Alcohol reshapes a liver premetastatic niche for cancer by extra- and intrahepatic crosstalk-mediated immune evasion.

Cancer metastatic organotropism is still a mystery. The liver is known to be susceptible to cancer metastasis and alcoholic injury. However, it is unclear whether and how alcohol facilitates liver metastasis and how to intervene. Here, we show that alcohol preferentially promotes liver metastasis in colon-cancer-bearing mice and post-surgery pancreatic cancer patients. The mechanism is that alcohol triggers an extra- and intrahepatic crosstalk to reshape an immunosuppressive liver microenvironment. In detail, alcohol upregulates extrahepatic IL-6 and hepatocellular IL-6 receptor expression, resulting in hepatocyte STAT3 signaling activation and downstream lipocalin-2 (Lcn2) upregulation. Furthermore, LCN2 promotes T cell-exhaustion neutrophil recruitment and cancer cell epithelial plasticity. In contrast, knocking out hepatocellular Stat3 or systemic Il6 in alcohol-treated mice preserves the liver microenvironment and suppresses liver metastasis. This mechanism is reflected in hepatocellular carcinoma patients, in that alcohol-associated signaling elevation in noncancerous liver tissue indicates adverse prognosis. Accordingly, we discover a novel application for BBI608, a small molecular STAT3 inhibitor that can prevent liver metastasis. BBI608 pretreatment protects the liver and suppresses alcohol-triggered premetastatic niche formation. In conclusion, under extra- and intrahepatic crosstalk, the alcoholic injured liver forms a favorable niche for cancer cell metastasis, while BBI608 is a promising anti-metastatic agent targeting such microenvironments.

Pregnancy-induced physiological hypertrophic preconditioning attenuates pathological myocardial hypertrophy by activation of FoxO3a.

Previous studies show a woman's pregnancy is correlated with post-reproductive longevity, and nulliparity is associated with higher risk of incident heart failure, suggesting pregnancy likely exerts a cardioprotection. We previously reported a cardioprotective phenomenon termed myocardial hypertrophic preconditioning, but it is unknown whether pregnancy-induced physiological hypertrophic preconditioning (PHP) can also protect the heart against subsequent pathological hypertrophic stress. We aimed to clarify the phenomenon of PHP and its mechanisms. The pluripara mice whose pregnancy-induced physiological hypertrophy regressed and the nulliparous mice underwent angiotensin II (Ang II) infusion or transverse aortic constriction (TAC). Echocardiography, invasive left ventricular hemodynamic measurement and histological analysis were used to evaluate cardiac remodeling and function. Silencing or overexpression of Foxo3 by adeno-associated virus was used to investigate the role of FoxO3a involved in the antihypertrophic effect. Compared with nulliparous mice, pathological cardiac hypertrophy induced by Ang II infusion, or TAC was significantly attenuated and heart failure induced by TAC was markedly improved in mice with PHP. Activation of FoxO3a was significantly enhanced in the hearts of postpartum mice. FoxO3a inhibited myocardial hypertrophy by suppressing signaling pathway of phosphorylated glycogen synthase kinase-3ß (p-GSK3ß)/ß-catenin/Cyclin D1. Silencing or overexpression of Foxo3 attenuated or enhanced the anti-hypertrophic effect of PHP in mice with pathological stimulation. Our findings demonstrate that PHP confers resistance to subsequent hypertrophic stress and slows progression to heart failure through activation of FoxO3a/GSK3ß pathway.

Reactive oxygen species-induced long intergenic noncoding RNA p21 accelerates abdominal aortic aneurysm formation by promoting secretary smooth muscle cell phenotypes.

