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Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent hereditary disorder that affects the kidneys, characterized by the development of an excessive number of fluid-filled cysts of varying sizes in both kidneys. Along with the progression of ADPKD, these enlarged cysts displace normal kidney tissue, often accompanied by interstitial fibrosis and inflammation, and significantly impair renal function, leading to end-stage renal disease. Currently, the precise mechanisms underlying ADPKD remain elusive, and a definitive cure has yet to be discovered. This review delineates the epidemiology, pathological features, and clinical diagnostics of ADPKD or ADPKD-like disease across human populations, as well as companion animals and other domesticated species. A light has been shed on pivotal genes and biological pathways essential for preventing and managing ADPKD, which underscores the importance of cross-species research in addressing this complex condition. Treatment options are currently limited to Tolvaptan, dialysis, or surgical excision of large cysts. However, comparative studies of ADPKD across different species hold promise for unveiling novel insights and therapeutic strategies to combat this disease.
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Rim Policístico Autossômico Dominante , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/terapia , Rim Policístico Autossômico Dominante/patologia , Humanos , Animais , Rim/patologia , Rim/metabolismo , Modelos Animais de DoençasRESUMO
Hypertrophic cardiomyopathy (HCM) is a disease in which the myocardium of the heart becomes asymmetrically thickened, malformed, disordered, and loses its normal structure and function. Recent studies have demonstrated the significant involvement of inflammatory responses in HCM. However, the precise role of immune-related long non-coding RNAs (lncRNAs) in the pathogenesis of HCM remains unclear. In this study, we performed a comprehensive analysis of immune-related lncRNAs in HCM. First, transcriptomic RNA-Seq data from both HCM patients and healthy individuals (GSE180313) were reanalyzed thoroughly. Key HCM-related modules were identified using weighted gene co-expression network analysis (WGCNA). A screening for immune-related lncRNAs was conducted within the key modules using immune-related mRNA co-expression analysis. Based on lncRNA-mRNA pairs that exhibit shared regulatory microRNAs (miRNAs), we constructed a competing endogenous RNA (ceRNA) network, comprising 9 lncRNAs and 17 mRNAs that were significantly correlated. Among the 26 lncRNA-mRNA pairs, only the MIR210HG-BPIFC pair was verified by another HCM dataset (GSE130036) and the isoprenaline (ISO)-induced HCM cell model. Furthermore, knockdown of MIR210HG increased the regulatory miRNAs and decreased the mRNA expression of BPIFC correspondingly in AC16 cells. Additionally, the analysis of immune cell infiltration indicated that the MIR210HG-BPIFC pair was potentially involved in the infiltration of naïve CD4+ T cells and CD8+ T cells. Together, our findings indicate that the decreased expression of the lncRNA-mRNA pair MIR210HG-BPIFC was significantly correlated with the pathogenesis of the disease and may be involved in the immune cell infiltration in the mechanism of HCM.
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Cardiomiopatia Hipertrófica , MicroRNAs , RNA Longo não Codificante , Humanos , RNA Mensageiro/genética , RNA Longo não Codificante/genética , Linfócitos T CD8-Positivos/metabolismo , Redes Reguladoras de Genes , MicroRNAs/genética , Perfilação da Expressão Gênica , Proteínas de Transporte/genéticaRESUMO
Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia among humans, with its incidence increasing significantly with age. Despite the high frequency of AF in clinical practice, its etiology and management remain elusive. To develop effective treatment strategies, it is imperative to comprehend the underlying mechanisms of AF; therefore, the establishment of animal models of AF is vital to explore its pathogenesis. While spontaneous AF is rare in most animal species, several large animal models, particularly those of pigs, dogs, and horses, have proven as invaluable in recent years in advancing our knowledge of AF pathogenesis and developing novel therapeutic options. This review aims to provide a comprehensive discussion of various animal models of AF, with an emphasis on the unique features of each model and its utility in AF research and treatment. The data summarized in this review provide valuable insights into the mechanisms of AF and can be used to evaluate the efficacy and safety of novel therapeutic interventions.
