The role of epicardial adipose tissue dysfunction in cardiovascular diseases: an overview of pathophysiology, evaluation, and management.

In recent decades, the epicardial adipose tissue (EAT) has been at the forefront of scientific research because of its diverse role in the pathogenesis of cardiovascular diseases (CVDs). EAT lies between the myocardium and the visceral pericardium. The same microcirculation exists both in the epicardial fat and the myocardium. Under physiological circumstances, EAT serves as cushion and protects coronary arteries and myocardium from violent distortion and impact. In addition, EAT acts as an energy lipid source, thermoregulator, and endocrine organ. Under pathological conditions, EAT dysfunction promotes various CVDs progression in several ways. It seems that various secretions of the epicardial fat are responsible for myocardial metabolic disturbances and, finally, leads to CVDs. Therefore, EAT might be an early predictor of CVDs. Furthermore, different non-invasive imaging techniques have been proposed to identify and assess EAT as an important parameter to stratify the CVD risk. We also present the potential therapeutic possibilities aiming at modifying the function of EAT. This paper aims to provide overview of the potential role of EAT in CVDs, discuss different imaging techniques to assess EAT, and provide potential therapeutic options for EAT. Hence, EAT may represent as a potential predictor and a novel therapeutic target for management of CVDs in the future.

LncRNA MHRT Prevents Angiotensin II-Induced Myocardial Oxidative Stress and NLRP3 Inflammasome via Nrf2 Activation.

The development of angiotensin II (Ang II)-induced cardiomyopathies is reportedly mediated via oxidative stress and inflammation. Nuclear factor erythroid 2-related factor (Nrf2) is an important regulator of cellular antioxidant defense, and reactive oxygen species (ROS) can activate the NLRP3 inflammasome. MHRT is a newly discovered lncRNA exhibiting cardioprotective effects, demonstrated by inhibiting myocardial hypertrophy via Brg1 and myocardial apoptosis via Nrf2 upregulation. However, the underlying mechanism of MHRT remains unclear. We explored the potential protective effects of MHRT against Ang II-induced myocardial oxidative stress and NLRP3-mediated inflammation by targeting Nrf2. Chronic Ang II administration induced NLRP3 inflammasome activation (increased NLRP3, caspase-1 and interleukin-1ß expression), oxidative stress (increased 3-nitrotyrosine and 4-hydroxy-2-nonenal), cardiac dysfunction and decreased MHRT and Nrf2 expression. Lentivirus-mediated MHRT overexpression inhibited Ang II (100 nM)-induced oxidative stress and NLRP3 inflammasome activation in AC16 human cardiomyocyte cells. Mechanistically, MHRT overexpression upregulated the expression and function of Nrf2, as determined by the increased transcription of downstream genes HO-1 and CAT, subsequently decreasing intracellular ROS accumulation and inhibiting the expression of thioredoxin-interacting protein (NLRP3 activator) and its direct binding to NLRP3. Accordingly, MHRT could protect against Ang II-induced myocardial injury by decreasing oxidative stress and NLRP3 inflammasome activation via Nrf2 activation.

AI support for accurate and fast radiological diagnosis of COVID-19: an international multicenter, multivendor CT study.

OBJECTIVES: Differentiation between COVID-19 and community-acquired pneumonia (CAP) in computed tomography (CT) is a task that can be performed by human radiologists and artificial intelligence (AI). The present study aims to (1) develop an AI algorithm for differentiating COVID-19 from CAP and (2) evaluate its performance. (3) Evaluate the benefit of using the AI result as assistance for radiological diagnosis and the impact on relevant parameters such as accuracy of the diagnosis, diagnostic time, and confidence. METHODS: We included n = 1591 multicenter, multivendor chest CT scans and divided them into AI training and validation datasets to develop an AI algorithm (n = 991 CT scans; n = 462 COVID-19, and n = 529 CAP) from three centers in China. An independent Chinese and German test dataset of n = 600 CT scans from six centers (COVID-19 / CAP; n = 300 each) was used to test the performance of eight blinded radiologists and the AI algorithm. A subtest dataset (180 CT scans; n = 90 each) was used to evaluate the radiologists' performance without and with AI assistance to quantify changes in diagnostic accuracy, reporting time, and diagnostic confidence. RESULTS: The diagnostic accuracy of the AI algorithm in the Chinese-German test dataset was 76.5%. Without AI assistance, the eight radiologists' diagnostic accuracy was 79.1% and increased with AI assistance to 81.5%, going along with significantly shorter decision times and higher confidence scores. CONCLUSION: This large multicenter study demonstrates that AI assistance in CT-based differentiation of COVID-19 and CAP increases radiological performance with higher accuracy and specificity, faster diagnostic time, and improved diagnostic confidence. KEY POINTS: • AI can help radiologists to get higher diagnostic accuracy, make faster decisions, and improve diagnostic confidence. • The China-German multicenter study demonstrates the advantages of a human-machine interaction using AI in clinical radiology for diagnostic differentiation between COVID-19 and CAP in CT scans.