Whether long noncoding RNAs participate in the formation of abdominal aortic aneurysms (AAAs) through the regulation of SMC phenotypic switching is unknown. lincRNA-p21 induced by reactive oxygen species (ROS) is likely functionally associated with SMC phenotypic switching. We thus investigated the role of lincRNA-p21 in SMC phenotypic switching-associated AAA formation and its underlying mechanisms. An analysis of human and mouse abdominal aortic samples revealed that the lincRNA-p21 levels were significantly higher in AAA tissue. Stimulation with hydrogen peroxide upregulated the expression of lincRNA-p21 in a dose-dependent manner and converted SMCs from a contractile phenotype to a synthetic, proteolytic, and proinflammatory phenotype in vitro. Moreover, lincRNA-p21 promoted fracture of elastic fibres, reconstruction of the vascular wall, and AAA formation in vivo by modulating SMC phenotypic switching in two mouse models of AAA induced by angiotensin II or porcine pancreatic elastase (PPE) perfusion. Using a bioinformatics prediction method and luciferase reporter gene assays, we further proved that lincRNA-p21 sponged miR-204-5p to release the transcriptional activity of Mekk3 and promoted the NF-κB pathway and thereby played a role in the SMC phenotypic switch and AAA formation. The ROS levels were positively correlated with the lincRNA-p21 levels in human and mouse AAA tissues. The knockdown of lincRNA-p21 in a PPE-induced mouse AAA model increased the miR-204-5p levels and reduced the expression of Mekk3, whereas lincRNA-p21 overexpression had the opposite effect. Collectively, the results indicated that ROS-induced lincRNA-p21 sponges miR-204-5p to accelerate synthetic and proinflammatory SMC phenotypes through the Mekk3/NF-κB pathway in AAA formation. Thus, lincRNA-p21 may have therapeutic potential for AAA formation.

Epigenetic Modification-Associated Molecular Classification of Gastric Cancer.

Epigenetic modification is involved in tumorigenesis and cancer progression. We developed an epigenetic modification-associated molecular classification of gastric cancer (GC) to identify signature genes that accurately predict prognosis and the efficacy of immunotherapy. Least absolute shrinkage and selection operator and multivariate Cox regression analysis were conducted to develop an epigenetic modification-associated molecular classification. We investigated the significance of PIP4P2, an independent prognostic factor of the classification system, in predicting the prognosis and immunotherapy efficacy of patients with GC. The epigenetic modification-associated molecular classification was highly associated with the clinicopathological characteristics of patients and the existing classification of GC. PIP4P2 was highly expressed in GC tissue and tumor-associated macrophages. High PIP4P2 expression in GC tissue-induced tumor progression by activating PI3K/AKT signal transduction had a negative impact on immunotherapy efficacy. High expression of PIP4P2 in macrophages was correlated with poor prognosis in patients with GC. PIP4P2 is an independent unfavorable prognostic factor of epigenetic modification-associated molecular classification, is involved in tumorigenic progression, and is essential for assessing the prognosis and immunotherapy efficacy of GC.

Safety and efficacy of liraglutide on reducing visceral and ectopic fat in adults with or without type 2 diabetes mellitus: A systematic review and meta-analysis.

AIM: To assess the efficacy and safety of liraglutide to reduce visceral and ectopic fat in adults with or without type 2 diabetes mellitus (T2DM). METHODS: Four databases were searched up to 6 May 2022 for randomized clinical trials assessing the effect of liraglutide on visceral and ectopic fat. The mean and standard deviation of the values of visceral fat, ectopic fat and body mass index were calculated. Subgroup analyses were performed based on the type of disease (T2DM or non-T2DM), duration of intervention, dosage of liraglutide and whether life interventions were added to liraglutide therapy. We extracted and integrated the safety assessments reported in each article. RESULTS: Sixteen randomized clinical trials with, in total, 845 participants were included in the meta-analysis. Liraglutide could significantly decrease visceral fat [standard mean difference (SMD) = -0.72, 95% confidence interval (CI; -1.12, -0.33)], liver fat [SMD = -0.78, 95% CI (-1.24, -0.32)] and body mass index [weighted mean difference = -1.44, 95% CI (-1.95, -0.92)] in adult patients with or without T2DM when compared with the control group. However, reduction of epicardial fat by liraglutide [SMD = -0.74, 95% CI (-1.82, 0.34)] was not statistically significant. Subgroup analysis revealed that an adequate dosage (≥1.8 mg/day) and appropriate duration of treatment (ranging from 16 to 40 weeks) were the decisive factors for liraglutide to reduce visceral fat effectively. Mild gastrointestinal reactions were the main adverse event of liraglutide. CONCLUSIONS: Liraglutide significantly and safely reduces visceral and ectopic liver fat irrespective of T2DM status, and reduces visceral fat provided adequate dosage and duration of therapy are ensured.

