Hypoxic tumor-associated macrophages (TAMs) acquire angiogenic and immunosuppressive properties. Yet it remains unknown if metabolic changes influence these functions. Here, we argue that hypoxic TAMs strongly upregulate the expression of REDD1, a negative regulator of mTOR. REDD1-mediated mTOR inhibition hinders glycolysis in TAMs and curtails their excessive angiogenic response, with consequent formation of abnormal blood vessels. Accordingly, REDD1 deficiency in TAMs leads to the formation of smoothly aligned, pericyte-covered, functional vessels, which prevents vessel leakiness, hypoxia, and metastases. Mechanistically, highly glycolytic REDD1-deficient TAMs outcompete endothelial cells for glucose usage that thwarts vascular hyperactivation and promotes the formation of quiescent vascular junctions. Tuning down glycolysis in REDD1 knockout TAMs re-establishes abnormal angiogenesis and metastases. On this basis, we prove that the anti-tumor effect of mTOR inhibitors is partly countered by the deleterious outcome of these drugs on TAMs. Our data provide a functional link between TAM metabolism and tumor angiogenesis.
Muscle regeneration is sustained by infiltrating macrophages and consequent satellite cell (SC) activation 1 – 4 . Macrophages and SC communicate in different ways 1 – 5 but their metabolic interplay was never investigated so far. Here, we found that muscle injuries and aging are characterized by intratissutal glutamine restriction. Low glutamine levels endow macrophages with the metabolic ability to secrete glutamine via enhanced glutamine synthetase (GS) activity at the expense of glutamate dehydrogenase-1 (GLUD1)-mediated glutamine oxidation. Glud1 knockout (KO) macrophages display constitutively high GS activity which prevents glutamine shortage. Import of macrophage-derived glutamine by SC through the glutamine-transporter SLC1A5 activates mTOR and promotes SC proliferation and differentiation. Consequently, macrophage-specific deletion or pharmacological inhibition of GLUD1 improves muscle regeneration and functional recovery in response to acute injury, ischemia, or aging. Conversely, SLC1A5 blockade in SC or GS inactivation in macrophages negatively affects SC functions and muscle regeneration. These results highlight a metabolic cross-talk between SC and macrophages whereby macrophage-derived glutamine sustains SC functions. Thus, GLUD1 targeting offers new therapeutic opportunities for the regeneration of injured or aged muscles.
In this study, we report two optical fiber-biolayer interferometry (FO-BLI)-based biosensors for the rapid detection of SARS-CoV-2 neutralizing antibodies (NAbs) and binding antibodies (BAbs) in human serum. The use of signal enhancer 3,3′-diaminobenzidine enabled the detection of NAbs, anti-receptor binding domain (anti-RBD) BAbs, and anti-extracellular domain of spike protein (anti-S-ECD) BAbs up to as low as 10 ng/mL in both buffer and 100-fold diluted serum. NAbs and BAbs could be detected individually over 7.5 and 13 min, respectively, or simultaneously by prolonging the detection time of the former. The protocol for the detection of BAbs could be utilized for detection of the RBD-N501Y variant with equal sensitivity and speed. Results of the NAbs and the anti-RBD BAbs biosensors correlated well with those of the corresponding commercial assay kit. Clinical utility of the two FO-BLI biosensors were further validated using a small cohort of samples randomly taken from 16 enrolled healthy participants who received inactivated vaccines. Two potent serum antibodies were identified, which showed high neutralizing capacities toward RBD and pseudovirus. Overall, the rapid automated biosensors can be used for an individual sample measurement of NAbs and BAbs as well as for high-throughput analysis. The findings of this study would be useful in COVID-19 related studies in vaccine trials, research on dynamics of the immune response, and epidemiology studies.
Myocardial ischemia reperfusion (I/R) injury is a complex process with intense inflammatory response and cardiomyocyte apoptosis. As a decoy receptor of IL-1β, Interleukin-1 receptor type 2 (IL-1R2) inhibits IL-1β signaling. However, its role in I/R injury remains unknown. Here we found that the serum levels of IL-1R2 were significantly increased in patients with acute myocardial infarction (AMI) following interventional therapy. Similarly, after myocardial I/R surgery, IL-1R2 expression was significantly increased in heart of wild-type mice. In addition, IL-1R2-deficient mice heart showed enlarged infarct size, increased cardiomyocyte apoptosis together with reduced cardiac systolic function. Following exposure to hypoxia and reoxygenation (H/R), neonatal rat ventricular myocytes (NRVM) significantly increased IL-1R2 expression relying on NF-κB activation. Consistently, IL-1R2-deficient mice increased immune cells infiltrating into heart after surgery, which was relevant with cardiac damage. Additionally, IL-1R2 overexpression in cardiomyocyte protected cardiomyocyte against apoptosis through reducing the IL-17RA expression both in vivo and in vitro. Our results indicate that IL-1R2 protects cardiomyocytes from apoptosis, which provides a therapeutic approach to turn down myocardial I/R injury.
