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Background: Type 2 diabetes (T2D) is a risk factor for female breast cancer (FBC). Obesity has also been associated with FBC, also depending on menopausal status. This study aimed to evaluate the impact of obesity and T2D on the development, aggressiveness, and invasiveness of FBC. Methods: Demographic, clinical, and histopathological data from 335 women with FBC were collected, and analyzed according to weight category (102 normal weight, 117 overweight, and 116 living with obesity) and the presence/absence of T2D. Results: Age at oncologic diagnosis was not statistically significantly different for body weight; women with overweight or obesity were more likely to have an oncologic diagnosis after menopause than normal weight (p < 0.001). The presence of overweight/obesity and T2D seemed to be associated with a higher incidence of metastasis, recurrence, and triple-negative breast cancer (TNBC) subtype (p < 0.001). Excess body weight was also associated with high histologic grade (G3) (p < 0.005). Conclusions: These results confirm excess body weight and T2D as unfavorable prognostic factors in terms of the presence of the TNBC subtype, tumor metastasis, recurrence, and aggressiveness (G3 and Ki-67 > 20%). This study highlights the importance of prevention in all women, with early screening, and adequate nutritional programs.
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Chronic smokers have increased risk of fibrosis-related atrial fibrillation. The use of heated-tobacco products (HTPs) is increasing exponentially, and their health impact is still uncertain. We aim to investigate the effects of circulating molecules in exclusive HTP chronic smokers on the fibrotic behavior of human atrial cardiac stromal cells (CSCs). CSCs were isolated from atrial tissue of elective cardiac surgery patients, and exposed to serum lots from young healthy subjects, stratified in exclusive HTP smokers, tobacco combustion cigarette (TCC) smokers, or nonsmokers (NS). CSCs treated with TCC serum displayed impaired migration and increased expression of pro-inflammatory cytokines. Cells cultured with HTP serum showed increased levels of pro-fibrotic markers, and reduced expression of connexin-43. Both TCC and HTP sera increased collagen release and reduced secretion of angiogenic protective factors from CSCs, compared to NS serum. Paracrine support to tube-formation by endothelial cells and to viability of cardiomyocytes was significantly impaired. Treatment with sera of both smokers groups impaired H2O2/NO release balance by CSCs and reduced early phosphorylation of several pathways compared to NS serum, leading to mTOR activation. Cotreatment with rapamycin was able to reduce mTOR phosphorylation and differentiation into aSMA-positive myofibroblasts in CSCs exposed to TCC and HTP sera. In conclusion, the circulating molecules in the serum of chronic exclusive HTP smokers induce fibrotic behavior in CSCs through activation of the mTOR pathway, and reduce their beneficial paracrine effects on endothelial cells and cardiomyocytes. These results point to a potential risk for cardiac fibrosis in chronic HTP users.
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Gut-dysbiosis-induced lipopolysaccharides (LPS) translocation into systemic circulation has been suggested to be implicated in nonalcoholic fatty liver disease (NAFLD) pathogenesis. This study aimed to assess if oleuropein (OLE), a component of extra virgin olive oil, lowers high-fat-diet (HFD)-induced endotoxemia and, eventually, liver steatosis. An immunohistochemistry analysis of the intestine and liver was performed in (i) control mice (CTR; n = 15), (ii) high-fat-diet fed (HFD) mice (HFD; n = 16), and (iii) HFD mice treated with 6 µg/day of OLE for 30 days (HFD + OLE, n = 13). The HFD mice developed significant liver steatosis compared to the controls, an effect that was significantly reduced in the HFD + OLE-treated mice. The amount of hepatocyte LPS localization and the number of TLR4+ macrophages were higher in the HFD mice in the than controls and were lowered in the HFD + OLE-treated mice. The number of CD42b+ platelets was increased in the liver sinusoids of the HFD mice compared to the controls and decreased in the HFD + OLE-treated mice. Compared to the controls, the HFD-treated mice showed a high percentage of intestine PAS+ goblet cells, an increased length of intestinal crypts, LPS localization and TLR4+ expression, and occludin downregulation, an effect counteracted in the HFD + OLE-treated mice. The HFD-fed animals displayed increased systemic levels of LPS and zonulin, but they were reduced in the HFD + OLE-treated animals. It can be seen that OLE administration improves liver steatosis and inflammation in association with decreased LPS translocation into the systemic circulation, hepatocyte localization of LPS and TLR4 downregulation in HFD-induced mouse model of NAFLD.
