardiomyopathy injury by reducing ROS in vitro and in vivo.

The hallmark feature of Diabetes mellitus (DM) is hyperglycemia which can lead to excess production of reactive oxygen species (ROS) in the myocardium, contributing to diabetic cardiomyopathy (DCM). Nuclear factor erythroid2-related factor2 (Nrf2), a transcriptional activator, enhances its ability to resist oxidative stress by activating multiple downstream anti-oxidants, anti-inflammatory proteins, and detoxifying enzymes. However, the mechanism of Nrf2 signaling in HG-induced DCM is unclear. In this study, we used HG pretreated H9c2 cells as the experimental basis in vitro, and established a high fat-diet, streptozotocin (STZ) induced Type 2 diabetic rat model in vivo. Meanwhile, we used shRNA-Nrf2 and curcumin (CUR) (as an activator) to affect H9c2 cells, to verify the role of the Nrf2 signaling pathway in DCM. The results showed that the excessive production of ROS caused by HG, which could inhibit the activation of Nrf2-related signaling, resulting in a decrease in cell energy metabolism and an increase in cell apoptosis. Surprisingly, we found that the activation of the Nrf2 signaling pathway significantly increased cardiomyocyte viability, reduced ROS formation, increased antioxidant enzyme activity, and inhibited cardiomyocyte apoptosis. In conclusion, these findings conclusively infer that CUR activation of the Nrf2/HO-1 signaling pathway exerts myocardial protection by reducing ROS formation.

Correction of the pathogenic mutation in TGM1 gene by adenine base editing in mutant embryos.

A couple diagnosed as carriers for lamellar ichthyosis, an autosomal recessive rare disease, encountered two pregnancy losses. Their blood samples showed the same heterozygous c.607C>T mutation in the TGM1 gene. However, we found that about 98.4% of the sperm had mutations, suggesting possible de novo germline mutation. To explore the probability of correcting this mutation, we used two different adenine base editors (ABEs) combined with related truncated single guide RNA (sgRNA) to repair the pathogenic mutation in mutant zygotes. Our results showed that the editing efficiency was 73.8% for ABEmax-NG combined with 20-bp-length sgRNA and 78.7% for Sc-ABEmax combined with 19-bp-length sgRNA. The whole-genome sequencing (WGS) and deep sequencing analysis demonstrated precise DNA editing. This study reveals the possibility of correcting the genetic mutation in embryos with the ABE system.

Clinical application of noninvasive chromosomal screening for elective single-blastocyst transfer in frozen-thawed cycles.

BACKGROUND: The objective of this study was to explore the clinical application of noninvasive chromosomal screening (NICS) for elective single-blastocyst transfer (eSBT) in frozen-thawed cycles. METHODS: This study retrospectively analysed the data of 212 frozen-thawed single-blastocyst transfers performed in our centre from January 2019 to July 2019. The frozen embryos were selected based on morphological grades and placed in preincubation for 6 h after warming. Then spent microdroplet culture media of frozen-thawed blastocysts were harvested and subjected to NICS. The clinical outcomes were evaluated and further stratified analysis were performed, especially different fertilization approaches. RESULTS: The clinical pregnancy, ongoing pregnancy, and live birth rates in the euploidy group were significantly higher than those in the aneuploidy group (56.2% versus 29.4%) but were nonsignificantly different from those in the chaotic abnormal/NA embryos group (56.2% versus 60.4%). Compared with day6 (D6) blastocysts, D5 blastocysts had a nonsignificantly different euploidy rate (40.4% versus 48.1%, P = 0.320) but significantly increased clinical pregnancy (57.7% versus 22.2%, P < 0.001), ongoing pregnancy (48.1% versus 14.8%, P < 0.001), and live birth rates (48.1% versus 13.0%, P < 0.001). The percentage of chaotic abnormal/NA embryos group was significantly higher among D5 embryos than among D6 embryos (30.1% versus 11.1%, P = 0.006). The percentage of aneuploid embryos was higher among the embryos with lower morphological quality(21.5% among 'good' embryos versus 34.6% among 'fair' embryos versus 46.0% among 'poor' embryos, P = 0.013); correspondingly, the overall clinical pregnancy, ongoing pregnancy and live birth rate rates showed similar declines. CONCLUSIONS: NICS combined with morphological assessment is an effective tool to guide frozen-thawed SBT. The optimal embryo for SBT is a 'euploid embryo with good morphology', followed sequentially by a 'chaotic abnormal/NA embryo with good morphology', 'euploid embryo with fair morphology', and 'chaotic abnormal/NA embryo with fair morphology'.

