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High-grade gliomas (HGG) comprising WHO grades 3 and 4 have a poor overall survival (OS) that has not improved in the past decade. Herein, markers representing four components of the tumor microenvironment (TME) were identified to define their linked expression in TME and predict the prognosis in HGG, namely, interleukin6 (IL6, inflammation), inducible nitric oxide synthase(iNOS), heat shock protein-70 (HSP70, hypoxia), vascular endothelial growth receptor (VEGF), and endothelin1 (ET1) (angiogenesis) and matrix metalloprotease-14 (MMP14) and intercellular adhesion molecule1 (ICAM1, extracellular matrix). To establish a non-invasive panel of biomarkers for precise prognostication in HGG. Eighty-six therapy-naive HGG patients with 45 controls were analyzed for the defined panel. Systemic expression of extracellular/secretory biomarkers was screened dot-immune assay (DIA), quantified by ELISA, and validated by immunocytochemistry (ICC). Expression of iNOS, HSP70, IL-6, VEGF, ET1, MMP14, and ICAM1 was found to be positively associated with grade. Quantification of circulating levels of the markers by ELISA and ICC presented a similar result. The biomarkers were observed to negatively correlate with OS (p < 0.0001). Cox-regression analysis yielded all biomarkers as good prognostic indicators and independent of confounders. On applying combination statistics, the biomarker panel achieved higher sensitivity than single markers to define survival. The intra-association of all seven biomarkers was significant, hinting of a cross-talk between the TME components and a hypoxia driven systemic inflammation upregulating the expression of other components. This is a first ever experimental study of a marker panel that can distinguish between histopathological grades and also delineate differential survival using liquid biopsy, suggesting that markers of hypoxia can be a cornerstone for personalized therapy. The panel of biomarkers of iNOS, HSP70, IL-6, VEGF, ET1, MMP14, and ICAM1 holds promise for prognostication in HGG. The cross-talk between the systemic biomarkers of four different partakers of tumor microenvironment [ABSTRACT FROM AUTHOR]

Aspirin is a non-steroidal, anti-inflammatory drug often used long term. However, long-term or large doses will cause gastrointestinal adverse reactions. To explore the mechanism of intestinal damage, we used non-targeted metabolomics; farnesoid X receptor (FXR) knockout mice, which were compared with wild-type mice; FXR agonists obeticholic acid (OCA) and chenodeoxycholic acid (CDCA); and endothelin-producing inhibitor estradiol to explore the mechanisms of acute and chronic intestinal injuries induced by aspirin from the perspective of molecular biology. Changes were found in the bile acids taurocholate acid (TCA) and tauro-β-muricholic acid (T-β-MCA) in the duodenum, and we detected a significant inhibition of FXR target genes. After additional administration of the FXR agonists OCA and CDCA, duodenal villus damage and inflammation were effectively improved. The results in the FXR knockout mice and wild-type mice showed that the overexpression of endothelin 1 (ET-1) was independent of FXR regulation after aspirin exposure, whereas CDCA was able to restore the activation of ET-1, which was induced by aspirin in wild-type mice in an FXR-dependent manner. The inhibition of ET-1 production could also effectively protect against small bowel damage. Therefore, the study revealed the key roles of the FXR and ET-1 pathways in acute and chronic aspirin-induced intestinal injuries, as well as strategies on alleviating aspirin-induced gastrointestinal injury by activating FXR and inhibiting ET-1 overexpression. [ABSTRACT FROM AUTHOR]

The prevalence of alopecia has increased recently. Hair loss is often accompanied by the resting phase of hair follicles (HFs). Dermal papilla (DP) plays a crucial role in HF development, growth, and regeneration. Activating DP can revive resting HFs. Augmenting WNT/β‐catenin signaling stimulates HF growth. However, the factors responsible for activating resting HFs effectively are unclear. In this study, we investigated epidermal cytokines that can activate resting HFs effectively. We overexpressed β‐catenin in both in vivo and in vitro models to observe its effects on resting HFs. Then, we screened potential epidermal cytokines from GEO DATASETs and assessed their functions using mice models and skin‐derived precursors (SKPs). Finally, we explored the molecular mechanism underlying the action of the identified cytokine. The results showed that activation of WNT/β‐catenin in the epidermis prompted telogen–anagen transition. Keratinocytes infected with Ctnnb1‐overexpressing lentivirus enhanced SKP expansion. Subsequently, we identified endothelin 1 (ET‐1) expressed higher in hair‐growing epidermis and induced the proliferation of DP cells and activates telogen‐phase HFs in vivo. Moreover, ET‐1 promotes the proliferation and stemness of SKPs. Western blot analysis and in vivo experiments revealed that ET‐1 induces the transition from telogen‐to‐anagen phase by upregulating the PI3K/AKT pathway. These findings highlight the potential of ET‐1 as a promising cytokine for HF activation and the treatment of hair loss. [ABSTRACT FROM AUTHOR]

Introduction: Psoriasis, one of the most frequent dermatoses, strongly associated with metabolic disorders which increase patients' comorbidity and mortality. Hence, it is essential to look for markers of such complications. Our aim was to assess the clinical utility of urinary tumor necrosis factor alpha (TNFα), endothelin 1 (ET-1) and α1-acid glycoprotein (α1AGP) as well as their serum concentrations as markers of metabolic complications in psoriatics, and to examine the relations of these markers to clinical and demographic parameters. Methods: The study involved 60 patients with plaque psoriasis and 30 volunteers without skin diseases (the control group). Serum and urinary concentrations of TNFα, ET-1 and α1AGP were measured by ELISA. Psoriasis severity was assessed using the psoriasis activity and severity index (PASI). Routine laboratory investigations were additionally performed. Results: All serum markers were significantly higher in the patients compared to the controls. TNFα was undetectable in the urine in half of the patients. The urinary ET-1/creatinine concentration ratio was significantly lower in the psoriatics than the controls, whereas the absolute urinary α1AGP was significantly higher and the α1AGP/creatinine ratio was insignificantly different. There was no correlation between serum or urinary markers and PASI. All serum markers were higher in patients with psoriasis lasting less than 15 years. Conclusions: Serum TNFα, ET-1 and α1AGP seem to be useful biomarkers of metabolic syndrome in psoriatics. ET-1 could perhaps become a urinary marker of metabolic disorders in psoriatics, but further studies are required to confirm that a decreased ET-1 concentration in urine is a reliable predictive tool. Increased urinary α1AGP also requires more in-depth research as a potential marker. TNFα urine assessment does not seem to be useful for screening for metabolic disorders in psoriatics. Serum or urinary TNFα, ET-1 and α1AGP do not seem to be associated with psoriasis severity or duration. [ABSTRACT FROM AUTHOR]

