ABSTRACT
The complex etiological factors associated with metabolic dysfunction-associated fatty liver disease (MAFLD), including perturbed iron homeostasis, and the unclear nature by which they contribute to disease progression have resulted in a limited number of effective therapeutic interventions. Here, we report that patients with metabolic dysfunction-associated steatohepatitis (MASH), a pathological subtype of MAFLD, exhibit excess hepatic iron and that it has a strong positive correlation with disease progression. FerroTerminator1 (FOT1) effectively reverses liver injury across multiple MASH models without notable toxic side effects compared with clinically approved iron chelators. Mechanistically, our multi-omics analyses reveal that FOT1 concurrently inhibits hepatic iron accumulation and c-Myc-Acsl4-triggered ferroptosis in various MASH models. Furthermore, MAFLD cohort studies suggest that serum ferritin levels might serve as a predictive biomarker for FOT1-based therapy in MASH. These findings provide compelling evidence to support FOT1 as a promising novel therapeutic option for all stages of MAFLD and for future clinical trials.
ABSTRACT
To date, nearly one-quarter of colorectal cancer (CRC) patients develop liver metastases (CRCLM), and its aggressiveness can be correlated to defined histopathological growth patterns (HGP). From the three main HGPs within CRCLM, the replacement HGP emerges as particularly aggressive, characterized by heightened tumor cell motility and vessel co-option. Here, we investigated the correlation between the expression of calcium- and integrin-binding protein 1 (CIB1), a ubiquitously expressed gene involved in various cellular processes including migration and adhesion, and disease-free (DFS) and overall survival (OS) in primary CRC patients. Additionally, we explored the correlation between CIB1 expression and different HGPs of CRCLM. Proteomic analysis was used to evaluate CIB1 expression in a cohort of 697 primary CRC patients. Additionally, single-cell and spatial RNA-sequencing datasets, along with publicly available bulk sequencing data were used to evaluate CIB1 expression in CRCLM. In silico data were further validated by formalin-fixed paraffin-embedded immunohistochemical stainings. We observed that high CIB1 expression is independently associated with worse DFS and OS, regardless of Union Internationale Contre le Cancer stage, gender, or age. Furthermore, the aggressive replacement CRCLM HGP is significantly associated with high CIB1 expression. Our findings show a correlation between CIB1 levels and the clinical aggressiveness of CRC. Moreover, CIB1 may be a novel marker to stratify HGP CRCLM.
ABSTRACT
Calcific aortic valve disease (CAVD) is becoming an increasingly important global medical problem, but effective pharmacological treatments are lacking. Noncoding RNAs play a pivotal role in the progression of cardiovascular diseases, but their relationship with CAVD remains unclear. Sequencing data revealed differential expression of many noncoding RNAs in normal and calcified aortic valves, with significant differences in circHIPK3 and miR-182-5p expression. Overexpression of circHIPK3 ameliorated aortic valve lesions in a CAVD mouse model. In vitro experiments demonstrated that circHIPK3 inhibits the osteogenic response of aortic valve interstitial cells. Mechanistically, DEAD-box helicase 5 (DDX5) recruits methyltransferase 3 (METTL3) to promote the N6-methyladenosine (m6A) modification of circHIPK3. Furthermore, m6A-modified circHIPK3 increases the stability of Kremen1 (Krm1) mRNA, and Krm1 is a negative regulator of the Wnt/ß-catenin pathway. Additionally, miR-182-5p suppresses the expression of Dickkopf2 (Dkk2), the ligand of Krm1, and attenuates the Krm1-mediated inhibition of Wnt signaling. Activation of the Wnt signaling pathway significantly contributes to the promotion of aortic valve calcification. Our study describes the role of the Krm1-Dkk2 axis in inhibiting Wnt signaling in aortic valves and suggests that noncoding RNAs are upstream regulators of this process.