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Fibrilação Atrial , Humanos , Animais , Cães , Cavalos , Suínos , Fibrilação Atrial/tratamento farmacológico , Modelos Animais de Doenças , Resultado do TratamentoRESUMO
Osteoarthritis (OA) is one of the most common joint diseases, there are no effective disease-modifying drugs, and the pathological mechanisms of OA need further investigation. Here, we show that H3K36 methylations were decreased in senescent chondrocytes and age-related osteoarthritic cartilage. Prrx1-Cre inducible H3.3K36M transgenic mice showed articular cartilage destruction and osteophyte formation. Conditional knockout Nsd1Prrx1-Cre mice, but not Nsd2Prrx1-Cre or Setd2Prrx1-Cre mice, replicated the phenotype of K36M/+; Prrx1-Cre mice. Immunostaining results showed decreased anabolic and increased catabolic activities in Nsd1Prrx1-Cre mice, along with decreased chondrogenic differentiation. Transcriptome and ChIP-seq data revealed that Osr2 was a key factor affected by Nsd1. Intra-articular delivery of Osr2 adenovirus effectively improved the homeostasis of articular cartilage in Nsd1Prrx1-Cre mice. In human osteoarthritic cartilages, both mRNA and protein levels of NSD1 and OSR2 were decreased. Our results indicate that NSD1-induced H3K36 methylations and OSR2 expression play important roles in articular cartilage homeostasis and OA. Targeting H3K36 methylation and OSR2 would be a novel strategy for OA treatment.
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Cartilagem Articular , Osteoartrite , Camundongos , Humanos , Animais , Condrócitos/metabolismo , Metiltransferases/metabolismo , Osteoartrite/patologia , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Camundongos Transgênicos , Homeostase , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismoRESUMO
Appropriate histone modifications emerge as essential cell fate regulators of neuronal identities across neocortical areas and layers. Here we showed that NSD1, the methyltransferase for di-methylated lysine 36 of histone H3 (H3K36me2), controls both area and layer identities of the neocortex. Nsd1-ablated neocortex showed an area shift of all four primary functional regions and aberrant wiring of cortico-thalamic-cortical projections. Nsd1 conditional knockout mice displayed defects in spatial memory, motor learning, and coordination, resembling patients with the Sotos syndrome carrying NSD1 mutations. On Nsd1 loss, superficial-layer pyramidal neurons (PNs) progressively mis-expressed markers for deep-layer PNs, and PNs remained immature both morphologically and electrophysiologically. Loss of Nsd1 in postmitotic PNs causes genome-wide loss of H3K36me2 and re-distribution of DNA methylation, which accounts for diminished expression of neocortical layer specifiers but ectopic expression of non-neural genes. Together, H3K36me2 mediated by NSD1 is required for the establishment and maintenance of region- and layer-specific neocortical identities.
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Histonas , Síndrome de Sotos , Animais , Humanos , Camundongos , Metilação de DNA , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Mutação , Processamento de Proteína Pós-Traducional , Síndrome de Sotos/genéticaRESUMO
Currently, antibiotics are the most common treatment for bacterial infections in clinical practice. However, with the abuse of antibiotics and the emergence of drug-resistant bacteria, the use of antibiotics has faced an unprecedented challenge. It is imminent to develop nonantibiotic antimicrobial agents. Based on the cation-π structure of barnacle cement protein, a polyphosphazene-based polymer poly[(N,N-dimethylethylenediamine)-g-(N,N,N,N-dimethylaminoethyl p-ammonium bromide (ammonium bromide)-g-(N,N,N,N-dimethylaminoethyl acetate ethylammonium bromide)] (PZBA) with potential adhesion and inherent antibacterial properties was synthesized, and a series of injectable antibacterial adhesive hydrogels (PZBA-PVA) were prepared by cross-linking with poly(vinyl alcohol) (PVA). PZBA-PVA hydrogels showed good biocompatibility, and the antibacterial rate of the best-performed hydrogel reached 99.81 ± 0.04% and 98.80 ± 2.16% against Staphylococcus aureus and Escherichia coli within 0.5 h in vitro, respectively. In the infected wound model, the healing rate of the PZBA-PVA-treated group was significantly higher than that of the Tegaderm film group due to the fact that the hydrogel suppressed inflammatory responses and modulated the infiltration of immune cells. Moreover, the wound healing mechanism of the PZBA-PVA hydrogel was further evaluated by real-time polymerase chain reaction and total RNA sequencing. The results indicated that the process of hemostasis and tissue development was prompted and the inflammatory and immune responses were suppressed to accelerate wound healing. Overall, the PZBA-PVA hydrogel is shown to have the potential for infected wound healing application.
