ABSTRACT
BACKGROUND: Hypertensive nephropathy (HN) is one of the main causes of end-stage renal disease (ESRD), leading to serious morbidity and mortality in hypertensive patients. However, existing treatment for hypertensive nephropathy are still very limited. It has been demonstrated that aerobic exercise has beneficial effects on the treatment of hypertension. However, the underlying mechanisms of exercise in HN remain unclear. METHODS: The spontaneously hypertensive rats (SHR) were trained for 8 weeks on a treadmill with different exercise prescriptions. We detected the effects of moderate intensity continuous training (MICT) and high intensity interval training (HIIT) on inflammatory response, renal function, and renal fibrosis in SHR. We further investigated the relationship between TLR4 and the NLRC4 inflammasome in vitro HN model. RESULTS: MICT improved renal fibrosis and renal injury, attenuating the inflammatory response by inhibiting TLR4/NF-κB pathway and the activation of NLRC4 inflammasome. However, these changes were not observed in the HIIT group. Additionally, repression of TLR4/NF-κB pathway by TAK-242 inhibited activation of NLRC4 inflammasome and alleviated the fibrosis in Ang II-induced HK-2 cells. CONCLUSION: MICT ameliorated renal damage, inflammatory response, and renal fibrosis via repressing TLR4/NF-κB pathway and the activation of NLRC4 inflammasome. This study might provide new references for exercise prescriptions of hypertension.
Subject(s)
Calcium-Binding Proteins , Inflammasomes , NF-kappa B , Nephritis , Rats, Inbred SHR , Signal Transduction , Toll-Like Receptor 4 , Animals , Toll-Like Receptor 4/metabolism , NF-kappa B/metabolism , Inflammasomes/metabolism , Rats , Calcium-Binding Proteins/metabolism , Male , Nephritis/metabolism , Nephritis/pathology , Hypertension, Renal/metabolism , Hypertension, Renal/pathology , Fibrosis , Down-Regulation , Humans , Exercise Therapy/methods , Kidney/pathology , Kidney/metabolismABSTRACT
The complex pathogenesis of kidney disease is closely related to the diversity of kidney intrinsic cells. In this study, single-cell transcriptome sequencing technology was used to sequence and analyze blood and kidney tissue cells in normal control rats and rats with chronic kidney disease (CKD), focusing on key cell populations and functional enrichment to explore the pathogenesis of CKD. Oil red O staining and enzyme-linked immunosorbent assay (ELISA) were used to detect lipid droplets and free fatty acid (FFA). Quantitative real-time polymerase chain reaction (RT-PCR), western blot (WB) were used to verify the differential gene hydroxyacid oxidase 2 (HAO2) and fatty acid metabolic process in tissue to ensure the reliability of single-cell sequencing results. We successfully established a single-cell transcriptome atlas of blood and kidney tissue in rats with CKD, which were annotated into 14 cell subsets (MPCs, PT, Tc, DCT, B-IC, A-IC, CNT, ALOH, BC, Neu, Endo, Pla, NKT, Baso) according to marker gene, and the integrated single-cell atlas of rats showed a significant increase and decrease of MPCs and PTs in the CKD group, respectively. Functional analysis found extensive enrichment of metabolic-related pathways in PT cells, includes fatty acid metabolic process, cellular amino acid metabolic process and generation of precursor metabolites and energy. Immunohistochemical experiments determined that the differential gene HAO2 was localized in the renal tubules, and its expression was significantly reduced in CKD group compared with control, and oil red O staining showed that lipid droplets increased in the CKD group, after overexpression of HAO2 the lipid droplets was inhibited. ELISA assay showed that ATP content decreased in the CKD group and FFA increased in the CKD group. Moreover, the mitochondrial membrane potential of the cells in the OE-HAO2 group was significantly increased compared with OE-NC. The acyl-CoA oxidase 1(ACOX1), peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) were decreased in the CKD group, while genes and proteins were increased after overexpression of HAO2, and the AMP-activated protein kinase (AMPK) phosphorylated proteins were increased, the acetyl-CoA carboxylase (ACC) phosphorylated proteins were decreased, reversely. Therefore, HAO2 may be an important regulator of fatty acid metabolic processes in CKD, and overexpression of HAO2 can enhance fatty acid metabolism by promoting fatty acid oxidation (FAO) pathway.