Application of Targeted Coronary Angiography in the Diagnosis of Sudden Cardiac Death.

OBJECTIVES: To diagnose coronary artery stenosis by using the postmortem computed tomography angiography (PMCTA), and to explore the diagnostic value of PMCTA in sudden cardiac death. METHODS: Six death cases were selected, and the contrast medium iohexol was injected under high pressure through femoral artery approach with 5F pigtail catheter to obtain coronary image data and then the data was analyzed. The results of targeted coronary imaging and coronary artery calcium score (CaS) were compared with the results of conventional autopsy and histopathological examination. RESULTS: The autopsy and histopathological examination of cases with coronary artery stenosis obtained similar results in targeted coronary angiography, with a diagnostic concordance rate of 83.3%. Targeted coronary angiography could effectively show coronary artery diseases, and the CaS was consistent with the results of conventional autopsy and histopathological examination. CONCLUSIONS: Targeted coronary angiography can be used as an effective auxiliary method for conventional autopsy in cases of sudden cardiac death.

Mesenchymal stem cells in radiation-induced lung injury: From mechanisms to therapeutic potential.

Radiotherapy (RT) is an effective treatment option for multiple thoracic malignant tumors, including lung cancers, thymic cancers, and tracheal cancers. Radiation-induced lung injury (RILI) is a serious complication of radiotherapy. Radiation causes damage to the pulmonary cells and tissues. Multiple factors contribute to the progression of Radiation-induced lung injury, including genetic alterations, oxidative stress, and inflammatory responses. Especially, radiation sources contribute to oxidative stress occurrence by direct excitation and ionization of water molecules, which leads to the decomposition of water molecules and the generation of reactive oxygen species (ROS), reactive nitrogen species (RNS). Subsequently, reactive oxygen species and reactive nitrogen species overproduction can induce oxidative DNA damage. Immune cells and multiple signaling molecules play a major role in the entire process. Mesenchymal stem cells (MSCs) are pluripotent stem cells with multiple differentiation potentials, which are under investigation to treat radiation-induced lung injury. Mesenchymal stem cells can protect normal pulmonary cells from injury by targeting multiple signaling molecules to regulate immune cells and to control balance between antioxidants and prooxidants, thereby inhibiting inflammation and fibrosis. Genetically modified mesenchymal stem cells can improve the natural function of mesenchymal stem cells, including cellular survival, tissue regeneration, and homing. These reprogrammed mesenchymal stem cells can produce the desired products, including cytokines, receptors, and enzymes, which can contribute to further advances in the therapeutic application of mesenchymal stem cells. Here, we review the molecular mechanisms of radiation-induced lung injury and discuss the potential of Mesenchymal stem cells for the prevention and treatment of radiation-induced lung injury. Clarification of these key issues will make mesenchymal stem cells a more fantastic novel therapeutic strategy for radiation-induced lung injury in clinics, and the readers can have a comprehensive understanding in this fields.

Unveiling the Vital Role of Long Non-Coding RNAs in Cardiac Oxidative Stress, Cell Death, and Fibrosis in Diabetic Cardiomyopathy.

Diabetes mellitus is a burdensome public health problem. Diabetic cardiomyopathy (DCM) is a major cause of mortality and morbidity in diabetes patients. The pathogenesis of DCM is multifactorial and involves metabolic abnormalities, the accumulation of advanced glycation end products, myocardial cell death, oxidative stress, inflammation, microangiopathy, and cardiac fibrosis. Evidence suggests that various types of cardiomyocyte death act simultaneously as terminal pathways in DCM. Long non-coding RNAs (lncRNAs) are a class of RNA transcripts with lengths greater than 200 nucleotides and no apparent coding potential. Emerging studies have shown the critical role of lncRNAs in the pathogenesis of DCM, along with the development of molecular biology technologies. Therefore, we summarize specific lncRNAs that mainly regulate multiple modes of cardiomyopathy death, oxidative stress, and cardiac fibrosis and provide valuable insights into diagnostic and therapeutic biomarkers and strategies for DCM.

Modulation of adipose tissue metabolism by microbial-derived metabolites.