Delayed PCI is not beneficial for STEMI patients with impaired renal function: a retrospective cohort study.

BACKGROUND: Preexisting impaired renal function (IRF) and contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) are important prognostic parameters, but it is unknown whether delayed PCI is still beneficial for STEMI patients with IRF. METHODS: A retrospective single-center cohort study was performed in 164 patients who presented at least 12 h after symptom onset, and were diagnosed with STEMI and IRF. They were assigned to two groups to receive PCI plus optimal medical therapy (OMT) and OMT alone respectively. Clinical outcomes at 30 days and 1 year were compared between two groups, and hazard ratio for survival was analyzed using Cox regression model. A power analysis demanded 34 patients in each group to produce a power of 90% and a P value of 0.05. RESULTS: The 30-day mortality was significantly lower in PCI group (n = 126) than in non-PCI group (n = 38) (11.1% versus 28.9%, P = 0.018), while there was no significant difference in the 1-year mortality and incidence of cardiovascular comorbidities between the two groups. Cox regression analysis showed that patients with IRF didn't benefit from receiving PCI on survival rate (P = 0.267). CONCLUSIONS: Delayed PCI is not beneficial on one-year clinical outcomes for STEMI patients with IRF.

CircRNA Samd4 induces cardiac repair after myocardial infarction by blocking mitochondria-derived ROS output.

Reactive oxygen species (ROS) derived from oxygen-dependent mitochondrial metabolism are the essential drivers of cardiomyocyte (CM) cell-cycle arrest in adulthood. Mitochondria-localized circular RNAs (circRNAs) play important roles in regulating mitochondria-derived ROS production, but their functions in cardiac regeneration are still unknown. Herein, we investigated the functions and underlying mechanism of mitochondria-localized circSamd4 in cardiac regeneration. We found that circSamd4 was selectively expressed in fetal and neonatal CMs. The transcription factor Nrf2 controlled circSamd4 expression by binding to the promoter of circSamd4 host gene. CircSamd4 overexpression reduced while circSamd4 silenced increased mitochondrial oxidative stress and subsequent oxidative DNA damage. Moreover, circSamd4 overexpression induced CM proliferation and prevented CM apoptosis, which reduced the size of the fibrotic area and improved cardiac function after myocardial infarction (MI). Mechanistically, circSamd4 reduced oxidative stress generation and maintained mitochondrial dynamics by inducing the mitochondrial translocation of the Vcp protein, which downregulated Vdac1 expression and prevented the mitochondrial permeability transition pore (mPTP) from opening. Our findings suggest that circSamd4 is a novel therapeutic target for heart failure after MI.

Circular RNA Cdyl promotes abdominal aortic aneurysm formation by inducing M1 macrophage polarization and M1-type inflammation.

Macrophage polarization plays a crucial role in regulating abdominal aortic aneurysm (AAA) formation. Circular RNAs (circRNAs) are important regulators of macrophage polarization during the development of cardiovascular diseases. How-ever, the roles of circRNAs in regulating AAA formation through modulation of macrophage polarization remain unknown. In the present study, we compared circRNA microarray data under two distinct polarizing conditions (M1 and M2 macrophages) and identified an M1-enriched circRNA, circCdyl. Loss- and gain-of-function assay results demonstrated that circCdyl overexpression accelerated angiotensin II (Ang II)- and calcium chloride (CaCl2)-induced AAA formation by promoting M1 polarization and M1-type inflammation, while circCdyl deficiency showed the opposite effects. RNA pulldown, mass spectrometry analysis, and RNA immunoprecipitation (RIP) assays were conducted to elucidate the underlying mechanisms by which circCdyl regulates AAA formation and showed that circCdyl promotes vascular inflammation and M1 polarization by inhibiting interferon regulatory factor 4 (IRF4) entry into the nucleus, significantly inducing AAA formation. In addition, circCdyl was shown to act as a let-7c sponge, promoting C/EBP-δ expression in macrophages to induce M1 polarization. Our results indicate an important role for circCdyl-mediated macrophage polarization in AAA formation and provide a potent therapeutic target for AAA treatment.