Subject(s)
Aortic Valve Stenosis , Aortic Valve , Calcinosis , Gene Expression Regulation , Intercellular Signaling Peptides and Proteins , MicroRNAs , Animals , Intercellular Signaling Peptides and Proteins/metabolism , Intercellular Signaling Peptides and Proteins/genetics , Aortic Valve/pathology , Aortic Valve/metabolism , Mice , Calcinosis/genetics , Calcinosis/metabolism , Calcinosis/pathology , Aortic Valve Stenosis/genetics , Aortic Valve Stenosis/metabolism , Aortic Valve Stenosis/pathology , MicroRNAs/genetics , MicroRNAs/metabolism , Wnt Signaling Pathway , Disease Models, Animal , Membrane Proteins/genetics , Membrane Proteins/metabolism , Humans , Methyltransferases/metabolism , Methyltransferases/genetics , RNA, Circular/genetics , RNA, Circular/metabolism , MaleABSTRACT
BACKGROUND: Aortic stenosis (AS) is one of the most common cardiac diseases and major cause of morbidity and mortality in the elderly. Transcatheter aortic valve implantation (TAVI) is performed in such patients with symptomatic severe AS and reduces mortality for the majority of these patients. However, a significant percentage dies within the first two years after TAVI, such that there is an interest to identify parameters, which predict outcome and could guide pre-TAVI patient selection. High levels of cardiac fibrosis have been identified as such independent predictor of cardiovascular mortality after TAVI. Promoter hypermethylation commonly leads to gene downregulation, and the Iroquois homeobox 3 (IRX3) gene was identified in a genome-wide transcriptome and methylome to be hypermethylated and downregulated in AS patients. In a well-described cohort of 100 TAVI patients in which cardiac fibrosis levels were quantified histologically in cardiac biopsies, and which had a follow-up of up to two years, we investigated if circulating methylated DNA of IRX3 in the peripheral blood is associated with cardiac fibrosis and/or mortality in AS patients undergoing TAVI and thus could serve as a biomarker to add information on outcome after TAVI. RESULTS: Patients with high levels of methylation in circulating IRX3 show a significantly increased survival as compared to patients with low levels of IRX3 methylation indicating that high peripheral IRX3 methylation is associated with an improved outcome. In the multivariable setting, peripheral IRX3 methylation acts as an independent predictor of all-cause mortality. While there is no significant correlation of levels of IRX3 methylation with cardiac death, there is a significant but very weak inverse correlation between circulating IRX3 promoter methylation level and the amount of cardiac fibrosis. Higher levels of peripheral IRX3 methylation further correlated with decreased cardiac IRX3 expression and vice versa. CONCLUSIONS: High levels of IRX3 methylation in the blood of AS patients at the time of TAVI are associated with better overall survival after TAVI and at least partially reflect myocardial IRX3 expression. Circulating methylated IRX3 might aid as a potential biomarker to help guide both pre-TAVI patient selection and post-TAVI monitoring.
Subject(s)
Aortic Valve Stenosis , Cell-Free Nucleic Acids , Transcatheter Aortic Valve Replacement , Humans , Aortic Valve Stenosis/genetics , Aortic Valve Stenosis/surgery , Biopsy , DNA Methylation , Homeodomain Proteins/genetics , Transcatheter Aortic Valve Replacement/adverse effects , Transcription Factors/geneticsABSTRACT
BACKGROUND: Calcific aortic valve disease (CAVD) is the most prevalent valvular disease and has high morbidity and mortality. CAVD is characterized by complex pathophysiological processes, including inflammation-induced osteoblastic differentiation in aortic valve interstitial cells (AVICs). Novel anti-CAVD agents are urgently needed. Protein tyrosine phosphatase nonreceptor type 22 (PTPN22), an intracellular nonreceptor-like protein tyrosine phosphatase, is involved in several chronic inflammatory diseases, including rheumatoid arthritis and diabetes. However, it is unclear whether PTPN22 is involved in the pathogenesis of CAVD. METHODS: We obtained the aortic valve tissue from human and cultured AVICs from aortic valve. We established CAVD mice model by wire injury. Transcriptome sequencing, western bolt, qPCR, and immunofluorescence were performed to elucidate the molecular mechanisms. RESULTS: Here, we determined that PTPN22 expression was upregulated in calcific aortic valve tissue, AVICs treated with osteogenic medium, and a mouse model of CAVD. In vitro, overexpression of PTPN22 induced osteogenic responses, whereas siRNA-mediated PTPN22 knockdown abolished osteogenic responses and mitochondrial stress in the presence of osteogenic medium. In vivo, PTPN22 ablation ameliorated aortic valve lesions in a wire injury-induced CAVD mouse model, validating the pathogenic role of PTPN22 in CAVD. Additionally, we discovered a novel compound, 13-hydroxypiericidin A 10-O-α-D-glucose (1 â 6)-ß-D-glucoside (S18), in a marine-derived Streptomyces strain that bound to PTPN22 with high affinity and acted as a novel inhibitor. Incubation with S18 suppressed osteogenic responses and mitochondrial stress in human AVICs induced by osteogenic medium. In mice with aortic valve injury, S18 administration markedly alleviated aortic valve lesions. CONCLUSION: PTPN22 plays an essential role in the progression of CAVD, and inhibition of PTPN22 with S18 is a novel option for the further development of potent anti-CAVD drugs. Therapeutic inhibition of PTPN22 retards aortic valve calcification through modulating mitochondrial dysfunction in AVICs.
