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Objective: To evaluate wolfram as a photon and beta absorber in the management of uveal melanoma with radiotherapy, examining its potential ocular adverse effects and physiologic tolerance using an in vivo rabbit ocular model., Methods: A method of manufacturing implants from mixtures of wolfram and silicone was developed. Their shielding effect on the radiation of sources used in ocular brachytherapy was investigated by dosimetric measurement in an eye phantom as well as numerical simulations. Different wolfram implantation techniques, such as extraocular fixation of a wolfram-silicone implant (n = 1), vitrectomy with silicone oil and intravitreal injection of a wolfram-silicone oil suspension (n = 2), and concurrent attachment of a wolfram implant onto the sclera (n = 2), were tested to investigate the long-term effects of wolfram. A vitrectomy with silicone oil without wolfram implantation was carried out in 2 rabbits (n = 2), constituting the control group. The eyes were enucleated after 3 months for histologic analysis., Results: Wolfram-silicone mixtures have been dosimetrically proven to be very effective radiation absorbers for use in ocular brachytherapy. Severe complications, such as endophthalmitis, secondary glaucoma, cornea decompensation, and vessel occlusion, were not documented in the tested rabbit eyes after the application of wolfram. Histologic examination of the bulbi after enucleation showed epiretinal gliosis without further pathologic findings in all eyes after vitrectomy., Conclusions: The results of this study show that wolfram and wolfram-silicone implants constitute a promising candidate as potential radiation shielding substrates., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Reliability of power supply for current implantable electronic devices is a critical issue for longevity and for reducing the risk of device failure. Energy harvesting is an emerging technology, representing a strategy for establishing autonomous power supply by utilizing biomechanical movements in human body. Here, a novel "Twistron energy cell harvester" (TECH), consisting of coiled carbon nanotube yarn that converts mechanical energy of the beating heart into electrical energy, is presented. The performance of TECH is evaluated in an in vitro artificial heartbeat system which simulates the deformation pattern of the cardiac surface, reaching a maximum peak power of 1.42 W kg -1 and average power of 0.39 W kg -1 at 60 beats per minute. In vivo implantation of TECH onto the left ventricular surface in a porcine model continuously generates electrical energy from cardiac contraction. The generated electrical energy is used for direct pacing of the heart as documented by extensive electrophysiology mapping. Implanted modified carbon nanotubes are applicable as a source for harvesting biomechanical energy from cardiac motion for power supply or cardiac pacing., (© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite local tumor control, no effective therapy has been found to prevent metastasis, resulting in a high mortality rate. In the present study, we evaluated the anti-tumor potential of non-selective ß-blockers in 3D tumor spheroids grown from UM cell lines. Of the various ß-blockers tested, carvedilol and its enantiomers were most potent in decreasing the viability of Mel270 spheroids. Carvedilol at a concentration of 10-50 µM significantly elicited cytotoxicity and induced apoptosis in spheroid cells. In result, carvedilol inhibited tumor spheroid growth and compactness, and furthermore prevented the long-term survival and repopulation of spreading spheroid cells. The drug sensitivity of the different spheroids grown from Mel270, 92-1, UPMD2, or UPMM3 cell lines was dependent on 3D morphology rather than on high-risk cytogenetic profile or adrenergic receptor expression levels. In fact, the monosomy-3-containing UPMM3 cell line was most responsive to carvedilol treatment compared to the other cell lines. The concurrent treatment of UPMM3 spheroids with carvedilol and 5 or 10 Gy irradiation revealed additive cytotoxic effects that provided tumor control. Collectively, our data demonstrate the anti-tumor properties of carvedilol and its enantiomers, which may serve as candidates for the co-adjuvant therapy of UM.

The chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) is a pivotal driver of acute and chronic inflammatory conditions, cardiovascular disease, autoimmunity, and cancer. MIF modulates the early inflammatory response through various mechanisms, including regulation of neutrophil recruitment and fate, but the mechanisms and the role of the more recently described MIF homolog MIF-2 (D-dopachrome tautomerase; D-DT) are incompletely understood. Here, we show that both MIF and MIF-2/D-DT inhibit neutrophil apoptosis. This is not a direct effect, but involves the activation of mononuclear cells, which secrete CXCL8 and other prosurvival mediators to promote neutrophil survival. Individually, CXCL8 and MIF (or MIF-2) did not significantly inhibit neutrophil apoptosis, but in combination they elicited a synergistic response, promoting neutrophil survival even in the absence of mononuclear cells. The use of receptor-specific inhibitors provided evidence for a causal role of the noncognate MIF receptor CXCR2 expressed on both monocytes and neutrophils in MIF-mediated neutrophil survival. We suggest that the ability to inhibit neutrophil apoptosis contributes to the proinflammatory role ascribed to MIF, and propose that blocking the interaction between MIF and CXCR2 could be an important anti-inflammatory strategy in the early inflammatory response., (© 2021 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology.)

Background: Treatment of symptomatic peripheral artery disease (PAD) through endovascular interventions is the primary revascularization strategy. Interventions restore perfusion but may cause severe injury to the vascular endothelium, which regulates vascular tone. Endothelial dysfunction is involved in the progression of cardiovascular disease, with higher incidences of vascular events. We aimed to determine the impact of percutaneous interventions on change in endothelial function. Patients and methods: Endothelial function was determined using flow-mediated dilation (FMD) before, the day after lower limb intervention with paclitaxel-coated balloons or stent guided interventions and after a six-month follow-up in the target limb, control limb and the systemic circulation in 42 PAD patients aged 70.2±9 years and 66% men. Additionally, macro- and microvascular function were assessed. Results: In PAD patients aged 70.2±9 years and 66% men, we observed an immediate enhancement of macro-, microvascular and endothelial function after endovascular treatment (FMD of superficial femoral artery (SFA) 3.7±0.2% to 4.1±0.1%, n=42, p=0.02), a sustained long-term improvement after 6-months (FMD SFA 3.7±0.2% to 4.2±0.1%, n=42, p=0.01), and moreover an improved systemic endothelial function (FMD brachial artery 4.3±0.1% to 4.7±0.2, n=42, p=0.01) following peripheral interventions. Subgroup analysis however revealed that following paclitaxel-based percutaneous intervention, the paclitaxel dosage applied was inversely related to the chronic improvement in local endothelial function (r=-0.6, n=22, p=0.005) without evidence for systemic effects (r=-0.25, p=0.27). Conclusions: We demonstrate an improved local and systemic endothelial function after treatment of atherosclerotic peripheral disease with a distinguished response after endovascular intervention with higher dosage of applied paclitaxel restraining the benefits. Further studies have to determine the optimal interventional strategy with respect to different treatment modalities to maintain vessel functions.

Coronavirus disease 2019 (COVID-19) is challenging the care for cardiovascular patients, resulting in serious consequences with increasing mortality in pre-diseased heart failure patients. In the current state of the pandemic, the physiopathology of COVID-19 affecting pre-diseased hearts and the management of terminal heart failure in COVID-19 patients remain unclear. We outline the findings of a young COVID-19 patient suffering from idiopathic cardiomyopathy who was treated for acute multi-organ failure and required cardiac surgery with implantation of a temporary right ventricular and durable left ventricular assist device (LVAD). For deeper translational insights, we used in-depth tissue analysis by electron and light sheet fluorescence microscopy revealing evidence for spatial distribution of severe acute respiratory syndrome coronavirus 2 in the heart. This indicates that in-depth analysis may represent a valuable tool in understanding indistinct clinical cases. We conclude that COVID-19 directly affects pre-diseased hearts, but the consequences can be treated successfully with LVAD implantation., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Nonalcoholic fatty liver disease (NAFLD) is quickly becoming the most common liver disease worldwide. Within the NAFLD spectrum, patients with nonalcoholic steatohepatitis (NASH) are at the highest risk of developing cirrhosis and disease progression to hepatocellular carcinoma. To date, therapeutic options for NASH patients have been ineffective, and therefore, new options are urgently needed. Hence, a model system to develop new therapeutic interventions is needed. Here, we introduce two new in vitro models of steatosis induction in HepG2 cells and primary murine hepatocytes. We used a recently discovered novel class of bioactive anti-inflammatory lipids called branched fatty acid esters of hydroxyl fatty acids. Among these bioactive lipids, palmitic-acid-9-hydroxy-stearic-acid (9-PAHSA) is the most promising as a representative nondrug therapy based on dietary supplements or nutritional modifications. In this study, we show a therapeutic effect of 9-PAHSA on lipotoxicity in steatotic primary hepatocytes and HepG2 cells. This could be shown be increased viability and decreased steatosis. Furthermore, we could demonstrate a preventive effect in HepG2 cells. The outcome of 9-PAHSA administration is both preventative and therapeutically effective for hepatocytes with limited damage. In conclusion, bioactive lipids like 9-PAHSA offer new hope for prevention or treatment in patients with fatty liver and steatosis.