Obesity and its complications, including type 2 diabetes, cardiovascular disease, and certain cancers, have posed a significant burden on health and healthcare systems over the years due to their high prevalence and incidence. Gut microbial derivatives are necessary for the regulation of energy metabolism and host immunity, as well as for maintaining homeostasis of the intestinal environment. Gut flora metabolites may be a link between gut microbes and diseases, such as obesity, and help understand why alterations in the microbiota can influence the pathophysiology of human disease. This is supported by emerging evidence that microbial-derived metabolites, such as short-chain fatty acids, bile acids, tryptophan, trimethylamine-N-oxide, and lipopolysaccharides, can be beneficial or detrimental to the host by affecting organs outside the gut, including adipose tissue. Adipose tissue is the largest lipid storage organ in the body and an essential endocrine organ that plays an indispensable role in the regulation of lipid storage, metabolism, and energy balance. Adipose tissue metabolism includes adipocyte metabolism (lipogenesis and lipolysis), thermogenesis, and adipose tissue metabolic maladaptation. Adipose tissue dysfunction causes the development of metabolic diseases, such as obesity. Here, we review the current understanding of how these microbial metabolites are produced and discuss both established mechanisms and the most recent effects of microbial products on host adipose tissue metabolism. We aimed to identify novel therapeutic targets or strategies for the prevention and treatment of obesity and its complications.

Essential role of Nrf2 in sulforaphane-induced protection against angiotensin II-induced aortic injury.

AIMS: Cardiovascular disease (CVD) is the leading cause of death worldwide. Inflammation and oxidative stress are the primary factors underlying angiotensin II (Ang II)-induced aortic damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important antioxidative stress factor. Sulforaphane (SFN), which is naturally found in cruciferous vegetables, is an Nrf2 agonist that is safe for oral administration. Here, we aimed to explore the potential of SFN in protecting against Ang II-induced aortic damage by upregulating Nrf2 expression via the extracellular signal-regulated kinase (ERK)/glycogen synthase kinase-3 beta (GSK-3ß)/Fyn pathway. MAIN METHODS AND KEY FINDINGS: Wild-type (WT) C57BL/6J and Nrf2-knockout (Nrf2-KO) mice were injected with Ang II to induce aortic inflammation, oxidative stress, and cardiac remodeling (increased fibrosis and wall thickness). SFN treatment prevented aortic damage via Nrf2 activation in the WT mice. However, the protective effect of SFN on Ang II-induced aortic damage and upregulation of genes downstream of Nrf2 were not observed in Nrf2-KO mice. SFN induced the upregulation of aortic Nrf2 and inhibited the accumulation of ERK, GSK-3ß, and Fyn in the nuclei. SIGNIFICANCE: These results revealed that Nrf2 plays a central role in protecting against Ang II-induced aortic injury. Furthermore, SFN prevented Ang II-induced aortic damage by activating Nrf2 through the ERK/GSK-3ß/Fyn pathway.

The Role of Apelin-APJ System in Diabetes and Obesity.

Nowadays, diabetes and obesity are two main health-threatening metabolic disorders in the world, which increase the risk for many chronic diseases. Apelin, a peptide hormone, exerts its effect by binding with angiotensin II protein J receptor (APJ) and is considered to be linked with diabetes and obesity. Apelin and its receptor are widely present in the body and are involved in many physiological processes, such as glucose and lipid metabolism, homeostasis, endocrine response to stress, and angiogenesis. In this review, we summarize the literatures on the role of the Apelin-APJ system in diabetes and obesity for a better understanding of the mechanism and function of apelin and its receptor in the pathophysiology of diseases that may contribute to the development of new therapies.

Differentially expressed LncRNAs as potential prognostic biomarkers for glioblastoma.

Glioblastoma (GBM) is the most common and aggressive brain tumor with the poor clinical outcome. LncRNAs (Long non-coding RNAs) play an important role in the occurrence and development of glioblastoma. We aimed to explore the role that lncRNAs play in regulating glioblastoma and the pathways they are enriched in. The expression data of a total of 516 GBM samples were downloaded from TCGA (The Cancer Genome Atlas). We identified the differentially expressed lncRNAs between cancer and normal tissues and performed annotation of differentially expressed lncRNAs to figure out the functions and pathways they were enriched in. Finally, cluster analysis was performed on the expression data of lncRNA and the samples were divided into four kinds, which were then used in the survival analysis. A total of 90 down-regulated lncRNAs and 224 up-regulated lncRNAs were screened out, which were mostly enriched in pathways of Alzhermer's disease and apoptosis. Their neighborhood genes were mostly enriched in genes sets of RTN1 and MAPK10.The characterization of differentially expressed lncRNAs was found out and the mostly enriched pathways were obtained to figure out the regulation mechanism of lncRNA. Our findings may provide evidence of the potential role of lncRNA in the diagnosis, prognosis and target therapy of GBM.