Subject(s)
Aortic Valve Stenosis , Aortic Valve , Humans , Animals , Mice , Aortic Valve/metabolism , Aortic Valve/pathology , Phosphoric Monoester Hydrolases , Aortic Valve Stenosis/drug therapy , Aortic Valve Stenosis/genetics , Cells, Cultured , Protein Tyrosine Phosphatase, Non-Receptor Type 22/metabolismABSTRACT
Luminescent reporters are due to their intrinsically high signal-to-noise ratio a powerful labelling tool for microscopy and macroscopic in vivo imaging in biomedical research. However, luminescence signal detection requires longer exposure times than fluorescence imaging and is consequently less suited for applications requiring high temporal resolution or throughput. Here we demonstrate that content aware image restoration can drastically reduce the exposure time requirements in luminescence imaging, thus overcoming one of the major limitations of the technique.
Subject(s)
Luminescence , Microscopy , Microscopy/methodsABSTRACT
Left ventricular (LV) dilatation, a prominent risk factor for heart failure (HF), precedes functional deterioration and is used to stratify patients at risk for arrhythmias and cardiac mortality. Aberrant DNA methylation contributes to maladaptive cardiac remodeling and HF progression following pressure overload and ischemic cardiac insults. However, no study has examined cardiac DNA methylation upon exposure to volume overload (VO) despite being relatively common among HF patients. We carried out global methylome analysis of LV harvested at a decompensated HF stage following exposure to VO induced by aortocaval shunt. VO resulted in pathological cardiac remodeling, characterized by massive LV dilatation and contractile dysfunction at 16 weeks after shunt. Although methylated DNA was not markedly altered globally, 25 differentially methylated promoter regions (DMRs) were identified in shunt vs. sham hearts (20 hypermethylated and 5 hypomethylated regions). The validated hypermethylated loci in Junctophilin-2 (Jph2), Signal peptidase complex subunit 3 (Spcs3), Vesicle-associated membrane protein-associated protein B (Vapb), and Inositol polyphosphate multikinase (Ipmk) were associated with the respective downregulated expression and were consistently observed in dilated LV early after shunt at 1 week after shunt, before functional deterioration starts to manifest. These hypermethylated loci were also detected peripherally in the blood of the shunt mice. Altogether, we have identified conserved DMRs that could be novel epigenetic biomarkers in dilated LV upon VO exposure.