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Infecções Estafilocócicas , Adesivos Teciduais , Humanos , Hidrogéis/farmacologia , Hidrogéis/química , Antibacterianos/farmacologia , Antibacterianos/químicaRESUMO
Diagnostic and therapeutic illumination on internal organs and tissues with high controllability and adaptability in terms of spectrum, area, depth, and intensity remains a major challenge. Here, we present a flexible, biodegradable photonic device called iCarP with a micrometer scale air gap between a refractive polyester patch and the embedded removable tapered optical fiber. ICarP combines the advantages of light diffraction by the tapered optical fiber, dual refractions in the air gap, and reflection inside the patch to obtain a bulb-like illumination, guiding light towards target tissue. We show that iCarP achieves large area, high intensity, wide spectrum, continuous or pulsatile, deeply penetrating illumination without puncturing the target tissues and demonstrate that it supports phototherapies with different photosensitizers. We find that the photonic device is compatible with thoracoscopy-based minimally invasive implantation onto beating hearts. These initial results show that iCarP could be a safe, precise and widely applicable device suitable for internal organs and tissue illumination and associated diagnosis and therapy.
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Óptica e Fotônica , Fototerapia , Fibras Ópticas , Fármacos Fotossensibilizantes , Desenho de EquipamentoRESUMO
Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease characterized by pulmonary vascular remodeling and right heart enlargement the pathogenesis of PAH is complicated; no biologic-based therapy is available for the treatment of PAH, but recent studies suggest that inflammatory response and abnormal proliferation of pulmonary artery smooth muscle cells are the main pathogenic mechanism, while the role of immune-related long non-coding RNAs (lncRNAs) remains unclear. The aim of this study was to systematically analyze immune-related lncRNAs in PAH. Here, we downloaded a publicly available microarray data from PAH and control patients (GSE113439). A total of 243 up-regulated and 203 down-regulated differentially expressed genes (DEGs) were screened, and immune-related DEGs were further obtained from ImmPort. The immune-related lncRNAs were obtained by co-expression analysis of immune-related mRNAs. Then, immune-related lncRNAs-mRNAs network including 2 lncRNAs and 6 mRNAs was constructed which share regulatory miRNAs and have significant correlation. Among the lncRNA-mRNA pairs, one pair (JPX-RABEP1) was verified in the validating dataset GSE53408 and PAH mouse model. Furthermore, the immune cell infiltration analysis of the GSE113439 dataset revealed that the JPX-RABEP1 pair may participate in the occurrence and development of PAH through immune cell infiltration. Together, our findings reveal that the lncRNA-mRNA pair JPX-RABEP1 may be a novel biomarker and therapeutic target for PAH.
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Hipertensão Arterial Pulmonar , RNA Longo não Codificante , Animais , Camundongos , Hipertensão Arterial Pulmonar/genética , RNA Longo não Codificante/genética , Hipertensão Pulmonar Primária Familiar , Biomarcadores , Biologia Computacional , RNA Mensageiro/genéticaRESUMO
Numerous missense mutations have been reported in autosomal dominant polycystic kidney disease which is one of the most common renal genetic disorders. The underlying mechanism for cystogenesis is still elusive, partly due to the lack of suitable animal models. Currently, we tried to establish a porcine transgenic model overexpressing human PKD2-D511V (hPKD2-D511V), which is a dominant-negative mutation in the vertebrate in vitro models. A total of six cloned pigs were finally obtained using somatic cell nuclear transfer. However, five with functional hPKD2-D511V died shortly after birth, leaving only one with the dysfunctional transgenic event to survive. Compared with the WT pigs, the demised transgenic pigs had elevated levels of hPKD2 expression at the mRNA and protein levels. Additionally, no renal malformation was observed, indicating that hPKD2-D511V did not alter normal kidney development. RNA-seq analysis also revealed that several ADPKD-related pathways were disturbed when overexpressing hPKD2-D511V. Therefore, our study implies that hPKD2-D511V may be lethal due to the dominant-negative effect. Hence, to dissect how PKD2-D511V drives renal cystogenesis, it is better to choose in vitro or invertebrate models.