Ischemic preconditioning/ischemic postconditioning alleviates anoxia/reoxygenation injury via the Notch1/Hes1/VDAC1 axis.

Ischemic preconditioning (IPC), and ischemic postconditioning (IPost) have a significant protective effect on myocardial ischemia/reperfusion (MI/R) injury by alleviating oxidative stress and mitochondrial disturbances, although the underlying molecular mechanisms are unclear. The study was to demonstrate that cardioprotection against anoxia/reoxygenation (A/R) injury is transduced via the Notch1/Hes1/VDAC1 signaling pathway. Using mass spectrometry and tandem affinity purification (TAP), to screen for differentially expressed proteins associated with Hes1, followed by standard bioinformatics analysis. The co-immunoprecipitation (Co-IP) assay confirmed an interaction between Hes1 and VDAC1 proteins. H9c2 cells were transfected with Hes1 adenoviral N-terminal TAP vector (AD-NTAP/Hes1) and Hes1-short hairpin RNA adenoviral vector (AD-Hes1-shRNA) to establish A/R injury, IPC, and IPost models, respectively. The expression of Hes1 and VDAC1 proteins were measured by western blot analysis, while the levels of reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and apoptosis were evaluated by flow cytometry. AD-NTAP/Hes1 can activate the exogenous protein expression of Hes1, thus decreasing creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) activity and promoting cell viability. The study found that VDAC1 was a potential target protein for Hes1 and the overexpression of Hes1 protein expression downregulated protein expression levels of VDAC1, reduced ROS production, stabilized ΔΨm, and inhibited apoptosis in H9c2 cells. Additionally, downregulation of Hes1 protein expression also upregulated VDAC1 protein expression, increased ROS production, imbalanced ΔΨm, promoted cell apoptosis, and attenuated the cardioprotection afforded by IPC and IPost. The Notch1/Hes1 signaling pathway activated by IPC/IPost can directly downregulate the protein expression of VDAC1 and consequently relieve A/R injury.

Preliminary application of brachytherapy with double-strand 125I seeds and biliary drainage for malignant obstructive jaundice.

AIM: To evaluate the efficacy and safety of brachytherapy with double-strand 125I seeds and biliary drainage for malignant obstructive jaundice. METHODS AND MATERIALS: 42 patients with obstructive jaundice because of extrahepatic cholangiocarcinoma were enrolled. 22 patients (group A) received a biliary stent with common drainage tube implantation, and 20 patients (group B) received a biliary stent with double-strand 125I seeds radiotherapy drainage tube placement. The length, location and pathological stage of biliary stricture were recorded in the two groups. Total bilirubin (TBIL), direct bilirubin (DBIL), IgA, IgG, IgM, alanine aminotransferase and white blood cell (WBC) count were measured before and after percutaneous transhepatic cholangial drainage (PTCD). Tumor diameter was measured before and three months after PTCD, and the difference were calculated. Stent patency time, survival time, and complications were recorded. RESULTS: There was no significant difference in the length, location and pathological stage of biliary stenosis between the two groups. There was no significant difference in TBIL, DBIL, IgA, IgG, IgM, alanine aminotransferase and WBC count between the two groups before or after PTCD (P > 0.05). Three months after PTCD, tumors growth in group A and tumors shrinkage in group B. The difference in tumor size between the two groups before and after PTCD was statistically significant (P < 0.05). The average stent patency times in groups A and B were 3.55 ± 0.76 months and 8.76 ± 1.85 months, respectively (P < 0.05). The average survival times in groups A and B were 133.5 ± 27.8 days and 252.5 ± 114.5 days, respectively (P < 0.05). There was no statistically significant difference in the incidence of complications between the two groups (P > 0.05). CONCLUSION: Double-strand 125I seeds radiotherapy biliary drainage tubes can safely and effectively control tumors, prolong the patency of biliary stents, and prolong patient survival.