Subject(s)
DNA Methylation , Heart Failure , Mice , Animals , Ventricular Remodeling/genetics , Heart , Heart Failure/metabolism , Cardiomegaly/genetics , Epigenesis, GeneticABSTRACT
BACKGROUND: The prevalence of diabetes mellitus has risen considerably and currently affects more than 422 million people worldwide. Cardiovascular diseases including myocardial infarction and heart failure represent the major cause of death in type 2 diabetes (T2D). Diabetes patients exhibit accelerated aortic stiffening which is an independent predictor of cardiovascular disease and mortality. We recently showed that aortic stiffness precedes hypertension in a mouse model of diabetes (db/db mice), making aortic stiffness an early contributor to cardiovascular disease development. Elucidating how aortic stiffening develops is a pressing need in order to halt the pathophysiological process at an early time point. METHODS: To assess EndMT occurrence, we performed co-immunofluorescence staining of an endothelial marker (CD31) with mesenchymal markers (α-SMA/S100A4) in aortic sections from db/db mice. Moreover, we performed qRT-PCR to analyze mRNA expression of EndMT transcription factors in aortic sections of db/db mice and diabetic patients. To identify the underlying mechanism by which EndMT contributes to aortic stiffening, we used aortas from db/db mice and diabetic patients in combination with high glucose-treated human umbilical vein endothelial cells (HUVECs) as an in vitro model of diabetes-associated EndMT. RESULTS: We demonstrate robust CD31/α-SMA and CD31/S100A4 co-localization in aortic sections of db/db mice which was almost absent in control mice. Moreover, we demonstrate a significant upregulation of EndMT transcription factors in aortic sections of db/db mice and diabetic patients. As underlying regulator, we identified miR-132-3p as the most significantly downregulated miR in the micronome of db/db mice and high glucose-treated HUVECs. Indeed, miR-132-3p was also significantly downregulated in aortic tissue from diabetic patients. We identified Kruppel-like factor 7 (KLF7) as a target of miR-132-3p and show a significant upregulation of KLF7 in aortic sections of db/db mice and diabetic patients as well as in high glucose-treated HUVECs. We further demonstrate that miR-132-3p overexpression and KLF7 downregulation ameliorates EndMT in high glucose-treated HUVECs. CONCLUSIONS: We demonstrate for the first time that EndMT contributes to aortic stiffening in T2D. We identified miR-132-3p and KLF7 as novel EndMT regulators in this context. Altogether, this gives us new insights in the development of aortic stiffening in T2D.
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BACKGROUND: Colorectal cancer liver metastases (CRCLM) are associated with a poor prognosis, reflected by a five-year survival rate of 14%. Anti-angiogenic therapy through anti-VEGF antibody administration is one of the limited therapies available. However, only a subgroup of metastases uses sprouting angiogenesis to secure their nutrients and oxygen supply, while others rely on vessel co-option (VCO). The distinct mode of vascularization is reflected by specific histopathological growth patterns (HGPs), which have proven prognostic and predictive significance. Nevertheless, their molecular mechanisms are poorly understood. METHODS: We evaluated CRCLM from 225 patients regarding their HGP and clinical data. Moreover, we performed spatial (21,804 spots) and single-cell (22,419 cells) RNA sequencing analyses to explore molecular differences in detail, further validated in vitro through immunohistochemical analysis and patient-derived organoid cultures. RESULTS: We detected specific metabolic alterations and a signature of WNT signalling activation in metastatic cancer cells related to the VCO phenotype. Importantly, in the corresponding healthy liver of CRCLM displaying sprouting angiogenesis, we identified a predominantly expressed capillary subtype of endothelial cells, which could be further explored as a possible predictor for HGP relying on sprouting angiogenesis. CONCLUSION: These findings may prove to be novel therapeutic targets to the treatment of CRCLM, in special the ones relying on VCO.