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Ischemic cardiomyopathy (ICM), which increases along with aging, is the leading cause of heart failure. Currently, immune response is believed to be critical in ICM whereas the roles of immune-related lncRNAs remain vague. In this study, we aimed to systematically analyze immune-related lncRNAs in the aging-related disease ICM. Here, we downloaded publicly available RNA-seq data from ischemic cardiomyopathy patients and non-failing controls (GSE116250). Weighted gene co-expression network analysis (WGCNA) was performed to identify key ICM-related modules. The immune-related lncRNAs of key modules were screened by co-expression analysis of immune-related mRNAs. Then, a competing endogenous RNA (ceRNA) network, including 5 lncRNAs and 13 mRNAs, was constructed using lncRNA-mRNA pairs which share regulatory miRNAs and have significant correlation. Among the lncRNA-mRNA pairs, one pair (AC011483.1-CCR7) was verified in another publicly available ICM dataset (GSE46224) and ischemic cell model. Further, the immune cell infiltration analysis of the GSE116250 dataset revealed that the proportions of monocytes and CD8+ T cells were negatively correlated with the expression of AC011483.1-CCR7, while plasma cells were positively correlated, indicating that AC011483.1-CCR7 may participate in the occurrence and development of ICM through immune cell infiltration. Together, our findings revealed that lncRNA-mRNA pair AC011483.1-CCR7 may be a novel biomarker and therapeutic target for ICM.
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Cardiomiopatias , MicroRNAs , RNA Longo não Codificante , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Cardiomiopatias/genética , Biologia Computacional , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR7/genéticaRESUMO
Weak tissue adhesion remains a major challenge in clinical translation of microneedle patches. Mimicking the structural features of honeybee stingers, stiff polymeric microneedles with unidirectionally backward-facing barbs were fabricated and embedded into various elastomer films to produce self-interlocking microneedle patches. The spirality of the barbing pattern was adjusted to increase interlocking efficiency. In addition, the micro-bleeding caused by microneedle puncturing adhered the porous surface of the patch substrate to the target tissue via coagulation. In the demonstrative application of myocardial infarction treatment, the bioinspired microneedle patches firmly fixed on challenging beating hearts, significantly reduced cardiac wall stress and strain in the infarct, and maintained left ventricular function and morphology. In addition, the microneedle patch was minimally invasively implanted onto beating porcine heart in 10 minutes, free of sutures and adhesives. Therefore, the honeybee stinger-inspired microneedles could provide an adaptive and convenient means to implant patches for various medical applications. STATEMENT OF SIGNIFICANCE: Adhesion between tissue and microneedle patches with smooth microneedles is usually weak. We introduce a novel barbing method of fabricating unidirectionally backward facing barbs with controllable spirality on the microneedles on microneedle patches. The microneedle patches self-interlock on mechanically dynamic beating hearts, similar to honeybee stingers. The micro-bleeding and coagulation on the porous surface provide additional adhesion force. The microneedle patches attenuate left ventricular remodeling via mechanical support and are compatible with minimally invasive implantation.
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Infarto do Miocárdio , Agulhas , Abelhas , Suínos , Animais , Microinjeções , Sistemas de Liberação de Medicamentos , Infarto do Miocárdio/terapia , PunçõesRESUMO
Although observational studies have shown that abnormal systemic iron status is associated with an increased risk of heart failure (HF), it remains unclear whether this relationship represents true causality. We aimed to explore the causal relationship between iron status and HF risk. Two-sample Mendelian randomisation (MR) was applied to obtain a causal estimate. Genetic summary statistical data for the associations (p < 5 × 10−8) between single nucleotide polymorphisms (SNPs) and four iron status parameters were obtained from the Genetics of Iron Status Consortium in genome-wide association studies involving 48,972 subjects. Statistical data on the association of SNPs with HF were extracted from the UK biobank consortium (including 1088 HF cases and 360,106 controls). The results were further tested using MR based on the Bayesian model averaging (MR-BMA) and multivariate MR (MVMR). Of the twelve SNPs considered to be valid instrumental variables, three SNPs (rs1800562, rs855791, and rs1799945) were associated with all four iron biomarkers. Genetically predicted iron status biomarkers were not causally associated with HF risk (all p > 0.05). Sensitivity analysis did not show evidence of potential heterogeneity and horizontal pleiotropy. Convincing evidence to support a causal relationship between iron status and HF risk was not found. The strong relationship between abnormal iron status and HF risk may be explained by an indirect mechanism.