Bioinformatics exploration of potential common therapeutic targets for systemic and pulmonary arterial hypertension-induced myocardial hypertrophy.

Systemic and pulmonary arterial hypertension (PAH) can induce left and right ventricular hypertrophy, respectively, but common therapeutic targets for both left and right hypertrophy are limited. In this study, we attempt to explore potential common therapeutic targets and screen out potential target drugs for further study. Cardiac mRNA expression profiles in mice with transverse aortic constriction (TAC) and pulmonary arterial constriction (PAC) are obtained from online databases. After bioinformatics analyses, we generate TAC and PAC mouse models to validate the phenotypes of cardiac remodelling as well as the identified hub genes. Bioinformatics analyses show that there are 214 independent differentially expressed genes (DEGs) in GSE136308 (TAC related) and 2607 independent DEGs in GSE30922 (PAC related), while 547 shared DEGs are associated with the function of the extracellular matrix (ECM) or involved in the PI3K-Akt signaling pathway, cytokine-cytokine receptor interactions, and ECM-receptor interactions. We identifyd Fn1, Il6, Col1a1, Igf1, Col1a2, Timp1, Col3a1, Cd44, Ctgf and Postn as hub genes of the shared DEGs, and most of them are associated with myocardial fibrosis. Those hub genes and phenotypes of cardiac remodelling are validated in our TAC and PAC mouse models. Furthermore, we identify dehydroisoandrosterone (DHEA), iloprost and 4,5-dianilinophthalimide (DAPH) as potential therapeutic drugs targeting both left and right ventricular hypertrophy and validate the effect of DHEA. These findings suggest that DHEA could be an effective drug for pressure overload-induced left or right ventricular hypertrophy by regulating the shared hub differentially expressed genes associated with fibrosis.

Antihypertrophic Memory After Regression of Exercise-Induced Physiological Myocardial Hypertrophy Is Mediated by the Long Noncoding RNA Mhrt779.

BACKGROUND: Exercise can induce physiological myocardial hypertrophy (PMH), and former athletes can live 5 to 6 years longer than nonathletic controls, suggesting a benefit after regression of PMH. We previously reported that regression of pathological myocardial hypertrophy has antihypertrophic effects. Accordingly, we hypothesized that antihypertrophic memory exists even after PMH has regressed, increasing myocardial resistance to subsequent pathological hypertrophic stress. METHODS: C57BL/6 mice were submitted to 21 days of swimming training to develop PMH. After termination of exercise, PMH regressed within 1 week. PMH regression mice (exercise hypertrophic preconditioning [EHP] group) and sedentary mice (control group) then underwent transverse aortic constriction or a sham operation for 4 weeks. Cardiac remodeling and function were evaluated with echocardiography, invasive left ventricular hemodynamic measurement, and histological analysis. LncRNA sequencing, chromatin immunoprecipitation assay, and comprehensive identification of RNA-binding proteins by mass spectrometry and Western blot were used to investigate the role of Mhrt779 involved in the antihypertrophic effect induced by EHP. RESULTS: At 1 and 4 weeks after transverse aortic constriction, the EHP group showed less increase in myocardial hypertrophy and lower expression of the Nppa and Myh7 genes than the sedentary group. At 4 weeks after transverse aortic constriction, EHP mice had less pulmonary congestion, smaller left ventricular dimensions and end-diastolic pressure, and a larger left ventricular ejection fraction and maximum pressure change rate than sedentary mice. Quantitative polymerase chain reaction revealed that the long noncoding myosin heavy chain-associated RNA transcript Mhrt779 was one of the markedly upregulated lncRNAs in the EHP group. Silencing of Mhrt779 attenuated the antihypertrophic effect of EHP in mice with transverse aortic constriction and in cultured cardiomyocytes treated with angiotensin II, and overexpression enhanced the antihypertrophic effect. Using chromatin immunoprecipitation assay and quantitative polymerase chain reaction, we found that EHP increased histone 3 trimethylation (H3K4me3 and H3K36me3) at the a4 promoter of Mhrt779. Comprehensive identification of RNA-binding proteins by mass spectrometry and Western blot showed that Mhrt779 can bind SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (Brg1) to inhibit the activation of the histone deacetylase 2 (Hdac2)/phosphorylated serine/threonine kinase (Akt)/phosphorylated glycogen synthase kinase 3ß(p-GSK3ß) pathway induced by pressure overload. CONCLUSIONS: Myocardial hypertrophy preconditioning evoked by exercise increases resistance to pathological stress via an antihypertrophic effect mediated by a signal pathway of Mhrt779/Brg1/Hdac2/p-Akt/p-GSK3ß.