Abstract Introduction Psoriasis, one of the most frequent dermatoses, strongly associated with metabolic disorders which increase patients’ comorbidity and mortality. Hence, it is essential to look for markers of such complications. Our aim was to assess the clinical utility of urinary tumor necrosis factor alpha (TNFα), endothelin 1 (ET-1) and α1-acid glycoprotein (α1AGP) as well as their serum concentrations as markers of metabolic complications in psoriatics, and to examine the relations of these markers to clinical and demographic parameters. Methods The study involved 60 patients with plaque psoriasis and 30 volunteers without skin diseases (the control group). Serum and urinary concentrations of TNFα, ET-1 and α1AGP were measured by ELISA. Psoriasis severity was assessed using the psoriasis activity and severity index (PASI). Routine laboratory investigations were additionally performed. Results All serum markers were significantly higher in the patients compared to the controls. TNFα was undetectable in the urine in half of the patients. The urinary ET-1/creatinine concentration ratio was significantly lower in the psoriatics than the controls, whereas the absolute urinary α1AGP was significantly higher and the α1AGP/creatinine ratio was insignificantly different. There was no correlation between serum or urinary markers and PASI. All serum markers were higher in patients with psoriasis lasting less than 15 years. Conclusions Serum TNFα, ET-1 and α1AGP seem to be useful biomarkers of metabolic syndrome in psoriatics. ET-1 could perhaps become a urinary marker of metabolic disorders in psoriatics, but further studies are required to confirm that a decreased ET-1 concentration in urine is a reliable predictive tool. Increased urinary α1AGP also requires more in-depth research as a potential marker. TNFα urine assessment does not seem to be useful for screening for metabolic disorders in psoriatics. Serum or urinary TNFα, ET-1 and α1AGP do not seem to be associated with psoriasis severity or duration.

Background: Endothelin-1 (ET-1) is a potent vasoconstrictor substance mainly secreted by endothelial cells. Increased ET-1 levels in plasma or cerebrospinal fluid (CSF) have been identified in multiple sclerosis (MS). We aimed to analyze tear ET-1 levels; visual evoked potential (VEP) and disability scores in patients with MS and in healthy controls. Methods: Adult patients (18-65 year-old) diagnosed with MS according to the McDonald criteria, and healthy controls were recruited for the study. Demographic features, VEP, and tear ET-1 levels were evaluated. Disability in the MS group was assessed and grouped by EDSS score (<3 vs. ≥3). The EDSS score in healthy controls was zero. Results: Both in the total number of patients overall and in the patients with EDSS score <3, tear ET-1 levels were higher in the MS group than that in the controls (p<0.001). In the MS group, the ET-1 level was higher in the patients with EDSS score ≥3 than in those with EDSS score <3 (p<0.001). The tear ET-1 level was positively correlated with age and EDSS score in the MS group (p<0.001). Conclusion: To the best of our knowledge, there is no study in the literature that measures tear ET-1 levels in MS and examines their relationship with EDSS score and VEP. Higher tear ET-1 levels seem to be associated with disability and abnormal VEP in MS. Tear ET-1 measurement may be a simple new noninvasive marker indicating the disability in the patients with MS in the future. [ABSTRACT FROM AUTHOR]

The pathogenesis of hypertension is not fully understood; endothelin 1 (EDN1) is involved in developing essential hypertension. EDN1 can promote vascular smooth muscle cell (VSMC) proliferation or hypertrophy through autocrine and paracrine effects. Proliferating smooth muscle cells in the aorta are 'dedifferentiated' cells that cause increased arterial stiffness and remodeling. Male SHRs had higher aortic stiffness than normal control male WKY rats. Male SHR VSMCs expressed high levels of the EDN1 gene, but endothelial cells did not. Therefore, it is necessary to understand the molecular mechanism of enhanced EDN1 expression in SHR VSMCs. We identified POU2F2 and CEBPB as the main molecules that enhance EDN1 expression in male SHR VSMCs. A promoter activity analysis confirmed that the enhancer region of the Edn1 promoter in male SHR VSMCs was from -1309 to -1279 bp. POU2F2 and CEBPB exhibited an additive role in the enh ancer region of the EdnET1 promoter. POU2F2 or CEBPB overexpression sufficiently increased EDN1 expression, and co-transfection with the CEBPB and POU2F2 expression plasmids had additive effects on the activity of the Edn1 promoter and EDN1 secretion level of male WKY VSMCs. In addition, the knockdown of POU2F2 also revea led that POU2F2 is necessary to enhance EDN1 expression in SHR VSMCs. The enhancer region of the Edn1 promoter is highly conserved in rats, mice, and humans. POU2F2 and CEBPB mRNA levels were significantly increased in remodeled human VMSCs. In conclusion, the novel regulation of POU2F2 and CEBPB in VSMCs will help us understand the pathogenesis of hypertension and support the development of future treatments for hypertension. [ABSTRACT FROM AUTHOR]

Activin A, a member of TGF-ß superfamily, has been implicated in the pathogenesis of pulmonary artery hypertension (PAH). PAH due to congenital heart disease (CHD-PAH) is a major problem in developing countries. Activin A may have a role in PAH development and progression among uncorrected CHD. In this comparative study, serum activin A level was significantly increased in subjects with uncorrected CHD without the presence of PH and were more significantly risen in CHD-PAH, as compared to control. The utilization of serum activin A measurement seems promising to identify uncorrected CHD patients with PAH development and progression. [ABSTRACT FROM AUTHOR]