The zone II aorta is not a forbidden zone for occlusion in women with morbidly adherent placenta.

AIM: To evaluate the safety and efficacy of balloon occlusion at the Zone II aorta for the management of morbidly adherent placenta. METHODS: From September 2015 to October 2018, a total of 80 consecutive patients who were prenatally diagnosed with morbidly adherent placenta were assigned into two groups: the balloon occlusion group (n = 40) and the non-balloon occlusion group (n = 40).The intraoperative estimated blood loss, blood transfusion, urine output, serum creatinine, blood urea nitrogen and hysterectomy rate were recorded and compared between the two groups. RESULTS: The estimated blood loss in the balloon occlusion group was significantly lower than that in the non-balloon occlusion group (811.75 ± 299.93 ml vs 1529.75 ± 808.01 ml, P < 0.001). The median amount of packed RBCs transfused in the balloon occlusion group and non-balloon occlusion group was 0 U and 2 U, respectively (P = 0.001). The women in the former group had a lower blood transfusion rate than those in the latter group (30% vs 57.5%, P = 0.013). Hysterectomy occurred in none in the balloon occlusion group but in six patients in the non-balloon occlusion group (P = 0.011). CONCLUSION: The middle abdominal aorta (Zone II) is not a forbidden zone for occlusion as long as the single occlusion time is limited to 15 min. Balloon occlusion at the Zone II aorta can effectively reduce blood loss, transfusion requirements and hysterectomy rates in patients with morbidly adherent placenta.

A novel immune classification reveals distinct immune escape mechanism and genomic alterations: implications for immunotherapy in hepatocellular carcinoma.

BACKGROUND: The tumor immunological microenvironment (TIME) has a prominent impact on prognosis and immunotherapy. However, the heterogeneous TIME and the mechanisms by which TIME affects immunotherapy have not been elucidated in hepatocellular carcinoma (HCC). METHODS: A total of 2195 eligible HCC patients from TCGA and GEO database were collected. We comprehensively explored the different heterogeneous TIME phenotypes and its clinical significance. The potential immune escape mechanisms and what genomic alterations may drive the formation of different phenotypes were further investigated. RESULTS: We identified three phenotypes in HCC: TIME-1, the "immune-deficiency" phenotype, with immune cell depletion and proliferation; TIME-2, the "immune-suppressed" phenotype, with enrichment of immunosuppressive cells; TIME-3, the "immune-activated phenotype", with abundant leukocytes infiltration and immune activation. The prognosis and sensitivity to both sorafenib and immunotherapy differed among the three phenotypes. We also underlined the potential immune escape mechanisms: lack of leukocytes and defective tumor antigen presentation capacity in TIME-1, increased immunosuppressive cells in TIME-2, and rich in immunoinhibitory molecules in TIME-3. The different phenotypes also demonstrated specific genomic events: TIME-1 characterized by TP53, CDKN2A, CTNNB1, AXIN1 and FOXD4 alterations; TIME-2 characterized by significant alteration patterns in the PI3K pathway; TIME-3 characterized by ARID1A mutation. Besides, the TIME index (TI) was proposed to quantify TIME infiltration pattern, and it was a superior prognostic and immunotherapy predictor. A pipeline was developed to classify single patient into one of these three subtypes and calculated the TI. CONCLUSIONS: We identified three TIME phenotypes with different clinical outcomes, immune escape mechanisms and genomic alterations in HCC, which could present strategies for improving the efficacy of immunotherapy. TI as a novel prognostic and immunotherapeutic signature that could guide personalized immunotherapy and clinical management of HCC.

Image-guided microwave ablation of hepatocellular carcinoma (≤5.0 cm): is MR guidance more effective than CT guidance?