ABSTRACT
Krüppel-like factor 13 (KLF13), a zinc finger transcription factor, is considered as a potential regulator of cardiomyocyte differentiation and proliferation during heart morphogenesis. However, its precise role in the dedifferentiation of vascular smooth muscle cells (VSMCs) during atherosclerosis and neointimal formation after injury remains poorly understood. In this study, we investigated the relationship between KLF13 and SM22α expression in normal and atherosclerotic plaques by bioanalysis, and observed a significant increase in KLF13 levels in the atherosclerotic plaques of both human patients and ApoE-/- mice. Knockdown of KLF13 was found to ameliorate intimal hyperplasia following carotid artery injury. Furthermore, we discovered that KLF13 directly binds to the SM22α promoter, leading to the phenotypic dedifferentiation of VSMCs. Remarkably, we observed a significant inhibition of platelet-derived growth factor BB-induced VSMCs dedifferentiation, proliferation, and migration when knocked down KLF13 in VSMCs. This inhibitory effect of KLF13 knockdown on VCMC function was, at least in part, mediated by the inactivation of p-AKT signaling in VSMCs. Overall, our findings shed light on a potential therapeutic target for treating atherosclerotic lesions and restenosis after vascular injury.
Subject(s)
Cell Dedifferentiation , Cell Proliferation , Kruppel-Like Transcription Factors , Microfilament Proteins , Muscle Proteins , Muscle, Smooth, Vascular , Myocytes, Smooth Muscle , Repressor Proteins , Animals , Humans , Male , Mice , Atherosclerosis/genetics , Atherosclerosis/pathology , Atherosclerosis/metabolism , Carotid Artery Injuries/pathology , Carotid Artery Injuries/genetics , Carotid Artery Injuries/metabolism , Cell Movement/genetics , Cell Proliferation/genetics , Cells, Cultured , Kruppel-Like Transcription Factors/metabolism , Kruppel-Like Transcription Factors/genetics , Mice, Inbred C57BL , Muscle Proteins/genetics , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Neointima/metabolism , Neointima/pathology , Neointima/genetics , Phenotype , Plaque, Atherosclerotic/pathology , Plaque, Atherosclerotic/metabolism , Plaque, Atherosclerotic/genetics , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins c-akt/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Signal Transduction , Cell Cycle Proteins , Microfilament Proteins/geneticsABSTRACT
Dapagliflozin (DAPA) has been demonstrated to reduce cardiovascular mortality and heart failure hospitalization rates in diabetic patients. However, the mechanism underlying its cardio-protective effect in non-diabetic patients remains unclear. Our study aimed to explore the cardio-protective impact of DAPA on myocardial infarction in non-diabetic mice. We induced myocardial infarction in C57BL/6 mice by ligating the descending branch of the left coronary artery. After surgery, the animals were randomly treated with either saline or DAPA. We employed echocardiography, Western blot analysis, and tissue staining to assess post-infarction myocardial injury. Additionally, we investigated the mechanism of action through cell experiments. Compared to the myocardial infarction group, DAPA treatment significantly attenuated ventricular remodeling and improved cardiac function. By mitigating myocardial oxidative stress and apoptosis, DAPA may activate the AMPKα signaling pathway, thereby exerting a protective effect. These findings suggest that DAPA could serve as a novel therapeutic approach for patients with cardiac infarction.