BACKGROUND: Microcirculation, as the only place for the energy metabolism of body substances, is closely related to the human movement ability. Resistance exercise is an effective way to improve the function of microcirculation, but some studies have also pointed out that blood flow restriction exercise can also improve the function of microcirculation and has the advantages of small load and high safety. OBJECTIVE: To compare the effects of 6-week low-load blood flow restriction exercise and high-intensity resistance exercise on the thigh microcirculation function of athletic young men, and to explore the possible mechanism by which exercises improve microcirculation function from the perspective of vascular endothelial function. METHODS: Sixty sports students from Hubei Minzu University were divided into control group, high-intensity resistance exercise group and low-load blood flow restriction exercise group according to the random number table method, with 20 students in each group. The low-load blood flow restriction exercise group performed a low-load blood flow restriction exercise for 6 weeks (three times a week, 90 minutes each, at an exercise intensity of 30% 1RM). The high-intensity resistance exercise group received a high-intensity resistance exercise for 6 weeks (three times a week, 90 minutes each, at an exercise intensity of 70% 1RM). The control group did not perform any form of exercise training during this period. Microcirculatory blood perfusion, transcutaneous partial pressure, muscle oxygen saturation, nitric oxide, endothelial nitric oxide synthase, endothelin 1, vascular endothelial cell growth factor, thigh circumference, and muscle strength were tested in each group on the day before the intervention and the morning after the end of the 6-week intervention. RESULTS AND CONCLUSION: After the exercise intervention, heating values of microcirculatory blood flow perfusion and blood cell movement speed in the low-load blood flow restriction exercise group and the high-intensity resistance exercise group were significantly different from those in the control group and before the exercise intervention (P < 0.05). The heating values of microcirculatory blood flow perfusion and blood cell movement speed showed significant differences between the low-load blood flow restriction exercise group and the high-intensity resistance exercise group (P < 0.05). After the exercise intervention, the levels of nitric oxide, endothelial nitric oxide synthase, endothelin 1, and vascular endothelial cell growth factor were significantly different in the low-load blood flow-limiting exercise group and the high-intensity resistance exercise group compared with the control group and the pre-exercise intervention (P < 0.05). After the exercise intervention, thigh circumference and thigh muscle strength were significantly different in low-load blood flow restriction group and high-intensity resistance exercise groups compared with the pre-exercise intervention (P < 0.05). All these findings indicate that 6-week low-load blood flow restriction exercise and high intensity resistance exercise may regulate the secretion of vascular factors such as endogenous nitric oxide synthase, endothelin-1 and vascular endothelial growth factor to improve the function of thigh microcirculation and increase the contractile strength of the thigh muscle. In addition, And low-load blood flow restriction exercise has better intervention effects on microcirculatory blood perfusion volume and blood cell movement speed, so low-load blood flow restriction exercise is more advantageous than high-intensity resistance exercise in improving microcirculation function. [ABSTRACT FROM AUTHOR]

Aspirin is a non-steroidal, anti-inflammatory drug often used long term. However, long-term or large doses will cause gastrointestinal adverse reactions. To explore the mechanism of intestinal damage, we used non-targeted metabolomics; farnesoid X receptor (FXR) knockout mice, which were compared with wild-type mice; FXR agonists obeticholic acid (OCA) and chenodeoxycholic acid (CDCA); and endothelin-producing inhibitor estradiol to explore the mechanisms of acute and chronic intestinal injuries induced by aspirin from the perspective of molecular biology. Changes were found in the bile acids taurocholate acid (TCA) and tauro-β-muricholic acid (T-β-MCA) in the duodenum, and we detected a significant inhibition of FXR target genes. After additional administration of the FXR agonists OCA and CDCA, duodenal villus damage and inflammation were effectively improved. The results in the FXR knockout mice and wild-type mice showed that the overexpression of endothelin 1 (ET-1) was independent of FXR regulation after aspirin exposure, whereas CDCA was able to restore the activation of ET-1, which was induced by aspirin in wild-type mice in an FXR-dependent manner. The inhibition of ET-1 production could also effectively protect against small bowel damage. Therefore, the study revealed the key roles of the FXR and ET-1 pathways in acute and chronic aspirin-induced intestinal injuries, as well as strategies on alleviating aspirin-induced gastrointestinal injury by activating FXR and inhibiting ET-1 overexpression.

Abstract Activin A, a member of TGF‐β superfamily, has been implicated in the pathogenesis of pulmonary artery hypertension (PAH). PAH due to congenital heart disease (CHD‐PAH) is a major problem in developing countries. Activin A may have a role in PAH development and progression among uncorrected CHD. In this comparative study, serum activin A level was significantly increased in subjects with uncorrected CHD without the presence of PH and were more significantly risen in CHD‐PAH, as compared to control. The utilization of serum activin A measurement seems promising to identify uncorrected CHD patients with PAH development and progression.

Endothelin and its two different cognate receptors have been implicated in a wide variety of pathophysiological conditions since it was first identified as a vasoactive local hormone. Especially in the last decade, the studies revealed that the aberrant expression of endothelin axis has critical importance in the cancer biology involving in neovascularization, cellular survival, metastasis as well as drug resistance, by taking part in different signalling mechanisms within the cell. This situation has attracted the attention of many scientists to investigate not only reveal the molecular mechanistic role of endothelin axis in cancer pathophysiology but also design new drugs targeting the endothelin axis. Further studies suggest that utilizing endothelin axis as a new diagnostic parameter to define malignant features and monitor the prognoses of cancer This study, which was compiled from both preclinical and clinical studies, was prepared to provide an overview of the potential role of the endothelin axis in cancer biology, as well as an overview of the drugs developed against the endothelin axis. [ABSTRACT FROM AUTHOR]

Hepatic ischemia-reperfusion injury (HIRI) is the main complication and even mortality in the setting of hepatic surgery or transplantation. Inflammation, especially the neutrophil response, plays important roles during the process of HIRI. In this study, we found that resveratrol preintervention ameliorated IRI-induced hepatic injury and neutrophil inflammatory responses in the liver. Moreover, RNA-sequencing analysis showed that resveratrol inhibited the functions of neutrophils, such as survival, cell cycle, migration and chemotaxis, oxidative stress and secretion of proinflammatory cytokines. Resveratrol restrained oxidative stress and the inflammatory response of neutrophils via inhibition of endothelin 1 autocrine signaling by suppressing the ERK signaling pathway. These data provide more evidence for the immunomodulatory role of resveratrol and enrich our understanding of immune strategies to improve HIRI.

Purpose: It has been hypothesized that epithelial–mesenchymal transition (EMT) may occur in the retinal pigment epithelium of advanced stage age‐related macular degeneration (AMD). Various serum and plasma growth factors and inflammatory mediators have been linked to AMD. We were interested in finding out whether systemic levels of EMT‐associated markers were altered in the serum of wet AMD patients. Serum biomarkers associated with the various pathological processes of AMD may present an avenue towards identifying and characterizing the birth mechanisms of wet AMD, its progression and severity, paving the way towards the application of precision medicine. Methods: We chose to measure the serum levels of known biomarkers of EMT – EGF (epidermal growth factor), ET‐1 (endothelin 1), IL‐8 (interleukin 8), TGF‐β1 and TGF‐β2 (transforming growth factor‐beta 1 and 2) and VEGF‐A (vascular endothelial growth factor A) – using enzyme‐linked immunosorbent assays. We measured them from 71 Finnish wet AMD patients who were receiving intravitreal anti‐VEGF‐A injection treatments, as well as 64 age‐adjusted controls. Results: We found significantly elevated levels of ET‐1, IL‐8 and TGF‐β2 in the serums of wet AMD patients. Conclusions: ET‐1, IL‐8 and TGF‐β2 appear to be useful serum biomarkers in understanding active wet AMD. However, we cannot conclude that local retinal EMT‐processes could be observed from the corresponding systemic serum biomarkers in patients undergoing anti‐VEGF‐A treatments. [ABSTRACT FROM AUTHOR]