Angiotensin (Ang)-(1-7) ameliorates vascular injury by increasing nitric oxide (NO) bioavailability. Evidence that Ang-(1-7) attenuates the development of atherosclerosis through a NO-dependent mechanism is still missing. Moreover, it has been postulated that Ang-(1-7) may mediate its effects by other mechanisms than Mas receptor activation. To investigate Ang-(1-7)-dependent Mas receptor function, we treated apoE-KO and apoE/Mas-KO mice chronically with Ang-(1-7) (82 μg/kg per hour) or saline for 6 weeks. Flow-mediated dilation (FMD), a measure for NO-dependent vasodilation and the most accepted prognostic marker for the development of atherosclerosis, was measured in vivo. Chronic Ang-(1-7) treatment improved FMD and attenuated the development of atherosclerosis in apolipoproteinE (apoE)-KO but not in apoE/Mas-KO mice. These effects were accompanied by increased aortic nitrite and cGMP levels. To test whether Ang-(1-7) modulates atherosclerosis through a NO-dependent mechanism, apoE-KO mice were treated with the NO synthase inhibitor L-NAME (20 mg/kg/day) in the presence or absence of Ang-(1-7). L-NAME treatment reduced aortic nitrite content and increased blood pressure and exaggerated atherosclerosis compared to untreated apoE-KO mice. In L-NAME-treated apoE-KO mice, chronic Ang-(1-7) treatment did not increase aortic nitrite content and consequently showed no effect on blood pressure and the development of atherosclerosis. The present study proves that Ang-(1-7) mediates its protective vascular effects through Mas receptor activation. Moreover, Ang-(1-7)-mediated NO generation is essential for improving vascular function and prevents atherosclerosis in apoE-KO mice.

Endothelial dysfunction with impaired bioavailability of nitric oxide (NO) is the hallmark in the development of cardiovascular disease. Endothelial dysfunction leads to atherosclerosis, characterized by chronic inflammation of the arterial wall and stepwise narrowing of the vessel lumen. Atherosclerosis causes deprivation of adequate tissue blood flow with compromised oxygen supply. To overcome this undersupply, remodeling of the vascular network is necessary to reconstitute and sustain tissue viability. This physiological response is often not sufficient and therapeutic angiogenesis remains an unmet medical need in critical limb ischemia or coronary artery disease. Feasible approaches to promote blood vessel formation are sparse. Administration of pro-angiogenic factors, gene therapy, or targeting of microRNAs has not yet entered the daily practice. Nitric oxide is an important mediator of angiogenesis that becomes limited under ischemic conditions and the maintenance of NO availability might constitute an attractive therapeutic target. Until recently it was unknown how the organism provides NO under ischemia. In recent years it could be demonstrated that NO can be formed independently of its enzymatic synthesis in the endothelium by reduction of inorganic nitrite under hypoxic conditions. Circulating nitrite derives from oxidation of NO or reduction of inorganic nitrate by commensal bacteria in the oral cavity. Intriguingly, nitrate is a common constituent of our everyday diet and particularly high concentrations are found in leafy green vegetables such as spinach, lettuce, or beetroot. Evidence suggests that dietary nitrate supplementation increases the regenerative capacity of ischemic tissue and that this effect may offer an attractive nutrition-based strategy to improve ischemia-induced revascularization. We here summarize and discuss the regenerative capacity of dietary nitrate on the vascular system.