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Glucósidos Iridoides , Iridoides , Lipopolisacáridos , Enfermedad del Hígado Graso no Alcohólico , Aceite de Oliva , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/metabolismo , Glucósidos Iridoides/farmacología , Ratones , Aceite de Oliva/farmacología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Masculino , Iridoides/farmacología , Regulación hacia Abajo/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Ratones Endogámicos C57BL , Inflamación/metabolismo , Hígado Graso/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/etiología , Hígado Graso/patologíaRESUMEN
Radiotherapy-induced cardiac toxicity and consequent diseases still represent potential severe late complications for many cancer survivors who undergo therapeutic thoracic irradiation. We aimed to assess the phenotypic and paracrine features of resident cardiac mesenchymal stromal cells (CMSCs) at early follow-up after the end of thoracic irradiation of the heart as an early sign and/or mechanism of cardiac toxicity anticipating late organ dysfunction. Resident CMSCs were isolated from a rat model of fractionated thoracic irradiation with accurate and clinically relevant heart dosimetry that developed delayed dose-dependent cardiac dysfunction after 1 year. Cells were isolated 6 and 12 weeks after the end of radiotherapy and fully characterized at the transcriptional, paracrine, and functional levels. CMSCs displayed several altered features in a dose- and time-dependent trend, with the most impaired characteristics observed in those exposed in situ to the highest radiation dose with time. In particular, altered features included impaired cell migration and 3D growth and a and significant association of transcriptomic data with GO terms related to altered cytokine and growth factor signaling. Indeed, the altered paracrine profile of CMSCs derived from the group at the highest dose at the 12-week follow-up gave significantly reduced angiogenic support to endothelial cells and polarized macrophages toward a pro-inflammatory profile. Data collected in a clinically relevant rat model of heart irradiation simulating thoracic radiotherapy suggest that early paracrine and transcriptional alterations of the cardiac stroma may represent a dose- and time-dependent biological substrate for the delayed cardiac dysfunction phenotype observed in vivo.
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Cardiopatías , Células Madre Mesenquimatosas , Traumatismos por Radiación , Ratas , Humanos , Animales , Cardiotoxicidad/metabolismo , Células Endoteliales/metabolismo , Células Madre Mesenquimatosas/metabolismo , Fenotipo , Cardiopatías/metabolismo , Traumatismos por Radiación/metabolismoRESUMEN
Tissue-based biopsy is the present main tool to explore the molecular landscape of cancer, but it also has many limits to be frequently executed, being too invasive with the risk of side effects. These limits and the ability of cancer to constantly evolve its genomic profile, have recently led to the need of a less invasive and more accurate alternative, such as liquid biopsy. By searching Circulating Tumor Cells and residues of their nucleic acids or other tumor products in body fluids, especially in blood, but also in urine, stools and saliva, liquid biopsy is becoming the future of clinical oncology. Despite the current lack of a standardization for its workflows, that makes it hard to be reproduced, liquid biopsy has already obtained promising results for cancer screening, diagnosis, prognosis, and risk of recurrence.Through a more accessible molecular profiling of tumors, it could become easier to identify biomarkers predictive of response to treatment, such as EGFR mutations in non-small cell lung cancer and KRAS mutations in colorectal cancer, or Microsatellite Instability and Mismatch Repair as predictive markers of pembrolizumab response.By monitoring circulating tumor DNA in longitudinal repeated sampling of blood we could also predict Minimal Residual Disease and the risk of recurrence in already radically resected patients.In this review we will discuss about the current knowledge of limitations and strengths of the different forms of liquid biopsies for its inclusion in normal cancer management, with a brief nod to their newest biomarkers and its future implications.