Single-cell analysis of a tumor-derived exosome signature correlates with prognosis and immunotherapy response.

BACKGROUND: Tumor-derived exosomes (TEXs) are involved in tumor progression and the immune modulation process and mediate intercellular communication in the tumor microenvironment. Although exosomes are considered promising liquid biomarkers for disease diagnosis, it is difficult to discriminate TEXs and to develop TEX-based predictive biomarkers. METHODS: In this study, the gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) database, IMvigor210 cohorts, and six independent Gene Expression Omnibus datasets. A TEXs-associated signature named TEXscore was established to predict overall survival in multiple cancer types and in patients undergoing immune checkpoint blockade therapies. RESULTS: Based on exosome-associated genes, we first constructed a tumor-derived exosome signature named TEXscore using a principal component analysis algorithm. In single-cell RNA-sequencing data analysis, ascending TEXscore was associated with disease progression and poor clinical outcomes. In the TCGA Pan-Cancer cohort, TEXscore was elevated in tumor samples rather than in normal tissues, thereby serving as a reliable biomarker to distinguish cancer from non-cancer sources. Moreover, high TEXscore was associated with shorter overall survival across 12 cancer types. TEXscore showed great potential in predicting immunotherapy response in melanoma, urothelial cancer, and renal cancer. The immunosuppressive microenvironment characterized by macrophages, cancer-associated fibroblasts, and myeloid-derived suppressor cells was associated with high TEXscore in the TCGA and immunotherapy cohorts. Besides, TEXscore-associated miRNAs and gene mutations were also identified. Further experimental research will facilitate the extending of TEXscore in tumor-associated exosomes. CONCLUSIONS: TEXscore capturing tumor-derived exosome features might be a robust biomarker for prognosis and treatment responses in independent cohorts.

Inhibition of SENP2-mediated Akt deSUMOylation promotes cardiac regeneration via activating Akt pathway.

Post-translational modification (PTM) by small ubiquitin-like modifier (SUMO) is a key regulator of cell proliferation and can be readily reversed by a family of SUMO-specific proteases (SENPs), making SUMOylation an ideal regulatory mechanism for developing novel therapeutic strategies for promoting a cardiac regenerative response. However, the role of SUMOylation in cardiac regeneration remains unknown. In the present study, we assessed whether targeting protein kinase B (Akt) SUMOylation can promote cardiac regeneration. Quantitative PCR and Western blotting results showed that small ubiquitin-like modifier-specific protease 2 (SENP2) is up-regulated during postnatal heart development. SENP2 deficiency promoted P7 and adult cardiomyocyte (CM) dedifferentiation and proliferation both in vitro and in vivo. Mice with SENP2 deficiency exhibited improved cardiac function after MI due to CM proliferation and angiogenesis. Mechanistically, the loss of SENP2 up-regulated Akt SUMOylation levels and increased Akt kinase activity, leading to a decrease in GSK3ß levels and subsequently promoting CM proliferation and angiogenesis. In summary, inhibition of SENP2-mediated Akt deSUMOylation promotes CM differentiation and proliferation by activating the Akt pathway. Our results provide new insights into the role of SUMOylation in cardiac regeneration.

Long-Term Manure Application Changes Bacterial Communities in Rice Rhizosphere and Arsenic Speciation in Rice Grains.