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Estudo de Associação Genômica Ampla , Insuficiência Cardíaca , Teorema de Bayes , Biomarcadores , Estudo de Associação Genômica Ampla/métodos , Insuficiência Cardíaca/genética , Humanos , Ferro , Análise da Randomização Mendeliana/métodosRESUMO
Ischemic cardiomyopathy (ICM) caused by coronary artery disease always leads to myocardial infarction and heart failure. Identification of novel transcriptional regulators in ICM is an effective method to establish new diagnostic and therapeutic strategies. In this study, we used two RNA-seq datasets and one microarray dataset from different studies, including 25 ICM and 21 non-failing control (NF) samples of human left ventricle tissues for further analysis. In total, 208 differentially expressed genes (DEGs) were found by combining two RNA-seq datasets with batch effects removed. GO and KEGG analyses of DEGs indicated that the response to wounding, positive regulation of smooth muscle contraction, chromatin, PI3K-Akt signaling pathway, and transporters pathways are involved in ICM. Simple Enrichment Analysis found that NFIC-binding motifs are enriched in promoter regions of downregulated genes. The Gene Importance Calculator further proved that NFIC is vital. NFIC and its downstream genes were verified in the validating microarray dataset. Meanwhile, in rat cardiomyocyte cell line H9C2 cells, two genes (Tspan1 and Hopx) were confirmed, which decreased significantly along with knocking down Nfic expression. In conclusion, NFIC participates in the ICM process by regulating TSPAN1 and HOPX. NFIC and its downstream genes may be marker genes and potential diagnostic and therapeutic targets for ICM.
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Cardiomiopatias , Proteínas de Homeodomínio , Isquemia Miocárdica , Fatores de Transcrição NFI , Tetraspaninas , Proteínas Supressoras de Tumor , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Biologia Computacional , Proteínas de Homeodomínio/genética , Humanos , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Fatores de Transcrição NFI/genética , RNA-Seq , Tetraspaninas/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
During the development of the mammalian cardiovascular system, the formation of a mature and fully functional cardiovascular system needs the fine coordination of the morphogenesis of various molecules, cells, tissues, and organs. Abnormalities in these processes usually lead to serious congenital heart defects. The determination and maintenance of cell fate in multicellular organisms depend to a large extent on the precise timing and control of RNA polymerase II (Pol II) transcription, and the transcription Mediator complex plays an irreplaceable role in the Pol II transcription process. Mediator is an evolutionarily conserved multi-subunit protein complex, including four parts: head, middle, tail, and kinase. It is a functional bridge between transcription factors and basic transcription machines. In recent years, due to the key role of Mediator in the transcriptional regulation of gene expression, many of human heart diseases have been confirmed to be related to specific Mediator gene mutations, such as heart valve defects, translocation of the great arteries, DiGeorge syndrome and some cardiovascular diseases related to energy homeostasis. In this review, we summarize the role of Mediator in cardiovascular development and disease, focusing on the role of Mediator in the development of cardiovascular disease, and provides a broad idea for the research on Mediator-related cardiovascular system development and diseases.
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Complexo Mediador , RNA Polimerase II , Animais , Núcleo Celular , Regulação da Expressão Gênica , Humanos , Mamíferos/genética , Complexo Mediador/genética , Complexo Mediador/metabolismo , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Fatores de Transcrição/genética , Transcrição GênicaRESUMO
Background: Early prediction and classification of prognosis is essential for patients in the coronary care unit (CCU). We applied a machine learning (ML) model using the eXtreme Gradient Boosting (XGBoost) algorithm to prognosticate CCU patients and compared XGBoost with traditional classification models. Methods: CCU patients' data were extracted from the MIMIC-III v1.4 clinical database, and divided into four groups based on the time to death: <30 days, 30 days-1 year, 1-5 years, and ≥5 years. Four classification models, including XGBoost, naïve Bayes (NB), logistic regression (LR), and support vector machine (SVM) were constructed using the Python software. These four models were tested and compared for accuracy, F1 score, Matthews correlation coefficient (MCC), and area under the curve (AUC) of the receiver operating characteristic curves. Subsequently, Local Interpretable Model-Agnostic Explanations method was performed to improve XGBoost model interpretability. We also constructed sub-models of each model based on the different categories of death time and compared the differences by decision curve analysis. The optimal model was further analyzed using a clinical impact curve. At last, feature ablation curves of the XGBoost model were conducted to obtain the simplified model. Results: Overall, 5360 CCU patients were included. Compared to NB, LR, and SVM, the XGBoost model showed better accuracy (0.663, 0.605, 0.632, and 0.622), micro-AUCs (0.873, 0.811, 0.841, and 0.818), and MCC (0.337, 0.317, 0.250, and 0.182). In subgroup analysis, the XGBoost model had a better predictive performance in acute myocardial infarction subgroup. The decision curve and clinical impact curve analyses verified the clinical utility of the XGBoost model for different categories of patients. Finally, we obtained a simplified model with thirty features. Conclusions: For CCU physicians, the ML technique by XGBoost is a potential predictive tool in patients with different conditions, and it may contribute to improvements in prognosis.