As survival in breast cancer patients from newer therapies increases, concerns for chemotherapy-induced cardiotoxicity (CIC) have offset some of these benefits, manifesting as a decline in left ventricular ejection fraction (LVEF). Patients receiving anthracycline-based chemotherapy followed by trastuzumab are at risk for CIC. Previous research evaluating whether clinical biomarkers predict cardiotoxicity has been inconsistent. Recently, angiotensin II type 1 receptor (ATR1) and endothelin 1 (ET1) have been shown to play a role in breast tumor growth. We evaluated ATR1 and ET1 expression in breast cancer tissue and its association with CIC. A total of 33 paraffin-embedded breast tissue specimens from women with breast cancer treated with anthracycline-based chemotherapy and trastuzumab were analyzed by immunohistochemistry (IHC) and qRT-PCR. We found that ET1 expression was increased in patients with an LVEF ≤ 50% (p = 0.032) with a lower LVEF correlating with higher ET1 expression (r = 0.377, p = 0.031). In patients with a change in LVEF of greater than 10%, greater ET1 expression was noted compared to those without a change in LVEF (p = 0.017). Increased ET1 expression in breast tumor tissue is associated with reduced LVEF. Future studies need to examine whether ET1 may be a tissue biomarker that helps predict the risk of developing CIC in women with breast cancer. [ABSTRACT FROM AUTHOR]

Hypertension is the most determinant risk factor for cardiovascular diseases. Early intervention and future therapies targeting hypertension mechanisms may improve the quality of life and clinical outcomes. Hypertension has a complex multifactorial aetiology and was recently associated with protein homeostasis (proteostasis). This work aimed to characterize proteostasis in easy-to-access plasma samples from 40 individuals, 20 with controlled hypertension and 20 age- and gender-matched normotensive individuals. Proteostasis was evaluated by quantifying the levels of protein aggregates through different techniques, including fluorescent probes, slot blot immunoassays and Fourier-transform infrared spectroscopy (FTIR). No significant between-group differences were observed in the absolute levels of various protein aggregates (Proteostat or Thioflavin T-stained aggregates; prefibrillar oligomers and fibrils) or total levels of proteostasis-related proteins (Ubiquitin and Clusterin). However, significant positive associations between Endothelin 1 and protein aggregation or proteostasis biomarkers (such as fibrils and ubiquitin) were only observed in the hypertension group. The same is true for the association between the proteins involved in quality control and protein aggregates. These results suggest that proteostasis mechanisms are actively engaged in hypertension as a coping mechanism to counteract its pathological effects in proteome stability, even when individuals are chronically medicated and presenting controlled blood pressure levels. [ABSTRACT FROM AUTHOR]

Background: Inflammatory response and endothelial dysfunction contribute to the progression of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to assess changes in biomarkers involved in those processes in inoperable CTEPH patients treated with balloon pulmonary angioplasty (BPA). Methods: We enrolled 20 patients with inoperable CTEPH qualified for BPA and a control group. Interleukin 6, 8, 10 (IL-6, IL-8, IL-10), monocyte chemoattractant protein-1 (MCP-1), and C-reactive protein (hsCRP) constituted the markers of systemic inflammation. Endothelin 1 (ET-1) served as a marker of endothelial dysfunction. Selected markers were assessed before the BPA treatment, 24 h after the first BPA, and six months after completion of the BPA treatment. Results: At baseline, the CTEPH patients had increased serum concentrations of IL-6, IL-8 and ET-1. Twenty-four hours after a BPA session, we observed an increase in concentrations of IL-6 (∆ = 3.67 (1.41; 7.16); p < 0.001), of IL-10 (∆ = 0.25 (0; 0.47); p = 0.003), of MCP-1 (∆ = 111 (60.1; 202.8); p = 0.002), and of hsCRP (∆ = 4.81 (3.46; 8.47); p < 0.001). Six months after completion of the BPA treatment, there was a decrease in concentrations of IL-6 (∆ = −1.61 (−3.11; −0.20); p = 0.03), of IL8 (∆ = −3.24 (−7.72; 0.82); p = 0.01), and of ET-1 (∆ = −0.47 (−0.96; 0.05); p = 0.005). Conclusions: Patients with inoperable CTEPH exhibit increased systemic inflammation and endothelial dysfunction, which improves after completion of the BPA treatment. A single BPA session evokes an acute inflammatory response. [ABSTRACT FROM AUTHOR]

The aortic endothelium is crucial in preserving vascular tone through endothelium-derived vasodilators and vasoconstrictors. Dysfunction in the endothelium is an early indicator of cardiovascular diseases. Our study explores the therapeutic potential of a dual-acting peptide (DAP) to co-activate Mas and pGCA receptors and restore the balance between vasodilators and vasoconstrictors on endothelial dysfunction in DOCA-salt-induced hypertensive rats. DOCA-salt was administered to male wistar rats to induce hypertension, and various parameters, including blood pressure (BP), water intake and body weight were monitored. DAP, Ang1–7, BNP, and losartan were administered to hypertensive rats for three weeks. Histological analysis and isometric tension studies were carried out to assess endothelial function. In addition to this, we used primary aortic endothelial cells for detailed mechanistic investigations. DOCA-salt administration significantly elevated systolic, diastolic, mean arterial BP, and water intake whereas, downregulated the gene expression of Mas and pGCA receptors. However, DAP co-administration attenuated BP increase, upregulated the gene expression of Mas and pGCA receptors, normalized serum and urinary parameters, and effectively reduced fibrosis, inflammation, and vascular calcification. Notably, DAP outperformed the standard drug, Losartan. Our findings indicate that DAP restores aortic function by balancing the NO and ET1-induced pathways. Co-activating Mas and pGCA receptors with DAP mitigates vascular damage and enhances endothelial function, emphasizing its potential to maintain a delicate balance between vasodilatory NO and vasoconstrictor ET1 in endothelial dysfunction. [Display omitted] • Ang1-7 & BNP, endogenous ligands of Mas & pGCA receptors, show heart & kidney protection, but use is limited by short half-life. • Simultaneous activation of multiple receptors may enhance effects beyond individual receptor activation. • Ang1-7 & BNP induce vasodilation, crucial for endothelial-dependent smooth muscle contraction and relaxation • New therapeutic targeting nitric oxide/cGMP & ET-1 pathways is the standalone therapy for vascular diseases. • Further research needed to explore Mas and pGCA receptors' role in regulating NO and ET1 balance in cardiovascular conditions [ABSTRACT FROM AUTHOR]