Bioavailability and speciation of arsenic (As) are impacted by fertilization and bacteria in the rice rhizosphere. In this study, we investigated the effects of long-term manure application on As bioavailability, microbial community structure, and functional genes in a rice paddy field. The results showed that manure application did not affect total As in the soil but increased soluble As forms by 19%, increasing arsenite (As(III)) accumulation in rice grains and roots by 34 and 64% compared to a control. A real-time quantitative polymerase chain reaction (qPCR) and high-throughput sequencing analysis demonstrated that manure application increased the relative abundance of Rhizobium, Burkholderia, Sphingobium, and Sphingomonas containing arsenate reductase genes (arsC) in the rhizosphere soil, consistent with the 529% increase in arsC, which may have promoted arsenate (As(V)) reduction and increased As availability in pore water. In addition, manure application significantly altered the iron (Fe)-plaque microbial community structure and diversity. The microbes, particularly, Bradyrhizobium, Burkholderia, and Ralstonia, were mostly associated with As, Fe, and sulfur (S) cycles. This result was consistent with changes in the functional genes related to As, Fe, and S transformation. Although manure application promoted As(V) reduction (arsC) in Fe-plaque by 682%, it inhibited Fe and S reduction by decreasing FeIII reduction bacteria (Geobacteraceae) and the sulfate-reducing gene (dsrA) abundance. Further, manure application changed the composition of the microbial community that contained the arsC gene. In short, caution needs to be excised even in the soil with a low As concentration as manure application increased As(III) accumulation in rice grains.

CircSEC24A promotes tumor progression through sequestering miR-455-3p in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) ranks third in the cause of death due to cancer. Circular RNA circSEC24 Homolog A (circSEC24A) has been uncovered to be upregulated in liver cancer. However, the function of circSEC24A in HCC is indistinct. We analyzed the microarray datasets GSE78520 and GSE94508 to search for differentially expressed circRNAs associated with HCC. Expression of circSEC24A, microRNA (miR)-455-3p, and protein phosphatase, Mg2+/Mn2+ dependent 1F (PPM1F) mRNA was detected by quantitative real-time polymerase chain reaction (RT-qPCR). Loss-of-function experiments were conducted to validate the biological function of circSEC24A in HCC cells in vitro and in vivo. Protein levels were evaluated by western blotting and immunohistochemistry (IHC). The relationship between circSEC24A or PPM1F and miR-455-3p was verified by a dual-luciferase reporter and/or RNA immunoprecipitation (RIP) assays. circSEC24A was overexpressed in HCC. circSEC24A silencing decreased xenograft tumor growth in vivo and repressed proliferation, metastasis, invasion, epithelial-to-mesenchymal transition (EMT), induced cell cycle arrest, and apoptosis of HCC cells in vitro. circSEC24A acted as a molecular sponge to sequester miR-455-3p, resulting in elevating the expression of PPM1F. miR-455-3p inhibitor reversed the suppressive impact of circSEC24A silencing on malignant behaviors of HCC cells. PPM1F overexpression offsets the inhibitory effect of miR-455-3p mimic on malignant behaviors of HCC cells. circSEC24A sponged miR-455-3p to elevate the PPM1F expression, resulting in accelerating malignant behaviors of HCC cells. The study provided a potential therapeutic target for patients with HCC.

Differences in the clinical presentation, management, and in-hospital outcomes of acute aortic dissection in patients with and without end-stage renal disease.

BACKGROUND: Few studies have evaluated the clinical presentation, management, and outcomes of patients with end-stage renal disease (ESRD) presenting with acute aortic dissection (AAD) in real-world clinical practice. Thus, this study investigated the clinical characteristics, management, and outcomes of AAD patients with ESRD. METHODS: A total of 217 patients were included. We evaluated the differences in the clinical features, management, and in-hospital outcomes of patients with and without a history of ESRD presenting with AAD. RESULTS: A history of ESRD was present in 71 of 217 patients. Patients with ESRD had atypical clinical manifestations (p < 0.001) and were more likely to be managed medically compared with patients without ESRD (p = 0.002). Hypertension and type B aortic dissection were significantly more common among patients with ESRD. Moreover, patients with ESRD had lower leucocyte and platelet counts than patients without ESRD in laboratory findings (p < 0.001). However, hospitalization days and in-hospital mortality were similar between the two groups (p > 0.05). Multivariate analysis identified Type A aortic dissection as an independent predictor of in-hospital mortality among patients without ESRD (OR, 13.68; 95% CI, 1.92 to 98.90; P = 0.006). CONCLUSIONS: This study highlights differences in the clinical characteristics, management, and outcomes of AAD patients with ESRD. These patients usually have atypical symptoms and more comorbid conditions and are managed more conservatively. However, these patients have no in-hospital survival disadvantage over those without ESRD. Further studies are needed to better understand and optimize care for patients with ESRD presenting with AAD.