BACKGROUND: Given their widespread availability and relatively low cost, percutaneous thermal ablation is commonly performed under the guidance of computed tomography (CT) or ultrasound (US). However, such imaging modalities may be restricted due to insufficient image contrast and limited tumor visibility, which results in imperfect intraoperative treatment or an increased risk of damage to critical anatomical structures. Currently, magnetic resonance (MR) guidance has been proven to be a possible solution to overcome the above shortcomings, as it provides more reliable visualization of the target tumor and allows for multiplanar capabilities, making it the modality of choice. Unfortunately, MR-guided ablation is limited to specialized centers, and the cost is relatively high. Is ablation therapy under MR guidance better than that under CT guidance? This study retrospectively compared the efficacy of CT-guided and MR-guided microwave ablation (MWA) for the treatment of hepatocellular carcinoma (HCC ≤ 5.0 cm). METHODS: In this retrospective study, 47 patients and 54 patients received MWA under the guidance of CT and MR, respectively. The inclusion criteria were a single HCC ≤ 5.0 cm or a maximum of three. The local tumor progression (LTP), overall survival (OS), prognostic factors for local progression, and safety of this technique were assessed. RESULTS: All procedures were technically successful. The complication rates of the two groups were remarkably different with respect to incidences of liver abscess and pleural effusion (P < 0.05). The mean LTP was 44.264 months in the CT-guided group versus 47.745 months in the MR-guided group of HCC (P = 0.629, log-rank test). The mean OS was 56.772 months in the patients who underwent the CT-guided procedure versus 58.123 months in those who underwent the MR-guided procedure (P = 0.630, log-rank test). Multivariate Cox regression analysis further illustrated that tumor diameter (< 3 cm) and the number of lesions (single) were important factors affecting LTP and OS. CONCLUSIONS: Both CT-guided and MR-guided MWA are comparable therapies for the treatment of HCC (< 5 cm), and there was no difference in survival between the two groups. However, MR-guided MWA could reduce the incidence of complications.

Making timely remedial measures after TACE based on the results of cone-beam CT liver perfusion.

OBJECTIVE: To evaluate the feasibility and safety of using cone-beam CT (CBCT) to measure changes in parenchymal blood volume (PBV) of patients with hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE) and to guide microwave ablation (MWA) for residual tumors. METHODS: A retrospective study was performed on 42 patients with HCC who completed TACE and received CBCT-guided perfusion imaging. The residual active lesions after TACE were supplemented with MWA to complete the treatment process according to the residual PBV. The outcomes were analyzed, including PBV changes, interventional-related complications, local tumor progression (LTP) and overall survival (OS). RESULTS: Technical success was achieved in all lesions. Correlation analysis revealed that greater volume of residual PBV after MWA is negatively correlated with LTP. (p = .000); and the decrease of PBV was positively correlated with LTP (p = .000). All adverse events and complications were CTCAE Grade 1/2. After combination treatment, the 1-, 3-, and 5-year LTP-free survival were 97.6%, 69.0% and 15.1%, respectively, with a median LTP of 49.0 months (95% CI:43.129,54.871). Multivariate Cox regression revealed that the residual PBV > 13 ml/1000 was an independent factor predicting a shorter OS and LTP (Both p< .05). For LTP, multivariate Cox regression showed that a tumor in a single lesion were independently predicted to have a longer LTP in patients with HCC (p = .033). CONCLUSION: CBCT is feasible and safe to use to measure changes in the PBV before and after TACE treatment, while it can also guide MWA for the treatment of residual tumors in one session.

Notch1 protects against myocardial ischaemia-reperfusion injury via regulating mitochondrial fusion and function.

Mitochondrial fusion and fission dynamic are critical to the myocardial protection against ischaemia-reperfusion injury. Notch1 signalling plays an important role in heart development, maturation and repair. However, the role of Notch1 in the myocardial mitochondrial fusion and fission dynamic remains elusive. Here, we isolated myocardial cells from rats and established myocardial ischaemia-reperfusion injury (IRI) model. We modulated Notch1, MFN1 and DRP1 expression levels in myocardial cells via infection with recombinant adenoviruses. The results showed that Notch1 improves the cell viability and mitochondrial fusion in myocardiocytes exposed to IRI. These improvements were dependent on the regulation of MFN1 and DRP1. On the mechanism, we found that MNF1 is transcriptionally activated by RBP-Jk in myocardiocytes. Notch1 also improves the mitochondrial membrane potential in myocardiocytes exposed to IRI. Moreover, we further confirmed the protection of the Notch1-MFN1/Drp1 axis on the post-ischaemic recovery of myocardial performance is associated with the preservation of the mitochondrial structure. In conclusion, this study presented a detailed mechanism by which Notch1 signalling improves mitochondrial fusion during myocardial protection.