Cardiovascular disease (CVD) is a serious health challenge, causing more deaths world-wide than cancer. The vascular endothelium, which forms the inner lining of blood vessels, plays a central role in maintaining vascular integrity and homeostasis and is in direct contact with the blood flow. Research over the past century has shown that mechanical perturbations of the vascular wall contribute to formation and progression of atherosclerosis. While the straight part of the artery is exposed to sustained laminar flow and physiological high shear stress, flow near branch points or in curved vessels can exhibit “disturbed” flow. Clinical studies as well as carefully controlled in vitro analyses have confirmed that these regions of disturbed flow, which can include low shear stress, recirculation, oscillation, or lateral flow, are preferential sites of atherosclerotic lesion formation. Because of their critical role in blood flow homeostasis, vascular endothelial cells (ECs) have mechanosensory mechanisms that allow them to react rapidly to changes in mechanical forces, and to execute context-specific adaptive responses to modulate EC functions. This review summarizes the current understanding of endothelial mechanobiology, which can guide the identification of new therapeutic targets to slow or reverse the progression of atherosclerosis.
Dilated cardiomyopathy (DCM) is a progressive heart muscle disease with left ventricular (LV) or biventricular dilatation and systolic dysfunction. 1 Structural or functional abnormalities of the myocardium accompanied with DCM potentially lead to life-threatening events such as arrhythmias, heart failure (HF) and sudden cardiac death. 2 Decades of research have revealed multiple causes of DCM,
Backgrounds and AimsNutritional Risk Screening 2002 (NRS-2002) has been widely recommended for identifying the nutritional risk. However, the association between NRS-2002 and the prognosis of heart failure has not been fully addressed. This study aimed to explore the association of NRS-2002 with 1-year re-hospitalization and the length of initial hospital stay in heart failure patients.MethodsThis retrospective study included 2,830 heart failure patients. The primary endpoint was 1-year re-hospitalization for heart failure. The secondary endpoint was the length of initial hospital stay. The Log-binomial regression analysis was performed to determine the association between NRS-2002 and re-hospitalization. The Cox regression model was fitted to estimate hazard of discharge. The cumulative incidence curves of discharge were plotted using Kaplan–Meier method and log-rank test was performed. Exploratory analysis was also conducted according to the classification of heart failure and the level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) fold-elevation.ResultsAmong 2,830 heart failure patients, the mean age was 64.3 years and 66.4% were male. A total of 122 (4.3%) patients were considered at high nutritional risk. Log-binomial regression analysis demonstrated that higher NRS-2002 score was an independent risk factor of re-hospitalization ([1 vs. 0]: relative risks [RR] = 1.383, 95% CI = 1.152 to 1.660; [2 vs. 0]: RR = 1.425, 95% CI = 1.108 to 1.832; [3–7 vs. 0]: RR = 1.770, 95% CI = 1.310 to 2.393). Kaplan–Meier curve showed that the cumulative incidence of discharge was lower in high nutritional risk group (Log rank p < 0.001). Cox regression analysis also found that higher NRS-2002 score (2 or ≥3) was strongly associated with longer length of initial hospital stay ([2 vs. 0]: Hazard ratios [HR] = 0.854, 95% CI = 0.748 to 0.976; [3–7 vs. 0]: HR = 0.609, 95% CI = 0.503 to 0.737). Exploratory analysis showed that such association still remained irrespective of NT-proBNP fold-elevation, but only existed in patients with heart failure with preserved ejection fraction (HFpEF).ConclusionIn patients with heart failure, high NRS-2002 score was strongly and independently associated with the incidence of 1-year re-hospitalization and the length of initial hospital stay.
Netrin-1 is a neural guidance cue that also regulates vascular development. Controversial results, however, have been obtained concerning the roles of netrin-1 in vascular development both in vivo and in vitro. In the present study, two in vitro angiogenesis assays were compared to evaluate the effects of netrin-1 secreted by retrovirally transduced melanoma cells (Mel2a-netrin1) on tube formation. The results showed that there was no obvious difference in tube formation induced by conditioned media (CM) from the control, Mel2a-netrin1 and Mel2a cells in a matrigel assay. The results of another in vitro assay, in which endothelial cells were co-cultured with human fibroblasts, however, showed that Mel2a-netrin1 CM inhibited the tube formation, supposedly through blocking the elongation and coalescence of human umbilical vein endothelial cells (HUVECs). These results confirmed that the matrigel assay is not able to demonstrate the anti-angiogenic roles of netrin-1.
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