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Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Humanos , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Biopsia Líquida/métodosRESUMEN
Radiological imaging is currently employed as the most effective technique for screening, diagnosis, and follow up of patients with breast cancer (BC), the most common type of tumor in women worldwide. However, the introduction of the omics sciences such as metabolomics, proteomics, and molecular genomics, have optimized the therapeutic path for patients and implementing novel information parallel to the mutational asset targetable by specific clinical treatments. Parallel to the "omics" clusters, radiological imaging has been gradually employed to generate a specific omics cluster termed "radiomics". Radiomics is a novel advanced approach to imaging, extracting quantitative, and ideally, reproducible data from radiological images using sophisticated mathematical analysis, including disease-specific patterns, that could not be detected by the human eye. Along with radiomics, radiogenomics, defined as the integration of "radiology" and "genomics", is an emerging field exploring the relationship between specific features extracted from radiological images and genetic or molecular traits of a particular disease to construct adequate predictive models. Accordingly, radiological characteristics of the tissue are supposed to mimic a defined genotype and phenotype and to better explore the heterogeneity and the dynamic evolution of the tumor over the time. Despite such improvements, we are still far from achieving approved and standardized protocols in clinical practice. Nevertheless, what can we learn by this emerging multidisciplinary clinical approach? This minireview provides a focused overview on the significance of radiomics integrated by RNA sequencing in BC. We will also discuss advances and future challenges of such radiomics-based approach.
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Neoplasias de la Mama , Radiología , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/genética , Radiología/métodos , Diagnóstico por Imagen , Genómica/métodos , RadiografíaRESUMEN
Cancer alters both local and distant tissue by influencing the microenvironment. In this regard, the interplay with the stromal fraction is considered critical as this latter can either foster or hamper the progression of the disease. Accordingly, the modality by which tumors may alter distant niches of stromal cells is still unclear, especially at early stages. In this short report, we attempt to better understand the biology of this cross-talk. In our "autologous stromal experimental setting," we found that remote adipose tissue-derived mesenchymal stem cells (mediastinal AMSC) obtained from patients with lung adenocarcinoma sustain proliferation and clonogenic ability of A549 and human primary lung adenocarcinoma cells similarly to the autologous stromal lung counterpart (LMSC). This effect is not observed in lung benign diseases such as the hamartochondroma. This finding was validated by conditioning benign AMSC with supernatants from LAC for up to 21 days. The new reconditioned media of the stromal fraction so obtained, was able to increase cell proliferation of A549 cells at 14 and 21 days similar to that derived from AMSC of patients with lung adenocarcinoma. The secretome generated by remote AMSC revealed overlapping to the corresponding malignant microenvironment of the autologous local LMSC. Among the plethora of 80 soluble factors analyzed by arrays, a small pool of 5 upregulated molecules including IL1-ß, IL-3, MCP-1, TNF-α, and EGF, was commonly shared by both malignant-like autologous A- and L-MSC derived microenvironments vs those benign. The bioinformatics analysis revealed that these proteins were strictly and functionally interconnected to lung fibrosis and proinflammation and that miR-126, 101, 486, and let-7-g were their main targets. Accordingly, we found that in lung cancer tissues and blood samples from the same set of patients here employed, miR-126 and miR-486 displayed the highest expression levels in tissue and blood, respectively. When the miR-126-3p was silenced in A549 treated with AMSC-derived conditioned media from patients with lung adenocarcinoma, cell proliferation decreased compared to control media.
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The biological heterogeneity of glioblastoma, IDH-wildtype (GBM, CNS WHO grade 4), the most aggressive type of brain cancer, is a critical hallmark, caused by changes in the genomic mutational asset and influencing clinical progression over time. The understanding and monitoring of the mutational profile is important not only to reveal novel therapeutic targets in this set of patients, but also to ameliorate the clinical stratification of subjects and the prognostic significance. As neurosurgery represents the primary technique to manage GBM, it is of utmost importance to optimize alternative and less invasive methods to monitor the dynamic mutation profile of these patients. Extracellular vesicles (EVs) are included in the liquid biopsy analysis and have emerged as the biological mirror of escaping and surviving mechanisms by many tumors, including glioblastoma. Very few studies have investigated the technical feasibility to detect and analyze the genomic profile by Next-Generation Sequencing (UMI system) in circulating EVs of patients with grade IV glioblastoma. Here, we attempted to characterize and to compare the corresponding matched tissue samples and potential variants with pathogenic significance of the DNA contained in peripheral-blood-derived EVs. The NGS analysis has revealed that patients with grade IV glioblastoma exhibited lesser DNA content in EVs than controls and that, both in EVs and matched cancer tissues, the NF1 gene was consistently mutated in all patients, with the c.2568C>G as the most common pathogenic variant expressed. This study supports the clinical utility of circulating EVs in glioblastoma as an eligible tool for personalized medicine.