ABSTRACT
BACKGROUND: Skin mottling is a common manifestation of peripheral tissue hypoperfusion, and its severity can be described using the skin mottling score (SMS). This study aims to evaluate the value of the SMS in detecting peripheral tissue hypoperfusion in critically ill patients following cardiac surgery. METHODS: Critically ill patients following cardiac surgery with risk factors for tissue hypoperfusion were enrolled (n = 373). Among these overall patients, we further defined a hypotension population (n = 178) and a shock population (n = 51). Hemodynamic and perfusion parameters were recorded. The primary outcome was peripheral hypoperfusion, defined as significant prolonged capillary refill time (CRT, > 3.0 s). The characteristics and hospital mortality of patients with and without skin mottling were compared. The area under receiver operating characteristic curves (AUROC) were used to assess the accuracy of SMS in detecting peripheral hypoperfusion. Besides, the relationships between SMS and conventional hemodynamic and perfusion parameters were investigated, and the factors most associated with the presence of skin mottling were identified. RESULTS: Of the 373-case overall population, 13 (3.5%) patients exhibited skin mottling, with SMS ranging from 1 to 5 (5, 1, 2, 2, and 3 cases, respectively). Patients with mottling had lower mean arterial pressure, higher vasopressor dose, less urine output (UO), higher CRT, lactate levels and hospital mortality (84.6% vs. 12.2%, p < 0.001). The occurrences of skin mottling were higher in hypotension population and shock population, reaching 5.6% and 15.7%, respectively. The AUROC for SMS to identify peripheral hypoperfusion was 0.64, 0.68, and 0.81 in the overall, hypotension, and shock populations, respectively. The optimal SMS threshold was 1, which corresponded to specificities of 98, 97 and 91 and sensitivities of 29, 38 and 67 in the three populations (overall, hypotension and shock). The correlation of UO, lactate, CRT and vasopressor dose with SMS was significant, among them, UO and CRT were identified as two major factors associated with the presence of skin mottling. CONCLUSION: In critically ill patients following cardiac surgery, SMS is a very specific yet less sensitive parameter for detecting peripheral tissue hypoperfusion.
Subject(s)
Cardiac Surgical Procedures , Hypotension , Shock, Septic , Humans , Critical Illness , Cardiac Surgical Procedures/adverse effects , Hypotension/diagnosis , Hypotension/complications , LactatesABSTRACT
Excessive reactive oxygen species production during acute lung injury (ALI) will aggravate the inflammatory process and endothelial barrier dysfunction. Carnosol is a natural phenolic diterpene with antioxidant and anti-inflammatory properties, but its role in treating sepsis-induced ALI remains unclear. This study aims to explore the protective effects and underlying mechanisms of carnosol in sepsis-induced ALI. C57BL/6 mouse were preconditioned with carnosol for 1 h, then the model of lipopolysaccharide (LPS)-induced sepsis was established. The degree of pulmonary edema, oxidative stress, and inflammation were detected. Endothelial barrier function was evaluated by apoptosis and cell junctions. In vitro, Mito Tracker Green probe, JC-1 staining, and MitoSOX staining were conducted to investigate the effect of carnosol on mitochondria. Finally, we investigated the role of nuclear factor-erythroid 2-related factor (Nrf2)/sirtuin-3 (SIRT3) in carnosol against ALI. Carnosol alleviated LPS-induced pulmonary oxidative stress and inflammation by inhibiting excess mitochondrial reactive oxygen species production and maintaining mitochondrial homeostasis. Furthermore, carnosol also attenuated LPS-induced endothelial cell barrier damage by reducing vascular endothelial cell apoptosis and restoring occludin, ZO-1, and vascular endothelial-Cadherin expression in vitro and in vivo. In addition, carnosol increased Nrf2 nuclear translocation to promote SIRT3 expression. The protective effects of carnosol on ALI were largely abolished by inhibition of Nrf2/SIRT3. Our study has provided the first evidence that the Nrf2/SIRT3 pathway is a protective target of the endothelial barrier in ALI, and carnosol can serve as a potential therapeutic candidate for ALI by utilizing its ability to target this pathway.