Dabigatran ameliorates airway smooth muscle remodeling in asthma by modulating Yes-associated protein.

Accumulating evidence indicates that thrombin, the major effector of the coagulation cascade, plays an important role in the pathogenesis of asthma. Interestingly, dabigatran, a drug used in clinical anticoagulation, directly inhibits thrombin activity. The aim of this study was to investigate the effects and mechanisms of dabigatran on airway smooth muscle remodeling in vivo and in vitro. Here, we found that dabigatran attenuated inflammatory pathology, mucus production, and collagen deposition in the lungs of asthmatic mice. Additionally, dabigatran suppressed Yes-associated protein (YAP) activation in airway smooth muscle of asthmatic mice. In human airway smooth muscle cells (HASMCs), dabigatran not only alleviated thrombin-induced proliferation, migration and up-regulation of collagen I, α-SMA, CTGF and cyclin D1, but also inhibited thrombin-induced YAP activation, while YAP activation mediated thrombin-induced HASMCs remodeling. Mechanistically, thrombin promoted actin stress fibre polymerization through the PAR1/RhoA/ROCK/MLC2 axis to activate YAP and then interacted with SMAD2 in the nucleus to induce downstream target genes, ultimately aggravating HASMCs remodeling. Our study provides experimental evidence that dabigatran ameliorates airway smooth muscle remodeling in asthma by inhibiting YAP signalling, and dabigatran may have therapeutic potential for the treatment of asthma.

A stroma-related lncRNA panel for predicting recurrence and adjuvant chemotherapy benefit in patients with early-stage colon cancer.

The heterogeneity in prognoses and chemotherapeutic responses of colon cancer patients with similar clinical features emphasized the necessity for new biomarkers that help to improve the survival prediction and tailor therapies more rationally and precisely. In the present study, we established a stroma-related lncRNA signature (SLS) based on 52 lncRNAs to comprehensively predict clinical outcome. The SLS model could not only distinguish patients with different recurrence and mortality risks through univariate analysis, but also served as an independent factor for relapse-free and overall survival. Compared with the conventionally used TNM stage system, the SLS model clearly possessed higher predictive accuracy. Moreover, the SLS model also effectively screened chemotherapy-responsive patients, as only patients in the low-SLS group could benefit from adjuvant chemotherapy. The following cell infiltration and competing endogenous RNA (ceRNA) network functional analyses further confirmed the association between the SLS model and stromal activation-related biological processes. Additionally, this study also identified three phenotypically distinct colon cancer subtypes that varied in clinical outcome and chemotherapy benefits. In conclusion, our SLS model may be a significant determinant of survival and chemotherapeutic decision-making in colon cancer and may have a strong clinical transformation value.

Loss of Super-Enhancer-Regulated circRNA Nfix Induces Cardiac Regeneration After Myocardial Infarction in Adult Mice.

BACKGROUND: circRNAs (circular RNAs) are emerging as powerful regulators of cardiac development and disease, but their roles in cardiac regeneration are still unknown. This study used superenhancers to distinguish key circRNAs in the regulation of cardiac regeneration and explored the mechanisms underlying circRNA functions. METHODS: We used integrated bioinformatics analysis of RNA sequencing data and superenhancer catalogs to identify superenhancer-associated circRNAs. Quantitative polymerase chain reactions and in situ hybridization were performed to determine the circRNA expression patterns in hearts. Gain- and loss-of-function assays were conducted to detect the role of circRNAs in cardiomyocyte proliferation and cardiac repair after myocardial infarction. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays were used to determine the binding of Meis1 (Meis homeobox 1) on circNfix-associated superenhancers. RNA pulldown and luciferase reporter assays were used to study circRNA interactions with proteins and miRNAs (micro RNAs). RESULTS: We identified a circRNA, Nfix circRNA (circNfix), that was regulated by a superenhancer and overexpressed in the adult heart in humans, rats, and mice. The transcription factor Meis1 bound to the superenhancer at the circNfix locus, and increased its expression. In vitro and in vivo, cardiomyocyte proliferation was increased by knockdown of circNfix, whereas it was inhibited by circNfix overexpression. Moreover, circNfix downregulation promoted cardiomyocyte proliferation and angiogenesis and inhibited cardiomyocyte apoptosis after myocardial infarction, attenuating cardiac dysfunction and improving the prognosis. Mechanistically, circNfix reinforced the interaction of Ybx1 (Y-box binding protein 1) with Nedd4l (an E3 ubiquitin ligase), and induced Ybx1 degradation through ubiquitination, repressing cyclin A2 and cyclin B1 expression. In addition, circNfix acted as a sponge for miR-214 to promote Gsk3ß (glycogen synthase kinase 3 ß) expression and repress ß-catenin activity. CONCLUSIONS: Loss of superenhancer-regulated circNfix promotes cardiac regenerative repair and functional recovery after myocardial infarction by suppressing Ybx1 ubiquitin-dependent degradation and increasing miR-214 activity and thus may be a promising strategy for improving the prognosis after MI.