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Before entering human clinical studies to evaluate their safety and effectiveness, new drugs and novel medical treatments are subject to extensive animal testing that are expensive and time-consuming. By contrast, advanced technologies enable the development of animal-free models that allow the efficacy of innovative therapies to be studied without sacrificing animals, while providing helpful information and details. We report on the powerful combination of 3D bioprinting (3DB) and photo-thermal therapy (PTT) applications. To this end, we realize a 3DB construct consisting of glioblastoma U87-MG cells in a 3D geometry, incorporating biomimetic keratin-coated gold nanoparticles (Ker-AuNPs) as a photo-thermal agent. The resulting plasmonic 3DB structures exhibit a homogeneous cell distribution throughout the entire volume while promoting the localization of Ker-AuNPs within the cells. A 3D immunofluorescence assay and transmission electron microscopy (TEM) confirm the uniform distribution of fluorescent-labeled Ker-AuNPs in the volume and their capability to enter the cells. Laser-assisted (λ = 532 nm) PTT experiments demonstrate the extraordinary ability of Ker-AuNPs to generate heating, producing the highest temperature rise of about 16 °C in less than 2 min.
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Glioblastoma , Hipertermia Inducida , Nanopartículas del Metal , Terapia Fototérmica , Materiales Biomiméticos , Glioblastoma/terapia , Oro/química , Humanos , Queratinas/química , Nanopartículas del Metal/química , Terapia Fototérmica/métodosRESUMEN
OBJECTIVES: Extracellular vesicles (EVs) are key biological mediators of several physiological functions within the cell microenvironment. Platelets are the most abundant source of EVs in the blood. Similarly, platelet lysate (PL), the best platelet derivative and angiogenic performer for regenerative purposes, is enriched of EVs, but their role is still too poorly discovered to be suitably exploited. Here, we explored the contribution of the EVs in PL, by investigating the angiogenic features extrapolated from that possessed by PL. METHODS: We tested angiogenic ability and molecular cargo in 3D bioprinted models and by RNA sequencing analysis of PL-derived EVs. RESULTS: A subset of small vesicles is highly represented in PL. The EVs do not retain aggregation ability, preserving a low redox state in human umbilical vein endothelial cells (HUVECs) and increasing the angiogenic tubularly-like structures in 3D endothelial bioprinted constructs. EVs resembled the miRNome profile of PL, mainly enriched with small RNAs and a high amount of miR-126, the most abundant angiogenic miRNA in platelets. The transfer of miR-126 by EVs in HUVEC after the in vitro inhibition of the endogenous form, restored angiogenesis, without involving VEGF as a downstream target in this system. CONCLUSION: PL is a biological source of available EVs with angiogenic effects involving a miRNAs-based cargo. These properties can be exploited for targeted molecular/biological manipulation of PL, by potentially developing a product exclusively manufactured of EVs.
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Vesículas Extracelulares , MicroARNs , Humanos , Células Endoteliales de la Vena Umbilical Humana , MicroARNs/genética , Neovascularización Patológica , PlaquetasRESUMEN
The cellular heterogeneity of the tumor environment of breast cancer (BC) is extremely complex and includes different actors such as neoplastic, stromal, and immunosuppressive cells, which contribute to the chemical and mechanical modification of the environment surrounding the tumor-exasperating immune-escaping mechanisms. In addition to molecular signals that make the tumor microenvironment (TME) unacceptable for the penetrance of the immune system, the physical properties of tumoral extracellular matrix (tECM) also have carved out a fundamental role in the processes of the protection of the tumor niche. Tumor-associated macrophages (TAMs), with an M2 immunosuppressive phenotype, are important determinants for the establishment of a tumor phenotype excluded from T cells. NF-κB transcription factors orchestrate innate immunity and represent the common thread between inflammation and cancer. Many studies have focused on canonical activation of NF-κB; however, activation of non-canonical signaling predicts poor survival and resistance to therapy. In this scenario, we demonstrated the existence of an unusual association of NF-κB components in TAMs that determines the deposition of HSPG2 that affects the stiffness of tECM. These results highlight a new mechanism counterbalanced between physical factors and a new perspective of mechano-pathology to be targeted to counteract immune evasion in BC.