Subject(s)
Abietanes , Acute Lung Injury , NF-E2-Related Factor 2 , Oxidative Stress , Reactive Oxygen Species , Sepsis , Signal Transduction , Animals , Male , Mice , Abietanes/pharmacology , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Antigens, CD , Antioxidants/pharmacology , Apoptosis/drug effects , Cadherins/metabolism , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Inflammation/drug therapy , Lipopolysaccharides/adverse effects , Lung/drug effects , Mice, Inbred C57BL , Mitochondria/drug effects , Mitochondria/metabolism , NF-E2-Related Factor 2/metabolism , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Sepsis/complications , Sepsis/drug therapy , Signal Transduction/drug effects , Sirtuin 3/metabolismABSTRACT
Cytokines are small signaling proteins that regulate the immune responses to infection and tissue damage. Surface charges of cytokines determine their in vivo fate in immune regulation, e.g., half-life and distribution. The overall negative charges in the extracellular microenvironment and the acidosis during inflammation and infection may differentially impact cytokines with different surface charges for fine-tuned immune regulation via controlling tissue residential properties. However, the trend and role of cytokine surface charges has yet to be elucidated in the literature. Interestingly, we have observed that most pro-inflammatory cytokines have a negative charge, while most anti-inflammatory cytokines and chemokines have a positive charge. In this review, we extensively examined the surface charges of all cytokines and chemokines, summarized the pharmacokinetics and tissue adhesion of major cytokines, and analyzed the link of surface charge with cytokine biodistribution, activation, and function in immune regulation. Additionally, we identified that the general trend of charge disparity between pro- and anti-inflammatory cytokines represents a unique opportunity to develop precise immune modulation approaches, which can be applied to many inflammation-associated diseases including solid tumors, chronic wounds, infection, and sepsis.
Subject(s)
Cytokines , Inflammation , Humans , Cytokines/immunology , Animals , Inflammation/immunology , Chemokines/immunologyABSTRACT
Inflammatory macrophages play a crucial role in atherosclerosis development. The long non-coding RNA growth arrest-specific 5 (GAS5) regulates THP-1 macrophage inflammation by sponging microRNAs. The purpose of this study was to investigate the regulatory mechanism of GAS5 in atherosclerosis development. GSE40231, GSE21545, and GSE28829 datasets from the Gene Expression Omnibus database were integrated after adjusting for batch effect. Differential analysis was performed on the integrated dataset and validated using the Genotype-Tissue Expression and GSE57691 datasets. Potential biological functions of GAS5 and annexin A2 (ANXA2) were identified using gene set enrichment analysis (GSEA). ssGSEA, CIBERSORTx, and ImmuCellAI algorithms were used to identify immune infiltration in plaque samples. GAS5 and ANXA2 expression levels in RAW264.7 cells treated with oxidized low-density lipoprotein (ox-LDL) were measured by qRT-PCR and Western blot. Small interfering and short hairpin RNA were used to silence GAS5 expression. Plasmids of ANXA2 were used to establish ANXA2 overexpression. Apoptosis and inflammatory markers in macrophages were detected by Western blot. Aortic samples from APOE-/- mice were collected to validate the expression of GAS5 and ANXA2. GAS5 expression was significantly increased during atherosclerosis. GAS5 expression was positively correlated with macrophage activation and ANXA2 expression in plaques. Furthermore, ANXA2 upregulation was also related to the activation of macrophage. GSEA indicated similar biological functions for GAS5 and ANXA2 in plaques. Moreover, in vitro experiments showed that both GAS5 and ANXA2 contributed to macrophage apoptosis and inflammation. Rescue assays revealed that the inflammatory effects of GAS5 on macrophages were ANXA2-dependent. In vivo experiments confirmed the highly expression of Gas5 and Anxa2 in the plaque group. We identified the atherogenic roles of GAS5 and ANXA2 in the inflammatory response of macrophages. The inflammatory response in ox-LDL-treated macrophages was found to be mediated by GAS5-ANXA2 regulation, opening new avenues for atherosclerosis therapy.