OBJECTIVES: To evaluate endothelin 1 (ET-1) serum levels in women with systemic sclerosis compared with healthy controls and to examine possible associations between ET-1 and markers of arterial stiffness. MATERIALS AND METHODS: A cross-sectional study was performed in San Cecilio Hospital, Granada, Spain, from November 2017 to May 2019. Women with systemic sclerosis and age and sex matched healthy controls were enrolled in this study. Pulse wave velocity was measured non-invasively along the carotid-femoral arterial segment. Serum ET-1 was analysed using indirect enzyme-linked immunosorbent assay (ELISA). RESULTS: Sixty-two women with systemic sclerosis and 62 healthy controls were included. There was a significant difference in ET-1 serum levels between systemic sclerosis women patients and healthy controls (p = 0.001). Serum levels of ET-1 were positively associated with pulse wave velocity (r = 0.26, p < 0.05), within the study group. CONCLUSIONS: ET-1 serum levels are associated with pulse wave velocity in women with systemic sclerosis. Therefore, drugs that block ET-1 may be effective in reducing large artery stiffness in women with systemic sclerosis, and thus cardiovascular risk. [ABSTRACT FROM AUTHOR]

Background Inadequate pulmonary vascular growth results in morbidity for many children with single‐ventricle heart disease (SVHD). Endothelin 1 (ET1) is a potent vasoconstrictor and stimulator of pulmonary artery smooth muscle proliferation. Circulating ET1 levels and their association with outcomes have not been studied during early SVHD palliation. We aimed to define circulating levels of ET1 in patients with SVHD undergoing stage 2 palliation and evaluate their relationship to postoperative hypoxemia. We hypothesized that patients with SVHD with higher ET1 concentration would have a greater post–stage 2 hypoxemia. Methods and Results Prospective cohort study of 55 subjects with SVHD undergoing stage 2 palliation and 50 controls. Samples for ET1 analysis were collected at preoperation (systemic and pulmonary vein) and 2, 24, and 48 hours postoperation for cases and a single time point for controls. The primary outcome was percentage of first 48 postoperative hours with clinically significant hypoxemia (saturation,

Objective: To investigate the effect of conbercept combined with retinal laser photocoagulation on Bulbar Conjunctival Microcirculation and vascular endothelial function in patients with ischemic central retinal vein occlusion. Methods: 90 ischemic CRVO patients who were admitted to our hospital from August 2016 to September 2019 were selected, patients were divided into control group (n=45, retinal laser photocoagulation treatment) and study group (n=45, retinal laser photocoagulation combined with conbercept treatment) according to the envelope drawing method. The central retinal thickness (CMT), bulbar conjunctival microcirculation index, best corrected visual acuity (BCVA), curative effect, serum VEGF, ET-1, NO levels and adverse reactions were compared between the two groups. Results: The total clinical effective rate of the study group at 6 months after treatment was higher than that of the control group (P<0.05). 6 months after treatment, the increased degree of BCVA, the enlarged degree of arteriole diameter and arteriole diameter of the study group were higher than those of the control group (P<0.05), and the decreased degree of CMT and erythrocyte aggregation score of the study group were higher than those of the control group(P<0.05). 3 d after treatment, the decrease degree of VEGF and ET-1 of the study group were higher than that of the control group (P<0.05), and the increase degree of NO was higher than that of the control group (P<0.05). There was no difference in the incidence of ADR between the two groups (P>0.05). Conclusion: Conbercept combined with retinal laser photocoagulation is effective in the treatment of ischemic CRVO, which can effectively improve patients' visual acuity and bulbar conjunctival microcirculation, as well as improve vascular endothelial function, which is safe and reliable. [ABSTRACT FROM AUTHOR]

As survival in breast cancer patients from newer therapies increases, concerns for chemotherapy-induced cardiotoxicity (CIC) have offset some of these benefits, manifesting as a decline in left ventricular ejection fraction (LVEF). Patients receiving anthracycline-based chemotherapy followed by trastuzumab are at risk for CIC. Previous research evaluating whether clinical biomarkers predict cardiotoxicity has been inconsistent. Recently, angiotensin II type 1 receptor (ATR1) and endothelin 1 (ET1) have been shown to play a role in breast tumor growth. We evaluated ATR1 and ET1 expression in breast cancer tissue and its association with CIC. A total of 33 paraffin-embedded breast tissue specimens from women with breast cancer treated with anthracycline-based chemotherapy and trastuzumab were analyzed by immunohistochemistry (IHC) and qRT-PCR. We found that ET1 expression was increased in patients with an LVEF ≤ 50% (p = 0.032) with a lower LVEF correlating with higher ET1 expression (r = 0.377, p = 0.031). In patients with a change in LVEF of greater than 10%, greater ET1 expression was noted compared to those without a change in LVEF (p = 0.017). Increased ET1 expression in breast tumor tissue is associated with reduced LVEF. Future studies need to examine whether ET1 may be a tissue biomarker that helps predict the risk of developing CIC in women with breast cancer.

Hypertension is the most determinant risk factor for cardiovascular diseases. Early intervention and future therapies targeting hypertension mechanisms may improve the quality of life and clinical outcomes. Hypertension has a complex multifactorial aetiology and was recently associated with protein homeostasis (proteostasis). This work aimed to characterize proteostasis in easy-to-access plasma samples from 40 individuals, 20 with controlled hypertension and 20 age- and gender-matched normotensive individuals. Proteostasis was evaluated by quantifying the levels of protein aggregates through different techniques, including fluorescent probes, slot blot immunoassays and Fourier-transform infrared spectroscopy (FTIR). No significant between-group differences were observed in the absolute levels of various protein aggregates (Proteostat or Thioflavin T-stained aggregates; prefibrillar oligomers and fibrils) or total levels of proteostasis-related proteins (Ubiquitin and Clusterin). However, significant positive associations between Endothelin 1 and protein aggregation or proteostasis biomarkers (such as fibrils and ubiquitin) were only observed in the hypertension group. The same is true for the association between the proteins involved in quality control and protein aggregates. These results suggest that proteostasis mechanisms are actively engaged in hypertension as a coping mechanism to counteract its pathological effects in proteome stability, even when individuals are chronically medicated and presenting controlled blood pressure levels.