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FN-kappa B , Neoplasias , Humanos , Macrófagos , Neoplasias/patología , Microambiente Tumoral , Macrófagos Asociados a TumoresRESUMEN
Smoking is still a major cardiovascular risk factor, despite many public awareness campaigns and dedicated interventions. Recently, modified risk products (MRP), e.g., heat-not-burn cigarettes (HNBCs), have been introduced as surrogates of traditional combustion cigarettes (TCCs). Although these products are promoted as healthier than TCCs, few studies have been conducted to assess it. This work is a sex-focused sub-study of a prospective observational study in which apparently healthy chronic TCC smokers were age-matched with regular HNBC users. Blood samples were collected for biochemical assays and blood pressure and flow-mediated dilation (FMD) were measured. Out of 60 subjects, 33 (55%) were women, and 27 (45%) men, with 11 (33%) vs. 9 (33%) non-smokers, respectively, 10 (30%) vs. 10 (37%) TCC smokers, and 12 (36%) vs. 8 (30%) HNBC smokers (p = 0.946). Bivariate and multivariable analyses showed no statistically significant between-sex differences in NO, H2O2, sCD40L, sNox2-dp, sP-selectin, platelet aggregation, cotinine or FMD, overall, in non-smokers, in TCC smokers, or in HNBC smokers (all p > 0.05). HNBCs appeared safer than TCCs when focusing on Nox2-dp (p = 0.026) and sP-selectin (p = 0.050) but had similar levels of the other measured markers. In conclusion, HNBCs have similar detrimental effects on women and men's oxidative stress (H2O2: p = 0.49; sNox2-dp: p = 0.31) and platelet activation (sP-selectin: p = 0.33; platelet aggregation p = 0.87).
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Cardiac stromal cells (CSCs) are the main players in fibrosis. Dysmetabolic conditions (metabolic syndrome-MetS, and type 2 diabetes mellitus-DM2) are strong pathogenetic contributors to cardiac fibrosis. Moreover, modulation of the oxidative state (OxSt) and autophagy is a fundamental function affecting the fibrotic commitment of CSCs, that are adversely modulated in MetS/DM2. We aimed to characterize CSCs from dysmetabolic patients, and to obtain a beneficial phenotypic setback from such fibrotic commitment by modulation of OxSt and autophagy. CSCs were isolated from 38 patients, stratified as MetS, DM2, or controls. Pharmacological modulation of OxSt and autophagy was obtained by treatment with trehalose and NOX4/NOX5 inhibitors (TREiNOX). Flow-cytometry and real-time quantitative polymerase chain reaction (RT-qPCR) analyses showed significantly increased expression of myofibroblasts markers in MetS-CSCs at baseline (GATA4, ACTA2, THY1/CD90) and after starvation (COL1A1, COL3A1). MetS- and DM2-CSCs displayed a paracrine profile distinct from control cells, as evidenced by screening of 30 secreted cytokines, with a significant reduction in vascular endothelial growth factor (VEGF) and endoglin confirmed by enzyme-linked immunoassay (ELISA). DM2-CSCs showed significantly reduced support for endothelial cells in angiogenic assays, and significantly increased H2 O2 release and NOX4/5 expression levels. Autophagy impairment after starvation (reduced ATG7 and LC3-II proteins) was also detectable in DM2-CSCs. TREiNOX treatment significantly reduced ACTA2, COL1A1, COL3A1, and NOX4 expression in both DM2- and MetS-CSCs, as well as GATA4 and THY1/CD90 in DM2, all versus control cells. Moreover, TREiNOX significantly increased VEGF release by DM2-CSCs, and VEGF and endoglin release by both MetS- and DM2-CSCs, also recovering the angiogenic support to endothelial cells by DM2-CSCs. In conclusion, DM2 and MetS worsen