ABSTRACT
An increasing body of studies has demonstrated the significance of long non-coding RNA (lncRNA) growth arrest specific 5 (GAS5) in inflammation and myocardial injury in septic shock. This research aims to determine whether GAS5 contributes to the pathological development of sepsis-induced cardiac damage and NLRP3 inflammasome-mediated myocardial cell pyroptosis. Cecal ligation and puncture (CLP) surgery was used to cause septic shock in C57BL/6 wild-type mice. After CLP, inflammatory, pyroptosis parameters of myocardial tissue, survival rate, and Murine Sepsis Score (MSS) were assessed to evaluate the involvement of GAS5 in the mouse myocardial depression. To investigate GAS5's function in lipopolysaccharide (LPS) induced myocardial cell pyroptosis, gain- and loss-of-function experiments were conducted in vitro on HL-1 cells. Our findings indicated that CLP dramatically reduced survival rates, MSS, SIRT3 and p-AMPK expression, and activated the Nuclear factor-κB (NF-κB) pathway and NLRP3 inflammasome-mediated pyroptosis. The NF-κB and pyroptosis pathways were greatly elevated while SIRT3/p-AMPKα was dramatically decreased as a result of GAS5 being downregulated. Meanwhile, the regulatory effect could be suppressed by SIRT3 and AMPKα activator. Our observations supported the idea that GAS5 has a crucial protective impact against myocardial inflammation and pyroptosis in sepsis.
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Manipulating working memory (WM) is a central yet challenging notion. Previous studies suggest that WM items with varied memory strengths reactivate at different latencies, supporting a time-based mechanism. Motivated by this view, here we developed a purely bottom-up "Leader-Follower" behavioral approach to manipulate WM in humans. Specifically, task-irrelevant flickering color disks that are bound to each of the memorized items are presented during the delay period, and the ongoing luminance sequences of the color disks follow a Leader-Follower relationship, that is, a hundreds of milliseconds temporal lag. We show that this dynamic behavioral approach leads to better memory performance for the item associated with the temporally advanced luminance sequence (Leader) than the item with the temporally lagged luminance sequence (Follower), yet with limited effectiveness. Together, our findings constitute evidence for the essential role of temporal dynamics in WM operation and offer a promising, noninvasive WM manipulation approach.
Subject(s)
Cognition , Memory, Short-Term , Humans , Memory, Short-Term/physiologyABSTRACT
BACKGROUND: Postoperative patients with Type A aortic dissection (TAAD) often experience severe inflammatory responses caused by multiple factors perioperatively. However, the effect of postoperative glucocorticoid (GC) use, which is a potent anti-inflammatory agent, on complications or all-cause mortality is unclear. METHODS: Patients with TAAD who underwent surgical repair requiring deep hypothermic circulatory arrest between January 2020 and December 2021 were included in the study. Characteristics of patients treated with and without GCs were compared. The primary outcome was in-hospital mortality, and a composite secondary outcome was defined as in-hospital death or any major complications. Propensity score matching was used to balance baseline differences between groups. Kaplan-Meier curves were used to compare survival probability. RESULTS: A total of 393 postoperative patients with TAAD were included in the study. Forty of them (10.2%) received GC treatment at a median daily methylprednisolone-equivalent dose of 0.6 mg/kg (0.4-0.7) for a median period of 2 (1-3) days. Patients on GCs had more intraoperative blood transfusions, higher postoperative APACHE II (12 vs 9, p = .004) and SOFA (9 vs 6, p < .001) scores, worse perioperative hepatic, renal and cardiac function. The in-hospital mortality in the matched cohort did not differ between groups [GC n = 11/40 (27.5%) versus Non-GC n = 19/80 (23.8%); p = .661]. CONCLUSIONS: The propensity to use GCs correlated with the critical status of the patient. However, low dose and short-term postoperative GC treatment did not reduce in-hospital mortality rates among patients with TAAD. A more appropriate regimen should be further investigated.