The role of adjunctive dexamethasone in the treatment of bacterial meningitis: an updated systematic meta-analysis.

BACKGROUND: Bacterial meningitis is a serious infection in children and adults worldwide, with considerable morbidity, mortality, and severe neurological sequelae. Dexamethasone is often used before antibiotics in cases of this disease, and improves outcomes. OBJECTIVE: Although several studies have identified the role of adjunctive dexamethasone therapy in the treatment of bacterial meningitis, the results are still inconclusive. The aim of this study was to systematically evaluate the therapeutic and adverse effect of adjunctive dexa-methasone in patients with bacterial meningitis. MATERIALS AND METHODS: Relevant randomized, double-blind, placebo-controlled trials of dexamethasone in bacterial meningitis published between 2000 and 2016 were retrieved from the common electronic databases. The odds ratio (OR) and risk ratio (RR) with their 95% confidence interval (CI) were employed to calculate the effect. RESULTS: A total of ten articles including 2,459 bacterial meningitis patients (1,245 in the dex-amethasone group and 1,214 in the placebo group) were included in this meta-analysis. Our result found that dexamethasone was not associated with a significant reduction in follow-up mortality (292 of 1,245 on dexamethasone versus 314 of 1,214 on placebo; OR =0.91, 95% CI =0.80-1.03, P=0.14) and severe neurological sequelae (22.4% versus 24.1%, OR =0.84, 95% CI =0.54-1.29, P=0.42). However, dexamethasone seemed to reduce hearing loss among survivors (21.2% versus 26.1%; OR =0.76, 95% CI =0.59-0.98, P=0.03). No significant difference was found between these two groups in adverse events. CONCLUSION: Our results suggested that adjunctive dexamethasone might not be beneficial in the treatment of bacterial meningitis. Future studies with more data are needed to further prove the role of dexamethasone in bacterial meningitis.

Reducing the radiation dose with the adaptive statistical iterative reconstruction technique for chest CT in adults: a parameter study.

BACKGROUND: Currently there is a trend towards reducing radiation dose while maintaining image quality during computer tomography (CT) examination. This results from the concerns about radiation exposure from CT and the potential increase in the incidence of radiation induced carcinogenesis. This study aimed to investigate the lowest radiation dose for maintaining good image quality in adult chest scanning using GE CT equipment. METHODS: Seventy-two adult patients were examined by Gemstone Spectral CT. They were randomly divided into six groups. We set up a different value of noise index (NI) when evaluating each group every other number from 13.0 to 23.0. The original images were acquired with a slice of 5 mm thickness. For each group, several image series were reconstructed using different levels of adaptive statistical iterative reconstruction (ASIR) (30%, 50%, and 70%). We got a total of 18 image sequences of different combinations of NI and ASIR percentage. On one hand, quantitative indicators, such as CT value and standard deviation (SD), were assessed at the region of interest. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. The volume CT dose index (CTDI) and dose length product (DLP) were recorded. On the other hand, two radiologists with ≥ 5 years of experience blindly reviewed the subjective image quality using the standards we had previously set. RESULTS: The different combinations of noise index and ASIR were assessed. There was no significant difference in CT values among the 18 image sequences. The SD value was reduced with the noise index's reduction or ASIR's increase. There was a trend towards gradually lower SNR and CNR with an NI increase. The CTDI and DLP were diminishing as the NI increased. The scores from subjective image quality evaluation were reduced in all groups as the ASIR increased. CONCLUSIONS: Increasing NI can reduce radiation dose. With the premise of maintaining the same image quality, using a suitable percentage of ASIR can increase the value of NI. To assure image quality, we concluded that when the NI was set at 17.0 and ASIR was 50%, the image quality could be optimal for not only satisfying the requirements of clinical diagnosis, but also achieving the purpose of low-dose scanning.

[A study of in vitro activity of daptomycin against 2679 Gram-positive cocci].