SM22α (Smooth Muscle 22α) Prevents Aortic Aneurysm Formation by Inhibiting Smooth Muscle Cell Phenotypic Switching Through Suppressing Reactive Oxygen Species/NF-κB (Nuclear Factor-κB).

Objective- Vascular smooth muscle cell phenotypic transition plays a critical role in the formation of abdominal aortic aneurysms (AAAs). SM22α (smooth muscle 22α) has a vital role in maintaining the smooth muscle cell phenotype and is downregulated in AAA. However, whether manipulation of the SM22α gene influences the pathogenesis of AAA is unclear. Here, we investigated whether SM22α prevents AAA formation and explored the underlying mechanisms. Approach and Results- In both human and animal AAA tissues, a smooth muscle cell phenotypic switch was confirmed, as manifested by the downregulation of SM22α and α-SMA (α-smooth muscle actin) proteins. The methylation level of the SM22α gene promoter was dramatically higher in mouse AAA tissues than in control tissues. SM22α knockdown in ApoE-/- (apolipoprotein E-deficient) mice treated with Ang II (angiotensin II) accelerated the formation of AAAs, as evidenced by a larger maximal aortic diameter and more medial elastin degradation than those found in control mice, whereas SM22α overexpression exerted opposite effects. Similar results were obtained in a calcium chloride-induced mouse AAA model. Mechanistically, SM22α deficiency significantly increased reactive oxygen species production and NF-κB (nuclear factor-κB) activation in AAA tissues, whereas SM22α overexpression produced opposite effects. NF-κB antagonist SN50 or antioxidant N-acetyl-L-cysteine partially abrogated the exacerbating effects of SM22α silencing on AAA formation. Conclusions- SM22α reduction in AAAs because of the SM22α promoter hypermethylation accelerates AAA formation through the reactive oxygen species/NF-κB pathway, and therapeutic approaches to increase SM22α expression are potentially beneficial for preventing AAA formation.

miR-577 Regulates TGF-ß Induced Cancer Progression through a SDPR-Modulated Positive-Feedback Loop with ERK-NF-κB in Gastric Cancer.

Transforming growth factor ß (TGF-ß) drives epithelial-mesenchymal transition (EMT), playing vital roles in cancer metastasis. The crosstalk between microRNAs (miRNAs) and TGF-ß are frequently observed and involved in TGF-ß-induced EMT. Here, we determine that miR-577 is significantly upregulated in gastric cancer (GC). miR-577 expression is positively correlated with GC metastasis status and poor patient prognosis. Functional assays demonstrate that miR-577 promotes metastasis and chemoresistance by inducing EMT and stemness-like properties. Moreover, TGF-ß promotes the expression of miR-577, and miR-577 participates TGF-ß-mediated cancer metastasis. Mechanistically, TGF-ß activates miR-577 via NF-κB-mediated transcription, and miR-577 enhances TGF-ß signaling by targeting the serum deprivation protein response (SDPR), which directly interacts with ERK to inactivate the ERK-NF-κB pathway, hence forming a feedback loop to drive tumor metastasis. A plausible mechanism of EMT induction by the TGF-ß network is elucidated. Our findings suggest that the TGF-ß-miR-577-SDPR axis may be a potential prognostic marker and therapeutic target against cancer metastasis in GC.