Curcumin inhibits the growth of triple-negative breast cancer cells by silencing EZH2 and restoring DLC1 expression.

Enhancer of zeste homolog 2 (EZH2), an oncogene, is a commonly up-regulated epigenetic factor in human cancer. Hepatocellular carcinoma deletion gene 1 (DLC1) is an antioncogene that is either expressed at low levels or not expressed in many malignant tumours. Curcumin is a promising anticancer drug that has antitumour effects in many tumours, but its mechanism of action is unclear. Our research demonstrated that EZH2 was up-regulated in breast cancer (BC) tissues and cells, whereas DLC1 was down-regulated, and the expression of EZH2 and DLC1 was negatively correlated in BC. By analysing the characteristics of clinical cases, we found that positive expression of EZH2 and negative expression of DLC1 may be predictors of poor prognosis in patients with triple-negative breast cancer (TNBC). Moreover, knockdown of EZH2 expression restored the expression of DLC1 and inhibited the migration, invasion and proliferation, promoted the apoptosis, and blocked the cell cycle of MDA-MB-231 cells. Furthermore, we found that curcumin restored the expression of DLC1 by inhibiting EZH2; it also inhibited the migration, invasion and proliferation of MDA-MB-231 cells, promoted their apoptosis and blocked the cell cycle. Finally, xenograft tumour models were used to demonstrate that curcumin restored DLC1 expression by inhibiting EZH2 and also inhibited the growth and promoted the apoptosis of TNBC cells. In conclusion, our results suggest that curcumin can inhibit the migration, invasion and proliferation, promote the apoptosis, block the cycle of TNBC cells and restore the expression of DLC1 by inhibiting the expression of EZH2.

Inhibition of the Notch1 pathway induces peripartum cardiomyopathy.

Increased expression and activity of cardiac and circulating cathepsin D and soluble fms-like tyrosine kinase-1 (sFlt-1) have been demonstrated to induce and promote peripartum cardiomyopathy (PPCM) via promoting cleavage of 23-kD prolactin (PRL) to 16-kD PRL and neutralizing vascular endothelial growth factor (VEGF), respectively. We hypothesized that activation of Hes1 is proposed to suppress cathepsin D via activating Stat3, leading to alleviated development of PPCM. In the present study, we aimed to investigate the role of Notch1/Hes1 pathway in PPCM. Pregnant mice between prenatal 3 days and postpartum 3 weeks were fed with LY-411575 (a notch inhibitor, 10 mg/kg/d). Ventricular function and pathology were evaluated by echocardiography and histological analysis. Western blotting analysis was used to examine the expression at the protein level. The results found that inhibition of Notch1 significantly promoted postpartum ventricular dilatation, myocardial hypertrophy and myocardial interstitial fibrosis and suppressed myocardial angiogenesis. Western blotting analysis showed that inhibition of Notch1 markedly increased cathepsin D and sFlt-1, reduced Hes1, phosphorylated Stat3 (p-Stat3), VEGFA and PDGFB, and promoted cleavage of 23k-D PRL to 16-kD PRL. Collectively, inhibition of Notch1/Hes1 pathway induced and promoted PPCM via increasing the expressions of cathepsin D and sFlt-1. Notch1/Hes1 was a promising target for prevention and therapeutic regimen of PPCM.

Notch1-Nrf2 signaling crosstalk provides myocardial protection by reducing ROS formation.

Both the Notch1 and Keap1-Nrf2 signaling pathways have cardioprotective effects, but the role of Notch1-Nrf2 crosstalk in myocardial ischemia-reperfusion injury is unclear. In this study, we established hypoxia-reoxygenation in neonate rat myocardial cells and employed γ-secretase inhibitor and curcumin to inhibit and activate the Notch1 and Keap1-Nrf2 signaling pathways, respectively. We found that the combined action of the Notch1 and Keap1-Nrf2 signaling pathways significantly increased cardiomyocyte viability, inhibited cardiomyocyte apoptosis, reduced the formation of reactive oxygen species, and increased antioxidant activities. In conclusion, these findings suggest that Notch1-Nrf2 crosstalk exerts myocardial protection by reducing the formation of reactive oxygen species.

Curcumin protects cardiomyopathy damage through inhibiting the production of reactive oxygen species in type 2 diabetic mice.