OBJECTIVE: To evaluate the in vitro activity of daptomycin against 2679 Gram-positive cocci. METHODS: A total of 2679 non-duplicate Gram-positive cocci isolates were collected from 17 teaching hospitals during January, 2010 and December, 2011. The minimal inhibitory concentrations (MICs) of daptomycin and other anti-microbial agents against 4 Gram-positive cocci were determined by micro-broth dilution method and agar dilution respectively. The data of drug susceptibility were analyzed by WHONET5.6 software. RESULTS: Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative Staphylococci (MRSCoN) detection rates were 45.8% and 84.2%, respectively. The susceptibility rates of sulfamethoxazole, chloramphenicol, erythromycin, tetracycline, clindamycin and rifampicin against MRSA were 93.1%, 85.5%, 13.8%, 26.6%, 63.2% and 50.0%, respectively. The susceptibility rates of daptomycin, vancomycin and linezolid against MRSA and MRSCoN were all 100.0%. The daptomycin MIC50 and MIC90 of MRSCoN and MRSA were 0.5 mg/L. The high level gentamicin resistance rate of 513 Enterococci isolates was 56.9%. The susceptibility rates of chloramphenicol and tetracycline were 76.0% and 44.1%, respectively. The susceptibility rates of tigecycline and daptomycin reached 100.0%. The MIC50 and MIC90 of daptomycin against 17 vancomycin-resistant Enterococci (VRE) were both 2 mg/L. The susceptibility rates of daptomycin against Streptococcus pneumoniae and ß-hemolytic Streptococcus were 100.0%. The prevalence of penicillin-nonsusceptible Streptococcus pneumoniae (PNSSP) was 63.1%. The MIC50 and MIC90 of daptomycin against PNSSP were 0.125 mg/L and 0.25 mg/L, respectively according to the breakpoint of oral penicillin. The MIC50 and MIC90 daptomycin against ß-hemolytic Streptococci were 0.008 mg/L and 0.032 mg/L. CONCLUSIONS: Daptomycin have excellent in vitro activity against common Gram-positive cocci, including multi-drug resistant bacteria. It may be a good choice for clinicians to treat drug-resistant Gram-positive cocci.

APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is increased in Alzheimer's disease brain.

APP-BP1, first identified as an amyloid precursor protein (APP) binding protein, is the regulatory subunit of the activating enzyme for the small ubiquitin-like protein NEDD8. We have shown that APP-BP1 drives the S- to M-phase transition in dividing cells, and causes apoptosis in neurons. We now demonstrate that APP-BP1 binds to the COOH-terminal 31 amino acids of APP (C31) and colocalizes with APP in a lipid-enriched fraction called lipid rafts. We show that coexpression of a peptide representing the domain of APP-BP1 that binds to APP, abolishes the ability of overexpressed APP or the V642I mutant of APP to cause neuronal apoptosis and DNA synthesis. A dominant negative mutant of the NEDD8 conjugating enzyme hUbc12, which participates in the ubiquitin-like pathway initiated by APP-BP1, blocks neuronal apoptosis caused by APP, APP(V642I), C31, or overexpression of APP-BP1. Neurons overexpressing APP or APP(V642I) show increased APP-BP1 protein levels in lipid rafts. A similar increase in APP-BP1 in lipid rafts is observed in the Alzheimer's disease brain hippocampus, but not in less-affected areas of Alzheimer's disease brain. This translocation of APP-BP1 to lipid rafts is accompanied by a change in the subcellular localization of the ubiquitin-like protein NEDD8, which is activated by APP-BP1.

ASPP2 inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1 and decreases APP-BP1-induced cell proliferation and neuronal apoptosis.

APP-BP1, first identified as a protein that interacts with the carboxyl (C) terminus of the amyloid precursor protein (APP), is one-half of the bipartite activating enzyme for the ubiquitin-like protein NEDD8. We report here that APP-BP1 also specifically interacts with apoptosis stimulating protein of p53 ASPP2 in non-transfected cells through the functional predominant N-terminal domain ASPP2(332-483). ASPP2 inhibits the ability of APP-BP1 to rescue the ts41 cell cycle mutation and inhibits APP-BP1 induced apoptosis in primary neurons. ASPP2 reduces the ability of NEDD8 to conjugate to Cullin-1, inhibits APP-BP1-dependent ts41 cell proliferation, and blocks the ability of APP-BP1 to cause apoptosis and to cause DNA synthesis in neurons. We also show that ASPP2 activates nuclear factor-kappaB (NF-kappaB) transcriptional activity, which seems to be inhibited by the neddylation pathway since the dominant negative NEDD8 activating enzyme causes enhanced NF-kappaB activity. Our data provide the first in vivo evidence that ASPP2 is a negative regulator of the neddylation pathway through specific interaction with APP-BP1 and suggest that dysfunction of the APP-BP1 interaction with APP may be one cause of Alzheimer's disease.