ABSTRACT
BACKGROUND: Patients receiving surgical treatment of acute type A Aortic Dissection (aTAAD) are common to suffer organ dysfunction in the intensive care unit due to overwhelming inflammation. Previous studies have revealed that glucocorticoids may reduce complications in certain patient groups, but evidence between postoperative glucocorticoids administration and improvement in organ dysfunction after aTAAD surgery are lacking. METHODS: This study will be an investigator-initiated, prospective, single-blind, randomized, single-center study. Subjects with confirmed diagnosis of aTAAD undergoing surgical treatment will be enrolled and 1:1 randomly assigned to receive either glucocorticoids or normal treatment. All patients in the glucocorticoids group will be given methylprednisolone intravenously for 3 days after enrollment. The primary endpoint will be the amplitude of variation of Sequential Organ Failure Assessment score on post-operative day 4 compared to baseline. DISCUSSION: The trial will explore the rationale for postoperative application of glucocorticoids in patients after aTAAD surgery. TRIAL REGISTRATION: This study has been registered on ClinicalTrials.gov (NCT04734418).
Subject(s)
Aortic Dissection , Glucocorticoids , Humans , Glucocorticoids/therapeutic use , Prospective Studies , Multiple Organ Failure , Single-Blind Method , Aortic Dissection/surgery , Treatment Outcome , Randomized Controlled Trials as TopicABSTRACT
To determine the effect of aerobic exercise in different intensities on renal injury and epithelial-mesenchymal transformation (EMT) in the kidney of spontaneously hypertensive rats (SHR) and explore possible mechanisms, we subjected SHR to different levels of 14-week aerobic treadmill training. We tested the effects of aerobic exercise on irisin level, renal function, and EMT modulators in the kidney. We also treated angiotensin II-induced HK-2 cells with irisin and tested the changes in EMT levels. The data showed low and moderate aerobic exercise improved renal function and inhibited EMT through promoting irisin expression in SHR. However, high-intensity exercise training had no effect on renal injury and EMT in SHR but did significantly activate STAT3 phosphorylation in the kidney. These results clarify the mechanisms of exercise in improving hypertension-related renal injury and suggest that irisin might be a therapeutic target for patients with kidney injury.
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BACKGROUND: Diabetes exacerbates vascular injury by triggering endothelial dysfunction. Endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) both play major roles in endothelial dysfunction. However, effects of hypoglycaemia, the main complication of the insulin therapy to the glycemic control in diabetes, on eNOS activity and iNOS expression, and underlying mechanisms in diabetes remain unknown. Hence, we aimed to determine the effects of hypoglycaemia on eNOS activity and iNOS expression in different arterial beds of diabetic rats. METHODS: Sprague-Dawley rats were subjected to Streptozotocin (STZ) combined with high fat diet (HFD) to induce diabetes and then received insulin injection to attain acute and recurrent hypoglycaemia. Immunoblotting was used to analyse the phosphorylation and O-glycosylation status of eNOS and iNOS level from thoracic aorta and mesenteric artery tissue. Indicators of oxidative stress from plasm were determined, and endothelial-dependent vasodilation was detected via wire myograph system. RESULTS: Hypoglycaemia was associated with a marked increase in eNOS O-GlcNAcylation and decrease in Serine (Ser)-1177 phosphorylation from thoracic aortas and mesenteric arteries. Moreover, hypoglycaemia resulted in elevated phosphorylation of eNOS at Threonine (Thr)-495 site in mesenteric arteries. Besides, changes in these post-translational modifications were associated with increased O-GlcNAc transferase (OGT), decreased phosphorylation of Akt at Ser-473, and increased protein kinase C α subunit (PKCα). iNOS expression was induced in hypoglycaemia. Furthermore, endothelial-dependent vasodilation was impaired under insulin-induced hypoglycaemia, and further in recurrent hypoglycaemia. CONCLUSIONS: Conclusively, these findings strongly indicate that hypoglycaemia-dependent vascular dysfunction in diabetes is mediated through altered eNOS activity and iNOS expression. Therefore, this implies that therapeutic modulation of eNOS activity and iNOS expression in diabetics under intensive glucose control may prevent and treat adverse cardiovascular events.