Subject(s)
Colorectal Neoplasms , Liver Neoplasms , Humans , Endothelial Cells/pathology , Liver Neoplasms/genetics , Neovascularization, Pathologic/pathology , Colorectal Neoplasms/pathologyABSTRACT
Metastatic pancreatic cancer (PDAC) has a poor clinical outcome with a 5-year survival rate below 3%. Recent transcriptome profiling of PDAC biopsies has identified 2 clinically distinct subtypes - the "basal-like" (BL) subtype with poor prognosis and therapy resistance compared with the less aggressive and drug-susceptible "classical" (CLA) subtype. However, the mechanistic events and environmental factors that promote the BL subtype identity are not very clear. Using preclinical models, patient-derived xenografts, and FACS-sorted PDAC patient biopsies, we report here that the axon guidance receptor, roundabout guidance receptor 3 (ROBO3), promotes the BL metastatic program via a potentially unique AXL/IL-6/phosphorylated STAT3 (p-STAT3) regulatory axis. RNA-Seq identified a ROBO3-mediated BL-specific gene program, while tyrosine kinase profiling revealed AXL as the key mediator of the p-STAT3 activation. CRISPR/dCas9-based ROBO3 silencing disrupted the AXL/p-STAT3 signaling axis, thereby halting metastasis and enhancing therapy sensitivity. Transcriptome analysis of resected patient tumors revealed that AXLhi neoplastic cells associated with the inflammatory stromal program. Combining AXL inhibitor and chemotherapy substantially restored a CLA phenotypic state and reduced disease aggressiveness. Thus, we conclude that a ROBO3-driven hierarchical network determines the inflammatory and prometastatic programs in a specific PDAC subtype.
Subject(s)
Axon Guidance , Pancreatic Neoplasms , Receptors, Cell Surface , Axon Guidance/genetics , Axon Guidance/physiology , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Humans , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Prognosis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Axl Receptor Tyrosine KinaseABSTRACT
Calcific aortic valve disease (CAVD) is a valvular disease frequently in the elderly individuals that can lead to the valve dysfunction. Osteoblastic differentiation of human aortic valve interstitial cells (HAVICs) induced by inflammation play a crucial role in CAVD pathophysiological processes. To date, no effective drugs for CAVD have been established, and new agents are urgently needed. Piericidin glycosides, obtained from a marine-derived Streptomyces strain, were revealed to have regulatory effects on mitochondria in previous studies. Here, we discovered that 13-hydroxypiericidin A 10-O-α-D-glucose (1â6)-ß-D-glucoside (S18), a specific piericidin diglycoside, suppresses lipopolysaccharide- (LPS) induced inflammatory responses of HAVICs by alleviating mitochondrial stress in an interleukin (IL)-37-dependent manner. Knockdown of IL-37 by siRNA not only exaggerated LPS-induced HAVIC inflammation and mitochondrial stress but also abrogated the anti-inflammatory effect of S18 on HAVICs. Moreover, S18 alleviated aortic valve lesions in IL-37 transgenic mice of CAVD model. Microscale thermophoresis (MST) and docking analysis of five piericidin analogues suggested that diglycosides, but not monoglycosides, exert obvious IL-37-binding activity. These results indicate that S18 directly binds to IL-37 to alleviate inflammatory responses in HAVICs and aortic valve lesions in mice. Piericidin diglycoside S18 is a potential therapeutic agent to prevent the development of CAVD.
Subject(s)
Aortic Valve Stenosis , Aortic Valve , Glycosides , Interleukin-1 , Animals , Aortic Valve/pathology , Calcinosis , Cells, Cultured , Glycosides/pharmacology , Humans , Inflammation , Interleukin-1/metabolism , Interleukins , Lipopolysaccharides , MiceABSTRACT
OBJECTIVE: To evaluate the association between serum galectin-3 and all-cause death (ACD) and cardiovascular death (CVD) in patients with chronic heart failure (CHF). METHODS: The PubMed and Embase databases and Clinical Trials Registry (www.clinicaltrials.gov) were searched for studies with data on serum galectin-3 and ACD and CVD in CHF patients. The hazard ratios (HRs) of ACD and CVD were calculated and presented with 95% CIs. HRs were pooled using fixed effects or random effects models when appropriate. Sensitivity analysis, meta-regression and subgroup analysis were applied to find the origin of heterogeneity. Visual inspection of Begg's funnel plot and Egger's test were performed to assess the possibility publication bias. RESULTS: Pooled data included the results from 6,440 patients from 12 studies in the meta-analysis. Higher serum galectin-3 was associated with a higher risk of ACD (HR, 1.38; 95% CI, 1.14-1.67) and CVD (HR, 1.13; 95% CI, 1.02-1.25) in CHF patients. In the subgroup analyses, higher serum galectin-3 was associated with an increased risk of ACD in all subgroups. The pooled HR of the shorter follow-up group (1.78; 95% CI, 1.50-2.11) was significantly higher than the pooled HR of the longer follow-up group (1.15; 95% CI, 1.05-1.25). Sensitivity analysis of eliminating one study in each turn indicated that Koukoui et al.'s study had the largest influence on the risk of all-cause death. All-cause death publication bias was not detected (Pr>|z| = 0.35 for Begg's test and P>|t| = 0.15 for Egger's test). CONCLUSIONS: Serum galectin-3 has prognostic value of both all-cause death and cardiovascular death in CHF. Serum galectin-3 could be useful for risk classification in patients with CHF. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=193399.