Acute coronary syndromes remain a leading single cause of death worldwide. Therapeutic strategies to treat cardiomyocyte threatening ischemia/reperfusion injury are urgently needed. Remote ischemic preconditioning (rIPC) applied by brief ischemic episodes to heart-distant organs has been tested in several clinical studies, and the major body of evidence points to beneficial effects of rIPC for patients. The underlying signaling, however, remains incompletely understood. This relates particularly to the mechanism by which the protective signal is transferred from the remote site to the target organ. Many pathways have been forwarded but none can explain the protective effects completely. In light of recent experimental studies, we here outline the current knowledge relating to the generation of the protective signal in the remote organ, the signal transfer to the target organ and the transduction of the transferred signal into cardioprotection. The majority of studies favors a humoral factor that activates cardiomyocyte downstream signaling - receptor-dependent and independently. Cellular targets include deleterious calcium (Ca(2+)) signaling, reactive oxygen species, mitochondrial function and structure, and cellular apoptosis and necrosis. Following an outline of the existing evidence, we will furthermore characterize the existing knowledge and discuss future perspectives with particular emphasis on the interaction between the recently discovered hypoxic nitrite-nitric oxide signaling in rIPC. This refers to the protective role of nitrite, which can be activated endogenously using rIPC and which then contributes to cardioprotection by rIPC.

Background: End stage renal disease (ESRD) patients are characterized by increased morbidity and mortality due to highest prevalence of cardiovascular disease. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that controls cellular signaling in human physiology, pathophysiology, and diseases. Increased MIF plasma levels promote vascular inflammation and development of atherosclerosis. We have shown that MIF is associated with vascular dysfunction in ESRD patients. Whether hemodialysis (HD) affects circulating MIF plasma levels is unknown. We here aimed to investigate whether HD influences the circulating MIF pool in ESRD patients., Methods and Results: An observational single-center study was conducted. MIF plasma levels in ESRD patients were assessed before, during, and after a HD session (n = 29). Healthy age-matched volunteers served as controls to compare correlations of MIF plasma levels with inflammatory plasma components (n = 20). MIF removed from the circulating blood pool could be detected in the dialysate and allowed for calculation of totally removed MIF (MIF content in dialysate 219±4 μg/HD-session). MIF plasma levels were markedly decreased 2 hour after initiation of HD (MIF plasma level pre-HD 84.8±6 ng/ml to intra-HD 61.2±5 ng/ml p<0.001) and were replenished already 20 min after termination of HD to basal levels (intra-HD 61.2±5 ng/ml to post-HD 79.8±5 ng/ml, p<0.001)., Conclusion: MIF is a dialyzable plasma component that is effectively filtrated during HD from the patient blood pool in large amounts. After removal of remarkable amounts of MIF during a single HD session, MIF plasma pool is early reconstituted after termination of HD from unknown sources.