microenvironmental conditioning by CSCs. Appropriate modulation of autophagy and OxSt in human CSCs appears to restore these features, mostly in DM2-CSCs, suggesting a novel strategy against cardiac fibrosis in dysmetabolic patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Diabetes Mellitus Tipo 2 , Factor A de Crecimiento Endotelial Vascular , Autofagia , Diabetes Mellitus Tipo 2/genética , Endoglina/metabolismo , Células Endoteliales/metabolismo , Fibrosis , Humanos , Estrés Oxidativo , Células del Estroma/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Cardiac stromal cells (CSCs) embrace multiple phenotypes and are a contributory factor in tissue homeostasis and repair. They can be exploited as therapeutic mediators against cardiac fibrosis and remodeling, but their survival and cardioprotective properties can be decreased by microenvironmental cues. We evaluated the impact of autophagy modulation by different pharmacological/genetic approaches on the viability and phenotype of murine CSCs, which had been subjected to nutrient deprivation or hyperglycemia, in order to mimic relevant stress conditions and risk factors of cardiovascular diseases. Our results show that autophagy is activated in CSCs by nutrient deprivation, and that autophagy induction by trehalose or autophagy-related protein 7 (ATG7)-overexpression can significantly preserve CSC viability. Furthermore, autophagy induction is associated with a higher proportion of primitive, non-activated stem cell antigen 1 (Sca1)-positive cells, and with a reduced fibrotic fraction (positive for the discoidin domain-containing receptor 2, DDR2) in the CSC pool after nutrient deprivation. Hyperglycemia, on the other hand, is associated with reduced autophagic flux in CSCs, and with a significant reduction in primitive Sca1+ cells. Autophagy induction by adenoviral-mediated ATG7-overexpression maintains a cardioprotective, anti-inflammatory and pro-angiogenic paracrine profile of CSCs exposed to hyperglycemia for 1 week. Finally, autophagy induction by ATG7-overexpression during hyperglycemia can significantly preserve cell viability in CSCs, which were subsequently exposed to nutrient deprivation, reducing hyperglycemia-induced impairment of cell resistance to stress. In conclusion, our results show that autophagy stimulation preserves CSC viability and function in response to metabolic stressors, suggesting that it may boost the beneficial functions of CSCs in cardiac repair mechanisms.
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Cardiac stromal cells have been long underestimated in their functions in homeostasis and repair. Recent evidence has changed this perspective in that many more players and facets than just "cardiac fibroblasts" have entered the field. Single cell transcriptomic studies on cardiac interstitial cells have shed light on the phenotypic plasticity of the stroma, whose transcriptional profile is dynamically regulated in homeostatic conditions and in response to external stimuli. Different populations and/or functional states that appear in homeostasis and pathology have been described, particularly increasing the complexity of studying the cardiac response to injury. In this review, we outline current phenotypical and molecular markers, and the approaches developed for identifying and classifying cardiac stromal cells. Significant advances in our understanding of cardiac stromal populations will provide a deeper knowledge on myocardial functional cellular components, as well as a platform for future developments of novel therapeutic strategies to counteract cardiac fibrosis and adverse cardiac remodeling.