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In mammals, histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Among these enzymes, SETD1B (SET domain containing 1b) has been linked to syndromic intellectual disability in human subjects, but its role in the mammalian postnatal brain has not been studied yet. Here, we employ mice deficient for Setd1b in excitatory neurons of the postnatal forebrain, and combine neuron-specific ChIP-seq and RNA-seq approaches to elucidate its role in neuronal gene expression. We observe that Setd1b controls the expression of a set of genes with a broad H3K4me3 peak at their promoters, enriched for neuron-specific genes linked to learning and memory function. Comparative analyses in mice with conditional deletion of Kmt2a and Kmt2b histone methyltransferases show that SETD1B plays a more pronounced and potent role in regulating such genes. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B-dependent regulation of H3K4me levels in postnatal neurons is critical for cognitive function.
Subject(s)
Gene Expression Regulation , Histone-Lysine N-Methyltransferase/metabolism , Learning/physiology , Neurons/metabolism , Animals , Animals, Newborn , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cell Nucleus/metabolism , Epigenesis, Genetic , Hippocampus/metabolism , Histone-Lysine N-Methyltransferase/genetics , Histones/metabolism , Integrases/metabolism , Memory/physiology , Mice, Inbred C57BL , Mice, Knockout , Myeloid-Lymphoid Leukemia Protein/metabolism , Transcription Initiation Site , Transcriptome/geneticsABSTRACT
OBJECTIVE: A meta-analysis was performed to compare the efficacy and safety of antithrombotic therapy with non-vitamin K antagonist oral anticoagulants (NOACs) versus standard care in patients after successful transcatheter aortic valve replacement (TAVR). METHODS: A systematic search of PubMed, Cochrane Central Register of Controlled Trials, and EMBASE databases and ClinicalTrials.gov website (through 21 October 2020) was performed. Risk ratios (RRs) with 95% confidence intervals (CIs) for all outcomes were calculated using random-effects models. RESULTS: Twelve studies (two studies were randomized controlled trials) comprising 6943 patients were included (5299 had indications for oral anticoagulation (OAC) and 1644 had none). No significant differences were found between NOACs and the standard care in the incidences of all stroke, a composite endpoint, and major/life-threatening bleeding. NOACs were associated with lower all-cause mortality than vitamin K antagonists (VKAs) in post-TAVR patients with indications for OAC after more than 1 year of follow-up [RR = 0.64; 95% CI, (0.42, 0.96); p = 0.03], whereas NOACs exhibited poor outcomes than antiplatelet therapy (APT) in patients without indications for OAC [RR = 1.66; 95% CI, (1.12, 2.45); p = 0.01]. In the prevention of valve thrombosis, NOACs and VKAs were not significantly different in patients with indications for OAC [RR = 0.66; 95% CI, (0.24, 1.84); p = 0.43], whereas NOACs were better than APT in patients without indications for OAC [RR = 0.19; 95% CI, (0.04, 0.83); p = 0.03]. CONCLUSIONS: In patients with indications for OAC, post-TAVR antithrombotic therapy with NOACs was more favorable due to its lower all-cause mortality after more than 1 year of follow-up. In those without indications for OAC, NOACs presented poorer outcomes due to its higher all-cause mortality.