Background: Inflammatory response and endothelial dysfunction contribute to the progression of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to assess changes in biomarkers involved in those processes in inoperable CTEPH patients treated with balloon pulmonary angioplasty (BPA). Methods: We enrolled 20 patients with inoperable CTEPH qualified for BPA and a control group. Interleukin 6, 8, 10 (IL-6, IL-8, IL-10), monocyte chemoattractant protein-1 (MCP-1), and C-reactive protein (hsCRP) constituted the markers of systemic inflammation. Endothelin 1 (ET-1) served as a marker of endothelial dysfunction. Selected markers were assessed before the BPA treatment, 24 h after the first BPA, and six months after completion of the BPA treatment. Results: At baseline, the CTEPH patients had increased serum concentrations of IL-6, IL-8 and ET-1. Twenty-four hours after a BPA session, we observed an increase in concentrations of IL-6 (∆ = 3.67 (1.41; 7.16); p < 0.001), of IL-10 (∆ = 0.25 (0; 0.47); p = 0.003), of MCP-1 (∆ = 111 (60.1; 202.8); p = 0.002), and of hsCRP (∆ = 4.81 (3.46; 8.47); p < 0.001). Six months after completion of the BPA treatment, there was a decrease in concentrations of IL-6 (∆ = −1.61 (−3.11; −0.20); p = 0.03), of IL8 (∆ = −3.24 (−7.72; 0.82); p = 0.01), and of ET-1 (∆ = −0.47 (−0.96; 0.05); p = 0.005). Conclusions: Patients with inoperable CTEPH exhibit increased systemic inflammation and endothelial dysfunction, which improves after completion of the BPA treatment. A single BPA session evokes an acute inflammatory response.

Background The novel estrogen receptor, G‐protein–coupled estrogen receptor (GPER), is responsible for rapid estrogen signaling. GPER activation elicits cardiovascular and nephroprotective effects against salt‐induced complications, yet there is no direct evidence for GPER control of renal Na+ handling. We hypothesized that GPER activation in the renal medulla facilitates Na+ excretion. Methods and Results Herein, we show that infusion of the GPER agonist, G1, to the renal medulla increased Na+ excretion in female Sprague Dawley rats, but not male rats. We found that GPER mRNA expression and protein abundance were markedly higher in outer medullary tissues from females relative to males. Blockade of GPER in the renal medulla attenuated Na+ excretion in females. Given that medullary endothelin 1 is a well‐established natriuretic factor that is regulated by sex and sex steroids, we hypothesized that GPER activation promotes natriuresis via an endothelin 1–dependent pathway. To test this mechanism, we determined the effect of medullary infusion of G1 after blockade of endothelin receptors. Dual endothelin receptor subtype A and endothelin receptor subtype B antagonism attenuated G1‐induced natriuresis in females. Unlike males, female mice with genetic deletion of GPER had reduced endothelin 1, endothelin receptor subtype A, and endothelin receptor subtype B mRNA expression compared with wild‐type controls. More important, we found that systemic GPER activation ameliorates the increase in mean arterial pressure induced by ovariectomy. Conclusions Our data uncover a novel role for renal medullary GPER in promoting Na+ excretion via an endothelin 1–dependent pathway in female rats, but not in males. These results highlight GPER as a potential therapeutic target for salt‐sensitive hypertension in postmenopausal women.

Copyright of Journal of China Medical University is the property of Journal of China Medical University Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Medical Journal of Istanbul Kanuni Sultan Süleyman / İstanbul Kanuni Sultan Süleyman Tıp Dergisi is the property of Logos Medical Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: The imbalance in oxidant/antioxidant status plays a pivotal role in diabetes mellitus (DM). Selenium is a integral component of the antioxidant enzyme glutathione peroxidase. Se treatment induces angiogenesis and improves endothelial function through increased expression of vascular endothelial growth factor (VEGF). The aim of this study is to investigate the effect of selenium on oxidative stress, VEGF, and endothelin 1 (ET1) in a DM rat model. Materials and Methods: We performed an experimental animal study with 64 adult male Wistar-Albino rats. Rats were divided into the following groups (n=8): control (C)7, C21, C+sodium selenite (Se)7, and C+Se21 (control rats), and DM7, DM21, DM+Se7, and DM+Se21 (diabetic rats). Diabetes was induced by 2-deoxy-2-(3-methyl-3-nitrosoureido)- D-glucopyranose [streptozotocin (STZ)]. Three weeks after STZ, DM+Se7 rats received intraperitoneal (i.p.) injections of 0.4 mg/kg Se for 7 days. The DM+Se21 rats received these injections for 21 days. The same dose/duration of Se was administered to the C+Se7 and C+Se21 groups. The remaining rats (C7, C21, DM7, DM21) received physiologic saline injections for 7 or 21 days. Ferric reducing antioxidant power (FRAP), malondialdehyde (MDA), advanced oxidation protein products (AOPP), and endothelial function markers (VEGF and ET1) in plasma samples were measured. Results: Diabetic rats (DM7 and DM21) had significantly increased plasma FRAP (P=0.002, P=0.001), AOPP (P=0.024, P=0.01), MDA (P=0.004, P=0.001), and ET1 (P=0.028, P=0.003) levels compared with C7 and C21 control rats. VEGF (P=0.02, P=0.01) significantly decreased in DM7 and DM21 diabetic rats compared with their controls (C7, C21). Se administration reversed the increased MDA and decreased VEGF levels, and lowered plasma glucose levels in the DM+Se7 and DM+Se21 diabetic groups compared with diabetic rats (DM7, DM21). We observed positive correlations between FRAP-AOPP (r=0.460), FRAP-ET1 (r=0.510), AOPP-MDA (r=0.270), and AOPP-ET1 (r=0.407), and a negative correlation between MDA-VEGF (r=-0.314). Conclusion: We observed accentuated oxidative stress and impaired endothelial function in diabetes. Se treatment reduced lipid peroxidation and hyperglycemia. Se probably improved endothelial dysfunction in diabetic rats because of the increased VEGF levels.

Background: A well balanced diet is important for normal function of endothelial cells. Diets high in fat and/or calories can lead to hypertriglyceridemia and postprandial lipidemia and thus are considered a risk factor for the development of atherosclerosis. Big meals may result in chronic elevations in the level of atherogenic lipoproteins as well as evoking chronic inflammatory response. Both may lead to pathological changes on the arterial vessel wall and myocardium. Objective(s): To study the effect of the size of a well-balanced meal on the lipid profile in the post prandial state and its effect on the endothelial function, ventricular filling and diastolic function. Methods: one group pretest-posttest study was carried out on 40 young healthy lean volunteers aged 30 to 39 years who after overnight fast were invited to eat a big breakfast meal. Postprandial blood samples were then drawn after 3-4 hours to determine changes induced by the big meal in the blood. On the following day, the same procedure was adopted but with a breakfast meal which contains only one third of the size of the big meal (small meal). The items of comparison between the two meals included: The changes induced by both types of meals on the lipid profile of the blood by assessing the postprandial levels of TG, TC, LDL-C, HDL-C and FFAs; assessment of the inflammatory response by assessing postprandial levels of CRP; The changes induced on endothelial cell functions by assessing the postprandial levels of ET1 and NO; and the changes induced by the two types of meals on the left ventricular function as determined by echo Doppler as well as tissue Doppler imaging (TDI). Results: The big meal was associated with elevations in TG, TC, LDL-C, CRP, ET1 and NO (P=0.001, 0.021, 0.057, 0.110, 0.002, 0.001respectively). The small meal showed significant increase in levels of HDL-C (P=0.001) and FFAs (P=0.048). The diastolic function of the left ventricle showed significant reduction after the ingestion of the big meal versus the small meal. Conclusions: The study concluded that big meal size negatively impact lipid homeostasis and endothelial function and the recognition of this possible danger of big meals can lead to the possibility of prevention of atherosclerosis through controlling of the meal size.