Aims: To characterize the time course of tumor necrosis factor-α (TNF-α) serum levels along with myocardial perfusion and contractile function in patients with ST-segment elevation myocardial infarction (STEMI) and successful primary percutaneous coronary intervention (PCI)., Methods: Serum levels of TNF-α, interleukin 6 (IL-6), and C-reactive protein (CRP) were measured in 42 patients with STEMI before, one and 6 days after successful PCI. Myocardial perfusion was assessed by contrast-enhanced echocardiography (ceEcho), contractile function by unenhanced two-dimensional (2DE) and real-time three-dimensional echocardiography. In a subset of 18 patients, infarct size was quantified by late gadolinium enhancement cardiovascular magnetic resonance imaging (LGE-CMR) on day six., Results: TNF-α serum levels were in the upper normal range within the first 12 h from symptom onset and increased continuously until day six, while IL-6 and CRP increased subsequently with a peak on day one after STEMI. Serum TNF-α on day one after PCI correlated with perfusion defects, wall motion abnormalities, and infarct size (ceEcho: r = 0.52, p = 0.005; 2DE: r = 0.56, p = 0.002; LGE-CMR: r = 0.83-0.86; p < 0.0001). Using multiple regression linear analysis, infarct size on day six was predicted by serum TNF-α 1 day after PCI (p = 0.006, adjusted R (2) 0.638)., Conclusion: Our data reflect the clinical significance of early TNF-α elevation in patients with STEMI and primary PCI (Controlled Clinical Trials number, NCT00529607).

There is growing evidence for nitric oxide (NO.) being involved in cell signaling and pathology. Much effort has been made to elucidate and characterize the different biochemical reaction pathways of NO.in vivo. However, a major obstacle in assessing the significance of nitrosated species and oxidized metabolites often remains: a reliable analytical technique for the detection of NO. in complex biological matrices. This chapter presents refined methodologies, such as chemiluminescence detection and flow injection analysis, compared with adequate sample processing procedures to reliably quantify and assess the circulating and resident NO(.) pool, consisting of nitrite, nitrate, nitroso, and nitrosylated species.

Although the primary function of myoglobin (Mb) has been considered to be cellular oxygen storage and supply, recent studies have suggested to classify Mb as a multifunctional allosteric enzyme. In the heart, Mb acts as a potent scavenger of nitric oxide (NO) and contributes to the attenuation of oxidative damage. Here we report that a dynamic cycle exists in which a decrease in tissue oxygen tension drives the conversion of Mb from being an NO scavenger in normoxia to an NO producer in hypoxia. The NO generated by reaction of deoxygenated Mb with nitrite is functionally relevant and leads to a downregulation of cardiac energy status, which was not observed in mice lacking Mb. As a consequence, myocardial oxygen consumption is reduced and cardiac contractility is dampened in wild-type mice. We propose that this pathway represents a novel homeostatic mechanism by which a mismatch between oxygen supply and demand in muscle is translated into the fractional increase of deoxygenated Mb exhibiting enhanced nitrite reductase activity. Thus, Mb may act as an oxygen sensor which through NO can adjust muscle energetics to limited oxygen supply.

Attenuation of endothelium-derived nitric oxide (NO) synthesis is a hallmark of endothelial dysfunction. Early detection of this disorder may have therapeutic and prognostic implications. Plasma nitrite mirrors acute and chronic changes in endothelial NO-synthase activity. We hypothesized that local plasma nitrite concentration increases during reactive hyperemia of the forearm, reflecting endothelial function. In healthy subjects (n = 11) plasma nitrite and nitrate were determined at baseline and during reactive hyperemia of the forearm using reductive gas-phase chemiluminescence and flow-injection analysis, respectively. Endothelium-dependent dilation of the brachial artery was measured as flow-mediated dilation (FMD) using high-resolution ultrasound. Results were compared to patients with endothelial dysfunction as defined by reduced FMD (n = 11). Reactive hyperemia of the forearm increased local plasma nitrite concentration from 68 +/- 5 to 126 +/- 13 nmol/L (p < 0.01), whereas in endothelial dysfunction nitrite remained unaffected (116 +/- 12 to 104 +/- 10 nmol/L; n.s.), corresponding to nitrite reserves of 94 +/- 21 and -8 +/- 4%. This was accompanied by a significantly greater increase in brachial artery diameter (FMD: 8.5 +/- 0.4% vs 2.9 +/- 0.5%, for healthy subjects and endothelial dysfunction, respectively; p < 0.001). This observation suggests that nitrite changes reflect endothelial function. Assessment of local plasma nitrite during reactive hyperemia may open new avenues in the diagnosis of vascular function.