Subject(s)
Diabetes Mellitus, Experimental , Hypoglycemia , Insulins , Vascular Diseases , Rats , Animals , Nitric Oxide Synthase Type III/metabolism , Vasodilation , Nitric Oxide Synthase Type II/metabolism , Rats, Sprague-Dawley , Endothelium, Vascular/metabolism , Phosphorylation , Insulins/metabolism , Insulins/pharmacology , Insulins/therapeutic use , Nitric Oxide/metabolismABSTRACT
Background: Hypoperfusion, a common manifestation of many critical illnesses, could lead to abnormalities in body surface thermal distribution. However, the interpretation of thermal images is difficult. Our aim was to assess the mortality risk of critically ill patients at risk of hypoperfusion in a prospective cohort by infrared thermography combined with deep learning methods. Methods: This post-hoc study was based on a cohort at high-risk of hypoperfusion. Patients' legs were selected as the region of interest. Thermal images and conventional hypoperfusion parameters were collected. Six deep learning models were attempted to derive the risk of mortality (range: 0 to 100%) for each patient. The area under the receiver operating characteristic curve (AUROC) was used to evaluate predictive accuracy. Results: Fifty-five hospital deaths occurred in a cohort consisting of 373 patients. The conventional hypoperfusion (capillary refill time and diastolic blood pressure) and thermal (low temperature area rate and standard deviation) parameters demonstrated similar predictive accuracies for hospital mortality (AUROC 0.73 and 0.77). The deep learning methods, especially the ResNet (18), could further improve the accuracy. The AUROC of ResNet (18) was 0.94 with a sensitivity of 84% and a specificity of 91% when using a cutoff of 36%. ResNet (18) presented a significantly increasing trend in the risk of mortality in patients with normotension (13 [7 to 26]), hypotension (18 [8 to 32]) and shock (28 [14 to 62]). Conclusions: Interpreting infrared thermography with deep learning enables accurate and non-invasive assessment of the severity of patients at risk of hypoperfusion.
ABSTRACT
Endothelial dysfunction develops gradually with age, and is the foundation of many age-related diseases in the elderly. The purpose of this study was to investigate the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in aging-related endothelial dysfunction. Endothelial functional parameters and biochemical indices of vascular function were examined in 2-, 6-, 12- and 24-month-old mice. Then, 6-month-old mice were administered RU.521, a specific inhibitor of cGAS, for 6 months, and endothelial functional parameters and biochemical indices of vascular function were re-examined. An in vitro model of cell senescence was established by treating human aortic endothelial cells (HAECs) with D-Galactose (D-GAL). Using inhibitors or siRNA interference, cGAS and STING were suppressed or silenced in senescent HAECs, and changes in the expression of eNOS, the senescence markers, p53, p21 and p16, components of the cGAS-STING pathway and Senescence-Associated ß-galactosidase (SA-ß-gal) staining were examined. Finally, cGAS, STING and p-IRF3 levels were measured in aorta tissue sections from eight patients. A decline in endothelial function, up-regulation of p53, p21 and p16 expression, and activation of the cGAS-STING pathway were observed in aging mice. Inhibition of cGAS was found to improve endothelial function and reverse the increased expression of aging markers. Our in vitro data demonstrated that D-GAL induced a decrease in eNOS expression and cell senescence, which could be partly reversed by cGAS inhibitor, STING inhibitor, siRNA-cGAS and siRNA-STING treatment. Higher expression levels of cGAS, STING and p-IRF3 were observed in aged human aortic intima tissue compared to young aortic intima tissue. Our study demonstrated that activation of the cGAS-STING pathway played a vital role in aging-related endothelial dysfunction. Thus, the cGAS-STING pathway may be a potential target for the prevention of cardiovascular diseases in the elderly.