Aim: to investigate the association of EDF factors: endothelin 1 (ET1), endothelial NO-synthase (eNOS), nitric oxide (NO), tumor necrosis factor (TNFα), and diene conjugates (DC) with severity of type 2 diabetes. Material and methods. Data were used for 152 hospital patients with type 2 diabetes at the age from 34 to 80 years (53.9±8.4 years). Women were 95 (62.5%), men – 57 (37.5%). According to the degree of severity of patients was divided into three groups: 1st (37.5% of patients) – the average stage in the compensation stage (HbA1s 7-9%), 2nd (41.4%) – the average stage in the stage of decompensation (HbA1s more than 9%), 3rd (21,1%) – a severe degree in the stage of decompensation. The control group included 95 practically healthy individuals. The plasma levels of the blood were determined by the enzyme-linked method: ЕТ1 (Biomedica Immunoassays, Austria), eNOS (BCM Diagnostics, USA) і TNFα (Bender Medsystems, Austria). The level of blood NO and DC were determined biochemically (spectrophotometer Specord, Germany). Statistica 10 (StatSoft, Inc., USA) was used to statistically process the data obtained. Results. Levels of EDF factors depended on the severity of DM 2 type. Thus, the level of ETI in patients exceeded control in 3.7-4.7 times (p

In the present study, we investigated the role of PKR‐like endoplasmic reticular kinase (PERK), an endoplasmic reticulum (ER) stress kinase, in endothelin 1 (ET‐1)‐ and thrombin‐induced pulmonary fibrosis (PF), and the preventive effects of curcumin (CUR). Using the human embryonic WI‐38 lung fibroblast cell line, ET‐1 and thrombin induced the expression of ER stress‐related proteins (CCAAT‐enhancer‐binding protein homologous protein, PERK, and binding immunoglobulin protein), a profibrogenic factor (cellular communication network factor 2 [CCN2]), and differentiation markers including α‐smooth muscle actin (α‐SMA), collagen I (Col I), and Col IV. Knockdown of PERK expression via small interfering RNA (siRNA) significantly reduced the increases in CCN2, α‐SMA, Col I, and Col IV proteins in WI‐38 cells according to western blot analysis and immunohistochemistry (IHC). Activation of c‐Jun N‐terminal kinase (JNK) was observed in ET‐1‐ and thrombin‐treated WI‐38 cells, and the addition of a JNK inhibitor (SP) suppressed the induction of the indicated proteins by ET‐1 and thrombin. Thapsigargin (TG), an ER stress inducer, elevated expressions of PERK and ER stress‐related proteins with increased differentiation of WI‐38 cells. Knockdown of PERK by siRNA or the PERK inhibitor glycogen synthesis kinase reduced expressions of the differentiation markers, α‐SMA and Col IV, in WI‐38 cells. CUR concentration‐dependently inhibited ET‐1‐ or thrombin‐induced CCN2, α‐SMA, and vimentin proteins with decreased levels of phosphorylated mitogen‐activated protein kinase and PERK in WI‐38 cells. An in vivo bleomycin‐induced PF study showed that an intraperitoneal injection of CUR (30 mg/kg) reduced expressions of α‐SMA, CCN2, Col IV, and vimentin in lung tissues via IHC staining using specific antibodies. This study is the first to demonstrate that PERK activation contributes to pulmonary fibroblast differentiation elicited by ET‐1 or thrombin, and the inhibitory activity of CUR against PF is demonstrated herein. [ABSTRACT FROM AUTHOR]

Background: The prevalence of pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is increasing. We aim to study the role of big endothelin 1 (Big ET1), endothelin 1 (ET1), and neprilysin (NE) in HFpEF with PH. Method: This was a single center prospective cohort study including 90 HFpEF patients; 30 with no PH, 30 with postcapillary PH, and 30 with combined post- and precapillary PH. After enrollment, pulmonary venous and pulmonary arterial samples of Big ET1, ET1, and NE were collected during right heart catheterization. Subjects were then followed long term for adverse outcomes which included echocardiographic evidence of right ventricular dysfunction, heart failure hospitalization, and all-cause mortality. Results: Patients with HFpEF-PH were found to have increased ET1 in pulmonary veins (endothelin from the wedge; ET1W) compared to controls (2.3 ± 1.4 and 1.6 ± 0.9 pg/mL, respectively). ET1W levels were associated with both PH (OR 2.7, 95% CI 1.5–4.7, p = 0.01) and pulmonary vascular resistance (OR 1.6, 95% CI 1.04–2.3, p = 0.03). No evidence of right ventricular dysfunction was observed after 1 year of follow-up. ET1W (OR 1.8, 95% CI 1.2–2.6, p = 0.01) and ET1 gradient (ET1G; OR 1.4, 95% CI 1.04–2, p = 0.03) were predictive of 1-year hospitalization. ET1G ≥0.2 pg/mL was associated with long-term mortality (log-rank 4.8, p = 0.03). Conclusion: In HFpEF patients, ET1W and ET1G are predictive of 1-year heart failure hospitalization, while elevated ET1G levels were found to be associated with long-term mortality in HFpEF. This study highlights the role of ET1 in developing PH in HFpEF patients and also explores the potential of ET1 as a prognostic biomarker. [ABSTRACT FROM AUTHOR]

Summary: We report a 46-yr-old woman with a history of breast cancer who presented with diffuse myalgias, bone pain, and osteosclerosis. She was found to have recurrent breast cancer producing endothelin-1. Introduction: Acquired osteosclerosis can be caused by various disorders. Endothelin -1 is believed to contribute to osteosclerosis caused by breast cancer. Methods: Although the bone marrow biopsy did not reveal breast cancer, she developed skin lesions consistent with metastatic breast cancer. She ultimately died from progressive disease. At autopsy immunohistochemistry for endothelin-1 was performed on a section from the L5 vertebral body. Results: The section from the L5 vertebral body showed small foci of cells consistent with metastatic carcinoma and a prominent sclerotic response. Immunohistochemistry for endothelin-1 was strongly positive. Conclusions: Recurrent breast cancer may present with diffuse osteosclerosis. Endothelin-1 may be a paracrine factor responsible for increased bone formation and osteosclerosis. [ABSTRACT FROM AUTHOR]