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Background: Heart failure (HF), primarily caused by conditions such as coronary heart disease or cardiomyopathy, is a global health problem with poor prognosis and heavy burden on healthcare systems. As biomarkers of myocardial injury and fibrosis, suppression of tumorigenicity 2 (ST2) and galectin-3 were recommended for prognosis stratification in HF guidelines. However, the causality between these two mediators and HF remains obscure. This study aimed to explore the causal relationship of genetically determined ST2 and galectin-3 with the risk of HF. Methods: We used the two-sample Mendelian randomization (MR) method, incorporating available genome-wide association summary statistics, to investigate the causal association of ST2 and galectin-3 with HF risk. We applied inverse-variance weighted analysis as the main method of analysis. Results: In our final MR analysis, 4 single-nucleotide polymorphisms (SNPs) of ST2 and galectin-3, respectively, were identified as valid instrumental variables. Fixed-effect inverse variance weighted (IVW) analysis indicated that genetically predicted ST2 and galectin-3 were not causally associated with HF risk 3. [odds ratio (OR) = 0.9999, 95% confidence interval [CI] = 0.9994-1.0004, p = 0.73; OR = 1.0002, 95% CI = 0.9994-1.0010, p = 0.60, respectively]. These findings were robust in sensitivity analyses, including MR-Egger regression and leave-one-out analysis. Conclusion: This MR study provided no evidence for the causal effects of ST2 and galectin-3 on HF risk.
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Coronaviruses (CoVs) are a family of RNA viruses that typically cause respiratory, enteric, and hepatic diseases in animals and humans. Here, we use porcine epidemic diarrhea virus (PEDV) as a model of CoVs to illustrate the reciprocal regulation between CoV infection and pyroptosis. For the first time, we elucidate the molecular mechanism of porcine gasdermin D (pGSDMD)-mediated pyroptosis and demonstrate that amino acids R238, T239, and F240 within pGSDMD-p30 are critical for pyroptosis. Furthermore, 3C-like protease Nsp5 from SARS-CoV-2, MERS-CoV, PDCoV, and PEDV can cleave pGSDMD at the Q193-G194 junction to produce two fragments unable to trigger pyroptosis. The two cleaved fragments could not inhibit PEDV replication. In addition, Nsp5 from SARS-CoV-2 and MERS-CoV also cleave human GSDMD (hGSDMD). Therefore, we provide clear evidence that PEDV may utilize the Nsp5-GSDMD pathway to inhibit pyroptosis and, thus, facilitate viral replication during the initial period, suggesting an important strategy for the coronaviruses to sustain their infection. IMPORTANCE Recently, GSDMD has been reported as a key executioner for pyroptosis. This study first demonstrates the molecular mechanism of pGSDMD-mediated pyroptosis and that the pGSDMD-mediated pyroptosis protects host cells against PEDV infection. Notably, PEDV employs its Nsp5 to directly cleave pGSDMD in favor of its replication. We found that Nsp5 proteins from other coronaviruses, such as porcine deltacoronavirus, severe acute respiratory syndrome coronavirus 2, and Middle East respiratory syndrome coronavirus, also had the protease activity to cleave human and porcine GSDMD. Thus, we provide clear evidence that the coronaviruses might utilize Nsp5 to inhibit the host pyroptotic cell death and facilitate their replication during the initial period, an important strategy for their sustaining infection. We suppose that GSDMD is an appealing target for the design of anticoronavirus therapies.