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The potential role of brown and beige adipose tissue against obesity has been recognized. Browning, or beiging of white adipose tissue (WAT) is associated with the remodeling of adipocytes and the improvement of their metabolic and secretory functions. Here, palmitoylethanolamide (PEA) restore the plasticity of brown and white adipocytes impaired in mice on a high-fat diet (HFD). Young male C57Bl/6J mice were fed with control (STD) diet or HFD for 12 weeks. Ultramicronized PEA (30 mg/kg/die p.o.) was administered for an additional 7 weeks, together with HFD. PEA recovered interscapular brown fat morphology and function, increasing UCP1 positivity, noradrenergic innervation, and inducing the mRNA transcription of several specialized thermogenic genes. PEA promotes the beige-conversion of the subcutaneous WAT, increasing thermogenic markers and restoring leptin signaling and tissue hormone sensitivity. The pivotal role of lipid-sensing peroxisome proliferator-activated receptor (PPAR)-α in PEA effects was determined in mature 3T3-L1. Moreover, PEA improved mitochondrial bioenergetics in mature adipocytes measured by a Seahorse analyzer and induced metabolic machinery via AMPK phosphorylation. All these outcomes were dampened by the receptor antagonist GW6471. Finally, PEA induced adipogenic differentiation and increased AMPK phosphorylation in human adipose-derived stromal cells (ASCs) obtained from subcutaneous WAT of normal-weight patients and patients with obesity. We identify PEA and PPAR-α activation as the main mechanism by which PEA can rewire energy-storing white into energy-consuming brown-like adipocytes via multiple and converging effects that restore WAT homeostasis and metabolic flexibility.
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BACKGROUND: New messenger RNA (mRNA) and adenovirus-based vaccines (AdV) against Coronavirus disease 2019 (COVID-19) have entered large scale clinical trials. Since healthcare professionals (HCPs) and armed forces personnel (AFP) represent a high-risk category, they act as a suitable target population to investigate vaccine-related side effects, including headache, which has emerged as a common complaint. METHODS: We investigated the side-effects of COVID-19 vaccines among HCPs and AFP through a 38 closed-question international survey. The electronic link was distributed via e-mail or via Whatsapp to more than 500 contacts. Responses to the survey questions were analyzed with bivariate tests. RESULTS: A total of 375 complete surveys have been analyzed. More than 88% received an mRNA vaccine and 11% received AdV first dose. A second dose of mRNA vaccine was administered in 76% of individuals. No severe adverse effects were reported, whereas moderate reactions and those lasting more than 1 day were more common with AdV (P=0.002 and P=0.024 respectively). Headache was commonly reported regardless of the vaccine type, but less frequently, with shorter duration and lower severity that usually experienced by participants, without significant difference irrespective of vaccine type. CONCLUSIONS: Both mRNA and AdV COVID-19 vaccines were safe and well tolerated in a real-life subset of HCPs and AFP subjects.
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Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , COVID-19/prevención & control , Cefalea/inducido químicamente , Vacunación/efectos adversos , Adolescente , Adulto , Anciano , Vacuna BNT162 , COVID-19/transmisión , ChAdOx1 nCoV-19 , Estudios Transversales , Femenino , Cefalea/diagnóstico , Cefalea/epidemiología , Encuestas de Atención de la Salud , Personal de Salud , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Salud Laboral , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
microRNAs (miRNAs) are emerging as relevant molecules in cancer development and progression. MiRNAs add a post-transcriptional level of control to the regulation of gene expression. The deregulation of miRNA expression results in changing the molecular circuitry in which miRNAs are involved, leading to alterations of cell fate determination. In this review, we describe the miRNAs that are emerging as innovative molecular biomarkers from liquid biopsies, not only for diagnosis, but also for post-surgery management in cancer. We focus our attention on renal cell carcinoma, in particular highlighting the crucial role of circulating miRNAs in clear cell renal cell carcinoma (ccRCC) management. In addition, the functional deregulation of miRNA expression in ccRCC is also discussed, to underline the contribution of miRNAs to ccRCC development and progression, which may be relevant for the identification and design of innovative clinical strategies against this tumor.
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Biomarcadores de Tumor/sangre , Carcinoma de Células Renales/sangre , Neoplasias Renales/sangre , MicroARNs/sangre , Carcinoma de Células Renales/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/genéticaRESUMEN
Tobacco habit still represents the leading preventable cause of morbidity and mortality worldwide. Heat-not-burn cigarettes (HNBCs) are considered as an alternative to traditional combustion cigarettes (TCCs) due to the lack of combustion and the absence of combustion-related specific toxicants. The aim of this observational study was to assess the effect of HNBC on endothelial function, oxidative stress and platelet activation in chronic adult TCC smokers and HNBC users. The results showed that both HNBC and TCC display an adverse phenotype in terms of endothelial function, oxidative stress and platelet activation. Future randomised studies are strongly warranted to confirm these data.