Background: Stroke leads to devastating impact on health as well as quality of life making it one of the leading causes of disability. Restoring the functions of upper extremities after ischemic (ISC) stroke is one of the challenges for rehabilitation. Lack of trained professionals and accessibility to rehabilitation centers are limited in many counties. Constraint induced movement therapy (CIMT) has been practiced in regaining the functional activity following stroke. CIMT can be practiced with minimum clinical set up which makes it cost effective. However, the neural plasticity mechanism underlying the recovery with CIMT is not well understood.Methods: In the current study, we sought to investigate the extent to which CIMT helps in ameliorating neurological deficits in rat model of ISC stroke, induced by Endothelin-1 (ET-1). As well as to understand the cortical plasticity with Golgi-Cox staining and interhemispheric interaction with biotinylated dextran amine (BDA) following CIMT. Neurological deficits were identified within 24 hours of ET-1 infusion.Results: CIMT restored the impaired skilled movements after ISC stroke and improved the quality of fine movements. Golgi-Cox staining showed significant decrease in dendritic arborization in the injured motor cortex following ISC stroke. CIMT was efficient in reversing this effect as indicated by increased dendritic arborization especially in layer III pyramidal neurons. Also, the stroke induced asymmetry in dendritic length across both hemispheres was found to be reduced with CIMT. BDA tracing showed a re-establishment of the axonal connections between the hemispheres after CIMT.Conclusions: Implications of CIMT can be one of the promising and low cost rehabilitative technique for the individuals with upper limb movement deficits. [ABSTRACT FROM AUTHOR]

We have already reported that glucosamine (GlcN) distinctly abrogates the pigmentation of human epidermal equivalents stimulated by stem cell factor + endothelin-1 (SE). In this study, we characterized the molecular mechanism involved in the anti-melanogenic effects of GlcN using normal human melanocytes (NHMs) in culture. The SE-stimulated gene (12 h) and protein (24 h) expression levels of melanocyte-specific proteins (at the indicated times post-stimulation) were significantly abrogated by pretreatment with GlcN for 72 h. Western blotting analysis of the phosphorylation of intracellular signaling molecules in the MAPK pathway revealed that despite the significantly decreased level of total CREB protein at all times post-stimulation, the SE-stimulated phosphorylation of ERK, CREB and MITF is not attenuated at 15 min post-stimulation in GlcN-treated NHMs. However, the SE-stimulated protein expression level of total MITF at 2 and 6 h post-stimulation was significantly abrogated by 72 h pretreatment with GlcN. Consistently, pretreatment with GlcN for 72 h abrogated the stimulated gene and protein expression levels of MITF at 1 h and 2 h post-stimulation, respectively. Analysis of gene and protein expression levels also demonstrated that pretreatment with GlcN for 72 h significantly reduced the protein levels of CREB and MITF without affecting their gene expression levels prior to the SE stimulation. Silencing with a CREB siRNA distinctly abrogated the SE-stimulated expression of MITF (at 2 h post-stimulation) and melanocyte-specific proteins (at 24 h post-stimulation). Similarly, transfection of MITF siRNA markedly abrogated the SE-stimulated expression of MITF protein and melanocyte-specific proteins at 2 and 24 h post-stimulation, respectively. Finally, the decreased levels of CREB and MITF proteins induced by 72 h pretreatment with GlcN were abrogated by the co-addition of the proteosomal degradation inhibitor MG132. These findings suggest that the anti-melanogenic effect elicited by GlcN is mediated via the decreased expression of MITF which results from the attenuated transcriptional activity of CREB due to proteolytic degradation. [ABSTRACT FROM AUTHOR]

In order to become established in the skeleton, metastatic cells disseminating from the breast carcinoma need to acquire organ-specific traits. There are no effective predictors for who will develop bone metastasis to guide long-term predictive therapy. Our purpose was to individuate events critical for bone colonization to make a molecular classification of breast carcinoma useful for bone-metastasis outcome. In dysplasia adjacent to carcinoma and in pair-matched specimens of bone metastasis we examined SPARC expression and localization as well as Endothelin 1/ETAR signals by immunohistochemistry, and the evaluation of plasma levels of SPARC by ELISA was also performed. In patients with breast carcinoma metastasizing to bone, SPARC and Endothelin 1/ETAR axis were highly expressed from dysplasia until bone metastasis, but the SPARC plasma level was as low as that of normal women, in contrast to patients that never develop bone metastasis, suggesting that circulating SPARC was counter adhesive. Altogether, the early identification of SPARC/Endothelin 1/ETAR in dysplastic lesions would be important to devise therapies preventing metastasis engraftment, since often carcinoma cells spread to distant organs at the time or even before patients present with cancer.

Cost- and time-intensive porcine translational disease models offer great opportunities to test drugs and therapies for pathological cardiac hypertrophy and can be supported by porcine cell culture models that provide further insights into basic disease mechanisms. Cardiac progenitor cells (CPCs) residing in the adult heart have been shown to differentiate in vitro into cardiomyocytes and could contribute to cardiac regeneration. Therefore, it is important to evaluate their changes on the cellular level caused by disease. We successfully isolated Isl1+Sca1+cKit+ porcine CPCs (pCPCs) from pig hearts and stimulated them with endothelin-1 (ET-1) and angiotensin II (Ang II) in vitro. We also performed a cardiac reprogramming transfection and tested the same conditions. Our results show that undifferentiated Isl1+Sca1+cKit+ pCPCs were significantly upregulated in GATA4, MEF2c, and miR-29a gene expressions and in BNP and MCP-1 protein expressions with Ang II stimulation, but they showed no significant changes in miR-29a and MCP-1 when stimulated with ET-1. Differentiated Isl1+Sca1+cKit+ pCPCs exhibited significantly higher levels of MEF2c, GATA4, miR-29a, and miR-21 as well as Cx43 and BNP with Ang II stimulation. pMx-MGT-transfected Isl1+Sca1+cKit+ pCPCs showed significant elevations in MEF2c, GATA4, and BNP expressions when stimulated with ET-1. Our model demonstrates that in vitro stimulation leads to successful Isl1+Sca1+cKit+ pCPC hypertrophy with upregulation of cardiac remodeling associated genes and profibrotic miRNAs and offers great possibilities for further investigations of disease mechanisms and treatment.