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COVID-19 , Vírus da Diarreia Epidêmica Suína , Animais , Humanos , Gasderminas , Peptídeo Hidrolases , Piroptose , SARS-CoV-2 , SuínosRESUMO
Myocardial infarction (MI) is still a major cause of mortality and morbidity worldwide. Elastomer cardiac patches have shown great potential in preventing left ventricle (LV) remodeling post-MI by providing mechanical support to the infarcted myocardium. Improved therapeutic outcomes are expected by mediating pathological processes in the necrosis phase, inflammation phase, and fibrosis phase, through orchestrated biological and mechanical treatments. In this study, a mechanically robust multifunctional cardiac patch integrating reactive oxygen species (ROS)-scavenging, anti-inflammatory, and pro-angiogenic capabilities was developed to realize the integrative strategy. An elastomeric polyurethane (PFTU) containing ROS-sensitive poly (thioketal) (PTK) and unsaturated poly (propylene fumarate) (PPF) segments was synthesized, which was further clicked with pro-angiogenic Arg-Glu-Asp-Val (REDV) peptides to obtain PFTU-g-REDV (PR), and was formulated into a macroporous patch containing rosuvastatin (PRR). The mechanical support and multifunctional effects of the patch were confirmed in a rat MI model in vivo compared to the patches with only mechanical support, leading to reduced cell apoptosis, suppressed local inflammatory response, alleviated fibrosis, and induced angiogenesis. The cardiac functions and LV morphology were also well maintained. These results demonstrate the advantages of the integrated and orchestrated treatment strategy in MI therapy.
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Infarto do Miocárdio , Remodelação Ventricular , Animais , Modelos Animais de Doenças , Elastômeros , Fibrose , Infarto do Miocárdio/patologia , Miocárdio/patologia , Ratos , Espécies Reativas de OxigênioRESUMO
Obesity mainly results from a chronic energy imbalance. Promoting browning of white adipocytes is a promising strategy to enhance energy expenditure and combat obesity. N6-methyladenosine (m6A), the most abundant mRNA modification in eukaryotes, plays an important role in regulating adipogenesis. However, whether m6A regulates white adipocyte browning was unknown. Here, we report that adipose tissue-specific deletion of Fto, an m6A demethylase, predisposes mice to prevent high-fat diet (HFD)-induced obesity by enhancing energy expenditure. Additionally, deletion of FTO in vitro promotes thermogenesis and white-to-beige adipocyte transition. Mechanistically, FTO deficiency increases the m6A level of Hif1a mRNA, which is recognized by m6A-binding protein YTHDC2, facilitating mRNA translation and increasing HIF1A protein abundance. HIF1A activates the transcription of thermogenic genes, including Ppaggc1a, Prdm16, and Pparg, thereby promoting Ucp1 expression and the browning process. Collectively, these results unveil an epigenetic mechanism by which m6A-facilitated HIF1A expression controls browning of white adipocytes and thermogenesis, providing a potential target to counteract obesity and metabolic disease.
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Tecido Adiposo Bege , Tecido Adiposo Branco , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Adenosina/análogos & derivados , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético , Metilação , Camundongos , Camundongos Endogâmicos C57BL , TermogêneseRESUMO
Pulmonary arterial hypertension (PAH) is a rare cardiovascular disease with very high mortality rate. The currently available therapeutic strategies, which improve symptoms, cannot fundamentally reverse the condition. Thus, new therapeutic strategies need to be established. Our research analyzed three microarray datasets of lung tissues from human PAH samples retrieved from the Gene Expression Omnibus (GEO) database. We combined two datasets for subsequent analyses, with the batch effects removed. In the merged dataset, 542 DEGs were identified and the key module relevant to PAH was selected using WGCNA. GO and KEGG analyses of DEGs and the key module indicated that the pre-ribosome, ribosome biogenesis, centriole, ATPase activity, helicase activity, hypertrophic cardiomyopathy, melanoma, and dilated cardiomyopathy pathways are involved in PAH. With the filtering standard (|MM| > 0.95 and |GS| > 0.90), 70 hub genes were identified. Subsequently, five candidate marker genes (CDC5L, AP3B1, ZFYVE16, DDX46, and PHAX) in the key module were found through overlapping with the top thirty genes calculated by two different methods in CytoHubb. Two of them (CDC5L and DDX46) were found to be significantly upregulated both in the merged dataset and the validating dataset in PAH patients. Meanwhile, expression of the selected genes in lung from PAH chicken measured by qRT-PCR and the ROC curve analyses further verified the potential marker genes' predictive value for PAH. In conclusion, CDC5L and DDX46 may be marker genes and potential therapeutic targets for PAH.