Type 2 diabetes mellitus (DM)-induced cardiomyopathy is a multifactorial and complex disease involving oxidative stress, lipids, and fibrosis. It is based on metabolic disorders and microvascular disease and causes extensive focal necrosis of the heart muscle. Curcumin (CUR) is a natural polyphenol isolated from turmeric rhizomes and plays an important role in the antioxidant, anti-apoptotic and anti-inflammatory effects of diabetes. Therefore, we established a mouse model of diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice in our study. We divided the experiment into three groups: the control group, DM group and DM + CUR group.We performed cardiac dissection on mice treated in different conditions and conducted special pathological staining on isolated cardiac tissue. We were surprised to find that a high glucose environment can promote cardiomyocyte apoptosis by TUNEL assay. In addition, after detecting dihydroethiidine (DHE), hematoxylin-eosin (H&E) and Oil Red O staining, we unexpectedly found that CUR can inhibit the production of reactive oxygen species (ROS), reduce myocardial apoptosis, and myocardial lipid accumulation. CUR upregulated the expression of Bcl-2, and downstream the expression of Bax and Caspase-3 proteins by immunohistochemical determination and western blotting. Therefore, these results suggest that CUR has a certain protective effect on diabetic cardiomyopathy by inhibiting the production of ROS.

NSD2 promotes ventricular remodelling mediated by the regulation of H3K36me2.

Histone lysine methylation plays an important role in the regulation of ventricular remodelling. NSD2 is involved in many types of tumours through enhancing H3K36me2 expression. However, the role of NSD2 in the regulation of histone lysine methylation during ventricular remodelling remains unclear. In this study, we established cardiac hypertrophy model in C57BL/6 mice by transverse aortic constriction and found that histone lysine methylation participated in ventricular remodelling regulation via the up-regulation of H3K27me2 and H3K36me2 expression. In addition, we constructed transgenic C57BL/6 mice with conditional knockout of NSD2 (NSD2-/- ) in the myocardium. NSD2-/- C57BL/6 mice had milder ventricular remodelling and significantly improved cardiac function compared with wild-type mice, and the expression of H3K36me2 but not H3K27me2 was down-regulated. In conclusion, NSD2 promotes ventricular remodelling mediated by the regulation of H3K36me2.

Notch signaling inhibits cardiac fibroblast to myofibroblast transformation by antagonizing TGF-ß1/Smad3 signaling.

PURPOSE: During myocardial infarction (MI), cardiac fibroblasts (CFs) transform into myofibroblast (CMT). This study aimed to investigate the crosstalk of Notch1 and transforming growth factor-ß1 (TGF-ß1)/Smad3 signaling in the regulation of CMT and myocardial fibrosis. METHODS: Primary CFs were isolated from young rats and treated with TGF-ß1 or adenovirus to overexpress or knockdown Notch1 intracellular domain (N1ICD) or Smad3. RESULTS: TGF-ß1 decreased the expression of fibroblast markers but increased the expression of myofibroblast markers in rat CFs. TGF-ß1 increased the proliferation, invasion, and adhesion, and the secretion of collagen I of CFs, and these effects were inhibited by N1ICD overexpression. Moreover, endogenous Smad3 phosphorylation in CFs was enhanced by N1ICD knockdown, whereas TGF-ß1 induced Smad3 phosphorylation was antagonized by the N1ICD overexpression. Conversely, endogenous N1ICD activation in CFs was antagonized by Smad3, whereas TGF-ß1 induced N1ICD inactivation was antagonized by Smad3 knockdown. Coimmunoprecipitation showed that N1ICD interacted with Smad3 and immunostaining revealed the colocalization of N1ICD and Smad3 in the nuclei of CFs. Moreover, we demonstrated the functional antagonism of N1ICD and Smad3 on the phenotypes of CFs. Finally, TGF-ß1/Smad3 signaling promoted whereas Notch signaling inhibited myocardial fibrosis in rat MI model. CONCLUSION: Notch signaling inhibits CMT by antagonizing TGF-ß1/Smad3 signaling. Notch signaling activators and TGF-ß1/Smad3 signaling inhibitors could be exploited for therapeutic intervention to inhibit myocardial fibrosis after MI.