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Vascular smooth muscle cells (VSMCs) play a central role in atherosclerosis progression, but the functional changes in VSMCs and the associated cellular crosstalk during atherosclerosis progression remain unknown. Here we show that scRNA-seq analysis of proximal adjacent (PA) and atherosclerotic core (AC) regions of human carotid artery plaques identifies functional alterations in macrophage-like VSMCs, elucidating the main state differences between PA and AC VSMCs. And, IL-1ß mediates macrophage-macrophage-like VSMC crosstalk through regulating key transcription factors involved in macrophage-like VSMCs functional alterations during atherosclerosis progression. In vitro assays reveal VSMCs trans-differentiated into a macrophage-like phenotype and then functional alterations in response to macrophage-derived stimuli. IL-1ß promots the adhesion, inflammation, and apoptosis of macrophage-like VSMCs in a STAT3 dependent manner. The current findings provide interesting insight into the macrophages-macrophage-like VSMC crosstalk, which would drive functional alterations in the latter cell type through IL-1ß/STAT3 axis during atherosclerosis progression.
Subject(s)
Atherosclerosis , Muscle, Smooth, Vascular , Humans , Myocytes, Smooth Muscle , Macrophages , Leukocyte Count , STAT3 Transcription FactorABSTRACT
OBJECTIVES: This study assessed the impact of early postoperative organ dysfunction (EPOD) on in-hospital mortality of patients with type A aortic dissection (TAAD) after surgery. METHODS: Patients with TAAD who underwent surgical repair requiring deep hypothermic circulatory arrest from January 2020 to December 2021 were included. The Sequential Organ Failure Assessment (SOFA) score was calculated for 3 days postoperatively to stratify the severity of organ dysfunction. Patients with the SOFA of 0-4, 5-8 or >8 were defined as mild, moderate or severe EPOD. The primary outcome was in-hospital mortality, and a composite secondary outcome was defined as in-hospital death or any major complications. Kaplan-Meier curves were used to compare survival probability. The area under the receiver operating characteristic curve and calibration plots were used to evaluate the predictive power and overall performance of SOFA. RESULTS: Of the 368 patients, 5 patients (3%) with moderate EPOD and 33 patients (23%) with severe EPOD died. No patient died with mild EPOD. The areas under the receiver operating characteristic curve of SOFA for predicting mortality and the composite outcome were 0.85 (0.81-0.88) and 0.81 (0.77-0.85) on postoperative day 1. Each point of postoperative day 1 SOFA score corresponded to an odds ratio of 1.65 (1.42-1.92) for mortality. Of the 6 components of the SOFA system, only coagulation (2.34 [1.32-4.13]), cardiovascular (1.47 [1.04-2.08]), central nervous system (1.96 [1.36-2.82]) and renal (1.67 [1.04-2.70]) functions were associated with the higher risk of mortality. CONCLUSIONS: EPOD stratified by the SOFA score was associated with a higher risk of death and predicted the clinical outcomes of patients with TAAD with good accuracy.
Subject(s)
Aortic Dissection , Multiple Organ Failure , Humans , Hospital Mortality , Multiple Organ Failure/etiology , ROC Curve , Aortic Dissection/surgery , Aortic Dissection/complications , Organ Dysfunction Scores , Prognosis , Retrospective Studies , Intensive Care UnitsABSTRACT
In this editorial, we comment on the current development and deployment of data science in intensive care units (ICUs). Data in ICUs can be classified into qualitative and quantitative data with different technologies needed to translate and interpret them. Data science, in the form of artificial intelligence (AI), should find the right interaction between physicians, data and algorithm. For individual patients and physicians, sepsis and mechanical ventilation have been two important aspects where AI has been extensively studied. However, major risks of bias, lack of generalizability and poor clinical values remain. AI deployment in the ICUs should be emphasized more to facilitate AI development. For ICU management, AI has a huge potential in transforming resource allocation. The coronavirus disease 2019 pandemic has given opportunities to establish such systems which should be investigated further. Ethical concerns must be addressed when designing such AI.