ABSTRACT
Heart failure with mid-range ejection fraction (HFmrEF) was first proposed by Lam and Solomon in 2014, and was listed as a new subtype of heart failure (HF) in 2016 European Society of Cardiology guidelines. Since then, HFmrEF has attracted an increasing amount of attention, and the number of related studies on this topic has grown rapidly. The diagnostic criteria on the basis of left ventricular ejection fraction (LVEF) are straightforward; however, LVEF is not a static parameter, and it changes dynamically during the course of HF. Thus, HFmrEF may not be an independent disease with a uniform pathophysiological process, but rather a collection of patients with different characteristics. HFmrEF is often associated with various cardiovascular and non-cardiovascular diseases. Thus, the pathophysiological mechanisms of HFmrEF are particularly complex, and its clinical phenotypes are diverse. The complexity and heterogeneity of HFmrEF may be one reason for inconsistent results between clinical studies. In fact, whether HFmrEF is a distinctive subtype or a transitional stage between HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) is controversial. In this review, we discuss the clinical characteristics, treatment and prognosis of patients with HFmrEF, as well as the differences among HFmrEF, HFrEF, and HFpEF.
ABSTRACT
Aberrant promoter hypermethylation leads to gene silencing and is associated with various pathologies including cancer and organ fibrosis. Active DNA demethylation is mediated by TET enzymes: TET1, TET2, and TET3, which convert 5-methylcytosine to 5-hydroxymethylcytosine. Induction of gene-specific hydroxymethylation via CRISPR/Cas9 gene technology provides an opportunity to reactivate a single target gene silenced in pathological conditions. We utilized a spCas9 variant fused with TET3 catalytic domain to mediate gene-specific hydroxymethylation with subsequent gene reactivation which holds promise for gene therapy. Here, we present guidelines for gene-specific hydroxymethylation targeting with a specific focus on designing sgRNA and functional assessments in vitro.
Subject(s)
5-Methylcytosine/analogs & derivatives , 5-Methylcytosine/chemistry , CRISPR-Cas Systems , DNA Methylation , DNA/analysis , Gene Editing , Mixed Function Oxygenases/metabolism , Proto-Oncogene Proteins/metabolism , Chromatin , Computational Biology/methods , DNA/chemistry , DNA/genetics , Epigenesis, Genetic , High-Throughput Nucleotide Sequencing , Humans , Mixed Function Oxygenases/antagonists & inhibitors , Mixed Function Oxygenases/genetics , Oxidation-Reduction , Promoter Regions, Genetic , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/genetics , Sulfites/chemistryABSTRACT
Heart failure (HF) is a common complication or late-stage manifestation of various heart diseases. Numerous risk factors and underlying causes may contribute to the occurrence and progression of HF. The pathophysiological mechanisms of HF are very complicated. Despite accumulating advances in treatment for HF during recent decades, it remains an intractable clinical syndrome with poor outcomes, significantly reducing the quality of life and expectancy of patients, and imposing a heavy economic burden on society and families. Although initially classified as antidiabetic agents, sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated reduced the prevalence of hospitalization for HF, cardiovascular death, and all-cause death in several large-scale randomized controlled clinical trials. These beneficial effects of SGLT-2 inhibitors can be attributed to multiple hemodynamic, inflammatory and metabolic mechanisms, not only reducing the serum glucose level. SGLT2 inhibitors have been used increasingly in treatment for patients with HF with reduced ejection fraction due to their surprising performance in improving the prognosis. In addition, their roles and mechanisms in patients with HF with preserved ejection fraction or acute HF have also attracted attention. In this review article, we discuss the possible mechanisms and applications of SGLT2 inhibitors in HF.
ABSTRACT
Atrial fibrillation (AF) is prevalent in patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Depending on the timing of AF detection, it is usually categorized as pre-existing AF or new-onset AF. Antiplatelet therapy, rather than a vitamin K antagonist, may be considered as the primary treatment for patients without an indication for oral anticoagulants who undergo TAVR. However, the optimal postprocedural antithrombotic regimen for patients with AF undergoing TAVR remains unknown. In this review, we briefly introduce the management strategies of antithrombotic therapy and list the evidence from related studies to elucidate the optimal antithrombotic management for patients with AF undergoing TAVR.